Liver failure in total artificial heart therapy.

PubMed

Dimitriou, Alexandros Merkourios; Dapunt, Otto; Knez, Igor; Wasler, Andrae; Oberwalder, Peter; Koerfer, Reiner; Tenderich, Gero; Spiliopoulos, Sotirios

2016-07-01

Congestive hepatopathy (CH) and acute liver failure (ALF) are common among biventricular heart failure patients. We sought to evaluate the impact of total artificial heart (TAH) therapy on hepatic function and associated clinical outcomes. A total of 31 patients received a Syncardia Total Artificial Heart. Preoperatively 17 patients exhibited normal liver function or mild hepatic derangements that were clinically insignificant and did not qualify as acute or chronic liver failure, 5 patients exhibited ALF and 9 various hepatic derangements owing to CH. Liver associated mortality and postoperative course of liver values were prospectively documented and retrospectively analyzed. Liver associated mortality in normal liver function, ALF and CH cases was 0%, 20% (P=0.03) and 44.4% (P=0.0008) respectively. 1/17 (5.8%) patients with a normal liver function developed an ALF, 4/5 (80%) patients with an ALF experienced a markedly improvement of hepatic function and 6/9 (66.6%) patients with CH a significant deterioration. TAH therapy results in recovery of hepatic function in ALF cases. Patients with CH prior to surgery form a high risk group with increased liver associated mortality.

Laparoscopic splenectomy for patients with liver cirrhosis: Improvement of liver function in patients with Child-Pugh class B.

PubMed

Yamamoto, Naoki; Okano, Keiichi; Oshima, Minoru; Akamoto, Shitaro; Fujiwara, Masao; Tani, Joji; Miyoshi, Hisaaki; Yoneyama, Hirohito; Masaki, Tsutomu; Suzuki, Yasuyuki

2015-12-01

We aimed to assess the short-term outcomes of laparoscopic splenectomy (LS) and liver function at 1 year after splenectomy in the patients with liver cirrhosis. Forty-five patients with liver cirrhosis and hypersplenism underwent LS. We reviewed electronic medical records regarding the liver functional reserve, the etiology of liver cirrhosis, and the presence of hepatocellular carcinoma and esophago-gastric varices. Prospectively collected data of perioperative variables, postoperative complications, and long-term liver function were analyzed. Forty-five patients had a chronic liver disease classified into Child-Pugh classes (A/B/C: 23/20/2). The etiologies of disease were hepatitis C virus infection in 34 patients, hepatitis B virus infection in 4, and others in 7. Fourteen patients underwent procedures in addition to LS, including hepatectomy (n = 7) and devascularization for esophagogastric varices (n = 8). Postoperative complications occurred in 11 patients (24%). Neither postoperative liver failure nor in-hospital mortality occurred. White blood cell and platelet counts determined 7 days, 1 month, and 1 year after LS doubled or increased more than twice compared with the preoperative values (P < .001). One year after LS, patients who had been classified preoperatively into Child-Pugh class B had decreased total serum bilirubin levels (P = .03), and increased prothrombin activity (P = 003) and decreased Child-Pugh scores (P = .001). The Child-Pugh classifications improved in 14 of 18 patients (78%) who had Child-Pugh class B preoperatively. LS is a safe and feasible procedure for hypersplenism in patients with liver cirrhosis. In addition, LS most likely ameliorates liver function at 1 year after LS in patients with Child-Pugh class B liver cirrhosis. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibition of glycogen synthase kinase (GSK)-3-β improves liver microcirculation and hepatocellular function after hemorrhagic shock.

PubMed

Jellestad, Lena; Fink, Tobias; Pradarutti, Sascha; Kubulus, Darius; Wolf, Beate; Bauer, Inge; Thiemermann, Chris; Rensing, Hauke

2014-02-05

Ischemia and reperfusion may cause liver injury and are characterized by hepatic microperfusion failure and a decreased hepatocellular function. Inhibition of glycogen synthase kinase (GSK)-3β, a serine-threonine kinase that has recently emerged as a key regulator in the modulation of the inflammatory response after stress events, may be protective in conditions like sepsis, inflammation and shock. Therefore, aim of the study was to assess the role of GSK-3β in liver microcirculation and hepatocellular function after hemorrhagic shock and resuscitation (H/R). Anesthetized male Sprague-Dawley rats underwent pretreatment with Ringer´s solution, vehicle (DMSO) or TDZD-8 (1 mg/kg), a selective GSK-3β inhibitor, 30 min before induction of hemorrhagic shock (mean arterial pressure 35±5 mmHg for 90 min) and were resuscitated with shed blood and Ringer´s solution (2h). 5h after resuscitation hepatic microcirculation was assessed by intravital microscopy. Propidium iodide (PI) positive cells, liver enzymes and alpha-GST were measured as indicators of hepatic injury. Liver function was estimated by assessment of indocyanine green plasma disappearance rate. H/R led to a significant decrease in sinusoidal diameters and impairment of liver function compared to sham operation. Furthermore, the number of PI positive cells in the liver as well as serum activities of liver enzymes and alpha-GST increased significantly after H/R. Pretreatment with TDZD-8 prevented the changes in liver microcirculation, hepatocellular injury and liver function after H/R. A significant rise in the plasma level of IL-10 was observed. Thus, inhibition of GSK-3β before hemorrhagic shock modulates the inflammatory response and improves hepatic microcirculation and hepatocellular function. Copyright © 2013 Elsevier B.V. All rights reserved.

 Albumin dialysis with MARS for the treatment of anabolic steroid-induced cholestasis.

PubMed

Díaz, Francia C; Sáez-González, Esteban; Benlloch, Salvador; Álvarez-Sotomayor, Diego; Conde, Isabel; Polo, Begoña; García, María; Rodríguez, María; Prieto, Martín

 Background and aims. Steroid-related hepatotoxicity has become one of the most relevant causes of drug induced liver cholestasis. Some patients do not improve after standard medical treatment (SMT) and may therefore require other approaches, like extracorporeal liver support. We report four cases of patients with pruritus, abnormal liver function tests and biopsy-proven anabolic steroid-induced cholestasis who were unresponsive to SMT. They underwent treatment with albumin dialysis (Molecular Adsorbent Recirculating System -MARS®-). A minimum of two MARS sessions were performed. After MARS® procedure, patients' symptoms improved, as well as liver function tests, thus avoiding liver transplantation. Albumin dialysis appears as a valuable therapeutic option for the management of anabolic steroid-induced cholestasis in patients that are unresponsive to SMT.

Changes in Life-Style After Liver Transplantation

PubMed Central

Zitelli, Basil J.; Miller, Joanne W.; Gartner, J. Carlton; Malatack, J. Jeffrey; Urbach, Andrew H.; Belle, Steven H.; Williams, Laurel; Kirkpatrick, Beverly; Starzl, Thomas E.

2010-01-01

Sixty-five pediatric patients who received liver transplants between May 1981 and May 1984 were observed for as many as 5 years and examined for changes in lifestyle. Children were less frequently hospitalized, spent less time hospitalized, required fewer medications, and generally had excellent liver and renal function after hepatic transplantation as compared with their pre-transplantation status. Most children were in age-appropriate and standard school classes or were only 1 year behind. Cognitive abilities remained unchanged. Children improved in gross motor function and patients’ behavior significantly improved according to parents’ perceptions. Enuresis was more prevalent, however, than in the population of children who had not received liver transplants. Parental divorce rates were no greater than those reported for other families with chronically ill children. Overall, objective changes in life-style as well as parents’ perceptions of behavior of children appear to be improved after liver transplantation. PMID:3041361

"Resuscitation" of marginal liver allografts for transplantation with machine perfusion technology.

PubMed

Graham, Jay A; Guarrera, James V

2014-08-01

As the rate of medically suitable donors remains relatively static worldwide, clinicians have looked to novel methods to meet the ever-growing demand of the liver transplant waiting lists worldwide. Accordingly, the transplant community has explored many strategies to offset this deficit. Advances in technology that target the ex vivo "preservation" period may help increase the donor pool by augmenting the utilization and improving the outcomes of marginal livers. Novel ex vivo techniques such as hypothermic, normothermic, and subnormothermic machine perfusion may be useful to "resuscitate" marginal organs by reducing ischemia/reperfusion injury. Moreover, other preservation techniques such as oxygen persufflation are explored as they may also have a role in improving function of "marginal" liver allografts. Currently, marginal livers are frequently discarded or can relegate the patient to early allograft dysfunction and primary non-function. Bench to bedside advances are rapidly emerging and hold promise for expanding liver transplantation access and improving outcomes. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Functional liver image guided hepatic therapy (FLIGHT) with hepatobiliary iminodiacetic acid (HIDA) scans.

PubMed

Long, David E; Tann, Mark; Huang, Ke Colin; Bartlett, Gregory; Galle, James O; Furukawa, Yukie; Maluccio, Mary; Cox, John A; Kong, Feng-Ming Spring; Ellsworth, Susannah G

2018-05-01

Hepatobiliary iminodiacetic acid (HIDA) scans provide global and regional assessments of liver function that can serve as a road map for functional avoidance in stereotactic body radiation therapy (SBRT) planning. Functional liver image guided hepatic therapy (FLIGHT), an innovative planning technique, is described and compared with standard planning using functional dose-volume histograms. Thresholds predicting for decompensation during follow up are evaluated. We studied 17 patients who underwent HIDA scans before SBRT. All SBRT cases were replanned using FLIGHT. The following dosimetric endpoints were compared for FLIGHT versus standard SBRT planning: functional residual capacity <15 Gy (FRC 15 HIDA), mean liver dose (MLD), equivalent uniform dose (EUD), and functional EUD (FEUD). Receiver operating characteristics curves were used to evaluate whether baseline HIDA values, standard cirrhosis scoring, and/or dosimetric data predicted clinical decompensation. Compared with standard planning, FLIGHT significantly improved FRC 15 HIDA (mean improvement: 5.3%) as well as MLD, EUD, and FEUD (P < .05). Considerable interindividual variations in the extent of benefit were noted. Decompensation during follow-up was associated with baseline global HIDA <2.915%/min/m 2 , FRC 15 HIDA <2.11%/min/m 2 , and MELD ≥11 (P < .05). FLIGHT with HIDA-based parameters may complement blood chemistry-based assessments of liver function and facilitate individualized, adaptive liver SBRT planning. Copyright © 2018. Published by Elsevier Inc.

Direct peritoneal resuscitation improves obesity-induced hepatic dysfunction after trauma.

PubMed

Matheson, Paul J; Franklin, Glen A; Hurt, Ryan T; Downard, Cynthia D; Smith, Jason W; Garrison, Richard N

2012-04-01

The metabolic syndrome and associated fatty liver disease are thought to contribute to poor outcomes in trauma patients. Experimentally, obesity compromises liver blood flow. We sought to correlate the effect of obesity, injury severity, and liver dysfunction with trauma outcomes. We hypothesized that obesity-related liver dysfunction could be mitigated with the novel technique of adjunctive direct peritoneal resuscitation (DPR). This study has clinical and experimental arms. The clinical study was a case-controlled retrospective analysis of ICU trauma patients (n = 72 obese, n = 187 nonobese). The experimental study was a hemorrhagic shock model in obese rats to assess the effect of DPR on liver blood flow, liver function, and inflammatory mediators. In trauma patients, univariate and multivariate analyses demonstrated increasing mortality (p < 0.05), septic complications (p < 0.05), liver dysfunction (p < 0.001), and renal impairment (p < 0.05) with increasing body mass index and injury severity score. Obesity in rats impairs liver blood flow, liver function, renal function, and inflammation (interleukin [IL]-1β, IL-6, high mobility group protein B1[HMGB-1]). The addition of DPR to shock resuscitation restores liver blood flow, improves organ function, and reverses the systemic proinflammatory response. Our clinical review substantiates that obesity worsens trauma outcomes regardless of injury severity. Obesity-related liver and renal dysfunction is aggravated by injury severity. In an obese rat model of resuscitated hemorrhagic shock, the addition of DPR abrogates trauma-induced liver, renal, and inflammatory responses. We conclude that the addition of DPR to the clinical resuscitation regimen will benefit the obese trauma patient. Published by Elsevier Inc.

Phase 1-2 pilot clinical trial in patients with decompensated liver cirrhosis treated with bone marrow-derived endothelial progenitor cells.

PubMed

D'Avola, Delia; Fernández-Ruiz, Verónica; Carmona-Torre, Francisco; Méndez, Miriam; Pérez-Calvo, Javier; Prósper, Felipe; Andreu, Enrique; Herrero, José Ignacio; Iñarrairaegui, Mercedes; Fuertes, Carmen; Bilbao, José Ignacio; Sangro, Bruno; Prieto, Jesús; Quiroga, Jorge

2017-10-01

The aim of this nonrandomized, open label, phase 1 clinical trial was to evaluate the safety and the feasibility of the treatment with autologous bone marrow-derived endothelial progenitor cells (EPC) in decompensated liver cirrhosis. In addition, the changes in liver function and hepatic venous pressure gradient (HVPG) and their relation with the characteristics of the cellular product were analyzed. Twelve patients with Child-Pugh ≥8 liver cirrhosis underwent bone marrow harvest for ex vivo differentiation of EPC. The final product was administered through the hepatic artery in a single administration. Patients underwent clinical and radiologic follow-up for 12 months. The phenotype and the ability to produce cytokines and growth factors of the final cellular suspension were analyzed. Eleven patients were treated (feasibility 91%). No treatment-related severe adverse events were observed as consequence of any study procedure or treatment. Model for end-stage liver disease score improved significantly (P 0.042) in the first 90 days after cells administration and 5 of the 9 patients alive at 90 days showed a decreased of HVPG. There was a direct correlation between the expression of acetylated-low density lipoprotein and von Willebrand factor in the cellular product and the improvement in liver function and HVPG. The treatment with EPCs in patients with decompensated liver cirrhosis is safe and feasible and might have therapeutic potential. Patients receiving a higher amount of functionally active EPC showed an improvement of liver function and portal hypertension suggesting that the potential usefulness of these cells for the treatment of liver cirrhosis deserves further evaluation. Copyright © 2016 Elsevier Inc. All rights reserved.

Genistein modifies liver fibrosis and improves liver function by inducing uPA expression and proteolytic activity in CCl4-treated rats.

PubMed

Salas, Alfonso Leija; Montezuma, Tania Díaz; Fariña, German Garrido; Reyes-Esparza, Jorge; Rodríguez-Fragoso, Lourdes

2008-01-01

To evaluate the effect of genistein on the fibrosis and matrix degradation caused by experimentally induced fibrosis in rats. Hepatic fibrosis was brought about by chronic administration of carbon tetrachloride to rats. To evaluate the effect of genistein on liver fibrosis and function, total collagen content and proteolytic activity in the liver were quantified. Urokinase-type plasminogen activator (uPA) expression during experimental fibrosis was localized by immunohistochemistry. Histopathological changes were evaluated using light and electron microscopy. Animals with fibrosis and treated with genistein showed an important reduction (73%) in hepatic collagen content as well as an improvement in liver function (p < 0.001). Genistein increased the capacity of the liver to degrade type I collagen and Matrigel (3.1- and 3.7-fold, respectively; p < 0.001) in animals with liver fibrosis. Genistein increased the number of uPA-immunoreactive cells. The increase in the uPA expression correlated with an increase in proteolytic activity. Histological analysis revealed a reduction in the number of fiber septa in pericentral and perisinusoidal areas. Transmission electron micrographs of livers from animals with fibrosis and treated with genistein showed a reduction in the number of hepatic stellate cells activated and a smaller number of collagen fibers. Genistein is able to improve the liver after injury and fibrosis induced by chronic administration of carbon tetrachloride. This finding suggests that genistein has antifibrogenic potential and could therefore be useful for treating chronic liver disease. (c) 2008 S. Karger AG, Basel.

Anti-inflammatory γ- and δ-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats.

PubMed

Wong, Weng-Yew; Ward, Leigh C; Fong, Chee Wai; Yap, Wei Ney; Brown, Lindsay

2017-02-01

This study tested the hypothesis that γ- and δ-tocotrienols are more effective than α-tocotrienol and α-tocopherol in attenuating the signs of diet-induced metabolic syndrome in rats. Five groups of rats were fed a corn starch-rich (C) diet containing 68 % carbohydrates as polysaccharides, while the other five groups were fed a diet (H) high in simple carbohydrates (fructose and sucrose in food, 25 % fructose in drinking water, total 68 %) and fats (beef tallow, total 24 %) for 16 weeks. Separate groups from each diet were supplemented with either α-, γ-, δ-tocotrienol or α-tocopherol (85 mg/kg/day) for the final 8 of the 16 weeks. H rats developed visceral obesity, hypertension, insulin resistance, cardiovascular remodelling and fatty liver. α-Tocopherol, α-, γ- and δ-tocotrienols reduced collagen deposition and inflammatory cell infiltration in the heart. Only γ- and δ-tocotrienols improved cardiovascular function and normalised systolic blood pressure compared to H rats. Further, δ-tocotrienol improved glucose tolerance, insulin sensitivity, lipid profile and abdominal adiposity. In the liver, these interventions reduced lipid accumulation, inflammatory infiltrates and plasma liver enzyme activities. Tocotrienols were measured in heart, liver and adipose tissue showing that chronic oral dosage delivered tocotrienols to these organs despite low or no detection of tocotrienols in plasma. In rats, δ-tocotrienol improved inflammation, heart structure and function, and liver structure and function, while γ-tocotrienol produced more modest improvements, with minimal changes with α-tocotrienol and α-tocopherol. The most important mechanism of action is likely to be reduction in organ inflammation.

Simultaneous acquisition sequence for improved hepatic pharmacokinetics quantification accuracy (SAHA) for dynamic contrast-enhanced MRI of liver.

PubMed

Ning, Jia; Sun, Yongliang; Xie, Sheng; Zhang, Bida; Huang, Feng; Koken, Peter; Smink, Jouke; Yuan, Chun; Chen, Huijun

2018-05-01

To propose a simultaneous acquisition sequence for improved hepatic pharmacokinetics quantification accuracy (SAHA) method for liver dynamic contrast-enhanced MRI. The proposed SAHA simultaneously acquired high temporal-resolution 2D images for vascular input function extraction using Cartesian sampling and 3D large-coverage high spatial-resolution liver dynamic contrast-enhanced images using golden angle stack-of-stars acquisition in an interleaved way. Simulations were conducted to investigate the accuracy of SAHA in pharmacokinetic analysis. A healthy volunteer and three patients with cirrhosis or hepatocellular carcinoma were included in the study to investigate the feasibility of SAHA in vivo. Simulation studies showed that SAHA can provide closer results to the true values and lower root mean square error of estimated pharmacokinetic parameters in all of the tested scenarios. The in vivo scans of subjects provided fair image quality of both 2D images for arterial input function and portal venous input function and 3D whole liver images. The in vivo fitting results showed that the perfusion parameters of healthy liver were significantly different from those of cirrhotic liver and HCC. The proposed SAHA can provide improved accuracy in pharmacokinetic modeling and is feasible in human liver dynamic contrast-enhanced MRI, suggesting that SAHA is a potential tool for liver dynamic contrast-enhanced MRI. Magn Reson Med 79:2629-2641, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Bone Marrow–Derived Stromal Cell Therapy in Cirrhosis: Clinical Evidence, Cellular Mechanisms, and Implications for the Treatment of Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vainshtein, Jeffrey M.; Kabarriti, Rafi; Mehta, Keyur J.

2014-07-15

Current treatment options for hepatocellular carcinoma (HCC) are often limited by the presence of underlying liver disease. In patients with liver cirrhosis, surgery, chemotherapy, and radiation therapy all carry a high risk of hepatic complications, ranging from ascites to fulminant liver failure. For patients receiving radiation therapy, cirrhosis dramatically reduces the already limited radiation tolerance of the liver and represents the most important clinical risk factor for the development of radiation-induced liver disease. Although improvements in conformal radiation delivery techniques have improved our ability to safely irradiate confined areas of the liver to increasingly higher doses with excellent local diseasemore » control, patients with moderate-to-severe liver cirrhosis continue to face a shortage of treatment options for HCC. In recent years, evidence has emerged supporting the use of bone marrow–derived stromal cells (BMSCs) as a promising treatment for liver cirrhosis, with several clinical studies demonstrating sustained improvement in clinical parameters of liver function after autologous BMSC infusion. Three predominant populations of BMSCs, namely hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells, seem to have therapeutic potential in liver injury and cirrhosis. Preclinical studies of BMSC transplantation have identified a range of mechanisms through which these cells mediate their therapeutic effects, including hepatocyte transdifferentiation and fusion, paracrine stimulation of hepatocyte proliferation, inhibition of activated hepatic stellate cells, enhancement of fibrolytic matrix metalloproteinase activity, and neovascularization of regenerating liver. By bolstering liver function in patients with underlying Child's B or C cirrhosis, autologous BMSC infusion holds great promise as a therapy to improve the safety, efficacy, and utility of surgery, chemotherapy, and hepatic radiation therapy in the treatment of HCC.« less

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

PubMed Central

Avraham, Y; Grigoriadis, NC; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, EM

2011-01-01

BACKGROUND AND PURPOSE Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. PMID:21182490

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.

PubMed

Avraham, Y; Grigoriadis, Nc; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, Em

2011-04-01

Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Liver maximum capacity (LiMAx) test as a helpful prognostic tool in acute liver failure with sepsis: a case report.

PubMed

Buechter, Matthias; Gerken, Guido; Hoyer, Dieter P; Bertram, Stefanie; Theysohn, Jens M; Thodou, Viktoria; Kahraman, Alisan

2018-06-20

Acute liver failure (ALF) is a life-threatening entity particularly when infectious complications worsen the clinical course. Urgent liver transplantation (LT) is frequently the only curative treatment. However, in some cases, recovery is observed under conservative treatment. Therefore, prognostic tools for estimating course of the disease are of great clinical interest. Since laboratory parameters sometimes lack sensitivity and specificity, enzymatic liver function measured by liver maximum capacity (LiMAx) test may offer novel and valuable additional information in this setting. We here report the case of a formerly healthy 20-year old male caucasian patient who was admitted to our clinic for ALF of unknown origin in December 2017. Laboratory parameters confirmed the diagnosis with an initial MELD score of 28 points. Likewise, enzymatic liver function was significantly impaired with a value of 147 [> 315] μg/h/kg. Clinical and biochemical analyses for viral-, autoimmune-, or drug-induced hepatitis were negative. Liver synthesis parameters further deteriorated reaching a MELD score of 40 points whilst clinical course was complicated by septic pneumonia leading to severe hepatic encephalopathy grade III-IV, finally resulting in mechanical ventilation of the patient. Interestingly, although clinical course and laboratory data suggested poor outcome, serial LiMAx test revealed improvement of the enzymatic liver function at this time point increasing to 169 μg/h/kg. Clinical condition and laboratory data slowly improved likewise, however with significant time delay of 11 days. Finally, the patient could be dismissed from our clinic after 37 days. Estimating prognosis in patients with ALF is challenging by use of the established scores. In our case, improvement of enzymatic liver function measured by the LiMAx test was the first parameter predicting beneficial outcome in a patient with ALF complicated by sepsis.

Metformin and/or clomiphene do not adversely affect liver or renal function in women with polycystic ovary syndrome.

PubMed

Aubuchon, Mira; Kunselman, Allen R; Schlaff, William D; Diamond, Michael P; Coutifaris, Christos; Carson, Sandra A; Steinkampf, Michael P; Carr, Bruce R; McGovern, Peter G; Cataldo, Nicholas A; Gosman, Gabriella G; Nestler, John E; Myers, Evan R; Legro, Richard S

2011-10-01

Nonalcoholic fatty liver disease is common to insulin-resistant states such as polycystic ovary syndrome (PCOS). Metformin (MET) is often used to treat PCOS but information is limited as to its effects on liver function. We sought to determine the effects of MET on serum hepatic parameters in PCOS patients. This was a secondary analysis of a randomized, doubled-blind trial from 2002-2004. This multi-center clinical trial was conducted in academic centers. Six hundred twenty-six infertile women with PCOS with serum liver function parameters less than twice the upper limit of normal were included. Clomiphene citrate (n = 209), MET (n = 208), or combined (n = 209) were given for up to 6 months. The percent change from baseline in renal and liver function between- and within-treatment arms was assessed. Renal function improved in all treatment arms with significant decreases in serum blood urea nitrogen levels (range, -14.7 to -21.3%) as well as creatinine (-4.2 to -6.9%). There were similar decreases in liver transaminase levels in the clomiphene citrate and combined arms (-10% in bilirubin, -9 to -11% in transaminases) without significant changes in the MET arm. When categorizing baseline bilirubin, aspartate aminotransferase, and alanine aminotransferase into tertiles, there were significant within-treatment arm differences between the tertiles with the highest tertile having the largest decrease from baseline regardless of treatment arm. Women with PCOS can safely use metformin and clomiphene even in the setting of mildly abnormal liver function parameters, and both result in improved renal function.

Computational Modeling in Liver Surgery

PubMed Central

Christ, Bruno; Dahmen, Uta; Herrmann, Karl-Heinz; König, Matthias; Reichenbach, Jürgen R.; Ricken, Tim; Schleicher, Jana; Ole Schwen, Lars; Vlaic, Sebastian; Waschinsky, Navina

2017-01-01

The need for extended liver resection is increasing due to the growing incidence of liver tumors in aging societies. Individualized surgical planning is the key for identifying the optimal resection strategy and to minimize the risk of postoperative liver failure and tumor recurrence. Current computational tools provide virtual planning of liver resection by taking into account the spatial relationship between the tumor and the hepatic vascular trees, as well as the size of the future liver remnant. However, size and function of the liver are not necessarily equivalent. Hence, determining the future liver volume might misestimate the future liver function, especially in cases of hepatic comorbidities such as hepatic steatosis. A systems medicine approach could be applied, including biological, medical, and surgical aspects, by integrating all available anatomical and functional information of the individual patient. Such an approach holds promise for better prediction of postoperative liver function and hence improved risk assessment. This review provides an overview of mathematical models related to the liver and its function and explores their potential relevance for computational liver surgery. We first summarize key facts of hepatic anatomy, physiology, and pathology relevant for hepatic surgery, followed by a description of the computational tools currently used in liver surgical planning. Then we present selected state-of-the-art computational liver models potentially useful to support liver surgery. Finally, we discuss the main challenges that will need to be addressed when developing advanced computational planning tools in the context of liver surgery. PMID:29249974

Platelets in liver disease, cancer and regeneration.

PubMed

Kurokawa, Tomohiro; Ohkohchi, Nobuhiro

2017-05-14

Although viral hepatitis treatments have evolved over the years, the resultant liver cirrhosis still does not completely heal. Platelets contain proteins required for hemostasis, as well as many growth factors required for organ development, tissue regeneration and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, can manifest from decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis, as well as the role of platelets in CLD, is poorly understood. In this paper, experimental evidence of platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. In addition, we describe our current perspective based on the results of these studies. Platelets improve liver fibrosis by inactivating hepatic stellate cells, which decreases collagen production. The regenerative effect of platelets in the liver involves a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these observations, we ascertained the direct effect of platelet transfusion on improving several indicators of liver function in patients with CLD and liver cirrhosis. However, unlike the results of our previous clinical study, the smaller incremental changes in liver function in patients with CLD who received eltrombopag for 6 mo were due to patient selection from a heterogeneous population. We highlight the current knowledge concerning the role of platelets in CLD and cancer and anticipate a novel application of platelet-based clinical therapies to treat liver disease.

Thymoquinone restores liver fibrosis and improves oxidative stress status in a lipopolysaccharide-induced inflammation model in rats.

PubMed

Asgharzadeh, Fereshteh; Bargi, Rahimeh; Beheshti, Farimah; Hosseini, Mahmoud; Farzadnia, Mehdi; Khazaei, Majid

2017-01-01

Liver fibrosis is the primary sign of chronic liver injury induced by various causes. Thymoquinone (TQ) is the major ingredient of Nigella sativa with several beneficial effects on the body. In the present study, we aimed to investigate the effect of TQ on liver fibrosis in a lipopolysaccharide (LPS)-induced inflammation in male rats. Fifty male Wistar rats were randomly divided into five groups (n=10 in each group) as follow: (1) control; (2) LPS (1 mg/kg/day; i.p); (3) LPS+TQ 2 mg/kg/day (i.p) (LPs+TQ2); (4) LPS+TQ 5 mg/kg/day (LPS+TQ5); (5) LPS+ TQ 10 mg/kg/day (LPS+ TQ10). After three weeks, blood samples were taken for evaluation of liver function tests. Then, the livers were harvested for histological evaluation of fibrosis and collagen content and measurement of oxidative stress markers including malondialdehyde (MDA), total thiol groups, superoxide dismutase (SOD) and catalase activity in tissue homogenates. LPS group showed higher levels of fibrosis and collagen content stained by Masson's trichrome in liver tissue with impaired liver function test and increased oxidative stress markers (p<0.05). Treatment by TQ restored liver fibrosis, improved liver function tests and increased the levels of anti-oxidative enzymes (SOD and catalase), while reduced MDA concentration (p<0.05). Treatment by TQ restores inflammation-induced liver fibrosis possibly through affecting oxidative stress status. It seems that administration of TQ can be considered as a part of liver fibrosis management.

Improvement of liver function and non-invasive fibrosis markers in hepatitis B virus-associated cirrhosis: 2 years of entecavir treatment.

PubMed

Shin, Seung Kak; Kim, Jeong Han; Park, Hyeonsu; Kwon, Oh Sang; Lee, Hyun Jung; Yeon, Jong Eun; Byun, Kwan Soo; Suh, Sang Jun; Yim, Hyung Joon; Kim, Yun Soo; Kim, Ju Hyun

2015-12-01

Entecavir (ETV) induces biochemical and histologic improvement of the liver in patients with chronic hepatitis B. This study aimed to confirm that 2 years of ETV treatment improves liver function and non-invasive fibrosis markers in patients with hepatitis B virus (HBV)-associated cirrhosis. A total 472 naïve patients with HBV-associated cirrhosis was treated with ETV for at least 2 years, between March 2007 and December 2012. Model for end-stage liver disease and Child-Pugh (CP) score were used to evaluate the improvement of liver function. Aspartate transaminase to platelet ratio index, FIB-4 index, and fibrosis index were used to evaluate the improvement of fibrosis. The final 370 of 472 patients with HBV-associated cirrhosis were enrolled. Mean age was 51 ± 10 years, and 240 patients (64.9%) were men. The distribution of CP class was 71.1% in A, 24.6% in B, and 4.3% in C. Mean end-stage liver disease and CP score changed over the study period from 8.5 ± 4.6 to 6.2 ± 4.2 (P < 0.001) and from 6.2 ± 1.6 to 5.6 ± 0.9 (P < 0.001), respectively. Aspartate transaminase to platelet ratio index, FIB-4 index, and fibrosis index changed from 3.6 ± 4.5 to 1.5 ± 1.5 (P < 0.001), from 7.0 ± 6.2 to 3.9 ± 2.8 (P < 0.001), and from 3.3 ± 0.9 to 2.5 ± 1.1 (P < 0.001), respectively. After 2 years of treatment, ETV improves liver function and non-invasive fibrosis markers in patients with HBV-associated cirrhosis. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Understanding the effect of corticosteroid pretreatment in brain-dead organ donors: new mechanistic insights for improvement of organ quality in liver transplantation.

PubMed

Dahrenmöller, Carola; Reding, Raymond

2017-09-15

Transplant surgeons are currently faced with the challenge to accept marginal liver transplants due to steatosis or old age. Improving organ quality by implementing a selective organ protective donor management could be the first step towards a graft of enhanced quality. However, the molecular mechanisms of such treatments are still poorly understood. Glucocorticoid medication in donor medicine has been carried out and discussed for a long time. In a recent study published in Clinical Science , Jiménez-Castro et al. [Clin. Sci. (2017) 131, 733-746] demonstrate how liver histology and transplant liver function can be improved by administration of glucocorticoids to brain-dead donor rats with steatotic livers. This work illustrates the need for further trials in order to selectively improve the quality of steatotic livers with a potential for liver transplantation. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Molecular adsorbent recirculating system dialysis in patients with acute liver failure who are assessed for liver transplantation.

PubMed

Camus, Christophe; Lavoué, Sylvain; Gacouin, Arnaud; Le Tulzo, Yves; Lorho, Richard; Boudjéma, Karim; Jacquelinet, Christian; Thomas, Rémi

2006-11-01

To assess the usefulness of dialysis with the molecular adsorbent recirculating system (MARS) in patients with acute liver failure who fulfil criteria for liver transplantation. Observational cohort study. ICU at a liver transplantation centre. Twenty-two patients (23 episodes) received MARS dialysis. They were either listed for LT (n=14), delayed (n=1), or not listed (contra-indication, n=7). A total of 56 MARS treatments (median per patient 2; mean duration 7.6+/-2.6h) were performed on haemodialysis. Clinical and biological variables were assessed before and 24[Symbol: see text]h after MARS therapy. The rate of recovery of liver function without transplantation was compared with an expected rate and survival was analysed. Following MARS dialysis, we observed an improvement in the grade of hepatic encephalopathy (P=0.02) and the Glasgow coma score (P=0.02), a decrease in conjugated bilirubin (P=0.05) and INR (P=0.006), and an increase in prothrombin index (P=0.005). Overall, liver function improved in seven patients (32%): four listed patients in whom transplantation could be avoided and three patients among those not listed due to contra-indications. The transplant-free recovery rate in listed patients was 29% (vs. expected 9%, P=0.036). Listed patients (n=14) had a higher 30-day survival rate [86% (12/14) vs 38% (3/8), P=0.05] and a higher long-term survival rate (P=0.02). A statistically significant improvement of liver function was observed after MARS therapy. Transplant-free recovery was more frequent than expected. The apparent benefit of MARS dialysis to treat acute liver failure needs to be confirmed by a controlled study.

Bioartificial liver devices: Perspectives on the state of the art.

PubMed

Ding, Yi-Tao; Shi, Xiao-Lei

2011-03-01

Acute liver failure remains a significant cause of morbidity and mortality. Bioartificial liver (BAL) devices have been in development for more than 20 years. Such devices aim to temporarily take over the metabolic and excretory functions of the liver until the patients' own liver has recovered or a donor liver becomes available for transplant. The important issues include the choice of cell materials and the design of the bioreactor. Ideal BAL cell materials should be of good viability and functionality, easy to access, and exclude immunoreactive and tumorigenic cell materials. Unfortunately, the current cells in use in BAL do not meet these requirements. One of the challenges in BAL development is the improvement of current materials; another key point concerning cell materials is the coculture of different cells. The bioreactor is an important component of BAL, because it determines the viability and function of the hepatocytes within it. From the perspective of bioengineering, a successful and clinically effective bioreactor should mimic the structure of the liver and provide an in vivo-like microenvironment for the growth of hepatocytes, thereby maintaining the cells' viability and function to the maximum extent. One future trend in the development of the bioreactor is to improve the oxygen supply system. Another direction for future research on bioreactors is the application of biomedical materials. In conclusion, BAL is, in principle, an important therapeutic strategy for patients with acute liver failure, and may also be a bridge to liver transplantation. It requires further research and development, however, before it can enter clinical practice.

Exercise improves adipose function and inflammation and ameliorates fatty liver disease in obese diabetic mice.

PubMed

Haczeyni, Fahrettin; Barn, Vanessa; Mridha, Auvro R; Yeh, Matthew M; Estevez, Emma; Febbraio, Mark A; Nolan, Christopher J; Bell-Anderson, Kim S; Teoh, Narci C; Farrell, Geoffrey C

2015-09-01

Adipose inflammation and dysfunction underlie metabolic obesity. Exercise improves glycemic control and metabolic indices, but effects on adipose function and inflammation are less clear. Accordingly, it was hypothesized that exercise improves adipose morphometry to reduce adipose inflammation in hyperphagic obese mice. Alms1 mutant foz/foz mice housed in pairs were fed an atherogenic or chow diet; half the cages were fitted with a computer-monitored wheel for voluntary exercise. Insulin-induced AKT-phosphorylation, adipocyte size distribution, and inflammatory recruitment were studied in visceral versus subcutaneous depots, and severity of fatty liver disease was determined. Exercise prevented obesity and diabetes development in chow-fed foz/foz mice and delayed their onset in atherogenic-fed counterparts. Insulin-stimulated phospho-AKT levels in muscle were improved with exercise, but not in adipose or liver. Exercise suppressed adipose inflammatory recruitment, particularly in visceral adipose, associated with an increased number of small adipocyte subpopulations, and enhanced expression of beige adipocyte factor PRDM16 in subcutaneous fat. In atherogenic-fed foz/foz mice liver, exercise suppressed development of nonalcoholic steatohepatitis and related liver fibrosis. Exercise confers metabo-protective effects in atherogenic-fed hyperphagic mice by preventing early onset of obesity and diabetes in association with enhanced muscle insulin sensitivity, improved adipose morphometry, and suppressed adipose and liver inflammation. © 2015 The Obesity Society.

Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems.

PubMed

Lee-Montiel, Felipe T; George, Subin M; Gough, Albert H; Sharma, Anup D; Wu, Juanfang; DeBiasio, Richard; Vernetti, Lawrence A; Taylor, D Lansing

2017-10-01

This article describes our next generation human Liver Acinus MicroPhysiology System (LAMPS). The key demonstration of this study was that Zone 1 and Zone 3 microenvironments can be established by controlling the oxygen tension in individual devices over the range of ca. 3 to 13%. The oxygen tension was computationally modeled using input on the microfluidic device dimensions, numbers of cells, oxygen consumption rates of hepatocytes, the diffusion coefficients of oxygen in different materials and the flow rate of media in the MicroPhysiology System (MPS). In addition, the oxygen tension was measured using a ratiometric imaging method with the oxygen sensitive dye, Tris(2,2'-bipyridyl) dichlororuthenium(II) hexahydrate (RTDP) and the oxygen insensitive dye, Alexa 488. The Zone 1 biased functions of oxidative phosphorylation, albumin and urea secretion and Zone 3 biased functions of glycolysis, α1AT secretion, Cyp2E1 expression and acetaminophen toxicity were demonstrated in the respective Zone 1 and Zone 3 MicroPhysiology System. Further improvements in the Liver Acinus MicroPhysiology System included improved performance of selected nonparenchymal cells, the inclusion of a porcine liver extracellular matrix to model the Space of Disse, as well as an improved media to support both hepatocytes and non-parenchymal cells. In its current form, the Liver Acinus MicroPhysiology System is most amenable to low to medium throughput, acute through chronic studies, including liver disease models, prioritizing compounds for preclinical studies, optimizing chemistry in structure activity relationship (SAR) projects, as well as in rising dose studies for initial dose ranging. Impact statement Oxygen zonation is a critical aspect of liver functions. A human microphysiology system is needed to investigate the impact of zonation on a wide range of liver functions that can be experimentally manipulated. Because oxygen zonation has such diverse physiological effects in the liver, we developed and present a method for computationally modeling and measuring oxygen that can easily be implemented in all MPS models. We have applied this method in a liver MPS in which we are then able to control oxygenation in separate devices and demonstrate that zonation-dependent hepatocyte functions in the MPS recapitulate what is known about in vivo liver physiology. We believe that this advance allows a deep experimental investigation on the role of zonation in liver metabolism and disease. In addition, modeling and measuring oxygen tension will be required as investigators migrate from PDMS to plastic and glass devices.

Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems

PubMed Central

Lee-Montiel, Felipe T; George, Subin M; Sharma, Anup D; Wu, Juanfang; DeBiasio, Richard; Vernetti, Lawrence A; Taylor, D Lansing

2017-01-01

This article describes our next generation human Liver Acinus MicroPhysiology System (LAMPS). The key demonstration of this study was that Zone 1 and Zone 3 microenvironments can be established by controlling the oxygen tension in individual devices over the range of ca. 3 to 13%. The oxygen tension was computationally modeled using input on the microfluidic device dimensions, numbers of cells, oxygen consumption rates of hepatocytes, the diffusion coefficients of oxygen in different materials and the flow rate of media in the MicroPhysiology System (MPS). In addition, the oxygen tension was measured using a ratiometric imaging method with the oxygen sensitive dye, Tris(2,2′-bipyridyl) dichlororuthenium(II) hexahydrate (RTDP) and the oxygen insensitive dye, Alexa 488. The Zone 1 biased functions of oxidative phosphorylation, albumin and urea secretion and Zone 3 biased functions of glycolysis, α1AT secretion, Cyp2E1 expression and acetaminophen toxicity were demonstrated in the respective Zone 1 and Zone 3 MicroPhysiology System. Further improvements in the Liver Acinus MicroPhysiology System included improved performance of selected nonparenchymal cells, the inclusion of a porcine liver extracellular matrix to model the Space of Disse, as well as an improved media to support both hepatocytes and non-parenchymal cells. In its current form, the Liver Acinus MicroPhysiology System is most amenable to low to medium throughput, acute through chronic studies, including liver disease models, prioritizing compounds for preclinical studies, optimizing chemistry in structure activity relationship (SAR) projects, as well as in rising dose studies for initial dose ranging. Impact statement Oxygen zonation is a critical aspect of liver functions. A human microphysiology system is needed to investigate the impact of zonation on a wide range of liver functions that can be experimentally manipulated. Because oxygen zonation has such diverse physiological effects in the liver, we developed and present a method for computationally modeling and measuring oxygen that can easily be implemented in all MPS models. We have applied this method in a liver MPS in which we are then able to control oxygenation in separate devices and demonstrate that zonation-dependent hepatocyte functions in the MPS recapitulate what is known about in vivo liver physiology. We believe that this advance allows a deep experimental investigation on the role of zonation in liver metabolism and disease. In addition, modeling and measuring oxygen tension will be required as investigators migrate from PDMS to plastic and glass devices. PMID:28409533

Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery

NASA Astrophysics Data System (ADS)

Rudolph, Karl Lenhard; Chang, Sandy; Millard, Melissa; Schreiber-Agus, Nicole; DePinho, Ronald A.

2000-02-01

Accelerated telomere loss has been proposed to be a factor leading to end-stage organ failure in chronic diseases of high cellular turnover such as liver cirrhosis. To test this hypothesis directly, telomerase-deficient mice, null for the essential telomerase RNA (mTR) gene, were subjected to genetic, surgical, and chemical ablation of the liver. Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. Adenoviral delivery of mTR into the livers of mTR-/- mice with short dysfunctional telomeres restored telomerase activity and telomere function, alleviated cirrhotic pathology, and improved liver function. These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of ``telomerase therapy'' for such diseases.

Metformin and/or Clomiphene Do Not Adversely Affect Liver or Renal Function in Women with Polycystic Ovary Syndrome

PubMed Central

Aubuchon, Mira; Kunselman, Allen R.; Schlaff, William D.; Diamond, Michael P.; Coutifaris, Christos; Carson, Sandra A.; Steinkampf, Michael P.; Carr, Bruce R.; McGovern, Peter G.; Cataldo, Nicholas A.; Gosman, Gabriella G.; Nestler, John E.; Myers, Evan R.

2011-01-01

Context: Nonalcoholic fatty liver disease is common to insulin-resistant states such as polycystic ovary syndrome (PCOS). Metformin (MET) is often used to treat PCOS but information is limited as to its effects on liver function. Objective: We sought to determine the effects of MET on serum hepatic parameters in PCOS patients. Design: This was a secondary analysis of a randomized, doubled-blind trial from 2002–2004. Setting: This multi-center clinical trial was conducted in academic centers. Patients: Six hundred twenty-six infertile women with PCOS with serum liver function parameters less than twice the upper limit of normal were included. Interventions: Clomiphene citrate (n = 209), MET (n = 208), or combined (n = 209) were given for up to 6 months. Main Outcome Measure: The percent change from baseline in renal and liver function between- and within-treatment arms was assessed. Results: Renal function improved in all treatment arms with significant decreases in serum blood urea nitrogen levels (range, −14.7 to −21.3%) as well as creatinine (−4.2 to −6.9%). There were similar decreases in liver transaminase levels in the clomiphene citrate and combined arms (−10% in bilirubin, −9 to −11% in transaminases) without significant changes in the MET arm. When categorizing baseline bilirubin, aspartate aminotransferase, and alanine aminotransferase into tertiles, there were significant within-treatment arm differences between the tertiles with the highest tertile having the largest decrease from baseline regardless of treatment arm. Conclusion: Women with PCOS can safely use metformin and clomiphene even in the setting of mildly abnormal liver function parameters, and both result in improved renal function. PMID:21832111

Extracorporeal Bioartificial Liver for Treating Acute Liver Diseases

PubMed Central

Kumar, Ashok; Tripathi, Anuj; Jain, Shivali

2011-01-01

Abstract: Liver is a vital organ of the human body performing myriad of essential functions. Liver-related ailments are often life-threatening and dramatically deteriorate the quality of life of patients. Management of acute liver diseases requires adequate support of various hepatic functions. Thus far, liver transplantation has been proven as the only effective solution for acute liver diseases. However, broader application of liver transplantation is limited by demand for lifelong immunosuppression, shortage of organ donors, relative high morbidity, and high cost. Therefore, research has been focused on attempting to develop alternative support systems to treat liver diseases. Earlier attempts have been made to use nonbiological therapies based on the use of conventional detoxification procedures such as filtration and dialysis. However, the absence of liver cells in such techniques reduced the overall survival rate of the patients and led to inadequate essential liver-specific functions. As a result, there has been growing interest in the development of biological therapy-based extracorporeal liver support systems as a bridge to liver transplantation or to support the ailing liver. A bioartificial liver support is an extracorporeal device through which plasma is circulated over living and functionally active hepatocytes packed in a bioreactor with the aim to aid the diseased liver until it regenerates or until a suitable graft for transplantation is available. This review article gives a brief overview of efficacy of various liver support systems that are currently available. Also, the development of advanced liver support systems, which has been analyzed for improving the important system component such as cell source and other culture and circulation conditions for the maintenance of the liver-specific functions, have been described. PMID:22416599

Effect of heme oxygenase-1 on the protection of ischemia reperfusion injury of bile duct in rats after liver transplantation.

PubMed

Zhan, Xi; Zhang, Zhiqing; Huang, Hanfei; Zhang, Yujun; Zeng, Zhong

2018-06-01

To investigate the effect of heme oxygenase-1 (HO-1) on the ischemic reperfusion injury (IRI) of bile duct in rat models after liver transplantation. 320 SD rats were equally and randomly divided into 5 groups, which were group A receiving injection of 3×10 8 /pfu/ml adenovirus (adv), group B with donor receiving Adv-HO-1 and recipient receiving Adv-HO-1-siRNA, group C with donor and recipient both receiving Adv-HO-1, group D with donor receiving Adv-HO-1-siRNA and recipient receiving Adv-HO-1, and group E with donor and recipient both receiving Adv-HO-1-siRNA at 24h before liver transplantation. Donor liver was stored in UW liquid at 4°C followed by measuring HO-1 level by western blot before transplantation. On d1, d3, d7 and d14, serum and liver was isolated for analysis of liver function, inflammatory cell infiltration by H&E staining, ultrastructure of liver by transmission electron microscopy as well as the expression of HO-1, Bsep, Mrp2 and Ntcp by western blot. Compared with group D and E, group B and C displayed improved liver function as demonstrated by lower level of ALT, AST, LDH, TBIL, ALP and GGT, increased secretion of TBA and PL as well as expression of transporter proteins (Bsep, Mrp2 and Ntcp), reduced inflammatory cells infiltration and liver injury. Our study demonstrated that overexpression of HO-1 in donor liver can ameliorate the damage to bile duct and liver, and improved liver function, suggesting HO-1 might be a new therapeutic target in the treatment of IRI after liver transplantation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: Therapeutic effect on liver fibrosis/cirrhosis.

PubMed

Zhang, Guo-Zun; Sun, Hui-Cong; Zheng, Li-Bo; Guo, Jin-Bo; Zhang, Xiao-Lan

2017-12-14

To investigate the hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and to evaluate their therapeutic effect on liver fibrosis/cirrhosis. A CCl 4 -induced liver fibrotic/cirrhotic rat model was used to assess the effect of hUC-MSCs. Histopathology was assessed by hematoxylin and eosin (H&E), Masson trichrome and Sirius red staining. The liver biochemical profile was measured using a Beckman Coulter analyzer. Expression analysis was performed using immunofluorescent staining, immunohistochemistry, Western blot, and real-time PCR. We demonstrated that the infused hUC-MSCs could differentiate into hepatocytes in vivo . Functionally, the transplantation of hUC-MSCs to CCl 4 -treated rats improved liver transaminases and synthetic function, reduced liver histopathology and reversed hepatobiliary fibrosis. The reversal of hepatobiliary fibrosis was likely due to the reduced activation state of hepatic stellate cells, decreased collagen deposition, and enhanced extracellular matrix remodeling via the up-regulation of MMP-13 and down-regulation of TIMP-1. Transplanted hUC-MSCs could differentiate into functional hepatocytes that improved both the biochemical and histopathologic changes in a CCl 4 -induced rat liver fibrosis model. hUC-MSCs may offer therapeutic opportunities for treating hepatobiliary diseases, including cirrhosis.

In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: Therapeutic effect on liver fibrosis/cirrhosis

PubMed Central

Zhang, Guo-Zun; Sun, Hui-Cong; Zheng, Li-Bo; Guo, Jin-Bo; Zhang, Xiao-Lan

2017-01-01

AIM To investigate the hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and to evaluate their therapeutic effect on liver fibrosis/cirrhosis. METHODS A CCl4-induced liver fibrotic/cirrhotic rat model was used to assess the effect of hUC-MSCs. Histopathology was assessed by hematoxylin and eosin (H&E), Masson trichrome and Sirius red staining. The liver biochemical profile was measured using a Beckman Coulter analyzer. Expression analysis was performed using immunofluorescent staining, immunohistochemistry, Western blot, and real-time PCR. RESULTS We demonstrated that the infused hUC-MSCs could differentiate into hepatocytes in vivo. Functionally, the transplantation of hUC-MSCs to CCl4-treated rats improved liver transaminases and synthetic function, reduced liver histopathology and reversed hepatobiliary fibrosis. The reversal of hepatobiliary fibrosis was likely due to the reduced activation state of hepatic stellate cells, decreased collagen deposition, and enhanced extracellular matrix remodeling via the up-regulation of MMP-13 and down-regulation of TIMP-1. CONCLUSION Transplanted hUC-MSCs could differentiate into functional hepatocytes that improved both the biochemical and histopathologic changes in a CCl4-induced rat liver fibrosis model. hUC-MSCs may offer therapeutic opportunities for treating hepatobiliary diseases, including cirrhosis. PMID:29290652

Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients

PubMed Central

Shi, Ming; Zhang, Zheng; Xu, Ruonan; Lin, Hu; Fu, Junliang; Zou, Zhengsheng; Zhang, Aimin; Shi, Jianfei; Chen, Liming; Lv, Sa; He, Weiping; Geng, Hua; Jin, Lei; Liu, Zhenwen

2012-01-01

Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cord-derived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients. PMID:23197664

Naringin Improves Diet-Induced Cardiovascular Dysfunction and Obesity in High Carbohydrate, High Fat Diet-Fed Rats

PubMed Central

Alam, Md. Ashraful; Kauter, Kathleen; Brown, Lindsay

2013-01-01

Obesity, insulin resistance, hypertension and fatty liver, together termed metabolic syndrome, are key risk factors for cardiovascular disease. Chronic feeding of a diet high in saturated fats and simple sugars, such as fructose and glucose, induces these changes in rats. Naturally occurring compounds could be a cost-effective intervention to reverse these changes. Flavonoids are ubiquitous secondary plant metabolites; naringin gives the bitter taste to grapefruit. This study has evaluated the effect of naringin on diet-induced obesity and cardiovascular dysfunction in high carbohydrate, high fat-fed rats. These rats developed increased body weight, glucose intolerance, increased plasma lipid concentrations, hypertension, left ventricular hypertrophy and fibrosis, liver inflammation and steatosis with compromised mitochondrial respiratory chain activity. Dietary supplementation with naringin (approximately 100 mg/kg/day) improved glucose intolerance and liver mitochondrial dysfunction, lowered plasma lipid concentrations and improved the structure and function of the heart and liver without decreasing total body weight. Naringin normalised systolic blood pressure and improved vascular dysfunction and ventricular diastolic dysfunction in high carbohydrate, high fat-fed rats. These beneficial effects of naringin may be mediated by reduced inflammatory cell infiltration, reduced oxidative stress, lowered plasma lipid concentrations and improved liver mitochondrial function in rats. PMID:23446977

Temporary Intraoperative Porto-Caval Shunts in Piggy-Back Liver Transplantation Reduce Intraoperative Blood Loss and Improve Postoperative Transaminases and Renal Function: A Meta-Analysis.

PubMed

Pratschke, Sebastian; Rauch, Alexandra; Albertsmeier, Markus; Rentsch, Markus; Kirschneck, Michaela; Andrassy, Joachim; Thomas, Michael; Hartwig, Werner; Figueras, Joan; Del Rio Martin, Juan; De Ruvo, Nicola; Werner, Jens; Guba, Markus; Weniger, Maximilian; Angele, Martin K

2016-12-01

The value of temporary intraoperative porto-caval shunts (TPCS) in cava-sparing liver transplantation is discussed controversially. Aim of this meta-analysis was to analyze the impact of temporary intraoperative porto-caval shunts on liver injury, primary non-function, time of surgery, transfusion of blood products and length of hospital stay in cava-sparing liver transplantation. A systematic search of MEDLINE/PubMed, EMBASE and PsycINFO retrieved a total of 909 articles, of which six articles were included. The combined effect size and 95 % confidence interval were calculated for each outcome by applying the inverse variance weighting method. Tests for heterogeneity (I 2 ) were also utilized. Usage of a TPCS was associated with significantly decreased AST values, significantly fewer transfusions of packed red blood cells and improved postoperative renal function. There were no statistically significant differences in primary graft non-function, length of hospital stay or duration of surgery. This meta-analysis found that temporary intraoperative porto-caval shunts in cava-sparing liver transplantation reduce blood loss as well as hepatic injury and enhance postoperative renal function without prolonging operative time. Randomized controlled trials investigating the use of temporary intraoperative porto-caval shunts are needed to confirm these findings.

Improvement of impaired albumin binding capacity in acute-on-chronic liver failure by albumin dialysis.

PubMed

Klammt, Sebastian; Mitzner, Steffen R; Stange, Jan; Loock, Jan; Heemann, Uwe; Emmrich, Jörg; Reisinger, Emil C; Schmidt, Reinhard

2008-09-01

Extracorporeal albumin dialysis (ECAD) enables the elimination of albumin bound substances and is used as artificial liver support system. Albumin binding function for the benzodiazepine binding site specific marker Dansylsarcosine was estimated in plasma samples of 22 patients with cirrhosis and hyperbilirubinaemia (ECAD: n = 12; control: n = 10) during a period of 30 days in a randomized controlled clinical ECAD trial. Albumin Binding Capacity (ABiC) at baseline was reduced to 31.8% (median; range 24%-74%) and correlated to the severity of liver disease. Within two weeks a significant improvement of ABiC and a reduction of the albumin bound markers bilirubin and bile acids were observed in the ECAD group. During single treatments a significant decrease of albumin bound substances (bilirubin and bile acids) as well as an increase in ABiC was observed. In the control group, baseline ABiC was significantly lower in patients who died during study period (34.2% vs. 41.7%; P < 0.028), whereas no significant differences were observed for CHILD, coagulation factors, albumin, bile acids nor bilirubin. At baseline 13 patients had a severely impaired ABiC (<40%), improvement of ABiC was more frequent in the ECAD group (5/6) than in the SMT group (2/7). Reduced albumin binding function is present in decompensated liver failure and is related to severity and 30 day survival. ABiC can be improved by ECAD. The beneficial effect of this treatment may be related to the improvement of albumin binding function more than to the elimination of specific substances. Characterization of albumin function by the ABiC test may help to evaluate different liver support systems and other therapeutic measures.

Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery.

PubMed

Kizawa, Hideki; Nagao, Eri; Shimamura, Mitsuru; Zhang, Guangyuan; Torii, Hitoshi

2017-07-01

The liver plays a central role in metabolism. Although many studies have described in vitro liver models for drug discovery, to date, no model has been described that can stably maintain liver function. Here, we used a unique, scaffold-free 3D bio-printing technology to construct a small portion of liver tissue that could stably maintain drug, glucose, and lipid metabolism, in addition to bile acid secretion. This bio-printed normal human liver tissue maintained expression of several kinds of hepatic drug transporters and metabolic enzymes that functioned for several weeks. The bio-printed liver tissue displayed glucose production via cAMP/protein kinase A signaling, which could be suppressed with insulin. Bile acid secretion was also observed from the printed liver tissue, and it accumulated in the culture medium over time. We observed both bile duct and sinusoid-like structures in the bio-printed liver tissue, which suggested that bile acid secretion occurred via a sinusoid-hepatocyte-bile duct route. These results demonstrated that our bio-printed liver tissue was unique, because it exerted diverse liver metabolic functions for several weeks. In future, we expect our bio-printed liver tissue to be applied to developing new models that can be used to improve preclinical predictions of long-term toxicity in humans, generate novel targets for metabolic liver disease, and evaluate biliary excretion in drug development.

A Polysaccharide from Ganoderma atrum Improves Liver Function in Type 2 Diabetic Rats via Antioxidant Action and Short-Chain Fatty Acids Excretion.

PubMed

Zhu, Ke-Xue; Nie, Shao-Ping; Tan, Le-He; Li, Chuan; Gong, De-Ming; Xie, Ming-Yong

2016-03-09

The present study was to evaluate the beneficial effect of polysaccharide isolated from Ganoderma atrum (PSG-1) on liver function in type 2 diabetic rats. Results showed that PSG-1 decreased the activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), while increasing hepatic glycogen levels. PSG-1 also exerted strong antioxidant activities, together with upregulated mRNA expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), glucose transporter-4 (GLUT4), phosphoinositide 3-kinase (PI3K), and phosphorylated-Akt (p-Akt) in the liver of diabetic rats. Moreover, the concentrations of short-chain fatty acids (SCFA) were significantly higher in the liver, serum, and faeces of diabetic rats after treating with PSG-1 for 4 weeks. These results suggest that the improvement of PSG-1 on liver function in type 2 diabetic rats may be due to its antioxidant effects, SCFA excretion in the colon from PSG-1, and regulation of hepatic glucose uptake by inducing GLUT4 translocation through PI3K/Akt signaling pathways.

Inhibition of cyclooxygenase-2 alleviates liver cirrhosis via improvement of the dysfunctional gut-liver axis in rats.

PubMed

Gao, Jin-Hang; Wen, Shi-Lei; Tong, Huan; Wang, Chun-Hui; Yang, Wen-Juan; Tang, Shi-Hang; Yan, Zhao-Ping; Tai, Yang; Ye, Cheng; Liu, Rui; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Tang, Cheng-Wei

2016-06-01

Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis. Copyright © 2016 the American Physiological Society.

Delisting HCV-infected liver transplant candidates who improved after viral eradication: Outcome 2 years after delisting.

PubMed

Perricone, Giovanni; Duvoux, Christophe; Berenguer, Marina; Cortesi, Paolo A; Vinaixa, Carmen; Facchetti, Rita; Mazzarelli, Chiara; Rockenschaub, Susanne-Rasoul; Martini, Silvia; Morelli, Cristina; Monico, Sara; Volpes, Riccardo; Pageaux, Georges-Philippe; Fagiuoli, Stefano; Belli, Luca S

2018-05-11

Treating patients with decompensated cirrhosis with direct-acting antiviral (DAA) therapy while on the waiting list for liver transplantation results in substantial improvement of liver function allowing 1 in 4 patients to be removed from the waiting list or delisted, as reported in a previous study promoted by the European Liver and Intestine Transplant Association (ELITA). The aim of this study was to report on clinical outcomes of delisted patients, including mortality risk, hepatocellular carcinoma development and clinical decompensation requiring relisting. One hundred and forty-two HCV-positive patients on the liver transplant waiting list for decompensated cirrhosis, negative for hepatocellular carcinoma, between February 2014 and June 2015 were treated with DAA therapy and were prospectively followed up. Forty-four patients (30.9%) were delisted following clinical improvement. This percentage was higher than in the original study because of a number of patients being delisted long after starting DAAs. The median Child-Pugh and MELD score of delisted patients was 5.5 and 9 respectively. Four patients were relisted, because of HCC diagnosis in 1 case and 3 patients developed ascites. One further patient died (2.4%) because of rapidly progressing hepatocellular carcinoma twenty-two months after delisting. Of the 70 patients who received a liver graft, 9 died (13%). Antiviral therapy allows for a long-term improvement of liver function and the delisting of one-third of treated patients with risk of liver-related complications after delisting being very low. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Correlation between red blood cell count and liver function status].

PubMed

Xie, Xiaomeng; Wang, Leijie; Yao, Mingjie; Wen, Xiajie; Chen, Xiangmei; You, Hong; Jia, Jidong; Zhao, Jingmin; Lu, Fengmin

2016-02-01

To investigate the changes in red blood cell count in patients with different liver diseases and the correlation between red blood cell count and degree of liver damage. The clinical data of 1427 patients with primary liver cancer, 172 patients with liver cirrhosis, and 185 patients with hepatitis were collected, and the Child-Pugh class was determined for all patients. The differences in red blood cell count between patients with different liver diseases were retrospectively analyzed, and the correlation between red blood cell count and liver function status was investigated. The Mann-Whitney U test, Kruskal-Wallis H test, rank sum test, Spearman rank sum correlation test, and chi-square test were performed for different types of data. Red blood cell count showed significant differences between patients with chronic hepatitis, liver cancer, and liver cirrhosis and was highest in patients with chronic hepatitis and lowest in patients with liver cirrhosis (P < 0.05). In the patients with liver cirrhosis, red blood cell count tended to decrease in patients with a higher Child-Pugh class (P < 0.05). For patients with liver cirrhosis, red blood cell count can reflect the degree of liver damage, which may contribute to an improved liver function prediction model for these patients.

Long-lasting improvements in liver fat and metabolism despite body weight regain after dietary weight loss.

PubMed

Haufe, Sven; Haas, Verena; Utz, Wolfgang; Birkenfeld, Andreas L; Jeran, Stephanie; Böhnke, Jana; Mähler, Anja; Luft, Friedrich C; Schulz-Menger, Jeanette; Boschmann, Michael; Jordan, Jens; Engeli, Stefan

2013-11-01

Weight loss reduces abdominal and intrahepatic fat, thereby improving metabolic and cardiovascular risk. Yet, many patients regain weight after successful diet-induced weight loss. Long-term changes in abdominal and liver fat, along with liver test results and insulin resistance, are not known. We analyzed 50 overweight to obese subjects (46 ± 9 years of age; BMI, 32.5 ± 3.3 kg/m2; women, 77%) who had participated in a 6-month hypocaloric diet and were randomized to either reduced carbohydrates or reduced fat content. Before, directly after diet, and at an average of 24 (range, 17-36) months follow-up, we assessed body fat distribution by magnetic resonance imaging and markers of liver function and insulin resistance. Body weight decreased with diet but had increased again at follow-up. Subjects also partially regained abdominal subcutaneous and visceral adipose tissue. In contrast, intrahepatic fat decreased with diet and remained reduced at follow-up (7.8 ± 9.8% [baseline], 4.5 ± 5.9% [6 months], and 4.7 ± 5.9% [follow-up]). Similar patterns were observed for markers of liver function, whole-body insulin sensitivity, and hepatic insulin resistance. Changes in intrahepatic fat und intrahepatic function were independent of macronutrient composition during intervention and were most effective in subjects with nonalcoholic fatty liver disease at baseline. A 6-month hypocaloric diet induced improvements in hepatic fat, liver test results, and insulin resistance despite regaining of weight up to 2 years after the active intervention. Body weight and adiposity measurements may underestimate beneficial long-term effects of dietary interventions.

[The current state of the surgery of portal hypertension].

PubMed

Mercado, M A; Orozco, H

1992-01-01

Surgery for bleeding portal hypertension has evolved widely in the last decades. The surgical procedures that preserve portal blood flow are the first operative choice for well selected patients. Operative procedures that deprive the portal blood flow to the liver, are most likely to promote deterioration of liver function in the late postoperative period. The operation most frequently performed are the selective shunts (Warren) and the thoraco abdominal devascularization (Sugiura). The best results are obtained in patients with a good liver function that are operated in an elective fashion. Non-selective shunts have a restricted indication and low diameter porto systemic shunts are still under evaluation. The combination of drug therapy and/or sclerotherapy with surgery appears to improve survival. Liver transplants are indicated for those patients with associated liver failure. For patients with good liver function, surgery is the therapy of choice.

Prevalence and causes of abnormal liver function in patients with coeliac disease.

PubMed

Casella, Giovanni; Antonelli, Elisabetta; Di Bella, Camillo; Villanacci, Vincenzo; Fanini, Lucia; Baldini, Vittorio; Bassotti, Gabrio

2013-08-01

Coeliac disease patients frequently display mild elevation of liver enzymes and this abnormality usually normalizes after gluten-free diet. To investigate the cause and prevalence of altered liver function tests in coeliac patients, basally and after 1 year of gluten-free diet. Data from 245 untreated CD patients (196 women and 49 men, age range 15-80 years) were retrospectively analysed and the liver function tests before and after diet, as well as associated liver pathologies, were assessed. Overall, 43/245 (17.5%) patients had elevated values of one or both aminotransferases; the elevation was mild (<5 times the upper reference limit) in 41 (95%) and marked (>10 times the upper reference limit) in the remaining 2 (5%) patients. After 1 year of gluten-free diet, aminotransferase levels normalized in all but four patients with HCV infection or primary biliary cirrhosis. In coeliac patients, hypertransaminaseaemia at diagnosis and the lack of normalization of liver enzymes after 12 months of diet suggest coexisting liver disease. In such instance, further evaluation is recommended to exclude the liver disease. Early recognition and treatment of coeliac disease in patients affected by liver disease are important to improve the liver function and prevent complications. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hepatocyte nuclear factor 4A improves hepatic differentiation of immortalized adult human hepatocytes and improves liver function and survival.

PubMed

Hang, Hua-Lian; Liu, Xin-Yu; Wang, Hai-Tian; Xu, Ning; Bian, Jian-Min; Zhang, Jian-Jun; Xia, Lei; Xia, Qiang

2017-11-15

Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes, but insufficient differentiation and phenotypic instability restrict their clinical application. This study aimed to determine the role of hepatocyte nuclear factor 4A (HNF4A) in hepatic differentiation of IHH, and whether encapsulation of IHH overexpressing HNF4A could improve liver function and survival in rats with acute liver failure (ALF). Primary human hepatocytes were transduced with lentivirus-mediated catalytic subunit of human telomerase reverse transcriptase (hTERT) to establish IHH. Cells were analyzed for telomerase activity, proliferative capacity, hepatocyte markers, and tumorigenicity (c-myc) expression. Hepatocyte markers, hepatocellular functions, and morphology were studied in the HNF4A-overexpressing IHH. Hepatocyte markers and karyotype analysis were completed in the primary hepatocytes using shRNA knockdown of HNF4A. Nuclear translocation of β-catenin was assessed. Rat models of ALF were treated with encapsulated IHH or HNF4A-overexpressing IHH. A HNF4A-positive IHH line was established, which was non-tumorigenic and conserved properties of primary hepatocytes. HNF4A overexpression significantly enhanced mRNA levels of genes related to hepatic differentiation in IHH. Urea levels were increased by the overexpression of HNF4A, as measured 24h after ammonium chloride addition, similar to that of primary hepatocytes. Chromosomal abnormalities were observed in primary hepatocytes transfected with HNF4A shRNA. HNF4α overexpression could significantly promote β-catenin activation. Transplantation of HNF4A overexpressing IHH resulted in better liver function and survival of rats with ALF compared with IHH. HNF4A improved hepatic differentiation of IHH. Transplantation of HNF4A-overexpressing IHH could improve the liver function and survival in a rat model of ALF. Copyright © 2017 Elsevier Inc. All rights reserved.

Why and how to measure renal function in patients with liver disease.

PubMed

Piano, Salvatore; Romano, Antonietta; Di Pascoli, Marco; Angeli, Paolo

2017-01-01

Patients with advanced liver disease frequently have impaired renal function. Both acute kidney injury (AKI) and chronic kidney disease (CKD) are quite common in patients with cirrhosis and both are associated with a worse prognosis in these patients. A careful assessment of renal function is highly important in these patients to help physicians determine their diagnosis, prognosis and therapeutic management and to define transplantation strategies (liver transplantation alone vs simultaneous liver and kidney transplantation). Although they are still widely used in clinical practice, conventional biomarkers of renal function such as serum creatinine have several limitations in these patients. Recent progress has been made in the evaluation of renal function and new diagnostic criteria for AKI have been proposed. However, certain issues such as the noninvasive assessment of the glomerular filtration rate and/or improvement in the differential diagnosis between hepatorenal syndrome and acute tubular necrosis must still be addressed. The purposes of this paper are: (i) to highlight the importance of the evaluation of renal function in patients with cirrhosis; (ii) to review the state of the art in the assessment of renal function in these patients as well as advances that we expect will be made to improve the accuracy of available tools. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Culture of C3A cells in alginate beads for fluidized bed bioartificial liver.

PubMed

Kinasiewicz, A; Gautier, A; Lewinska, D; Bukowski, J; Legallais, C; Weryński, A

2007-11-01

Extracorporeal bioartificial liver has been designed to sustain the detoxification and synthetic function of the failed liver in patients suffering from acute liver failure until the time of liver allotransplantation or regeneration of their own. A fluidized bed, bioartificial liver improves the mass transfer velocity between the medium and the hepatocytes. Detoxification functions of the liver could be replaced by completely artificial systems, but the synthetic functions of hepatocytes may be obtained only by metabolically active cells. The aim of our study was to investigate the influence of C3A cell culture in alginate beads on synthetic function in a fluidized bed, bioartificial liver. Cells in alginate beads were prepared using an electrostatic droplet generator of our own design using low-viscosity alginate. Beads were cultured for 24 hours then 7 days in static conditions and then 24 hours of fluidization in the bioreactor to assess albumin production. We observed significantly increased albumin production by C3A cells entrapped in alginate beads during static culture. Fluidization increased albumin production compared with static culture. Fluidization performed after 7 days of static culture resulted in a significant increase in albumin synthesis. In conclusion, static culture of alginate beads hosting hepatic cells facilitates restoration of cell function.

Three-dimensional culture in a microgravity bioreactor improves the engraftment efficiency of hepatic tissue constructs in mice.

PubMed

Zhang, Shichang; Zhang, Bo; Chen, Xia; Chen, Li; Wang, Zhengguo; Wang, Yingjie

2014-12-01

Tissue-engineered liver using primary hepatocytes has been considered a valuable new therapeutic modality as an alternative to whole organ liver transplantation for different liver diseases. The development of clinically feasible liver tissue engineering approaches, however, has been hampered by the poor engraftment efficiency of hepatocytes. We developed a three-dimensional (3D) culture system using a microgravity bioreactor (MB), biodegradable scaffolds and growth-factor-reduced Matrigel to construct a tissue-engineered liver for transplantation into the peritoneal cavity of non-obese diabetic severe combined immunodeficient mice. The number of viable cells in the hepatic tissue constructs was stably maintained in the 3D MB culture system. Hematoxylin-eosin staining and zonula occludens-1 expression revealed that neonatal mouse liver cells were reorganized to form tissue-like structures during MB culture. Significantly upregulated hepatic functions (albumin secretion, urea production and cytochrome P450 activity) were observed in the MB culture group. Post-transplantation analysis indicated that the engraftment efficiency of the hepatic tissue constructs prepared in MB cultures was higher than that of those prepared in the static cultures. Higher level of hepatic function in the implants was confirmed by the expression of albumin. These findings suggest that 3D MB culture systems may offer an improved method for creating tissue-engineered liver because of the higher engraftment efficiency and the reduction of the initial cell function loss.

Implantation of healthy matrix-embedded endothelial cells rescues dysfunctional endothelium and ischemic tissue in liver engraftment

PubMed Central

Melgar-Lesmes, Pedro; Balcells, Mercedes; Edelman, Elazer R.

2017-01-01

Objective Liver transplantation is limited by ischemic injury which promotes endothelial cell and hepatocyte dysfunction and eventually organ failure. We sought to understand how endothelial state determines liver recover after hepatectomy and engraftment. Design Matrix-embedded endothelial cells (MEECs) with retained healthy phenotype or control acellular matrices were implanted in direct contact with the remaining median lobe of donor mice undergoing partial hepatectomy (70%), or in the interface between the remaining median lobe and an autograft or isograft from the left lobe in hepatectomized recipient mice. Hepatic vascular architecture, DNA fragmentation and apoptosis in the median lobe and grafts, serum markers of liver damage and phenotype of macrophage and lymphocyte subsets in the liver after engraftment were analyzed 7 days post-op. Results Healthy MEECs create a functional vascular splice in donor and recipient liver after 70% hepatectomy in mouse protecting these livers from ischemic injury, hepatic congestion and inflammation. Macrophages recruited adjacent to the vascular nodes into the implants switched to an anti-inflammatory and regenerative profile M2. MEECs improved liver function and the rate of liver regeneration and prevented apoptosis in donor liver lobes, autologous grafts, and allogeneic engraftment. Conclusions Implants with healthy endothelial cells rescue liver donor and recipient endothelium and parenchyma from ischemic injury after major hepatectomy and engraftment. This study highlights endothelial-hepatocyte crosstalk in hepatic repair and provides a promising new approach to improve regenerative medicine outcomes and liver transplantation. PMID:26851165

Long term results of balloon-occluded retrograde transvenous obliteration for portosystemic shunt encephalopathy in patients with liver cirrhosis and portal hypertension.

PubMed

Inoue, Hiroto; Emori, Keigo; Toyonaga, Atsushi; Oho, Kazuhiko; Kumamoto, Masafumi; Haruta, Tsuyoshi; Mitsuyama, Keiichi; Tsuruta, Osamu; Sata, Michio

2014-01-01

This study examined 19 patients with portosystemic shunt encephalopathy caused by a splenorenal shunt (SRS), which was treated with balloon-occluded retrograde transvenous obliteration (B-RTO). Long-term treatment outcomes were evaluated based on hepatic functional reserve and vital prognosis. Encephalopathy improved in all patients after shunt embolization and closure. Albumin, serum ammonia, and the Child-Pugh score, a measure of liver function, were significantly improved 3 years after B-RTO, and exacerbation of damage to liver function was avoided (p<0.01). During the follow-up period, three patients died from liver failure and two patients from hepatocellular carcinoma. Patients had a poor prognosis if their albumin levels were less than 2.8 mg / dL before B-RTO (p<0.05). Encephalopathy patients had complete response to B-RTO, but long-term prognosis was affected by hepatic functional reserve before B-RTO and by concurrent hepatocellular carcinoma. The results of this study suggest that in patients with SRS, it is important to perform B-RTO at an early stage when the hepatic functional reserve is still satisfactory.

Therapeutic effect comparison of hepatocyte-like cells and bone marrow mesenchymal stem cells in acute liver failure of rats.

PubMed

Li, Dongliang; Fan, Jingjing; He, Xiuhua; Zhang, Xia; Zhang, Zhiqiang; Zeng, Zhiyu; Ruan, Mei; Cai, Lirong

2015-01-01

To evaluate the therapeutic efficacy of rat bone marrow mesenchymal stem cells (BMSCs) induced into hepatocyte-like cells and of un-induced BMSCs in acute liver failure rats. BMSCs in highly homogenous passage 3 were cultured using the whole bone marrow adherent culture method. Hepatic-related characters were confirmed with morphology, RT-PCR analysis, glycogen staining and albumin (ALB) immunofluorescence assay. Carbon tetrachloride (CCl4) was injected intraperitoneally to establish an acute rat liver failure model. Hepatocyte-like cells or un-induced BMSCs were respectively injected into the models to examine rats' appearance, liver function assay and liver tissue pathology. Hepatocyte-like morphology, higher expression of cytokeratin 18 (CK18) mRNA and ALB protein, and glycogen accumulation were confirmed in the induced BMSCs. The transplanted DAPI-labeled BMSCs were localized in the liver tissue 3-14 days after transplantation. The levels of liver function indicators (AST, ALT, ALP, and TBIL) from transplanted rats were significant decreased and pathology was improved, indicating the recovery of liver function. However, the differences were statistically insignificant. Both hepatocyte-like cells and un-induced BMSCs had a similarly positively therapeutic efficacy on liver regeneration in rat liver failure model.

Caffeine and acetaminophen association: Effects on mitochondrial bioenergetics.

PubMed

Gonçalves, Débora F; de Carvalho, Nelson R; Leite, Martim B; Courtes, Aline A; Hartmann, Diane D; Stefanello, Sílvio T; da Silva, Ingrid K; Franco, Jéferson L; Soares, Félix A A; Dalla Corte, Cristiane L

2018-01-15

Many studies have been demonstrating the role of mitochondrial function in acetaminophen (APAP) hepatotoxicity. Since APAP is commonly consumed with caffeine, this work evaluated the effects of the combination of APAP and caffeine on hepatic mitochondrial bioenergetic function in mice. Mice were treated with caffeine (20mg/kg, intraperitoneal (i.p.)) or its vehicle and, after 30minutes, APAP (250mg/kg, i.p.) or its vehicle. Four hours later, livers were removed, and the parameters associated with mitochondrial function and oxidative stress were evaluated. Hepatic cellular oxygen consumption was evaluated by high-resolution respirometry (HRR). APAP treatment decreased cellular oxygen consumption and mitochondrial complex activities in the livers of mice. Additionally, treatment with APAP increased swelling of isolated mitochondria from mice livers. On the other hand, caffeine administered with APAP was able to improve hepatic mitochondrial bioenergetic function. Treatment with APAP increased lipid peroxidation and reactive oxygen species (ROS) production and decreased glutathione levels in the livers of mice. Caffeine administered with APAP was able to prevent lipid peroxidation and the ROS production in mice livers, which may be associated with the improvement of mitochondrial function caused by caffeine treatment. We suggest that the antioxidant effects of caffeine and/or its interactions with mitochondrial bioenergetics may be involved in its beneficial effects against APAP hepatotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

Native kidney function following liver transplantation using calcineurin inhibitors: single-center analysis with 20 years of follow-up.

PubMed

LaMattina, John C; Mezrich, Joshua D; Fernandez, Luis A; D'Alessandro, Anthony M; Djamali, Arjang; Musat, Alexandru I; Pirsch, John D; Foley, David P

2013-01-01

The incidence of chronic kidney disease (CKD) in liver transplant recipients has been estimated to be from 18% to 28% at 10 yr after transplantation. As outcomes from liver transplantation continue to improve, long-term native kidney function in these recipients becomes more critical to patient survival. We analyzed 1151 adult, deceased-donor, single-organ primary liver transplantations performed at our center between 7/17/84 and 12/31/07. Analysis of renal function was performed on 972 patients with liver allograft survival >1 yr. Kaplan-Meier analysis revealed that 3%, 7%, and 18% of liver transplant recipients with allograft survival >1 yr developed end-stage renal disease (ESRD) at five, 10, and 20 yr, respectively. Significant independent risk factors for ESRD included dialysis during the transplant hospitalization, the stage of CKD at one yr, hypercholesterolemia, non-Caucasian race, and hepatitis C as the primary indication for liver transplantation. The initial immunosuppression of essentially all recipients was a calcineurin inhibitor-based regimen. Close, long-term follow-up of liver transplant recipients permits optimal management of liver allograft and native renal function and can lead to excellent long-term outcomes despite a calcineurin inhibitor-based immunosuppressive regimen. © 2013 John Wiley & Sons A/S.

[ACTION OF L-CARNITINE, CORVITIN AND THEIR COMBINATION ON FUNCTIONAL STATE OF LIVER IN EXPERIMENTAL MODEL OF REYE SYNDROME IN RATS].

PubMed

Ghonghadze, M; Antelava, N; Liluashvili, K; Okujava, M; Pachkoria, K

2017-02-01

Administration of Aacetylsalicylic acid in children with viral infections (influence B, chickenpox) can be related with development of Reye syndrome - severe encephalopathy and liver insufficiency with mortality in 50% of cases. During Reye syndrome most important is deficiency of carnitine and hepatocyte damage. Decreased amount of carnitine impairs the energy function of mitochondria and gluconeogenesis as well as production of urea. As a result develops toxic encephalopathy and liver insufficiency. The goal of the research was assessment of efficacy of L-Carnitine, Corvitin and their combination on functional state of liver in experimental model of Reye Syndrome in rats. The study was performed on mature white male Wistar rates with body mass 150-180g. 50 rats were randomly divided into 5 groups (10 rats in each group). The model of Reye syndrome was induced in accordance with A.Vengersky's method. Intraperitoneal administration of 4-pentenoic acid was performed once daily during seven days, the used dosage was 20mg/kg. The treatment of toxic hepatitis was carried with intraperitoneal administration of L-Carnitine 300mg/kg, Corvitine 100mg/kg and concurrent administration of these drugs. Monotherapy with Corvitin and L-Carnitin successfully improved liver function and equally decreased indicators of hepatocyte's cytolyses and increased levels of glucose and urea. The markers of cholestasis was slightly more improved during use of L-Carnitine. Simultaneous use of both drugs was effective in rats with Reye syndrome, indicators of liver damage normalized and herewith, no mortality outcome was observed. The most pronounced hepatoprotective effect of concurrent administration of L-Carnitine and Corvitin may be due to synergic action of these drugs and such regime can be recommended for correction of liver function during Reye syndrome.

COMBINATION OF MOLECULAR ADSORBENT RECIRCULATING SYSTEM AND RADIOIODINE FOR THE TREATMENT OF CONCURRENT HYPERTHYROIDISM AND SEVERE LIVER DYSFUNCTION: A RETROSPECTIVE COHORT STUDY.

PubMed

Zhang, Qing; Guan, Yanxing; Xiang, Tianxin; Liu, Shaozheng; Chen, Qingjie; Zhang, Qing

2017-02-01

The treatment of hyperthyroidism associated with severe liver dysfunction (LD) is a clinical challenge, and there has been no unified examination of this problem. The objective of this study was to assess the efficacy and safety of radioiodine ( 131 I) in combination with a molecular adsorbent recirculating system (MARS) for the treatment of hyperthyroidism complicated by severe liver LD. A total of 116 hyperthyroidism patients with concomitant LD who received MARS treatment were studied retrospectively. The patients were grouped according to whether or not they also received 131 I treatment: Group 1 (59 patients) received 131 I following MARS treatment, while Group 2 (57 cases) received only MARS. Clinical outcomes, including thyroid hormone levels, liver function parameters, and therapeutic efficacy were calculated. The overall response rate was significantly greater in Group 1 than in Group 2 (P<.01). The clinical indicators improved significantly in both groups 3 months after treatment compared with before treatment (P<.05), but Group 1 showed a greater improvement. Compared with Group 1, patients in Group 2 had a longer stay in hospital (P<.05), and received more frequent MARS treatments (P<.05). The combination of MARS and 131 I for the treatment of hyperthyroidism complicated by severe LD was effective and safe. The use of this system could rapidly improve liver function and metabolism, allowing 131 I therapy to be applied as early as possible with a shortened recovery time of liver function. ALSS = artificial liver support system ALT = alanine transaminase AST = aspartate transaminase ATD = antithyroid drugs DBil = direct bilirubin FT3 = free tri-iodothyronine FT4 = free thyroxine 131 I = radioiodine INR = international normalized ratio LD = liver dysfunction MARS = molecular adsorbent recirculating system MELD = model for end-stage liver disease PT = prothrombin time TBil = total bilirubin TSH = thyroid-stimulating hormone.

Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression.

PubMed

Szalay, László; Shimizu, Tomoharu; Suzuki, Takao; Yu, Huang-Ping; Choudhry, Mashkoor A; Schwacha, Martin G; Rue, Loring W; Bland, Kirby I; Chaudry, Irshad H

2006-03-01

Although studies indicate that 17beta-estradiol administration after trauma-hemorrhage (T-H) improves cardiac and hepatic functions, the underlying mechanisms remain unclear. Because the induction of heat shock proteins (HSPs) can protect cardiac and hepatic functions, we hypothesized that these proteins contribute to the salutary effects of estradiol after T-H. To test this hypothesis, male Sprague-Dawley rats ( approximately 300 g) underwent laparotomy and hemorrhagic shock (35-40 mmHg for approximately 90 min) followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17beta-estradiol (1 mg/kg body wt) was administered at the end of the resuscitation. Five hours after T-H and resuscitation there was a significant decrease in cardiac output, positive and negative maximal rate of left ventricular pressure. Liver function as determined by bile production and indocyanine green clearance was also compromised after T-H and resuscitation. This was accompanied by an increase in plasma alanine aminotransferase (ALT) levels and liver perfusate lactic dehydrogenase levels. Furthermore, circulating levels of TNF-alpha, IL-6, and IL-10 were also increased. In addition to decreased cardiac and hepatic function, there was an increase in cardiac HSP32 expression and a reduction in HSP60 expression after T-H. In the liver, HSP32 and HSP70 were increased after T-H. There was no change in heart HSP70 and liver HSP60 after T-H and resuscitation. Estradiol administration at the end of T-H and resuscitation increased heart/liver HSPs expression, ameliorated the impairment of heart/liver functions, and significantly prevented the increase in plasma levels of ALT, TNF-alpha, and IL-6. The ability of estradiol to induce HSPs expression in the heart and the liver suggests that HSPs, in part, mediate the salutary effects of 17beta-estradiol on organ functions after T-H.

Simplified technique for auxiliary orthotopic liver transplantation using a whole graft

PubMed Central

ROCHA-SANTOS, Vinicius; NACIF, Lucas Souto; PINHEIRO, Rafael Soares; DUCATTI, Liliana; ANDRAUS, Wellington; D'ALBURQUERQUE, Luiz Carneiro

2015-01-01

Background Acute liver failure is associated with a high mortality rate and the main purposes of treatment are to prevent cerebral edema and infections, which often are responsible for patient death. The orthotopic liver transplantation is the gold standard treatment and improves the 1-year survival. Aim To describe an alternative technique to auxiliary liver transplant on acute liver failure. Method Was performed whole auxiliary liver transplantation as an alternative technique for a partial auxiliary liver transplantation using a whole liver graft from a child removing the native right liver performed a right hepatectomy. The patient met the O´Grady´s criteria and the rational to indicate an auxiliary orthotopic liver transplantation was the acute classification without hemodynamic instability or renal failure in a patient with deterioration in consciousness. Results The procedure improved liver function and decreased intracranial hypertension in the postoperative period. Conclusion This technique can overcome some postoperative complications that are associated with partial grafts. As far as is known, this is the first case of auxiliary orthotopic liver transplantation in Brazil. PMID:26176253

Long-Lasting Improvements in Liver Fat and Metabolism Despite Body Weight Regain After Dietary Weight Loss

PubMed Central

Haufe, Sven; Haas, Verena; Utz, Wolfgang; Birkenfeld, Andreas L.; Jeran, Stephanie; Böhnke, Jana; Mähler, Anja; Luft, Friedrich C.; Schulz-Menger, Jeanette; Boschmann, Michael; Jordan, Jens; Engeli, Stefan

2013-01-01

OBJECTIVE Weight loss reduces abdominal and intrahepatic fat, thereby improving metabolic and cardiovascular risk. Yet, many patients regain weight after successful diet-induced weight loss. Long-term changes in abdominal and liver fat, along with liver test results and insulin resistance, are not known. RESEARCH DESIGN AND METHODS We analyzed 50 overweight to obese subjects (46 ± 9 years of age; BMI, 32.5 ± 3.3 kg/m2; women, 77%) who had participated in a 6-month hypocaloric diet and were randomized to either reduced carbohydrates or reduced fat content. Before, directly after diet, and at an average of 24 (range, 17–36) months follow-up, we assessed body fat distribution by magnetic resonance imaging and markers of liver function and insulin resistance. RESULTS Body weight decreased with diet but had increased again at follow-up. Subjects also partially regained abdominal subcutaneous and visceral adipose tissue. In contrast, intrahepatic fat decreased with diet and remained reduced at follow-up (7.8 ± 9.8% [baseline], 4.5 ± 5.9% [6 months], and 4.7 ± 5.9% [follow-up]). Similar patterns were observed for markers of liver function, whole-body insulin sensitivity, and hepatic insulin resistance. Changes in intrahepatic fat und intrahepatic function were independent of macronutrient composition during intervention and were most effective in subjects with nonalcoholic fatty liver disease at baseline. CONCLUSIONS A 6-month hypocaloric diet induced improvements in hepatic fat, liver test results, and insulin resistance despite regaining of weight up to 2 years after the active intervention. Body weight and adiposity measurements may underestimate beneficial long-term effects of dietary interventions. PMID:23963894

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial.

PubMed

Loguercio, Carmela; Andreone, Pietro; Brisc, Ciprian; Brisc, Michaela Cristina; Bugianesi, Elisabetta; Chiaramonte, Maria; Cursaro, Carmela; Danila, Mirela; de Sio, Ilario; Floreani, Annarosa; Freni, Maria Antonietta; Grieco, Antonio; Groppo, Marzia; Lazzari, Roberta; Lobello, Salvatore; Lorefice, Elisabetta; Margotti, Marzia; Miele, Luca; Milani, Stefano; Okolicsanyi, Lajos; Palasciano, Giuseppe; Portincasa, Piero; Saltarelli, Patrizia; Smedile, Antonina; Somalvico, Francesco; Spadaro, Aldo; Sporea, Ioan; Sorrentino, Paolo; Vecchione, Raffaela; Tuccillo, Concetta; Del Vecchio Blanco, Camillo; Federico, Alessandro

2012-05-01

The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with improvement in liver enzymes, insulin resistance, and liver histology, without increases in body weight. These findings warrant further investigation. Copyright © 2012 Elsevier Inc. All rights reserved.

Approach to the patient with abnormal liver tests.

PubMed

Mahl, T C

1998-01-01

Patients with abnormal liver blood tests are frequently encountered by primary care practitioners. An understanding of the cellular implications of these abnormalities is helpful in determining the etiology of liver injury. Elevated serum aminotransferases suggest injury of hepatocytes. Elevations in alkaline phosphatase suggest injury to any part of the biliary tree. Neither of these enzymes measures liver function. Serum bilirubin and albumin levels, as well as prothrombin time, do measure function and can be used in conjunction with the physical examination and the specific etiology of the patient's disorder to determine a patient's prognosis. Many diverse disorders result in similar biochemical patterns of liver injury. The history, physical examination, and use of specific disease markers (hepatitis serology, autoimmune markers, and so forth) help to narrow the differential diagnosis. The definitive diagnosis of all liver diseases usually rests on histology: the liver biopsy is the gold standard. With the advent of treatments for liver disease, identifying and accurately diagnosing patients with liver disorders will result in improved quality of life and survival.

Liver-Directed Human Amniotic Epithelial Cell Transplantation Improves Systemic Disease Phenotype in Hurler Syndrome Mouse Model.

PubMed

Rodriguez, Natalie S; Yanuaria, Lisa; Parducho, Kevin Murphy R; Garcia, Irving M; Varghese, Bino A; Grubbs, Brendan H; Miki, Toshio

2017-07-01

Mucopolysaccharidosis type 1 (MPS1) is an inherited lysosomal storage disorder caused by a deficiency in the glycosaminoglycan (GAG)-degrading enzyme α-l-iduronidase (IDUA). In affected patients, the systemic accumulation of GAGs results in skeletal dysplasia, neurological degeneration, multiple organ dysfunction, and early death. Current therapies, including enzyme replacement and bone marrow transplant, improve life expectancy but the benefits to skeletal and neurological phenotypes are limited. In this study, we tested the therapeutic efficacy of liver-directed transplantation of a placental stem cell, which possesses multilineage differentiation potential, low immunogenicity, and high lysosomal enzyme activity. Unfractionated human amniotic epithelial cells (hAECs) were transplanted directly into the liver of immunodeficient Idua knockout mouse neonates. The hAECs engraftment was immunohistochemically confirmed with anti-human mitochondria staining. Enzyme activity assays indicated that hAECs transplantation restored IDUA function in the liver and significantly decreased urinary GAG excretion. Histochemical and micro-computed tomography analyses revealed reduced GAG deposition in the phalanges joints and composition/morphology improvement of cranial and facial bones. Neurological assessment in the hAEC treated mice showed significant improvement of sensorimotor coordination in the hAEC treated mice compared to untreated mice. Results confirm that partial liver cell replacement with placental stem cells can provide long-term (>20 weeks) and systemic restoration of enzyme function, and lead to significant phenotypic improvement in the MPS1 mouse model. This preclinical data indicate that liver-directed placental stem cell transplantation may improve skeletal and neurological phenotypes of MPS1 patients. Stem Cells Translational Medicine 2017;6:1583-1594. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Proliferative human cell sources applied as biocomponent in bioartificial livers: a review.

PubMed

Nibourg, Geert A A; Chamuleau, Robert A F M; van Gulik, Thomas M; Hoekstra, Ruurdtje

2012-07-01

Bioartificial livers (BALs) are urgently needed to bridge severe liver failure patients to liver transplantation or liver regeneration. When based on primary hepatocytes, their efficacy has been shown in animal experiments and their safety was confirmed in clinical trials. However, a proliferative human cell source with therapeutic functionality is needed to secure availability and move BAL application forward. This review compares the performance of BALs based on proliferative human biocomponents and primary hepatocytes. This review evaluates relevant studies identified by searching the MEDLINE database until July 2011 and some of our own unpublished data. All the discussed hepatocyte-like biocomponents show deficiencies in their hepatic functionality compared with primary hepatocytes, particularly functions occurring late in liver development. Nonetheless, the HepaRG, HepG2-GS-CYP3A4, and mesenchymal stem cells show efficacy in a statistically well-powered animal model of acute liver failure, when applied in a BAL device. Various methods to gain higher functionality of BALs, including genetic modification, the usage of combinatory cell sources, and improvement of culture methods, have scarcely been applied, but may further pave the path for BAL application. Clinical implementation of a BAL based on a human proliferative biocomponent is still several years away.

Effects of Oral L-Carnitine on Liver Functions after Transarterial Chemoembolization in Intermediate-Stage HCC Patients.

PubMed

Hassan, Abeer; Tsuda, Yasuhiro; Asai, Akira; Yokohama, Keisuke; Nakamura, Ken; Sujishi, Tetsuya; Ohama, Hideko; Tsuchimoto, Yusuke; Fukunishi, Shinya; Abdelaal, Usama M; Arafa, Usama A; Hassan, Ali T; Kassem, Ali M; Higuchi, Kazuhide

2015-01-01

Transarterial chemoembolization (TACE) is usually followed by hepatic dysfunction. We evaluated the effects of L-carnitine on post-TACE impaired liver functions. Methods. 53 cirrhotic hepatocellular carcinoma patients at Osaka Medical College were enrolled in this study and assigned into either L-carnitine group receiving 600 mg oral L-carnitine daily or control group. Liver functions were evaluated at pre-TACE and 1, 4, and 12 weeks after TACE. Results. The L-carnitine group maintained Child-Pugh (CP) score at 1 week after TACE and exhibited significant improvement at 4 weeks after TACE (P < 0.01). Conversely, the control group reported a significant CP score deterioration at 1 week (P < 0.05) and 12 weeks after TACE (P < 0.05). L-carnitine suppressed serum albumin deterioration at 1 week after TACE. There were significant differences between L-carnitine and control groups regarding mean serum albumin changes from baseline to 1 week (P < 0.05) and 4 weeks after TACE (P < 0.05). L-carnitine caused prothrombin time improvement from baseline to 1, 4 (P < 0.05), and 12 weeks after TACE. Total bilirubin mean changes from baseline to 1 week after TACE exhibited significant differences between L-carnitine and control groups (P < 0.05). The hepatoprotective effects of L-carnitine were enhanced by branched chain amino acids combination. Conclusion. L-carnitine maintained and improved liver functions after TACE.

Esculetin ameliorates hepatic fibrosis in high fat diet induced non-alcoholic fatty liver disease by regulation of FoxO1 mediated pathway.

PubMed

Pandey, Anuradha; Raj, Priyank; Goru, Santosh Kumar; Kadakol, Almesh; Malek, Vajir; Sharma, Nisha; Gaikwad, Anil Bhanudas

2017-08-01

Non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder is associated with oxidative stress, inflammation and fibrotic cascades. In this study, we aimed to examine the effects of Esculetin, a well-known anti-oxidant on TGF-β1 mediated liver fibrosis and FoxO1 activity. A non-genetic murine model for NAFLD was developed by chronic high fat diet (HFD) (58% calories from fats) feeding in Wistar rats. The plasma biochemical parameters, liver function tests, oxidative stress, and histopathological alterations were assessed. The alterations in extracellular matrix (ECM) deposition and FoxO1 activity were assessed by immunohistochemistry. The aberrations in plasma parameters, liver functioning, morphometric and microscopic changes in liver structure of HFD fed rats were significantly improved by treatment with Esculetin. Liver fibrosis, identified in the form of collagen deposition and expression of fibrotic proteins like TGF-β1 and fibronectin was also markedly controlled by Esculetin. The expression of phospho-FoxO1 was found to be reduced in HFD fed rats' liver, showing an increase in activation of FoxO1 under insulin resistant and hyperglycemic states. Esculetin treatment could improve phospho-FoxO1 expression, thus showing its ability to act on Akt/PI3K/FoxO1 pathway. As per the previous studies, a potential therapy for NAFLD may be the one with multi-faceted actions on insulin resistance, oxidative stress, inflammation and fibrosis. This study demonstrates the efficiency of Esculetin in improving liver fibrosis in HFD induced NAFLD. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Transplant of Hepatocytes, Undifferentiated Mesenchymal Stem Cells, and In Vitro Hepatocyte-Differentiated Mesenchymal Stem Cells in a Chronic Liver Failure Experimental Model: A Comparative Study.

PubMed

El Baz, Hanan; Demerdash, Zeinab; Kamel, Manal; Atta, Shimaa; Salah, Faten; Hassan, Salwa; Hammam, Olfat; Khalil, Heba; Meshaal, Safa; Raafat, Inas

2018-02-01

Liver transplant is the cornerstone line of treatment for chronic liver diseases; however, the long list of complications and obstacles stand against this operation. Searching for new modalities for treatment of chronic liver illness is a must. In the present research, we aimed to compare the effects of transplant of undifferentiated human mesenchymal stem cells, in vitro differentiated mesenchymal stem cells, and adult hepatocytes in an experimental model of chronic liver failure. Undifferentiated human cord blood mesenchymal stem cells were isolated, pro-pagated, and characterized by morphology, gene expression analysis, and flow cytometry of surface markers and in vitro differentiated into hepatocyte-like cells. Rat hepatocytes were isolated by double perfusion technique. An animal model of chronic liver failure was developed, and undifferentiated human cord blood mesenchymal stem cells, in vitro hepato-genically differentiated mesenchymal stem cells, or freshly isolated rat hepatocytes were transplanted into a CCL4 cirrhotic experimental model. Animals were killed 3 months after transplant, and liver functions and histopathology were assessed. Compared with the cirrhotic control group, the 3 cell-treated groups showed improved alanine aminotransferase, aspartate aminotransferase, albumin, and bilirubin levels, with best results shown in the hepatocyte-treated group. Histopathologic examination of the treated groups showed improved fibrosis, with best results obtained in the undifferentiated mesenchymal stem cell-treated group. Both adult hepatocytes and cord blood mesenchymal stem cells proved to be promising candidates for cell-based therapy in liver regeneration on an experimental level. Improved liver function was evident in the hepatocyte-treated group, and fibrosis control was more evident in the undifferentiated mesenchymal stem cell-treated group.

Mixed microencapsulation of rat primary hepatocytes and Sertoli cells improves the metabolic function in a D-galactosamine and lipopolysaccharide-induced rat model of acute liver failure.

PubMed

Zheng, Ming-Hua; Lin, Hai-Long; Qiu, Li-Xin; Cui, Yao-Li; Sun, Qing-Feng; Chen, Yong-Ping

2009-01-01

Hepatocyte transplantation is an alternative to transplantation of the whole liver. Compared with xenogeneic hepatocytes, primary hepatocytes have some advantages, such as a more powerful function and a smaller frequency of rejection caused by the host. Cell microencapsulation prevents direct access of host cells to the graft but cannot impede transfer of transplant-derived peptides, which can cross the physical barrier. Sertoli cells are central to the immune privilege demonstrated in the testis, and their actions have been utilized to protect cell transplants. Co-microencapsulating Sertoli cells with HepG2 cells has proved to be a valuable strategy in hepatocyte transplantation. Thus mixed microcapsules of primary rat hepatocytes and primary Sertoli cells may improve metabolic function in a d-galactosamine and lipopolysaccharide-induced rat model of acute liver failure.

Pyruvate dehydrogenase complex and lactate dehydrogenase are targets for therapy of acute liver failure.

PubMed

Ferriero, Rosa; Nusco, Edoardo; De Cegli, Rossella; Carissimo, Annamaria; Manco, Giuseppe; Brunetti-Pierri, Nicola

2018-03-24

Acute liver failure is a rapidly progressive deterioration of hepatic function resulting in high mortality and morbidity. Metabolic enzymes can translocate to the nucleus to regulate histone acetylation and gene expression. Levels and activities of pyruvate dehydrogenase complex (PDHC) and lactate dehydrogenase (LDH) were evaluated in nuclear fractions of livers of mice exposed to various hepatotoxins including CD95-antibody, α-amanitin, and acetaminophen. Whole-genome gene expression profiling by RNA-seq was performed in livers of mice with acute liver failure and analyzed by gene ontology enrichment analysis. Cell viability was evaluated in cell lines knocked-down for PDHA1 or LDH-A and in cells incubated with the LDH inhibitor galloflavin after treatment with CD95-antibody. We evaluated whether the histone acetyltransferase inhibitor garcinol or galloflavin could reduce liver damage in mice with acute liver failure. Levels and activities of PDHC and LDH were increased in nuclear fractions of livers of mice with acute liver failure. The increase of nuclear PDHC and LDH was associated with increased concentrations of acetyl-CoA and lactate in nuclear fractions, and histone H3 hyper-acetylation. Gene expression in livers of mice with acute liver failure suggested that increased histone H3 acetylation induces the expression of genes related to damage response. Reduced histone acetylation by the histone acetyltransferase inhibitor garcinol decreased liver damage and improved survival in mice with acute liver failure. Knock-down of PDHC or LDH improved viability in cells exposed to a pro-apoptotic stimulus. Treatment with the LDH inhibitor galloflavin that was also found to inhibit PDHC, reduced hepatic necrosis, apoptosis, and expression of pro-inflammatory cytokines in mice with acute liver failure. Mice treated with galloflavin also showed a dose-response increase in survival. PDHC and LDH translocate to the nucleus, leading to increased nuclear concentrations of acetyl-CoA and lactate. This results in histone H3 hyper-acetylation and expression of damage response genes. Inhibition of PDHC and LDH reduces liver damage and improves survival in mice with acute liver failure. Thus, PDHC and LDH are targets for therapy of acute liver failure. Acute liver failure is a rapidly progressive deterioration of liver function resulting in high mortality. In experimental mouse models of acute liver failure, we found that two metabolic enzymes, namely pyruvate dehydrogenase complex and lactic dehydrogenase, translocate to the nucleus resulting in detrimental gene expression. Treatment with an inhibitor of these two enzymes was found to reduce liver damage and to improve survival. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Shuangbai San for Treating Primary Liver Cancer Patients With Cancer Pain.

PubMed

Ye, Xiaowei; Lu, Dongyan; Chen, Xinlin; Li, Suihui; Chen, Yao; Deng, Li

2016-06-01

Shuangbai San is a Chinese herb preparation used externally to treat pain. There have been few randomized controlled trials addressing the safety and usefulness of Shuangbai San, such as its effect on pain relief and quality of life (QOL) improvement. This study was conducted to evaluate the effect of Shuangbai San on relieving pain and improving QOL in primary liver cancer patients with cancer pain. A total of 134 primary liver cancer patients with mild pain (numerical rating scale [NRS] ≤ 3), either locally in the liver or in the upper abdomen, were enrolled and randomly allocated to the group receiving Shuangbai San or the control group (receiving placebo). The primary outcome measures were the NRS score and QOL scales, including the QOL scale for patients with liver cancer, version 2.0 and the European Organization for Research and Treatment of Cancer QOL Questionnaire-C30. The secondary outcome measures included the Karnofsky Performance Status score, blood indicators, and liver and kidney function before and after treatment. The NRS scores decreased more significantly in the Shuangbai San group than in the placebo group (P < 0.05) at the corresponding time points. The changes in the scores for the physical function, psychological function, and symptoms/adverse effects domains of the QOL scale for patients with liver cancer, version 2.0 and the physical, emotional, and cognitive domains of the European Organization for Research and Treatment of Cancer QOL Questionnaire-C30 were significantly greater in the Shuangbai San group than in the placebo group (P < 0.05). The changes in the scores for the other domains were not significantly different (P > 0.05). The use of Shuangbai San can relieve mild pain in liver cancer patients and improve their QOL. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Characterization of genetically engineered mouse hepatoma cells with inducible liver functions by overexpression of liver-enriched transcription factors.

PubMed

Yamamoto, Hideaki; Tonello, Jane Marie; Sambuichi, Takanori; Kawabe, Yoshinori; Ito, Akira; Kamihira, Masamichi

2018-01-01

New cell sources for the research and therapy of organ failure could significantly alleviate the shortage of donor livers that are available to patients who suffer from liver disease. Liver carcinoma derived cells, or hepatoma cells, are the ideal cells for developing bioartificial liver systems. Such cancerous liver cells are easy to prepare in large quantities and can be maintained over long periods under standard culture conditions, unlike primary hepatocytes. However, hepatoma cells possess only a fraction of the functions of primary hepatocytes. In a previous study, by transducing cells with liver-enriched transcription factors that could be inducibly overexpressed-hepatocyte nuclear factor (HNF)1α, HNF1β, HNF3β [FOXA2], HNF4α, HNF6, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ and C/EBPγ-we created mouse hepatoma cells with high liver-specific gene expression called the Hepa/8F5 cell line. In the present study, we performed functional and genetic analyses to characterize the Hepa/8F5 cell line. Further, in three-dimensional cultures, the function of these cells improved significantly compared to parental cells. Ultimately, these cells might become a new resource that can be used in basic and applied hepatic research. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Shunt occlusion for portosystemic shunt syndrome related refractory hepatic encephalopathy-A single-center experience in 21 patients from Kerala.

PubMed

Philips, Cyriac Abby; Kumar, Lijesh; Augustine, Philip

2017-09-01

Large spontaneous portosystemic shunts (SPSS) are seen in a subset of patients with liver disease and medically refractory recurrent/persistent hepatic encephalopathy (MRHE). Shunt occlusion has been shown to improve clinical outcomes. We retrospectively analyzed patient characteristics, SPSS attributes, procedural features, baseline clinical and investigational parameters, neurological outcomes, adverse effects (procedure and portal hypertension related), and risk factors predicting outcomes in liver disease patients undergoing shunt occlusion procedure for MRHE. Between October 2016 and July 2017, 21 patients (Child-Pugh score, CTP 6 to 13) with mean model of end-stage liver disease (MELD) and MELD-sodium scores 15.7 and 19.3 respectively with MRHE [3-cirrhotic Parkinsonism (CP)] were diagnosed to have single or multiple large SPSSs. A total of 29 shunts were occluded (1 surgical, 20 non-surgical). Recurrent and persistent HE and CP markedly improved in the short (n=20, 1 to 3 months), intermediate (n=12, 3 to 6 months), and long (n=7, 6 to 9 months) follow up. None had spontaneous or persistent HE at a median follow up 105 (30 to 329) days (p<0.05). Motor, speech, sleep abnormalities, daily activities of living, and liver disease severity scores improved significantly on follow up. Baseline arterial ammonia showed a statistically significant reduction in all time periods of follow up after shunt occlusion (p<0.05). CTP >11 predicted mortality post shunt occlusion (p=0.04). Embolization of large SPSS in liver disease patients with MRHE and modestly preserved liver function is safe and efficacious and associated with improved quality of life and can function as a bridge to liver transplantation in accurately selected patients.

[EFFECT OF ACETYLCYSTEINE, CORVITIN AND THEIR COMBINATION ON THE FUNCTIONAL STATE OF LIVER IN RATS WITH PARACETAMOL INDUCED TOXIC HEPATITIS].

PubMed

Ghonghadze, M; Antelava, N; Liluashvili, K; Okujava, M; Pachkoria, K

2017-02-01

Nowadays drug-induced hepatotoxicity is urgent problem worldwide. Currently more than 1000 drugs are hepatotoxic and most often are the reason of acute fulminant hepatitis and hepatocellular failure, the states requiring liver transplantation. The paracetamol induced liver toxicity is related with accumulation of its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is the free radical and enhances peroxidation of lipids, disturbs the energy status and causes death of hepatocytes. During our research we investigated and assessed the efficacy of acetylcysteine, corvitin and their combination in rat model of paracetamol induced acute toxic hepatitis. The study was performed on mature white male Wistar rates with body mass 150-180 g. 50 rats were randomly divided into 5 groups (10 rats in each group). To get the model of acute toxic hepatitis single intraperitoneal injection of paracetamol solution was used (750 mg/kg). Toxic hepatitis was treated with intrapertoneal administration of 40mg/kg acetylcysteine or 100mg/kg corvitin, as well as with combination of these drugs. Monotherapy with acetylcysteine and corvitin of paracetamol induced toxic hepatitis improved the liver function, decreased relative mass of the liver and animal mortality. The treatment of toxic hepatitis was most effective in the case of simultaneous administration of acetylcysteine and corvitin. The normal value of laboratory tests (ALT, ACT, alkaline phosphatase, total and unconjugated bilirubin) was reached and mortality was not more observed. On the bases of obtained data was concluded that acetylcysteine and corvitin have almost equal hepatoprotective activity. The combination of two drugs actually improves the liver function. The most pronounced hepatoprotective effect may be due to synergic action of acetylcysteine and corvitin and such regime can be recommended for correction of liver function.

Reduced size liver transplantation from a donor supported by a Berlin Heart.

PubMed

Misra, M V; Smithers, C J; Krawczuk, L E; Jenkins, R L; Linden, B C; Weldon, C B; Kim, H B

2009-11-01

Patients on cardiac assist devices are often considered to be high-risk solid organ donors. We report the first case of a reduced size liver transplant performed using the left lateral segment of a pediatric donor whose cardiac function was supported by a Berlin Heart. The recipient was a 22-day-old boy with neonatal hemochromatosis who developed fulminant liver failure shortly after birth. The transplant was complicated by mild delayed graft function, which required delayed biliary reconstruction and abdominal wall closure, as well as a bile leak. However, the graft function improved quickly over the first week and the patient was discharged home with normal liver function 8 weeks after transplant. The presence of a cardiac assist device should not be considered an absolute contraindication for abdominal organ donation. Normal organ procurement procedures may require alteration due to the unusual technical obstacles that are encountered when the donor has a cardiac assist device.

Adipokines in Liver Cirrhosis.

PubMed

Buechler, Christa; Haberl, Elisabeth M; Rein-Fischboeck, Lisa; Aslanidis, Charalampos

2017-06-29

Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively.

Adipokines in Liver Cirrhosis

PubMed Central

Haberl, Elisabeth M.; Rein-Fischboeck, Lisa; Aslanidis, Charalampos

2017-01-01

Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively. PMID:28661458

[Vitamin D deficiency in chronic liver disease, clinical-epidemiological analysis and report after vitamin d supplementation].

PubMed

Fernández Fernández, Nereida; Linares Torres, Pedro; Joáo Matias, Diana; Jorquera Plaza, Francisco; Olcoz Goñi, Jose Luis

2016-05-01

Vitamin D (VD) is known to have multiple extra-skeletal health functions. There is emerging interest in exploring the relationship between vitamin D and chronic liver disease (CLD). To determine the prevalence of VD deficiency in patients with CLD in our setting and to assess whether VD supplementation influences plasma levels and is associated with improved liver function. We conducted a study in 2 phases. First, we analysed clinical and epidemiological characteristics in 94 patients with CLD; second, different doses of calcifediol (25-OH-VD) were administered to patients with VD deficiency (<20ng/mL) and insufficiency (20-30ng/mL). Plasma concentrations and liver function (Child-Pugh and MELD) at the end of treatment were compared with baseline data. Deficient or insufficient VD levels were found in 87% of the patients, with an average concentration of 18.8ng/mL. Levels were lower in patients with cirrhosis (15.9ng/mL) (P=.002) and in alcoholic liver disease. VD levels were inversely proportional to the degree of liver function: Child A (16.52ng/mL) vs C (7.75ng/mL). After VD supplementation, optimal serum levels were achieved in 94% of patients and significant improvements were observed in platelet count, albumin levels (P<.05) and functional status assessed by the Child-Pugh scale (P<.05). Given the high prevalence of VD deficiency or insufficiency, the need for screening should be considered in the population with CLD. VD supplementation could be safe and effective. Copyright © 2015 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

Capybara Oil Improves Hepatic Mitochondrial Dysfunction, Steatosis, and Inflammation in a Murine Model of Nonalcoholic Fatty Liver Disease.

PubMed

Marinho, Polyana C; Vieira, Aline B; Pereira, Priscila G; Rabelo, Kíssila; Ciambarella, Bianca T; Nascimento, Ana L R; Cortez, Erika; Moura, Aníbal S; Guimarães, Fernanda V; Martins, Marco A; Barquero, Gonzalo; Ferreira, Rodrigo N; de Carvalho, Jorge J

2018-01-01

Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of liver dysfunction worldwide and is commonly associated with obesity. Evidences suggest that NAFLD might be a mitochondrial disease, which contributes to the hepatic steatosis, oxidative stress, cytokine release, and cell death. Capybara oil (CO) is a rich source of polyunsaturated fatty acids (PUFA), which is known to improve inflammation and oxidative stress. In order to determine the effects of CO on NAFLD, C57Bl/6 mice were divided into 3 groups and fed a high-fat diet (HFD) (NAFLD group and NAFLD + CO group) or a control diet (CG group) during 16 weeks. The CO (1.5 g/kg/daily) was administered by gavage during the last 4 weeks of the diet protocol. We evaluated plasma liver enzymes, hepatic steatosis, and cytokine expression in liver as well as hepatocyte ultrastructural morphology and mitochondrial function. CO treatment suppressed hepatic steatosis, attenuated inflammatory response, and decreased plasma alanine aminotransferase (ALT) in mice with NAFLD. CO was also capable of restoring mitochondrial ultrastructure and function as well as balance superoxide dismutase and catalase levels. Our findings indicate that CO treatment has positive effects on NAFLD improving mitochondrial dysfunction, steatosis, acute inflammation, and oxidative stress.

Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis.

PubMed

Neef, Markus; Ledermann, Monika; Saegesser, Hans; Schneider, Vreni; Reichen, Juerg

2006-12-01

Mammalian target of rapamycin (mTOR) signalling is central in the activation of hepatic stellate cells (HSCs), the key source of extracellular matrix (ECM) in fibrotic liver. We tested the therapeutic potential of the mTOR inhibitor rapamycin in advanced cirrhosis. Cirrhosis was induced by bile duct-ligation (BDL) or thioacetamide injections (TAA). Rats received oral rapamycin (0.5 mg/kg/day) for either 14 or 28 days. Untreated BDL and TAA-rats served as controls. Liver function was quantified by aminopyrine breath test. ECM and ECM-producing cells were quantified by morphometry. MMP-2 activity was measured by zymography. mRNA expression of procollagen-alpha1, transforming growth factor-beta1 (TGF-beta1) and beta2 was quantified by RT-PCR. Fourteen days of rapamycin improved liver function. Accumulation of ECM was decreased together with numbers of activated HSCs and MMP-2 activity in both animal models. TGF-beta1 mRNA was downregulated in TAA, TGF-beta2 mRNA was downregulated in BDL. 28 days of rapamycin treatment entailed a survival advantage of long-term treated BDL-rats. Low-dose rapamycin treatment is effectively antifibrotic and attenuates disease progression in advanced fibrosis. Our results warrant the clinical evaluation of rapamycin as an antifibrotic drug.

Successful management of neonatal hemochromatosis by exchange transfusion and immunoglobulin: a case report.

PubMed

Babor, F; Hadzik, B; Stannigel, H; Mayatepek, E; Hoehn, T

2013-01-01

Neonatal hemochromatosis (NH) is a rare and severe liver disease of mainly intra-uterine onset, characterized by neonatal liver failure, hepatic and extrahepatic iron accumulation. This leads to an altered iron metabolism with resulting siderosis. The disease represents the most common cause of liver failure in neonates and is also the most common indication for neonatal liver transplantation. We present a case of a newborn diagnosed with NH and life threatening liver failure. Initial treatment consisted of chelation therapy and antioxidants, but lack of laboratory and clinical improvement led to an exchange transfusion followed by the singular substitution of intravenous immunoglobulin (IVIG). Both, exchange transfusion and IVIG were tolerated well and led to an improvement of the general condition of the patient and recovery of liver synthetic function. The subsequent favorable course of the disease is described in this case report.

Anatomic Peculiarities of Pig and Human Liver.

PubMed

Nykonenko, Andriy; Vávra, Petr; Zonča, Pavel

2017-02-01

Many investigations on surgical methods and medical treatment are currently done on pigs. This is possible because the pig is sufficiently close genetically to humans. In recent years, progress in liver surgery has opened new possibilities in surgical treatment of liver diseases. Because the methods are relatively novel, various improvements are still needed, and it is thus helpful to conduct experimental surgeries on pig livers. We reviewed the literature to compare the anatomic and functional features of pig and human livers, information that will be of great importance for improving surgical techniques. During the literature review, we used various sources, such as PubMed, Scopus, and veterinary journals. Our results were summarized in diagrams to facilitate understanding of the vascular structure and biliary systems. We conclude that, although the shapes of the human and pig livers are quite different, the pig liver is divided into the same number of segments as the human liver, which also shows a common structure of the vascular system. Thus, with the anatomic and structural features of the pig liver taken into account, this animal model can be used in experimental hepatic surgery.

MicroRNAs in liver tissue engineering - New promises for failing organs.

PubMed

Raschzok, Nathanael; Sallmon, Hannes; Pratschke, Johann; Sauer, Igor M

2015-07-01

miRNA-based technologies provide attractive tools for several liver tissue engineering approaches. Herein, we review the current state of miRNA applications in liver tissue engineering. Several miRNAs have been implicated in hepatic disease and proper hepatocyte function. However, the clinical translation of these findings into tissue engineering has just begun. miRNAs have been successfully used to induce proliferation of mature hepatocytes and improve the differentiation of hepatic precursor cells. Nonetheless, miRNA-based approaches beyond cell generation have not yet entered preclinical or clinical investigations. Moreover, miRNA-based concepts for the biliary tree have yet to be developed. Further research on miRNA based modifications, however, holds the promise of enabling significant improvements to liver tissue engineering approaches due to their ability to regulate and fine-tune all biological processes relevant to hepatic tissue engineering, such as proliferation, differentiation, growth, and cell function. Copyright © 2015 Elsevier B.V. All rights reserved.

Quantitative PET of liver functions

PubMed Central

Keiding, Susanne; Sørensen, Michael; Frisch, Kim; Gormsen, Lars C; Munk, Ole Lajord

2018-01-01

Improved understanding of liver physiology and pathophysiology is urgently needed to assist the choice of new and upcoming therapeutic modalities for patients with liver diseases. In this review, we focus on functional PET of the liver: 1) Dynamic PET with 2-deoxy-2-[18F]fluoro-D-galactose (18F-FDGal) provides quantitative images of the hepatic metabolic clearance K met (mL blood/min/mL liver tissue) of regional and whole-liver hepatic metabolic function. Standard-uptake-value (SUV) from a static liver 18F-FDGal PET/CT scan can replace K met and is currently used clinically. 2) Dynamic liver PET/CT in humans with 11C-palmitate and with the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) can distinguish between individual intrahepatic transport steps in hepatic lipid metabolism and in hepatic transport of bile acid from blood to bile, respectively, showing diagnostic potential for individual patients. 3) Standard compartment analysis of dynamic PET data can lead to physiological inconsistencies, such as a unidirectional hepatic clearance of tracer from blood (K 1; mL blood/min/mL liver tissue) greater than the hepatic blood perfusion. We developed a new microvascular compartment model with more physiology, by including tracer uptake into the hepatocytes from the blood flowing through the sinusoids, backflux from hepatocytes into the sinusoidal blood, and re-uptake along the sinusoidal path. Dynamic PET data include information on liver physiology which cannot be extracted using a standard compartment model. In conclusion, SUV of non-invasive static PET with 18F-FDGal provides a clinically useful measurement of regional and whole-liver hepatic metabolic function. Secondly, assessment of individual intrahepatic transport steps is a notable feature of dynamic liver PET. PMID:29755841

Quantitative PET of liver functions.

PubMed

Keiding, Susanne; Sørensen, Michael; Frisch, Kim; Gormsen, Lars C; Munk, Ole Lajord

2018-01-01

Improved understanding of liver physiology and pathophysiology is urgently needed to assist the choice of new and upcoming therapeutic modalities for patients with liver diseases. In this review, we focus on functional PET of the liver: 1) Dynamic PET with 2-deoxy-2-[ 18 F]fluoro- D -galactose ( 18 F-FDGal) provides quantitative images of the hepatic metabolic clearance K met (mL blood/min/mL liver tissue) of regional and whole-liver hepatic metabolic function. Standard-uptake-value ( SUV ) from a static liver 18 F-FDGal PET/CT scan can replace K met and is currently used clinically. 2) Dynamic liver PET/CT in humans with 11 C-palmitate and with the conjugated bile acid tracer [ N -methyl- 11 C]cholylsarcosine ( 11 C-CSar) can distinguish between individual intrahepatic transport steps in hepatic lipid metabolism and in hepatic transport of bile acid from blood to bile, respectively, showing diagnostic potential for individual patients. 3) Standard compartment analysis of dynamic PET data can lead to physiological inconsistencies, such as a unidirectional hepatic clearance of tracer from blood ( K 1 ; mL blood/min/mL liver tissue) greater than the hepatic blood perfusion. We developed a new microvascular compartment model with more physiology, by including tracer uptake into the hepatocytes from the blood flowing through the sinusoids, backflux from hepatocytes into the sinusoidal blood, and re-uptake along the sinusoidal path. Dynamic PET data include information on liver physiology which cannot be extracted using a standard compartment model. In conclusion , SUV of non-invasive static PET with 18 F-FDGal provides a clinically useful measurement of regional and whole-liver hepatic metabolic function. Secondly, assessment of individual intrahepatic transport steps is a notable feature of dynamic liver PET.

Serum from CCl4-induced acute rat injury model induces differentiation of ADSCs towards hepatic cells and reduces liver fibrosis.

PubMed

Baig, Maria Tayyab; Ali, Gibran; Awan, Sana Javaid; Shehzad, Umara; Mehmood, Azra; Mohsin, Sadia; Khan, Shaheen N; Riazuddin, Sheikh

2017-10-01

Cellular therapies hold promise to alleviate liver diseases. This study explored the potential of allogenic serum isolated from rat with acute CCl 4 injury to differentiate adipose derived stem cells (ADSCs) towards hepatic lineage. Acute liver injury was induced by CCl 4 which caused significant increase in serum levels of VEGF, SDF1α and EGF. ADSCs were preconditioned with 3% serum isolated from normal and acute liver injury models. ADSCs showed enhanced expression of hepatic markers (AFP, albumin, CK8 and CK19). These differentiated ADSCs were transplanted intra-hepatically in CCl 4 -induced liver fibrosis model. After one month of transplantation, fibrosis and liver functions (alkaline phosphatase, ALAT and bilirubin) showed marked improvement in acute injury group. Elevated expression of hepatic (AFP, albumin, CK 18 and HNF4a) and pro survival markers (PCNA and VEGF) and improvement in liver architecture as deduced from results of alpha smooth muscle actin, Sirius red and Masson's trichome staining was observed.

Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells.

PubMed

Takebe, Takanori; Sekine, Keisuke; Kimura, Masaki; Yoshizawa, Emi; Ayano, Satoru; Koido, Masaru; Funayama, Shizuka; Nakanishi, Noriko; Hisai, Tomoko; Kobayashi, Tatsuya; Kasai, Toshiharu; Kitada, Rina; Mori, Akira; Ayabe, Hiroaki; Ejiri, Yoko; Amimoto, Naoki; Yamazaki, Yosuke; Ogawa, Shimpei; Ishikawa, Momotaro; Kiyota, Yasujiro; Sato, Yasuhiko; Nozawa, Kohei; Okamoto, Satoshi; Ueno, Yasuharu; Taniguchi, Hideki

2017-12-05

Organoid technology provides a revolutionary paradigm toward therapy but has yet to be applied in humans, mainly because of reproducibility and scalability challenges. Here, we overcome these limitations by evolving a scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC). By conducting massive "reverse" screen experiments, we identified three progenitor populations that can effectively generate liver buds in a highly reproducible manner: hepatic endoderm, endothelium, and septum mesenchyme. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>10 8 ). Vascularized and functional liver tissues generated entirely from iPSCs significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacturing platform for multicellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Normothermic ex-situ liver preservation: the new gold standard.

PubMed

Laing, Richard W; Mergental, Hynek; Mirza, Darius F

2017-06-01

Normothermic machine perfusion of the liver (NMP-L) is a novel technology recently introduced into the practice of liver transplantation. This review recapitulates benefits of normothermic perfusion over conventional static cold storage and summarizes recent publications in this area. The first clinical trials have demonstrated both safety and feasibility of NMP-L. They have shown that machine perfusion can entirely replace cold storage or be commenced following a period of cold ischaemia. The technology currently allows transplant teams to extend the period of organ preservation for up to 24 h. Results from the first randomized control trial comparing NMP-L with static cold storage will be available soon. One major advantage of NMP-L technology over other parallel technologies is the potential to assess liver function during NMP-L. Several case series have suggested parameters usable for liver viability testing during NMP-L including bile production and clearance of lactic acidosis. NMP-L allows viability testing of high-risk livers. It has shown the potential to increase utilization of donor organs and improve transplant procedure logistics. NMP-L is likely to become an important technology that will improve organ preservation as well as have the potential to improve utilization of extended criteria donor livers.

[Therapeutic effect of saxagliptin in rat models of nonalcoholic fatty liver and type 2 diabetes].

PubMed

Liu, Yan; Zhang, Zhen; Chen, Rongping; Sun, Jia; Chen, Hong

2014-06-01

To observe the therapeutic effect of saxagliptin in a rat model of nonalcoholic fatty liver and type 2 diabetes and investigate the possible mechanism. Rats models of nonalcoholic fatty liver and type 2 diabetes established by feeding on a high glucose and fat diet and streptozotocin injection were treated with saxagliptin (daily dose of 10 mg/kg) gavage for 8 weeks, using saline as the control. After the treatment, fasting blood glucose, serum insulin, blood lipids, liver function, liver oxidative indices, and hepatic pathologies were evaluated in all the rats, and the expressions of Bcl-2 and Bax in the liver tissue were detected with immunohistochemistry and Western blotting. Compared with the model group, saxagliptin intervention significantly reduced blood glucose and HOMA-IR, improved the liver function and SOD activity (P<0.01), lowered the liver weight, liver index (P<0.01) and MDA level (P<0.05), and slightly lowered the body weight and blood lipids (P>0.05); AST level was similar between the normal control group and saxagliptin intervention group (P>0.05). HE and oil red staining showed obvious hepatic pathologies in the model group, and saxagliptin intervention significantly reduced lipid droplets in the hepatocytes and improved the structural damage of the liver. Hepatic Bax expression significantly increased and Bcl-2 expression decreased in the model group, and these changes were reversed by saxagliptin. Saxagliptin shows good therapeutic effect in rat models of nonalcoholic fatty liver and type 2 diabetes possibly by controlling blood glucose, lowering insulin resistance, alleviating hepatic oxidative stress and hepatocyte damage, and regulating the expression of apoptosis-related proteins.

DPP-4 inhibitors improve liver dysfunction in type 2 diabetes mellitus.

PubMed

Kanazawa, Ippei; Tanaka, Ken-ichiro; Sugimoto, Toshitsugu

2014-09-17

Dipeptidyl peptidase-4 (DPP-4) inhibitors might have pleiotropic effects because receptors for incretin exist in various tissues, including liver. We examined whether DPP-4 inhibitors affect liver function in patients with type 2 diabetes. A retrospective review of 459 patients with type 2 diabetes who were prescribed DPP-4 inhibitors was performed. After exclusion of patients with hepatitis B or C, steroid use, and other diseases that might affect liver function and diabetes status, 224 patients were included in the analysis. Forty-four patients (19.6%) with liver injury defined by aspartate transaminase (AST) or alanine transaminase (ALT) over the normal level of 40 U/L. In the patients with liver injury, AST and ALT were significantly decreased after 6 months from the first date of DPP-4 prescription, with mean changes of -6.2 U/L [95% confidence interval (CI) -10.9 to -1.4, p=0.012] and of -11.9 U/L (95%CI -19.5 to -4.2, p=0.003), respectively. Percent changes in AST were significantly and negatively correlated with baseline AST and ALT (r=-0.27, p<0.001 and r=-0.23, p=0.002, respectively), and percent changes in ALT were also negatively correlated with them (r=-0.23, p=0.001 and r=-0.27, p<0.001, respectively). DPP-4 inhibitors improved liver dysfunction in patients with type 2 diabetes.

Liver transplantation: Current status and challenges

PubMed Central

Jadlowiec, Caroline C; Taner, Timucin

2016-01-01

Great progress has been made in the field of liver transplantation over the past two decades. This progress, however, also brings up the next set of challenges: First, organ shortage remains a major limitation, and accounts for a large proportion of wait list mortality. While living donation has successfully increased the total number of liver transplants done in Asian countries, the total number of such transplants has been stagnant in the western hemisphere. As such, there has been a significant effort over the past decade to increase the existing deceased donor pool. This effort has resulted in a greater use of liver allografts following donation after cardiac death (DCD) along with marginal and extended criteria donors. Improved understanding of the pathophysiology of liver allografts procured after circulatory arrest has not only resulted in better selection and management of DCD donors, but has also helped in the development of mechanical perfusion strategies. Early outcomes demonstrating the clinical applicability of both hypothermic and normothermic perfusion and its potential to impact patient survival and allograft function have generated much interest. Second, long-term outcomes of liver transplant recipients have not improved significantly, as recipients continue to succumb to complications of long-term immunosuppression, such as infection, malignancy and renal failure. Furthermore, recent evidence suggests that chronic immune-mediated injury to the liver may also impact graft function. PMID:27182155

A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kostadinova, Radina; Boess, Franziska; Applegate, Dawn

2013-04-01

Drug-induced liver injury (DILI) is the major cause for liver failure and post-marketing drug withdrawals. Due to species-specific differences in hepatocellular function, animal experiments to assess potential liabilities of drug candidates can predict hepatotoxicity in humans only to a certain extent. In addition to animal experimentation, primary hepatocytes from rat or human are widely used for pre-clinical safety assessment. However, as many toxic responses in vivo are mediated by a complex interplay among different cell types and often require chronic drug exposures, the predictive performance of hepatocytes is very limited. Here, we established and characterized human and rat in vitromore » three-dimensional (3D) liver co-culture systems containing primary parenchymal and non-parenchymal hepatic cells. Our data demonstrate that cells cultured on a 3D scaffold have a preserved composition of hepatocytes, stellate, Kupffer and endothelial cells and maintain liver function for up to 3 months, as measured by the production of albumin, fibrinogen, transferrin and urea. Additionally, 3D liver co-cultures maintain cytochrome P450 inducibility, form bile canaliculi-like structures and respond to inflammatory stimuli. Upon incubation with selected hepatotoxicants including drugs which have been shown to induce idiosyncratic toxicity, we demonstrated that this model better detected in vivo drug-induced toxicity, including species-specific drug effects, when compared to monolayer hepatocyte cultures. In conclusion, our results underline the importance of more complex and long lasting in vitro cell culture models that contain all liver cell types and allow repeated drug-treatments for detection of in vivo-relevant adverse drug effects. - Highlights: ► 3D liver co-cultures maintain liver specific functions for up to three months. ► Activities of Cytochrome P450s remain drug- inducible accross three months. ► 3D liver co-cultures recapitulate drug-induced liver toxicity observed in vivo. ► 3D liver co-cultures can detect species-specific drug toxicity observed in vivo. ► This in vitro model may improve assessment of human relevance of preclinical findings.« less

Potential protection of vitamin C against liver-lesioned mice.

PubMed

Su, Min; Chen, Hongqiu; Wei, Chaohe; Chen, Ning; Wu, Wei

2014-10-01

Pathologically, liver injury can result from sustained trauma to hepatocytes, including acute damage. Thus, attenuation of hepatocellular lesion may help improve liver functions. The purpose of this study was to explore the potential advantages of vitamin C (VC) intake on acutely intralesional liver in carbon tetrachloride (CCl4)-exposed mice. Here our data showed that VC supplementation contributed to ameliorated vital signs of CCl4-lesioned mice, resulting in dose-dependent reduction of hepatomegaly. VC lowered the levels of liver functional enzymes including alanine aminotransferase (ALT) and glutamic-oxaloacetic transaminase (AST) in serum, while concentration of lactic acid concentration in blood plasma was decreased. VC-administered CCl4-lesioned mice manifested increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), while the malondialdehyde (MDA) content was reduced in liver tissue. Moreover, VC consumption attenuated hepatotoxic injuries of CCl4-lesioned mice, in which the number of TNF-α positive cells was dose-dependently reduced. Furthermore, intrahepatic expression of TRL-4 mRNA, a vital inflammation-regulator, was down-regulated in VC-administered mice. Overall, we conclude that VC has the potentiality of anti-hepatotoxicity that is capable of ameliorating liver functions, speculating that therapeutic mechanism relates to normalizing metabolism and blocking inflammatory stress in the liver. Copyright © 2014 Elsevier B.V. All rights reserved.

IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats.

PubMed

Zhao, Tian-Yu; Su, Li-Ping; Ma, Chun-Ye; Zhai, Xiao-Han; Duan, Zhi-Jun; Zhu, Ying; Zhao, Gang; Li, Chun-Yan; Wang, Li-Xia; Yang, Dong

2015-07-08

Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines. We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings. Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells. Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Wenxuan; Lu, Chunfeng; Yao, Lu

Alcoholic liver disease (ALD) is a common etiology of liver diseases, characterized by hepatic steatosis. We previously identified farnesoid X receptor (FXR) as a potential therapeutic target for ALD. Dihydroartemisinin (DHA) has been recently identified to possess potent pharmacological activities on liver diseases. This study was aimed to explore the impact of DHA on ALD and further elaborate the underlying mechanisms. Gain- or loss-of-function analyses of FXR were applied in both in vivo and in vitro studies. Results demonstrated that DHA rescued FXR expression and activity in alcoholic rat livers. DHA also reduced serodiagnostic markers of liver injury, including aspartatemore » aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase. DHA improved alcohol-induced liver histological lesions, expression of inflammation genes, and inflammatory cell infiltration. In addition, DHA not only attenuated hyperlipidemia but also reduced hepatic steatosis through regulating lipogenesis and lipolysis genes. In vitro experiments further consolidated the concept that DHA ameliorated ethanol-caused hepatocyte injury and steatosis. Noteworthily, DHA effects were reinforced by FXR agonist obeticholic acid or FXR expression plasmids but abrogated by FXR antagonist Z-guggulsterone or FXR siRNA. In summary, DHA significantly improved alcoholic liver injury by inhibiting hepatic steatosis, which was dependent on its activation of FXR in hepatocytes. - Highlights: • DHA rescues FXR expression in alcoholic livers. • DHA improves alcoholic liver inflammation and steatosis in a FXR-dependent way. • DHA alleviates ethanol-induced hepatocyte steatosis by activation of FXR.« less

Experimental and clinical evidence for modification of hepatic ischaemia–reperfusion injury by N-acetylcysteine during major liver surgery

PubMed Central

Jegatheeswaran, Santhalingam; Siriwardena, Ajith K

2011-01-01

Background Hepatic ischaemia–reperfusion (I/R) injury occurs in both liver resectional surgery and in transplantation. The biochemistry of I/R injury involves short-lived oxygen free radicals. N-acetylcysteine (NAC) is a thiol-containing synthetic compound used in the treatment of acetaminophen toxicity. The present study is a detailed overview of the experimental and clinical evidence for the use of NAC as a pharmaco-protection agent in patients undergoing major liver surgery or transplantation. Methods A computerized search of the Medline, Embase and SCI databases for the period from 1st January 1988 to 31st December 2008 produced 40 reports. For clinical studies, the quality of reports was assessed according to the criteria reported by the Cochrane communication review group. Results Nineteen studies evaluated NAC in experimental liver I/R injury. NAC was administered before induction of ischaemia in 13. The most widely used concentration was 150 mg/kg by intravenous bolus. Fifteen studies report an improvement in outcome, predominantly a reduction in transaminase. Seven studies used an isolated perfused liver model with all showing improvement (predominantly an improvement in bile production after N-acetylcysteine). Two out of four transplantation models showed an improvement in hepatic function. Clinical studies in transplantation show a modest improvement in transaminase levels with no beneficial effect on either patient or graft survival. Conclusion N-acetylcysteine, given before induction of a liver I/R injury in an experimental model can ameliorate liver injury. Clinical outcome data are limited and there is currently little evidence to justify use either in liver transplantation or in liver resectional surgery. PMID:21241423

Differentiation and Transplantation of Human Embryonic Stem Cell-Derived Hepatocytes

PubMed Central

Basma, Hesham; Soto-Gutiérrez, Alejandro; Yannam, Govardhana Rao; Liu, Liping; Ito, Ryotaro; Yamamoto, Toshiyuki; Ellis, Ewa; Carson, Steven D.; Sato, Shintaro; Chen, Yong; Muirhead, David; Navarro-Álvarez, Nalu; Wong, Ron; Roy-Chowdhury, Jayanta; Platt, Jeffrey L.; Mercer, David F.; Miller, John D.; Strom, Stephen C.; Kobayashi, Noaya; Fox, Ira J.

2009-01-01

Background & Aims The ability to obtain unlimited numbers of human hepatocytes would improve development of cell-based therapies for liver diseases, facilitate the study of liver biology and improve the early stages of drug discovery. Embryonic stem cells are pluripotent, can potentially differentiate into any cell type and could therefore be developed as a source of human hepatocytes. Methods To generate human hepatocytes, human embryonic stem cells were differentiated by sequential culture in fibroblast growth factor 2 and human Activin-A, hepatocyte growth factor, and dexamethasone. Functional hepatocytes were isolated by sorting for surface asialoglycoprotein receptor expression. Characterization was performed by real-time PCR, imunohistochemistry, immunoblot, functional assays and transplantation. Results Embryonic stem cell-derived hepatocytes expressed liver-specific genes but not genes representing other lineages, secreted functional human liver-specific proteins similar to those of primary human hepatocytes and demonstrated human hepatocyte cytochrome P450 metabolic activity. Serum from rodents given injections of embryonic stem cell-derived hepatocytes contained significant amounts of human albumin and alpha-1-antitrypsin. Colonies of cytokeratin-18 and human albumin-expressing cells were present in the livers of recipient animals. Conclusion Human embryonic stem cells can be differentiated into cells with many characteristics of primary human hepatocytes. Hepatocyte-like cells can be enriched and recovered based on asialoglycoprotein receptor expression and could potentially be used in drug discovery research and developed as therapeutics. PMID:19026649

Measurement of liver function using hepatobiliary scintigraphy improves risk assessment in patients undergoing major liver resection.

PubMed

Cieslak, Kasia P; Bennink, Roelof J; de Graaf, Wilmar; van Lienden, Krijn P; Besselink, Marc G; Busch, Olivier R C; Gouma, Dirk J; van Gulik, Thomas M

2016-09-01

(99m)Tc-mebrofenin-hepatobiliary-scintigraphy (HBS) enables measurement of future remnant liver (FRL)-function and was implemented in our preoperative routine after calculation of the cut-off value for prediction of postoperative liver failure (LF). This study evaluates our results since the implementation of HBS. Additionally, CT-volumetric methods of FRL-assessment, standardized liver volumetry and FRL/body-weight ratio (FRL-BWR), were evaluated. 163 patients who underwent major liver resection were included. Insufficient FRL-volume and/or FRL-function <2.7%/min/m(2) were indications for portal vein embolization (PVE). Non-PVE patients were compared with a historical cohort (n = 55). Primary endpoints were postoperative LF and LF related mortality. Secondary endpoint was preoperative identification of patients at risk for LF using the CT-volumetric methods. 29/163 patients underwent PVE; 8/29 patients because of insufficient FRL-function despite sufficient FRL-volume. According to FRL-BWR and standardized liver volumetry, 16/29 and 11/29 patients, respectively, would not have undergone PVE. LF and LF related mortality were significantly reduced compared to the historical cohort. HBS appeared superior in the identification of patients with increased surgical risk compared to the CT-volumetric methods. Implementation of HBS in the preoperative work-up led to a function oriented use of PVE and was associated with a significant decrease in postoperative LF and LF related mortality. Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Predictive factors of short term outcome after liver transplantation: A review

PubMed Central

Bolondi, Giuliano; Mocchegiani, Federico; Montalti, Roberto; Nicolini, Daniele; Vivarelli, Marco; De Pietri, Lesley

2016-01-01

Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1th and the 5th day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function. PMID:27468188

Predictive factors of short term outcome after liver transplantation: A review.

PubMed

Bolondi, Giuliano; Mocchegiani, Federico; Montalti, Roberto; Nicolini, Daniele; Vivarelli, Marco; De Pietri, Lesley

2016-07-14

Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1(th) and the 5(th) day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function.

Prospective Longitudinal Assessment of Quality of Life for Liver Cancer Patients Treated With Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klein, Jonathan, E-mail: jonathan.klein@rmp.uhn.on.ca; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario; Dawson, Laura A.

Purpose: To evaluate quality of life (QoL), an important outcome owing to poor long-term survival, after stereotactic body radiation therapy (SBRT) to the liver. Methods and Materials: Patients (n=222) with hepatocellular carcinoma (HCC), liver metastases, or intrahepatic cholangiocarcinoma and Child-Pugh A liver function received 24-60 Gy of 6-fraction image-guided SBRT. Prospective QoL assessment was completed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30) and/or Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep, version 4) questionnaires at baseline and 1, 3, 6, and 12 months after treatment. Ten HCC patients with Child-Pugh B liver function were alsomore » treated. Results: The QLQ-C30 was available for 205 patients, and 196 completed the FACT-Hep. No difference in baseline QoL (P=.17) or overall survival (P=.088) was seen between the HCC, liver metastases, and intrahepatic cholangiocarcinoma patients. Appetite loss and fatigue measured by the QLQ-C30 clinically and statistically worsened by 1 month after treatment but recovered by 3 months. At 3 and 12 months after treatment, respectively, the FACT-Hep score had improved relative to baseline in 13%/19%, worsened in 36%/27%, and remained stable in 51%/54%. Using the QLQ-C30 Global Health score, QoL improved in 16%/23%, worsened in 34%/39%, and remained stable in 50%/38% at 3 and 12 months, respectively. Median survival was 17.0 months (95% confidence interval [CI] 12.3-19.8 months). Higher baseline scores on both FACT-Hep and QLQ-C30 Global Health were associated with improved survival. Hazard ratios for death, per 10-unit decrease in QoL, were 0.90 (95% CI 0.83-0.98; P=.001) and 0.88 (95% CI 0.82-0.95; P=.001), respectively. Tumor size was inversely correlated with survival. Conclusions: Liver SBRT temporarily worsens appetite and fatigue, but not overall QoL. Stereotactic body radiation therapy is well tolerated and warrants comparison against other liver-directed therapies.« less

The Protective Effects of Trypsin Inhibitor on Hepatic Ischemia-Reperfusion Injury and Liver Graft Survival

PubMed Central

Guan, Lianyue; Liu, Hongyu; Fu, Peiyao; Li, Zhuonan; Li, Peidong; Xie, Lijuan; Xin, Mingang; Wang, Zhanpeng

2016-01-01

The aim of this study was to explore the protective effects of ulinastatin (urinary trypsin inhibitor, UTI) on liver ischemia-reperfusion injury (IRI) and graft survival. We employed mouse liver cold IRI and orthotopic liver transplantation (OLTx) models. UTI was added to lactated Ringer's (LR) solution for liver perfusion and preservation in vitro or combined with UTI injection intraperitoneally to the liver graft recipient. Our results indicated that UTI supplementation protected the liver from cold IRI in a dose-dependent manner and prolonged liver graft survival from extended cold preserved liver donors significantly. The underlying mechanism of UTI on liver IRI may be mediated by inhibition of proinflammatory cytokine release, increasing the expression of the antiapoptotic gene Bcl-2 and decreasing the expression of the proapoptosis genes of Caspase-3 and Bax, and further protects hepatocytes from apoptotic death and improves liver function. PMID:26783413

The Protective Effects of Trypsin Inhibitor on Hepatic Ischemia-Reperfusion Injury and Liver Graft Survival.

PubMed

Guan, Lianyue; Liu, Hongyu; Fu, Peiyao; Li, Zhuonan; Li, Peidong; Xie, Lijuan; Xin, Mingang; Wang, Zhanpeng; Li, Wei

2016-01-01

The aim of this study was to explore the protective effects of ulinastatin (urinary trypsin inhibitor, UTI) on liver ischemia-reperfusion injury (IRI) and graft survival. We employed mouse liver cold IRI and orthotopic liver transplantation (OLTx) models. UTI was added to lactated Ringer's (LR) solution for liver perfusion and preservation in vitro or combined with UTI injection intraperitoneally to the liver graft recipient. Our results indicated that UTI supplementation protected the liver from cold IRI in a dose-dependent manner and prolonged liver graft survival from extended cold preserved liver donors significantly. The underlying mechanism of UTI on liver IRI may be mediated by inhibition of proinflammatory cytokine release, increasing the expression of the antiapoptotic gene Bcl-2 and decreasing the expression of the proapoptosis genes of Caspase-3 and Bax, and further protects hepatocytes from apoptotic death and improves liver function.

Effect of Chinese traditional compound, Gan-fu-kang, on CCl(4)-induced liver fibrosis in rats and its probable molecular mechanisms.

PubMed

Xu, Ting-Ting; Jiang, Miao-Na; Li, Cong; Che, Ying; Jia, Yu-Jie

2007-03-01

To explore the antifibrotic effect of traditional Chinese medicine compound Gan-fu-kang (GFK) on CCl(4)-induced liver fibrosis in rats and its probable mechanisms. The effects of GFK on CCl(4)-induced liver fibrosis were tested in rats. The liver histopathology was examined by light microscope, polaring microscope and electron microscope. The activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assayed and the content of albumin (ALB) and hydroxyproline in the liver was measured. The expression of transforming growth factor-beta(1) (TGF-beta(1)) and laminin (LN) was determined by immunohistochemistry. Semi-quantitive computation of collagen types I and III and laminin was done. The expression of MMP-2 and TIMP-1 was assayed by reverse transcription polymerase chain reaction (RT-PCR). Upon pathological examination, GFK treatment had significantly reversed liver fibrosis. Hepatic extracellular matrix (ECM) deposition was significantly reduced, as evidenced by the reduction of the content of hydroxyproline, collagen types I and III, and laminin. Hepatic function was improved by GFK treatment, as evidenced by the increase of plasma ALB and A/G, and by the decrease of serum ALT and AST. TGF-beta(1) in liver was significantly reduced. A significant expression of MMP-2 and TIMP-1 mRNA in liver were downregulated after GFK treatment. The traditional Chinese medicine compound recipe GFK has an antifibrotic effect on CCl(4)-induced liver fibrosis in rats, which improves hepatic function and lessens the deposition of collagen in the liver. The probable antifibrotic mechanisms were: inhibiting the expression of TGF-beta(1) and decreasing expressions of MMP-2 and TIMP-1.

Pulmonary Vascular Complications of Liver Disease

PubMed Central

Fritz, Jason S.; Fallon, Michael B.

2013-01-01

Hepatopulmonary syndrome and portopulmonary hypertension are two pulmonary vascular complications of liver disease. The pathophysiology underlying each disorder is distinct, but patients with either condition may be limited by dyspnea. A careful evaluation of concomitant symptoms, the physical examination, pulmonary function testing and arterial blood gas analysis, and echocardiographic, imaging, and hemodynamic studies is crucial to establishing (and distinguishing) these diagnoses. Our understanding of the pathobiology, natural history, and treatment of these disorders has advanced considerably over the past decade; however, the presence of either still increases the risk of morbidity and mortality in patients with underlying liver disease. There is no effective medical treatment for hepatopulmonary syndrome. Although liver transplantation can resolve hepatopulmonary syndrome, there appears to be worse survival even with transplantation. Liver transplantation poses a very high risk of death in those with significant portopulmonary hypertension, where targeted medical therapies may improve functional status and allow successful transplantation in a small number of select patients. PMID:23155142

Hemoglobin Regulates the Metabolic, Synthetic, Detoxification, and Biotransformation Functions of Hepatoma Cells Cultured in a Hollow Fiber Bioreactor

PubMed Central

Chen, Guo

2010-01-01

Hepatic hollow fiber (HF) bioreactors constitute one type of extracorporeal bioartificial liver assist device (BLAD). Ideally, cultured hepatocytes in a BLAD should closely mimic the in vivo oxygenation environment of the liver sinusoid to yield a device with optimal performance. However, most BLADs, including hepatic HF bioreactors, suffer from O2 limited transport toward cultured hepatocytes, which reduces their performance. We hypothesize that supplementation of hemoglobin-based O2 carriers into the circulating cell culture medium of hepatic HF bioreactors is a feasible and effective strategy to improve bioreactor oxygenation and performance. We examined the effect of bovine hemoglobin (BvHb) supplementation (15 g/L) in the circulating cell culture medium of hepatic HF bioreactors on hepatocyte proliferation, metabolism, and varied liver functions, including biosynthesis, detoxification, and biotransformation. It was observed that BvHb supplementation supported the maintenance of a higher cell mass in the extracapillary space, improved hepatocyte metabolic efficiency (i.e., hepatocytes consumed much less glucose), improved hepatocyte capacity for drug metabolism, and conserved both albumin synthesis and ammonia detoxification functions compared to controls (no BvHb supplementation) under the same experimental conditions. PMID:20528678

Molindone and hepatotoxicity.

PubMed

Bhatia, S C; Banta, L E; Ehrlich, D W

1985-10-01

An adolescent male with chronic schizophrenic disorder, paranoid type, was treated with molindone. He developed hepatotoxicity in the early treatment phase as evidenced by flu-like symptoms and laboratory abnormalities of liver functions. These symptoms and his hepatic functions improved on discontinuing molindone. Similar liver function trends were seen on reintroduction and subsequent withdrawal of the drug. Hepatic hypersensitivity has not been reported previously with the use of this drug. It is suggested that clinicians should be aware of this association and should assess hepatic functions in patients who develop a prodromal flu-like syndrome with this drug, especially in the early treatment phase.

Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers.

PubMed

Op den Dries, Sanna; Karimian, Negin; Westerkamp, Andrie C; Sutton, Michael E; Kuipers, Michiel; Wiersema-Buist, Janneke; Ottens, Petra J; Kuipers, Jeroen; Giepmans, Ben N; Leuvenink, Henri G D; Lisman, Ton; Porte, Robert J

2016-07-01

Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS-preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 ± 0.02 and 7.74 ± 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 ± 0.02 and 7.49 ± 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation. Liver Transplantation 22 994-1005 2016 AASLD. © 2016 American Association for the Study of Liver Diseases.

Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential.

PubMed

Telange, Darshan R; Patil, Arun T; Pethe, Anil M; Fegade, Harshal; Anand, Sridhar; Dave, Vivek S

2017-10-15

The apigenin-phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design-optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride-induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design-optimized levels of formulation and process variables. The physical-chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36-fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride-elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid-based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility. Copyright © 2016 Elsevier B.V. All rights reserved.

Cognition Predicts Quality of Life Among Patients With End-Stage Liver Disease.

PubMed

Paulson, Daniel; Shah, Mona; Miller-Matero, Lisa Renee; Eshelman, Anne; Abouljoud, Marwan

2016-01-01

Impaired cognitive functioning and poor quality of life (QoL) are both common among patients with end-stage liver disease; however, it is unclear how these are related. This study examines how specific cognitive domains predict QoL among liver transplant candidates by replicating Stewart and colleagues' (2010) 3-factor model of cognitive functioning, and determining how variability in these cognitive domains predicts mental health and physical QoL. The sample included 246 patients with end-stage liver disease who were candidates for liver transplant at a large, Midwestern health care center. Measures, including the Repeatable Battery for the Assessment of Neuropsychological Status, Trail Making Test, Shipley Institute of Living Scale, Short-Form Health Survey-36 Version 2, and Hospital Anxiety and Depression Scale, comprised latent variables representing global intellectual functioning, psychomotor speed, and learning and memory functioning. Confirmatory factor analysis results indicate that the 3-factor solution model comprised of global intellectual functioning, psychomotor speed, and learning and memory functioning fit the data well. Addition of physical and mental health QoL latent factors resulted in a structural model also with good fit. Results related physical QoL to global intellectual functioning, and mental health QoL to global intellectual functioning and psychomotor functioning. Findings elucidate a relationship between cognition and QoL and support the use of routine neuropsychological screening with end-stage liver disease patients, specifically examining the cognitive domains of global intellectual, psychomotor, and learning and memory functioning. Subsequently, screening results may inform implementation of targeted interventions to improve QoL. Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Elasticity-based development of functionally enhanced multicellular 3D liver encapsulated in hybrid hydrogel.

PubMed

Lee, Ho-Joon; Son, Myung Jin; Ahn, Jiwon; Oh, Soo Jin; Lee, Mihee; Kim, Ansoon; Jeung, Yun-Ji; Kim, Han-Gyeul; Won, Misun; Lim, Jung Hwa; Kim, Nam-Soon; Jung, Cho-Rock; Chung, Kyung-Sook

2017-12-01

Current in vitro liver models provide three-dimensional (3-D) microenvironments in combination with tissue engineering technology and can perform more accurate in vivo mimicry than two-dimensional models. However, a human cell-based, functionally mature liver model is still desired, which would provide an alternative to animal experiments and resolve low-prediction issues on species differences. Here, we prepared hybrid hydrogels of varying elasticity and compared them with a normal liver, to develop a more mature liver model that preserves liver properties in vitro. We encapsulated HepaRG cells, either alone or with supporting cells, in a biodegradable hybrid hydrogel. The elastic modulus of the 3D liver dynamically changed during culture due to the combined effects of prolonged degradation of hydrogel and extracellular matrix formation provided by the supporting cells. As a result, when the elastic modulus of the 3D liver model converges close to that of the in vivo liver (≅ 2.3 to 5.9 kPa), both phenotypic and functional maturation of the 3D liver were realized, while hepatic gene expression, albumin secretion, cytochrome p450-3A4 activity, and drug metabolism were enhanced. Finally, the 3D liver model was expanded to applications with embryonic stem cell-derived hepatocytes and primary human hepatocytes, and it supported prolonged hepatocyte survival and functionality in long-term culture. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. We provide a functionally improved 3D liver model that recapitulates in vivo liver stiffness. We have experimentally addressed the issues of orchestrated effects of mechanical compliance, controlled matrix formation by stromal cells in conjunction with hepatic differentiation, and functional maturation of hepatocytes in a dynamic 3D microenvironment. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. Additionally, recent advances in the stem-cell technologies have made the development of 3D organoid possible, and thus, our study also provides further contribution to the development of physiologically relevant stem-cell-based 3D tissues that provide an elasticity-based predefined biomimetic 3D microenvironment. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Purpose-driven biomaterials research in liver-tissue engineering.

PubMed

Ananthanarayanan, Abhishek; Narmada, Balakrishnan Chakrapani; Mo, Xuejun; McMillian, Michael; Yu, Hanry

2011-03-01

Bottom-up engineering of microscale tissue ("microtissue") constructs to recapitulate partially the complex structure-function relationships of liver parenchyma has been realized through the development of sophisticated biomaterial scaffolds, liver-cell sources, and in vitro culture techniques. With regard to in vivo applications, the long-lived stem/progenitor cell constructs can improve cell engraftment, whereas the short-lived, but highly functional hepatocyte constructs stimulate host liver regeneration. With regard to in vitro applications, microtissue constructs are being adapted or custom-engineered into cell-based assays for testing acute, chronic and idiosyncratic toxicities of drugs or pathogens. Systems-level methods and computational models that represent quantitative relationships between biomaterial scaffolds, cells and microtissue constructs will further enable their rational design for optimal integration into specific biomedical applications. Copyright © 2010 Elsevier Ltd. All rights reserved.

Hepatocyte transplantation for liver-based metabolic disorders.

PubMed

Dhawan, Anil; Mitry, Ragai R; Hughes, Robin D

2006-01-01

Hepatocyte transplantation is being investigated as an alternative to orthotopic liver transplantation in patients with liver-based metabolic disorders. The progress made in this field to date is reviewed. Protocols have been developed using collagenase perfusion to isolate human hepatocytes from unused donor liver tissue. Hepatocytes with a high viability can often be obtained and can be cryopreserved for later use, though with loss of function on thawing. For clinical use, hepatocytes must be prepared in clean GMP conditions with cells meeting criteria of function and lack of microbial contamination before patient use. Hepatocytes are infused intraportally into the patient's liver, where a proportion of cells will engraft and replace the deficient metabolic function without the need for major surgery. Twenty patients have now received hepatocyte transplantation, including eight children at King's College Hospital. There was a range of aetiologies of liver disease: familial hypercholesterolaemia, Crigler-Najjar syndrome type 1, urea cycle defects, infantile Refsum disease, glycogen storage disease type Ia, inherited factor VII deficiency and progressive familial intrahepatic cholestasis type 2. Clinical improvement and partial correction of the metabolic abnormality was observed in most cases. Considerable progress has been made in developing the technique, but hepatocyte transplantation is limited by the available supply of liver tissue. Hepatocytes derived from stem cells could provide alternative sources of cells in the future.

Aerobic interval exercise improves parameters of nonalcoholic fatty liver disease (NAFLD) and other alterations of metabolic syndrome in obese Zucker rats.

PubMed

Kapravelou, Garyfallia; Martínez, Rosario; Andrade, Ana M; Nebot, Elena; Camiletti-Moirón, Daniel; Aparicio, Virginia A; Lopez-Jurado, Maria; Aranda, Pilar; Arrebola, Francisco; Fernandez-Segura, Eduardo; Bermano, Giovanna; Goua, Marie; Galisteo, Milagros; Porres, Jesus M

2015-12-01

Metabolic syndrome (MS) is a group of metabolic alterations that increase the susceptibility to cardiovascular disease and type 2 diabetes. Nonalcoholic fatty liver disease has been described as the liver manifestation of MS. We aimed to test the beneficial effects of an aerobic interval training (AIT) protocol on different biochemical, microscopic, and functional liver alterations related to the MS in the experimental model of obese Zucker rat. Two groups of lean and obese animals (6 weeks old) followed a protocol of AIT (4 min at 65%-80% of maximal oxygen uptake, followed by 3 min at 50%-65% of maximal oxygen uptake for 45-60 min, 5 days/week, 8 weeks of experimental period), whereas 2 control groups remained sedentary. Obese rats had higher food intake and body weight (P < 0.0001) and suffered significant alterations in plasma lipid profile, area under the curve after oral glucose overload (P < 0.0001), liver histology and functionality, and antioxidant status. The AIT protocol reduced the severity of alterations related to glucose and lipid metabolism and increased the liver protein expression of PPARγ, as well as the gene expression of glutathione peroxidase 4 (P < 0.001). The training protocol also showed significant effects on the activity of hepatic antioxidant enzymes, although this action was greatly influenced by rat phenotype. The present data suggest that AIT protocol is a feasible strategy to improve some of the plasma and liver alterations featured by the MS.

Simultaneous Administration of ADSCs-Based Therapy and Gene Therapy Using Ad-huPA Reduces Experimental Liver Fibrosis.

PubMed

Meza-Ríos, Alejandra; García-Benavides, Leonel; García-Bañuelos, Jesus; Salazar-Montes, Adriana; Armendáriz-Borunda, Juan; Sandoval-Rodríguez, Ana

2016-01-01

hADSCs transplantation in cirrhosis models improves liver function and reduces fibrosis. In addition, Ad-huPA gene therapy diminished fibrosis and increased hepatocyte regeneration. In this study, we evaluate the combination of these therapies in an advanced liver fibrosis experimental model. hADSCs were expanded and characterized before transplantation. Ad-huPA was simultaneously administrated via the ileac vein. Animals were immunosuppressed by CsA 24 h before treatment and until sacrifice at 10 days post-treatment. huPA liver expression and hADSCs biodistribution were evaluated, as well as the percentage of fibrotic tissue, hepatic mRNA levels of Col-αI, TGF-β1, CTGF, α-SMA, PAI-I, MMP2 and serum levels of ALT, AST and albumin. hADSCs homed mainly in liver, whereas huPA expression was similar in Ad-huPA and hADSCs/Ad-huPA groups. hADSCs, Ad-huPA and hADSCs/Ad-huPA treatment improves albumin levels, reduces liver fibrosis and diminishes Collagen α1, CTGF and α-SMA mRNA liver levels. ALT and AST serum levels showed a significant decrease exclusively in the hADSCs group. These results showed that combinatorial effect of cell and gene-therapy does not improve the antifibrogenic effects of individual treatments, whereas hADSCs transplantation seems to reduce liver fibrosis in a greater proportion.

A Modified Protocol for the Isolation of Primary Human Hepatocytes with Improved Viability and Function from Normal and Diseased Human Liver.

PubMed

Bartlett, David C; Newsome, Philip N

2017-01-01

Successful hepatocyte isolation is critical for continued development of cellular transplantation. However, most tissue available for research is from diseased liver and the results of hepatocyte isolation from such tissue are inferior compared to normal tissue. Here we describe a modified method, combining the use of Liberase and N-acetylcysteine (NAC), for the isolation of primary human hepatocytes with high viability from normal and diseased liver.

Cell sources for in vitro human liver cell culture models.

PubMed

Zeilinger, Katrin; Freyer, Nora; Damm, Georg; Seehofer, Daniel; Knöspel, Fanny

2016-09-01

In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described. © 2016 by the Society for Experimental Biology and Medicine.

Cell sources for in vitro human liver cell culture models

PubMed Central

Freyer, Nora; Damm, Georg; Seehofer, Daniel; Knöspel, Fanny

2016-01-01

In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro. However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro. Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described. PMID:27385595

Hepatocyte transplantation and advancements in alternative cell sources for liver-based regenerative medicine.

PubMed

Lee, Charlotte A; Sinha, Siddharth; Fitzpatrick, Emer; Dhawan, Anil

2018-06-01

Human hepatocyte transplantation has been actively perused as an alternative to liver replacement for acute liver failure and liver-based metabolic defects. Current challenges in this field include a limited cell source, reduced cell viability following cryopreservation and poor engraftment of cells into the recipient liver with consequent limited life span. As a result, alternative stem cell sources such as pluripotent stem cells, fibroblasts, hepatic progenitor cells, amniotic epithelial cells and mesenchymal stem/stromal cells (MSCs) can be used to generate induced hepatocyte like cells (HLC) with each technique exhibiting advantages and disadvantages. HLCs may have comparable function to primary human hepatocytes and could offer patient-specific treatment. However, long-term functionality of transplanted HLCs and the potential oncogenic risks of using stem cells have yet to be established. The immunomodulatory effects of MSCs are promising, and multiple clinical trials are investigating their effect in cirrhosis and acute liver failure. Here, we review the current status of hepatocyte transplantation, alternative cell sources to primary human hepatocytes and their potential in liver regeneration. We also describe recent clinical trials using hepatocytes derived from stem cells and their role in improving the phenotype of several liver diseases.

Hepatic stellate cells in liver development, regeneration, and cancer

PubMed Central

Yin, Chunyue; Evason, Kimberley J.; Asahina, Kinji; Stainier, Didier Y.R.

2013-01-01

Hepatic stellate cells are liver-specific mesenchymal cells that play vital roles in liver physiology and fibrogenesis. They are located in the space of Disse and maintain close interactions with sinusoidal endothelial cells and hepatic epithelial cells. It is becoming increasingly clear that hepatic stellate cells have a profound impact on the differentiation, proliferation, and morphogenesis of other hepatic cell types during liver development and regeneration. In this Review, we summarize and evaluate the recent advances in our understanding of the formation and characteristics of hepatic stellate cells, as well as their function in liver development, regeneration, and cancer. We also discuss how improved knowledge of these processes offers new perspectives for the treatment of patients with liver diseases. PMID:23635788

Physiological and biochemical basis of clinical liver function tests: a review.

PubMed

Hoekstra, Lisette T; de Graaf, Wilmar; Nibourg, Geert A A; Heger, Michal; Bennink, Roelof J; Stieger, Bruno; van Gulik, Thomas M

2013-01-01

To review the literature on the most clinically relevant and novel liver function tests used for the assessment of hepatic function before liver surgery. Postoperative liver failure is the major cause of mortality and morbidity after partial liver resection and develops as a result of insufficient remnant liver function. Therefore, accurate preoperative assessment of the future remnant liver function is mandatory in the selection of candidates for safe partial liver resection. A MEDLINE search was performed using the key words "liver function tests," "functional studies in the liver," "compromised liver," "physiological basis," and "mechanistic background," with and without Boolean operators. Passive liver function tests, including biochemical parameters and clinical grading systems, are not accurate enough in predicting outcome after liver surgery. Dynamic quantitative liver function tests, such as the indocyanine green test and galactose elimination capacity, are more accurate as they measure the elimination process of a substance that is cleared and/or metabolized almost exclusively by the liver. However, these tests only measure global liver function. Nuclear imaging techniques ((99m)Tc-galactosyl serum albumin scintigraphy and (99m)Tc-mebrofenin hepatobiliary scintigraphy) can measure both total and future remnant liver function and potentially identify patients at risk for postresectional liver failure. Because of the complexity of liver function, one single test does not represent overall liver function. In addition to computed tomography volumetry, quantitative liver function tests should be used to determine whether a safe resection can be performed. Presently, (99m)Tc-mebrofenin hepatobiliary scintigraphy seems to be the most valuable quantitative liver function test, as it can measure multiple aspects of liver function in, specifically, the future remnant liver.

Improved hepatic arterial fraction estimation using cardiac output correction of arterial input functions for liver DCE MRI

NASA Astrophysics Data System (ADS)

Chouhan, Manil D.; Bainbridge, Alan; Atkinson, David; Punwani, Shonit; Mookerjee, Rajeshwar P.; Lythgoe, Mark F.; Taylor, Stuart A.

2017-02-01

Liver dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling could be useful in the assessment of diffuse liver disease and focal liver lesions, but is compromised by errors in arterial input function (AIF) sampling. In this study, we apply cardiac output correction to arterial input functions (AIFs) for liver DCE MRI and investigate the effect on dual-input single compartment hepatic perfusion parameter estimation and reproducibility. Thirteen healthy volunteers (28.7  ±  1.94 years, seven males) underwent liver DCE MRI and cardiac output measurement using aortic root phase contrast MRI (PCMRI), with reproducibility (n  =  9) measured at 7 d. Cardiac output AIF correction was undertaken by constraining the first pass AIF enhancement curve using the indicator-dilution principle. Hepatic perfusion parameters with and without cardiac output AIF correction were compared and 7 d reproducibility assessed. Differences between cardiac output corrected and uncorrected liver DCE MRI portal venous (PV) perfusion (p  =  0.066), total liver blood flow (TLBF) (p  =  0.101), hepatic arterial (HA) fraction (p  =  0.895), mean transit time (MTT) (p  =  0.646), distribution volume (DV) (p  =  0.890) were not significantly different. Seven day corrected HA fraction reproducibility was improved (mean difference 0.3%, Bland-Altman 95% limits-of-agreement (BA95%LoA)  ±27.9%, coefficient of variation (CoV) 61.4% versus 9.3%, ±35.5%, 81.7% respectively without correction). Seven day uncorrected PV perfusion was also improved (mean difference 9.3 ml min-1/100 g, BA95%LoA  ±506.1 ml min-1/100 g, CoV 64.1% versus 0.9 ml min-1/100 g, ±562.8 ml min-1/100 g, 65.1% respectively with correction) as was uncorrected TLBF (mean difference 43.8 ml min-1/100 g, BA95%LoA  ±586.7 ml min-1/ 100 g, CoV 58.3% versus 13.3 ml min-1/100 g, ±661.5 ml min-1/100 g, 60.9% respectively with correction). Reproducibility of uncorrected MTT was similar (uncorrected mean difference 2.4 s, BA95%LoA  ±26.7 s, CoV 60.8% uncorrected versus 3.7 s, ±27.8 s, 62.0% respectively with correction), as was and DV (uncorrected mean difference 14.1%, BA95%LoA  ±48.2%, CoV 24.7% versus 10.3%, ±46.0%, 23.9% respectively with correction). Cardiac output AIF correction does not significantly affect the estimation of hepatic perfusion parameters but demonstrates improvements in normal volunteer 7 d HA fraction reproducibility, but deterioration in PV perfusion and TLBF reproducibility. Improved HA fraction reproducibility maybe important as arterialisation of liver perfusion is increased in chronic liver disease and within malignant liver lesions.

The effects of blueberry anthocyanins on histone acetylation in rat liver fibrosis

PubMed Central

Zhan, Wei; Liao, Xin; Xie, Ru-Jia; Tian, Tian; Yu, Lei; Liu, Xing; Liu, Jing; Li, Po; Han, Bing; Yang, Ting; Zhang, Bei; Cai, Li-Jun; Li, Rui; Yang, Qin

2017-01-01

To determine the effects ofanthocyanins from blueberries on hepatic stellate cell (HSCs-T6) and on histone acetylation during liver fibrosis induced by CCl4 in rats. Fifty male SD rats weighing 180 ± 20g were randomly placed into a control group, a hepatic fibrosis group, a blueberry treatment group, a blueberry intervention group, and a natural recovery group. After the rats were sacrificed, the livers and the liver indexes were measured, and the pathological changes were observed by HE staining and Masson staining. The blood was analyzed for the four indexes of liver fibrosis and liver function; nucleoprotein from liver tissues and karyoplasm were isolated to determine the expression of acH3K9, acH3K14, and acH3K18 by Western blotting. Compared with the lethal rate of the control group, the median lethal rate of HSCs-T6 cells treated with a the 50μmol/L concentration was 66.94% (P < 0.05). The protein expression on α-SMA, type I collagen, TIMP1 significantly decreased (P < 0.05) following treatment with 50 ug/ml of anthocyanin for 36 h; moreover, the expression of acH3K9, acH3K14 and acH3K18 modification were up-regulated (P < 0.05). Furthermore, compared with the liver in the model group, the liver in the intervention group showed the most obvious improvement (P < 0.01), and its karyoplasm had increased expression of acH3K9, acH3K14 and acH3K18 (P<0.01). Regulating histone acetylation could improve liver function and liver fibrosis indexes in rats with hepatic fibrosis. The mechanism might be related to certain genes that promote apoptosis, so as to inhibit the effect of anti hepatic fibrosis. PMID:29228569

Monitoring of Total and Regional Liver Function after SIRT.

PubMed

Bennink, Roelof J; Cieslak, Kasia P; van Delden, Otto M; van Lienden, Krijn P; Klümpen, Heinz-Josef; Jansen, Peter L; van Gulik, Thomas M

2014-01-01

Selective internal radiation therapy (SIRT) is a promising treatment modality for advanced hepatocellular carcinoma or metastatic liver cancer. SIRT is usually well tolerated. However, in most patients, SIRT will result in a (temporary) decreased liver function. Occasionally patients develop radioembolization-induced liver disease (REILD). In case of a high tumor burden of the liver, it could be beneficial to perform SIRT in two sessions enabling the primary untreated liver segments to guarantee liver function until function in the treated segments has recovered or functional hypertrophy has occurred. Clinically used liver function tests provide evidence of only one of the many liver functions, though all of them lack the possibility of assessment of segmental (regional) liver function. Hepatobiliary scintigraphy (HBS) has been validated as a tool to assess total and regional liver function in liver surgery. It is also used to assess segmental liver function before and after portal vein embolization. HBS is considered as a valuable quantitative liver function test enabling assessment of segmental liver function recovery after regional intervention and determination of future remnant liver function. We present two cases in which HBS was used to monitor total and regional liver function in a patient after repeated whole liver SIRT complicated with REILD and a patient treated unilaterally without complications.

Acute kidney injury in acute liver failure: a review.

PubMed

Moore, Joanna K; Love, Eleanor; Craig, Darren G; Hayes, Peter C; Simpson, Kenneth J

2013-11-01

Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.

Cyclin D1 in the Liver: Role of Noncanonical Signaling in Liver Steatosis and Hormone Regulation

PubMed Central

Núñez, Kelley G.; Gonzalez-Rosario, Janet; Thevenot, Paul T.; Cohen, Ari J.

2017-01-01

Background: Cyclin D1 is an important protein for cell cycle progression; however, functions independent of the cell cycle have been described in the liver. Cyclin D1 is also involved in DNA repair, is overexpressed in many cancers, and functions as a proto-oncogene. The lesser-known roles of Cyclin D1, specifically in hepatocytes, impact liver steatosis and hormone regulation in the liver. Methods: A comprehensive search of PubMed was conducted using the keywords Cyclin D1, steatosis, lipogenesis, and liver transplantation. In this article, we review the results from this literature search, with a focus on the role of Cyclin D1 in hepatic lipogenesis and gluconeogenesis, as well as the impact and function of this protein in hepatic steatosis. Results: Cyclin D1 represses carbohydrate response element binding protein (ChREBP) and results in a decrease in transcription of fatty acid synthase (FAS) and acetyl-coenzyme A carboxylase (ACC). Cyclin D1 also inhibits peroxisome proliferator-activated receptor gamma (PPARγ) which is involved in hepatic lipogenesis. Cyclin D1 inhibits both hepatocyte nuclear factor 4 alpha (HNF4α) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) and represses transcription of lipogenic genes FAS and liver-type pyruvate kinase (Pklr), along with the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Conclusion: Cyclin D1 represses multiple proteins involved in both lipogenesis and gluconeogenesis in the liver. Targeting Cyclin D1 to decrease hepatic steatosis in patients with nonalcoholic fatty liver disease or alcoholic fatty liver disease may help improve patient health and the quality of the donor liver pool. PMID:28331449

Changes in Regional Adiposity and Cardio-Metabolic Function Following a Weight Loss Program with Sibutramine in Obese Men with Obstructive Sleep Apnea

PubMed Central

Phillips, Craig L.; Yee, Brendon J.; Trenell, Mike I.; Magnussen, John S.; Wang, David; Banerjee, Dev; Berend, Norbert; Grunstein, Ronald R.

2009-01-01

Background: Although obstructive sleep apnea (OSA) is strongly linked with obesity, both conditions have been associated with increased cardiovascular risk including glucose intolerance, dyslipidemia, and hypertension independent of one another. Weight loss is known to improve both cardiovascular risk and OSA severity. The aim of this study was to evaluate cardiovascular and metabolic changes, including compartment-specific fat loss in obese OSA subjects undergoing a weight loss program. Design: Observational study. Participants: 93 men with moderate-severe OSA. Interventions: 6-month open-label weight loss trial combining sibutramine (a serotonin and noradrenaline reuptake inhibitor) with a 600-kcal deficit diet and exercise. Measurements and Results: At baseline and following 6 months of weight loss, OSA was assessed together with CT-quantified intra-abdominal and liver fat and markers of metabolic and cardiovascular function. At 6 months, weight loss and improvements in OSA were accompanied by improved insulin resistance (HOMA), increased HDL cholesterol, and reduced total cholesterol/HDL ratio. There were also reductions in measures of visceral and subcutaneous abdominal fat and liver fat. Reductions in liver fat and sleep time spent below 90% oxyhemoglobin saturation partly explained the improvement in HOMA (R2 = 0.18). In contrast, arterial stiffness (aortic augmentation index), heart rate, blood pressure, and total cholesterol did not change. Conclusions: Weight loss with sibutramine was associated with improvements in metabolic and body composition risk factors but not blood pressure or arterial stiffness. Improved insulin resistance was partly associated with reductions in liver fat and hypoxemia associated with sleep apnea. Citation: Phillips CL; Yee BJ; Trenell MI; Magnussen JS; Wang D; Banerjee D; Berend N; Grunstein RR. Changes in regional adiposity and cardio-metabolic function following a weight loss program with sibutramine in obese men with obstructive sleep apnea. J Clin Sleep Med 2009;5(5):416-421. PMID:19961024

Long-term obestatin treatment of mice type 2 diabetes increases insulin sensitivity and improves liver function.

PubMed

Kołodziejski, Paweł A; Pruszyńska-Oszmałek, Ewa; Strowski, Mathias Z; Nowak, Krzysztof W

2017-06-01

Obestatin and ghrelin are peptides encoded by the preproghrelin gene. Obestatin inhibits food intake, in addition to regulation of glucose and lipid metabolism. Here, we test the ability of obestatin at improving metabolic control and liver function in type 2 diabetic animals (type 2 diabetes mellitus). The effects of chronic obestatin treatment of mice with experimentally induced type 2 diabetes mellitus on serum levels of glucose and lipids, and insulin sensitivity are characterized. In addition, alterations of hepatic lipid and glycogen contents are evaluated. Obestatin reduced body weight and decreased serum glucose, fructosamine, and β-hydroxybutyrate levels, as well as total and low-density lipoprotein fractions of cholesterol. In addition, obestatin increased high-density lipoproteins cholesterol levels and enhanced insulin sensitivity in mice with type 2 diabetes mellitus. Moreover, obestatin diminished liver mass, hepatic triglycerides and cholesterol contents, while glycogen content was higher in livers of healthy and mice with type 2 diabetes mellitus treated with obestatin. These changes were accompanied by reduction of increased alanine aminotransferase, aspartate aminotransferase, and gamma glutamyl transpeptidase in T2DM mice with type 2 diabetes mellitus. Obestatin increased adiponectin levels and reduced leptin concentration. Obestatin influenced the expression of genes involved in lipid and carbohydrate metabolism by increasing Fabp5 and decreasing G6pc, Pepck, Fgf21 mRNA in the liver. Obestatin increased both, AKT and AMPK phosphorylation, and sirtuin 1 (SIRT1) protein levels as well as mRNA expression in the liver. Obestatin improves metabolic abnormalities in type 2 diabetes mellitus, restores hepatic lipid contents and decreases hepatic enzymes. Therefore, obestatin could potentially have a therapeutic relevance in treating of insulin resistance and metabolic dysfunctions in type 2 diabetes mellitus.

TAT-MTS-MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM-deficient cells.

PubMed

Erlich-Hadad, Tal; Hadad, Rita; Feldman, Anat; Greif, Hagar; Lictenstein, Michal; Lorberboum-Galski, Haya

2018-03-01

Methylmalonic aciduria (MMA) is a disorder of organic acid metabolism resulting from a functional defect of the mitochondrial enzyme, methylmalonyl-CoA mutase (MCM). The main treatments for MMA patients are dietary restriction of propiogenic amino acids and carnitine supplementation. Liver or combined liver/kidney transplantation has been used to treat those with the most severe clinical manifestations. Thus, therapies are necessary to help improve quality of life and prevent liver, renal and neurological complications. Previously, we successfully used the TAT-MTS-Protein approach for replacing a number of mitochondrial-mutated proteins. In this targeted system, TAT, an 11 a.a peptide, which rapidly and efficiently can cross biological membranes, is fused to a mitochondrial targeting sequence (MTS), followed by the mitochondrial mature protein which sends the protein into the mitochondria. In the mitochondria, the TAT-MTS is cleaved off and the native protein integrates into its natural complexes and is fully functional. In this study, we used heterologous MTSs of human, nuclear-encoded mitochondrial proteins, to target the human MCM protein into the mitochondria. All fusion proteins reached the mitochondria and successfully underwent processing. Treatment of MMA patient fibroblasts with these fusion proteins restored mitochondrial activity such as ATP production, mitochondrial membrane potential and oxygen consumption, indicating the importance of mitochondrial function in this disease. Treatment with the fusion proteins enhanced cell viability and most importantly reduced MMA levels. Treatment also enhanced albumin and urea secretion in a CRISPR/Cas9-engineered HepG2 MUT (-/-) liver cell line. Therefore, we suggest using this TAT-MTS-Protein approach for the treatment of MMA. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Effect of compound glycyrrhizin injection on liver function and cellular immunity of children with infectious mononucleosis complicated liver impairment.

PubMed

Cao, Zong-xin; Zhao, Zhong-fang; Zhao, Xiu-fen

2006-12-01

To investigate the effects of Compound Glycyrrhizin Injection (CGI) on liver function and cellular immunity of children with infectious mononucleosis complicated liver impairment (IM-LI) and to explore its clinical therapeutic effect. Forty-two patients with IM-LI were randomly assigned, according to the randomizing number table, to two groups, 20 in the control group and 22 in the treated group. All the patients were treated with conventional treatment, but to those in the treated group, CGI was given additionally once a day, at the dosage of 10 ml for children aged below 2 years, 20 ml for 2-4 years old, 30 ml for 5-7 years old and 40 ml for 8- 12 years old, in 100-200 ml of 5% glucose solution by intravenous dripping. The treatment lasted for 2 weeks. T lymphocyte subsets and serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) were detected before and after treatment. Besides, a normal control group consisting of 20 healthy children was also set up. Baseline of the percentage of CD3 + , CD8 + lymphocyte and serum levels of ALT, AST, TBiL in the children with IM-LI were markedly higher, while the percentage of CD4 + lymphocyte and the CD4 + /CD8 + ratio was markedly lower in IM-LI children as compared with the corresponding indices in the healthy children ( P<0.01). These indices were improved after treatment in both groups of patients, but the improvement in the treated group was better than that in the control group (P<0.01). Cellular immunity dysfunction often occurs in patients with IM-LI, and CGI treatment can not only obviously promote the recovery of liver function, but also regulate the immune function in organism.

Electronic Monitoring Device of Patient-Reported Outcomes and Function in Improving Patient-Centered Care in Patients With Gastrointestinal Cancer Undergoing Surgery

ClinicalTrials.gov

2018-06-06

Stage I Adult Liver Cancer; Stage I Colorectal Cancer; Stage IA Gastric Cancer; Stage IA Pancreatic Cancer; Stage IB Gastric Cancer; Stage IB Pancreatic Cancer; Stage II Adult Liver Cancer; Stage IIA Colorectal Cancer; Stage IIA Gastric Cancer; Stage IIA Pancreatic Cancer; Stage IIB Colorectal Cancer; Stage IIB Gastric Cancer; Stage IIB Pancreatic Cancer; Stage IIC Colorectal Cancer; Stage III Pancreatic Cancer; Stage IIIA Adult Liver Cancer; Stage IIIA Colorectal Cancer; Stage IIIA Gastric Cancer; Stage IIIB Adult Liver Cancer; Stage IIIB Colorectal Cancer; Stage IIIB Gastric Cancer; Stage IIIC Adult Liver Cancer; Stage IIIC Colorectal Cancer; Stage IIIC Gastric Cancer; Stage IV Gastric Cancer; Stage IVA Colorectal Cancer; Stage IVA Liver Cancer; Stage IVA Pancreatic Cancer; Stage IVB Colorectal Cancer; Stage IVB Liver Cancer; Stage IVB Pancreatic Cancer

Effect of Au-dextran NPs as anti-tumor agent against EAC and solid tumor in mice by biochemical evaluations and histopathological investigations.

PubMed

Medhat, Dalia; Hussein, Jihan; El-Naggar, Mehrez E; Attia, Mohamed F; Anwar, Mona; Latif, Yasmine Abdel; Booles, Hoda F; Morsy, Safaa; Farrag, Abdel Razik; Khalil, Wagdy K B; El-Khayat, Zakaria

2017-07-01

Dextran-capped gold nanoparticles (Au-dextran NPs) were prepared exploiting the natural polysaccharide polymer as both reducing and stabilizing agent in the synthesis process, aiming at studying their antitumor effect on solid carcinoma and EAC-bearing mice. To this end, Au-dextran NPs were designed via simple eco-friendly chemical reaction and they were characterized revealing the monodispersed particles with narrow distributed size of around 49nm with high negative charge. In vivo experiments were performed on mice. Biochemical analysis of liver and kidney functions and oxidation stress ratio in addition to histopathological investigations of such tumor tissues were done demonstrating the potentiality of Au-dextran NPs as antitumor agent. The obtained results revealed that EAC and solid tumors caused significant increase in liver and kidney functions, liver oxidant parameters, alpha feto protein levels and diminished liver antioxidant accompanied by positive expression of tumor protein p53 of liver while the treatment with Au-dextran NPs for both types caused improvement in liver and kidney functions, increased liver antioxidant, increased the expression level of B-cell lymphoma 2 gene and subsequently suppressed the apoptotic pathway. As a result, the obtained data provides significant antitumor effects of the Au-dextran NPs in both Ehrlich ascites and solid tumor in mice models. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Study on the effects of blueberry treatment on histone acetylation modification of CCl4-induced liver disease in rats.

PubMed

Zhan, W; Liao, X; Tian, T; Yu, L; Liu, X; Li, B; Liu, J; Han, B; Xie, R J; Ji, Q H; Yang, Q

2017-02-16

The objective of this study was to investigate the effects of blueberry treatment on histone acetylation modification of carbon tetrachloride (CCl 4 )-induced liver disease in rats. Laboratory rats were randomly divided into control, hepatic fibrosis, blueberry treatment, blueberry intervention, and natural recovery groups. Rats in the model groups were treated with CCl 4 administered subcutaneously at 4- and 8-week intervals, and then executed. Both the 4- and 8-week treatment groups were treated with blueberry juice for 8 weeks, and then executed after 12 and 16 weeks, respectively. Following the experiment, four liver function and hepatic fibrosis indices were measured. Liver index was calculated, hematoxylin-eosin staining was conducted, and H3K9, H3K14, and H3K18 expressions were evaluated among the nuclear proteins of the liver tissues. No differences in alanine transaminase were noted between the control and intervention groups, but significant differences were detected among the model, treatment, and natural recovery groups (P < 0.01). Significant differences were also observed in aspartate transaminase, hyaluronic acid, and collagen IV among the model, treatment, intervention, and natural recovery groups (P < 0.01, P < 0.01, P < 0.01). Liver index, and H3K9 and H3K14 expression were significantly different among the model groups (P < 0.05 and P < 0.01), whereas H3K18 expression was dramatically different among model, treatment, intervention, and natural recovery groups (P < 0.01). Following blueberry treatment, rat liver function and hepatic fibrosis improved, potentially indicating that blueberry components could regulate histone acetylation and improve liver pathologic changes in rats with CCl 4 -induced disease.

Isofuranodiene, the main volatile constituent of wild celery (Smyrnium olusatrum L.), protects d-galactosamin/lipopolysacchride-induced liver injury in rats.

PubMed

Li, Wenping; Shi, Jingshan; Papa, Fabrizio; Maggi, Filippo; Chen, Xiuping

2016-01-01

Isofuranodiene is a natural sesquiterpene rich occurring in Smyrnium olusatrum, a forgotten culinary herb which was marginalised after the domestication of the improved form of celery. Our recent data showed that isofuranodiene inhibited the proliferation and induced apoptosis in cancer cells. In this study, we investigated its protective effect on d-galactosamine/lipopolysacchride (GalN/LPS)-induced liver injury in SD rats. Oral administration of isofuranodiene (20 and 50 mg/kg) dramatically inhibited GalN/LPS-induced serum elevation of aspartate aminotransferase, alanine aminotransferase and malondialdehyde levels, and significantly ameliorated liver injury as evidenced by the histological improvement in H&E staining. Furthermore, isofuranodiene treatment significantly inhibited GalN/LPS-induced mRNA expression of IL-1β, IL-6 and inducible nitric oxide synthase in liver tissues. The results from this study showed that isofuranodiene protects GalN/LPS-induced liver injury in SD rats and suggested that it may be a potential functional food ingredient for the prevention and treatment of liver diseases.

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

PubMed Central

Taut, F J H; Schmidt, H; Zapletal, C M; Thies, J C; Grube, C; Motsch, J; Klar, E; Martin, E

2001-01-01

In orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P ≤ 0·02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment. PMID:11422213

Systems biology in hepatology: approaches and applications.

PubMed

Mardinoglu, Adil; Boren, Jan; Smith, Ulf; Uhlen, Mathias; Nielsen, Jens

2018-06-01

Detailed insights into the biological functions of the liver and an understanding of its crosstalk with other human tissues and the gut microbiota can be used to develop novel strategies for the prevention and treatment of liver-associated diseases, including fatty liver disease, cirrhosis, hepatocellular carcinoma and type 2 diabetes mellitus. Biological network models, including metabolic, transcriptional regulatory, protein-protein interaction, signalling and co-expression networks, can provide a scaffold for studying the biological pathways operating in the liver in connection with disease development in a systematic manner. Here, we review studies in which biological network models were used to integrate multiomics data to advance our understanding of the pathophysiological responses of complex liver diseases. We also discuss how this mechanistic approach can contribute to the discovery of potential biomarkers and novel drug targets, which might lead to the design of targeted and improved treatment strategies. Finally, we present a roadmap for the successful integration of models of the liver and other human tissues with the gut microbiota to simulate whole-body metabolic functions in health and disease.

Simultaneous Administration of ADSCs-Based Therapy and Gene Therapy Using Ad-huPA Reduces Experimental Liver Fibrosis

PubMed Central

Meza-Ríos, Alejandra; García-Benavides, Leonel; García-Bañuelos, Jesus; Salazar-Montes, Adriana; Armendáriz-Borunda, Juan; Sandoval-Rodríguez, Ana

2016-01-01

Background and Aims hADSCs transplantation in cirrhosis models improves liver function and reduces fibrosis. In addition, Ad-huPA gene therapy diminished fibrosis and increased hepatocyte regeneration. In this study, we evaluate the combination of these therapies in an advanced liver fibrosis experimental model. Methods hADSCs were expanded and characterized before transplantation. Ad-huPA was simultaneously administrated via the ileac vein. Animals were immunosuppressed by CsA 24 h before treatment and until sacrifice at 10 days post-treatment. huPA liver expression and hADSCs biodistribution were evaluated, as well as the percentage of fibrotic tissue, hepatic mRNA levels of Col-αI, TGF-β1, CTGF, α-SMA, PAI-I, MMP2 and serum levels of ALT, AST and albumin. Results hADSCs homed mainly in liver, whereas huPA expression was similar in Ad-huPA and hADSCs/Ad-huPA groups. hADSCs, Ad-huPA and hADSCs/Ad-huPA treatment improves albumin levels, reduces liver fibrosis and diminishes Collagen α1, CTGF and α-SMA mRNA liver levels. ALT and AST serum levels showed a significant decrease exclusively in the hADSCs group. Conclusions These results showed that combinatorial effect of cell and gene-therapy does not improve the antifibrogenic effects of individual treatments, whereas hADSCs transplantation seems to reduce liver fibrosis in a greater proportion. PMID:27992438

Bioimmunological responses to Schistosoma mansoni and Fasciola gigantica worm homogenates either with or without saponin.

PubMed

Maghraby, Amany Sayed; Hamed, Manal Abdel-Aziz; Ali, Sanaa Ahmed

2010-06-03

In this study, we evaluated the biochemical, immunological, histopathological and antischistosomal activities of Schistosoma mansoni or Fasciola gigantica worm homogenates mixed either with or without saponin that was extracted from Atriplex nummularia. The immunization schedule was based on subcutaneous administration of two doses (50 microg /100 microl PBS) of each homogenate with time intervals of 15 days. After 15 days of the last homogenate inoculation, all mice were challenged with 100 Schistosoma mansoni cercariae and sacrificed after two months. Free radical scavengers and liver function enzymes were determined in mice liver. Worm counting and the histopathological picture of the liver were also done. Immunization with Schistosoma or Fasciola worm homogenates, mixed either with or without saponin, recorded an amelioration of the free radical scavenger levels, liver function enzymes and reduction in worm burden, as well as improvement of the histological feature of the liver, the number and size of granuloma, evidence of increased immune reaction manifested by a lymphocytic cuff surrounding the granuloma, diminution of its fibrotic and collagen content, and destruction of Schistosoma ova. Fasciola or Schistosoma worm antigens mixed with or without saponin succeeded to eliminate the product of oxidative stress and assistance in immune-mediated destruction of eggs that ameliorate the histopathological picture of the liver cells and preserve its function.

A Mechanistic Pharmacokinetic Model for Liver Transporter Substrates Under Liver Cirrhosis Conditions

PubMed Central

Li, R; Barton, HA; Maurer, TS

2015-01-01

Liver cirrhosis is a disease characterized by the loss of functional liver mass. Physiologically based pharmacokinetic (PBPK) modeling was applied to interpret and predict how the interplay among physiological changes in cirrhosis affects pharmacokinetics. However, previous PBPK models under cirrhotic conditions were developed for permeable cytochrome P450 substrates and do not directly apply to substrates of liver transporters. This study characterizes a PBPK model for liver transporter substrates in relation to the severity of liver cirrhosis. A published PBPK model structure for liver transporter substrates under healthy conditions and the physiological changes for cirrhosis are combined to simulate pharmacokinetics of liver transporter substrates in patients with mild and moderate cirrhosis. The simulated pharmacokinetics under liver cirrhosis reasonably approximate observations. This analysis includes meta-analysis to obtain system-dependent parameters in cirrhosis patients and a top-down approach to improve understanding of the effect of cirrhosis on transporter-mediated drug disposition under cirrhotic conditions. PMID:26225262

[Partial parenteral nutrition in severe virus hepatitis].

PubMed

Kleinberger, G; Schneeweiss, B; Druml, W; Laggner, A; Lenz, K

1984-03-01

Patients with severe virus hepatitis and a prothrombin concentration below 25% have a bad prognosis. This is due to direct consequences of hepatic failure and to the rather frequent complications of this disease. The clinical course of such patients is essentially dependent upon the degree of liver regeneration, which again is dependent upon the mass of hepatocytes which are able to regenerate and upon the so called hepatotrophic factors. Patients with severe hepatitis suffer during the first weeks rather frequently from nausea and loss of appetite and for that reason their nutrition is insufficient. In the study recorded here 9 cases were investigated (7 patients with hepatitis B, 2 patients with hepatitis non A non B). The question was asked, if partial parenteral nutrition in addition to a liver diet not containing meat would improve liver function. It could be shown that the prothrombin concentration, which could not be improved by vitamine K1 supplements, was increased during a 7 day parenteral nutrition period from 19,3 +/- 2,9% to 41,5 +/- 8,1% (p less than 0,05), serum albumine and cholinesterase activity improved as well. During the first day of treatment there was a significant fall of ammoniac from 115 +/- 10 mumol to 73 +/- 10 mumol/l (p less than 0,05), at the same time production of urea did not increase. All patients survived. The results show, that parenteral nutrition can improve liver function and decrease the catabolic status of metabolism.

Beetroot and Sodium Nitrate Ameliorate Cardiometabolic Changes in Diet-Induced Obese Hypertensive Rats.

PubMed

Bhaswant, Maharshi; Brown, Lindsay; McAinch, Andrew J; Mathai, Michael L

2017-12-01

Dietary intake of beetroot by humans reduces blood pressure but whether this is caused by nitrate or betanin is not well-defined; neither are effects on other signs of metabolic syndrome. Rats fed a high-carbohydrate, high-fat diet (H) for 16 weeks developed abdominal obesity, hypertension, altered cardiovascular and liver structure and function, and impaired glucose tolerance compared to rats fed a corn starch diet (C). H rats treated with ∼16 mg/kg/day of nitrate either from beetroot juice (H+B) or sodium nitrate (H+N) for the last 8 weeks reduced systolic blood pressure by ∼25 mmHg, improved cardiac structure and function, plasma lipid profile and plasma markers of liver function, reduced inflammatory cell infiltration in heart and liver and decreased left ventricular fibrosis. In the left ventricle, H rats increased mRNA expression of connective tissue growth factor (CTGF), monocyte chemoattractant protein 1 (MCP-1), matrix metalloproteinase-2 (MMP-2), and adenosine monophosphate-activated protein kinase-alpha (AMPK-α) and decreased mRNA expression of peroxisome proliferator-activated receptor-alpha (PPAR-α); both beetroot and sodium nitrate diet-fed rats decreased CTGF threefold, MCP-1, and MMP-2 twofold, and doubled PPAR-α mRNA expression in left ventricular tissue. The similar functional and molecular responses to beetroot and sodium nitrate indicate that the nitrate content of beetroot reduced inflammation and improved cardiovascular, liver, and metabolic function in rats with metabolic syndrome, rather than betanin. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diet Supplementation with Allicin Protects against Alcoholic Fatty Liver Disease in Mice by Improving Anti-inflammation and Antioxidative Functions.

PubMed

Panyod, Suraphan; Wu, Wei-Kai; Ho, Chi-Tang; Lu, Kuan-Hung; Liu, Chun-Ting; Chu, Yung-Lin; Lai, Yi-Syuan; Chen, Wei-Cheng; Lin, Yu-En; Lin, Shih-Hang; Sheen, Lee-Yan

2016-09-28

This study investigated the liver-protective effects of allicin, an active compound in fresh garlic, against alcoholic fatty liver disease (AFLD) and liver inflammation. Its effects were investigated in an AFLD model in male C57BL/6 mice, which were fed Lieber-DeCarli liquid diet containing ethanol. Allicin (5 and 20 mg/kg bw/day) was orally administered daily in the AFLD mice for 4 weeks. The results indicate that allicin promotes hepatoprotection by significantly reducing aspartate transaminase (AST) and alanine transaminase (ALT) levels (p < 0.05) in the plasma, which are key indicators of liver damage. Allicin reduced fat accumulation, increased glutathione and catalase levels, and decreased microsomal protein cytochrome P450 2E1 (CYP2E1) expression (p < 0.05) in the livers of the AFLD mice. Furthermore, allicin supplementation significantly decreased the levels of proinflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 and suppressed the expression of sterol regulatory element-binding protein-1 (SREBP-1) (p < 0.05). Additionally, it improved the hepatic alcohol dehydrogenase (ADH) activity (p < 0.05). Collectively, these findings demonstrate that allicin attenuates liver oxidative stress and inflammation.

Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases

PubMed Central

Movsesyan, Nina; Platt, Frances M.

2017-01-01

In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters. PMID:29119141

Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.

PubMed

Fuhrmeister, Jessica; Zota, Annika; Sijmonsma, Tjeerd P; Seibert, Oksana; Cıngır, Şahika; Schmidt, Kathrin; Vallon, Nicola; de Guia, Roldan M; Niopek, Katharina; Berriel Diaz, Mauricio; Maida, Adriano; Blüher, Matthias; Okun, Jürgen G; Herzig, Stephan; Rose, Adam J

2016-06-01

Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Coordinated improvement in glucose tolerance, liver steatosis and obesity-associated inflammation by cannabinoid 1 receptor antagonism in fat Aussie mice.

PubMed

Bell-Anderson, K S; Aouad, L; Williams, H; Sanz, F R; Phuyal, J; Larter, C Z; Farrell, G C; Caterson, I D

2011-12-01

Fat Aussie mice (foz/foz) are morbidly obese, glucose intolerant and have liver steatosis that develops into steatohepatitis on a high-fat diet. The cannabinoid 1 receptor (CB1) antagonist SR141716 has been shown to improve obesity-associated metabolic complications in humans and rodent models. The aim of this study was to assess the effect of SR141716 in foz/foz mice. Male wildtype (WT) and foz/foz mice were fed a chow or high-fat diet (45% saturated fat). Vehicle or SR141716 (10 mg kg(-1) per day) was administered in jelly once daily for 4 weeks from 4 months of age. Foz/foz mice were obese but had less epididymal adipose tissue mass than fat-fed WT mice despite being significantly heavier. Liver weight was increased by twofold in foz/foz compared with WT mice and showed significant steatogenesis associated with impaired liver function. Foz/foz and fat-fed WT mice were glucose intolerant as determined by oral glucose tolerance test. In chow-fed foz/foz mice, SR141716 reduced body weight, liver weight, reversed hepatosteatosis and glucose intolerance. Subcutaneous white adipose tissue gene expression of the macrophage-specific marker Cd68 reflected the improvements in the metabolic status by SR141716 in these mice. The results are consistent with the hypothesis that foz/foz mice have defective lipid metabolism, are unable to adequately store fat in adipose tissue but instead sequester fat ectopically in other metabolic tissues (liver) leading to insulin resistance and hepatic steatosis associated with inflammation. Our findings suggest that SR141716 can improve liver lipid metabolism in foz/foz mice in line with improved insulin sensitivity and adipose tissue inflammation.

Knockdown of microRNA-155 in Kupffer cells results in immunosuppressive effects and prolongs survival of mouse liver allografts.

PubMed

Li, Jinzheng; Gong, Junhua; Li, Peizhi; Li, Min; Liu, Yiming; Liang, Shaoyong; Gong, Jianping

2014-03-27

Our previous studies have shown that Kupffer cells (KCs) play a crucial role in postoperative pathologic changes. Recent reports have demonstrated that microRNA-155 (miR-155) is associated with inflammation and upregulation of proinflammatory mediators in the peripheral blood and allografts of transplant patients. However, the precise mechanism for this remains unknown. KCs isolated from BALB/c mice were transfected with miR-155 mimic or inhibitor. Levels of suppressor of cytokine signaling 1/Janus kinase/signal transducer and activator of transcription (SOCS1/JAK/STAT) proteins and surface molecules (MHC-II, CD40, and CD86) were then measured. T-cell proliferation and apoptosis were evaluated in mixed lymphocyte reactions. Orthotopic liver transplantation was performed in mice after miR-155 short hairpin RNA lentivirus treatment, and postoperative survival, liver function and histology, and mRNA and protein expression were analyzed. miR-155 knockdown in KCs decreased MHC-II, CD40, and CD86 expression, suppressed antigen-presenting function, and affected SOCS1/JAK/STAT inflammatory pathways. In addition, KCs transfected with miR-155 inhibitor and cocultured with T lymphocytes showed reduced T-cell responses but a greater number of apoptotic T cells. Finally, miR-155 suppression in graft liver prolonged liver allograft survival and improved liver function. The changes were closely associated with the levels of T helper 1 and 2 (Th1/Th2) cytokines and T-cell apoptosis, but a direct mechanistic link in vivo was not established. These data suggest miR-155 regulates the balance of Th1/Th2 cytokines and the maturation and function of KCs in mice. miR-155 repression in KCs positively regulates KC function toward immunosuppression and prolongs liver allograft survival.

Transplantation of umbilical cord mesenchymal stem cells via different routes in rats with acute liver failure.

PubMed

Zheng, Sheng; Yang, Juan; Yang, Jinhui; Tang, Yingmei; Shao, Qinghua; Guo, Ling; Liu, Qinghua

2015-01-01

This study aimed to compare the therapeutic efficacy of transplantation of human umbilical cord mesenchymal stem cells (hUCMSC) in different routes in acute hepatic failure (ALF) in rats. hUCMSCs were isolated and identified by detection of surface antigens via flow cytometry. In T group and H group, ALF rats received hUCMSC transplantation through the tail vein and intrahepatic injection, respectively. In hUCMSC group, healthy rats received hUCMSCs transplantation via the tail vein. In ALF group, rats received injection of normal saline through the tail vein. The TBil and ALT in ALF rats with and without transplantation were significantly higher than in healthy rats (P<0.05). HE staining of the liver showed obvious hepatocyte regeneration and reduced infiltration of inflammatory cells, and liver pathology was improved in T group and H group as compared to ALF group. At 3 d after transplantation, CK18 expression was detectable in both H group and T group. At 1 w and 2 w, the mRNA expressions of CK8, CK18 and AFP in H group and T group were significantly different from those in ALF group (P<0.05). The liver function and differentiation of stem cells were comparable between H group and T group (P>0.05). hUCMSCs transplantation can improve the liver function and promote the liver repair following ALF. hUCMSCs transplantation via tail vein has similar therapeutic efficacy to that through intrahepatic injection.

Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.

PubMed

Jegatheesan, Prasanthi; Beutheu, Stéphanie; Ventura, Gabrielle; Sarfati, Gilles; Nubret, Esther; Kapel, Nathalie; Waligora-Dupriet, Anne-Judith; Bergheim, Ina; Cynober, Luc; De-Bandt, Jean-Pascal

2016-02-01

Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease. Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Volatile Biomarkers in Breath Associated With Liver Cirrhosis — Comparisons of Pre- and Post-liver Transplant Breath Samples

PubMed Central

Fernández del Río, R.; O'Hara, M.E.; Holt, A.; Pemberton, P.; Shah, T.; Whitehouse, T.; Mayhew, C.A.

2015-01-01

Background The burden of liver disease in the UK has risen dramatically and there is a need for improved diagnostics. Aims To determine which breath volatiles are associated with the cirrhotic liver and hence diagnostically useful. Methods A two-stage biomarker discovery procedure was used. Alveolar breath samples of 31 patients with cirrhosis and 30 healthy controls were mass spectrometrically analysed and compared (stage 1). 12 of these patients had their breath analysed after liver transplant (stage 2). Five patients were followed longitudinally as in-patients in the post-transplant period. Results Seven volatiles were elevated in the breath of patients versus controls. Of these, five showed statistically significant decrease post-transplant: limonene, methanol, 2-pentanone, 2-butanone and carbon disulfide. On an individual basis limonene has the best diagnostic capability (the area under a receiver operating characteristic curve (AUROC) is 0.91), but this is improved by combining methanol, 2-pentanone and limonene (AUROC curve 0.95). Following transplant, limonene shows wash-out characteristics. Conclusions Limonene, methanol and 2-pentanone are breath markers for a cirrhotic liver. This study raises the potential to investigate these volatiles as markers for early-stage liver disease. By monitoring the wash-out of limonene following transplant, graft liver function can be non-invasively assessed. PMID:26501124

Japanese-style intensive medical care improves prognosis for acute liver failure and the perioperative management of liver transplantation.

PubMed

Inoue, K; Watanabe, T; Maruoka, N; Kuroki, Y; Takahashi, H; Yoshiba, M

2010-12-01

The Japanese style of intensive medical care for acute liver failure has yielded high survival rates. The care system comprises artificial liver support (ALS) together with treatment for the underlying disease. Plasma exchange in combination with high-volume hemodiafiltration using an high performance membrane has become the standard ALS system. It is safe, efficiently removing more low and middle molecular weight toxic substances than other methods because of the large volumes of buffer (more than 200 L per session), resulting in recovery from coma in patients with severe fulminant hepatitis, a status comparable with the ahepatic state. This ALS is therefore an effective tool to sustain patients with fulminant hepatitis in a favorable condition until liver function recovers or liver transplantation becomes available. The accompanying treatment for underlying disease serves to limit the liver destruction that hampers regeneration. The treatment has remarkably improved the prognosis for patients with subacute types of fulminant hepatitis, which generally carry a less favorable prognosis than the acute type. This treatment system thus provides more time for physicians to assess the indications for liver transplantation as well as giving the patient a greater chance of undergoing transplantation. Copyright © 2010 Elsevier Inc. All rights reserved.

8-pCPT-cGMP prevents mitochondrial depolarization and improves the outcome of steatotic partial liver transplantation

PubMed Central

Liu, Qinlong; Rehman, Hasibur; Krishnasamy, Yasodha; Lemasters, John J; Zhong, Zhi

2017-01-01

Permeant cGMP analogs prevent the mitochondria permeability transition (MPT) in vitro. In this study, we explored whether 8-pCPT-cGMP prevents the MPT and decreases post-transplant damage to fatty partial liver grafts (FPG) in vivo. Rats were fed a control or high-fat, high-fructose diet for 2-week. Lean and fatty liver explants were reduced in size ex vivo to ~35% and stored in the University of Wisconsin solution with and without 8-pCPT-cGMP (300 µM) for 2 h. After transplantation, alanine aminotransferase release (indicator of hepatocellular injury), hyperbilirubinemia (indicator of poor liver function), and cell death were all higher in FPG than in lean partial grafts (LPG). Liver regeneration increased in LPG but was suppressed in FPG. 8-pCPT-cGMP blunted graft injury, improved liver regeneration and function, and increased survival of FPG. Hepatic mitochondrial depolarization detected by intravital multiphoton microscopy of rhodamine 123 in living rats was ~3.5-fold higher in FPG than in LPG. 8-pCPT-cGMP decreased mitochondrial depolarization in FPG almost to the level of LPG. Activation of mammalian target of rapamycin (mTOR), an energy sensitive kinase that stimulates cell proliferation and growth, and p70S6 kinase, a downstream signaling molecule of mTOR, was increased in LPG but suppressed in FPG. 8-pCPT-cGMP restored the activity of mTOR and p70S6 kinase in FPG. 8-pCPT-cGMP also increased activation of cAMP response element-binding protein (CREB) and expression of cyclins D1 and E in FPG. Non-alcoholic steatosis increases injury and suppresses regeneration after partial liver transplantation, at least in part, due to more severe mitochondrial dysfunction. Protection of mitochondria with a cGMP analog effectively improves outcomes of FPG transplantation. PMID:28694919

Application of tissue-specific NK and NKT cell activity for tumor immunotherapy

PubMed Central

Subleski, Jeff J.; Wiltrout, Robert H.; Weiss, Jonathan M.

2009-01-01

Natural killer (NK) and NKT cells are a first line of defense against pathogens and transformed cells. However, dysregulation of their function can lead to autoimmune disease. A better understanding of the mechanisms controlling NK and NKT effector function should lead to the development of improved strategies for the treatment of many diseases. The site in which NK and NKT cells reside should be taken into account, because accumulating evidence suggests that the tissue microenvironment strongly influences their function. In this regard, the liver represents a unique immunologic organ in which the balance between the need for tolerance and the ability to respond rapidly to pathogens and tissue injury is tightly regulated. NK cells in the liver have augmented cytolytic activity as compared to other organs, which is consistent with a role for liver-associated NK cells in being critical effector cells for inhibiting tumor metastasis in the liver. Several studies also suggest that hepatic NKT cells have different functions than those in other organs. Whereas splenic and thymic NKT cells have been shown to suppress diabetes development, facilitate the induction of systemic tolerance and are regulated by IL-4 and other Th2 cytokines, certain subsets of NKT cells in the liver are important sources of Th1 cytokines such as Interferon gamma, and are the primary mediators of anti-tumor responses. The unique properties and roles as critical effector cells make NK and NKT cells within the liver microenvironment attractive targets of immunotherapeutic approaches that have the goal of controlling tumor metastasis in the liver. PMID:19682859

Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial.

PubMed

Hallsworth, Kate; Thoma, Christian; Hollingsworth, Kieren G; Cassidy, Sophie; Anstee, Quentin M; Day, Christopher P; Trenell, Michael I

2015-12-01

Although lifestyle changes encompassing weight loss and exercise remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management, the effect of different types of exercise on NAFLD is unknown. This study defines the effect of modified high-intensity interval training (HIIT) on liver fat, cardiac function and metabolic control in adults with NAFLD. Twenty-three patients with NAFLD [age 54±10 years, body mass index (BMI) 31±4 kg/m(2), intra-hepatic lipid >5%) were assigned to either 12 weeks HIIT or standard care (controls). HIIT involved thrice weekly cycle ergometry for 30-40 min. MRI and spectroscopy were used to assess liver fat, abdominal fat and cardiac structure/function/energetics. Glucose control was assessed by oral glucose tolerance test and body composition by air displacement plethysmography. Relative to control, HIIT decreased liver fat (11±5% to 8±2% compared with 10±4% to 10±4% P=0.019), whole-body fat mass (35±7 kg to 33±8 kg compared with 31±9 kg to 32±9 kg, P=0.013), alanine (52±29 units/l to 42±20 units/l compared with 47±22 units/l to 51±24 units/l, P=0.016) and aspartate aminotransferase (AST; 36±18 units/l to 33±15 units/l compared with 31±8 units/l to 35±8 units/l, P=0.017) and increased early diastolic filling rate (244±84 ml/s to 302±107 ml/s compared with 255±82 ml/s to 251±82 ml/s, P=0.018). There were no between groups differences in glucose control. Modified HIIT reduces liver fat and improves body composition alongside benefits to cardiac function in patients with NAFLD and should be considered as part of the broader treatment regimen by clinical care teams. ISRCTN trial ID: ISRCTN78698481. © 2015 Authors; published by Portland Press Limited.

The utility of liver function tests for mortality prediction within one year in primary care using the algorithm for liver function investigations (ALFI).

PubMed

McLernon, David J; Dillon, John F; Sullivan, Frank M; Roderick, Paul; Rosenberg, William M; Ryder, Stephen D; Donnan, Peter T

2012-01-01

Although liver function tests (LFTs) are routinely measured in primary care, raised levels in patients with no obvious liver disease may trigger a range of subsequent expensive and unnecessary management plans. The aim of this study was to develop and validate a prediction model to guide decision-making by general practitioners, which estimates risk of one year all-cause mortality in patients with no obvious liver disease. In this population-based historical cohort study, biochemistry data from patients in Tayside, Scotland, with LFTs performed in primary care were record-linked to secondary care and prescription databases to ascertain baseline characteristics, and to mortality data. Using this derivation cohort a survival model was developed to predict mortality. The model was assessed for calibration, discrimination (using the C-statistic) and performance, and validated using a separate cohort of Scottish primary care practices. From the derivation cohort (n = 95 977), 2.7% died within one year. Predictors of mortality included: age; male gender; social deprivation; history of cancer, renal disease, stroke, ischaemic heart disease or respiratory disease; statin use; and LFTs (albumin, transaminase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase). The C-statistic for the final model was 0.82 (95% CI 0.80-0.84), and was similar in the validation cohort (n = 11 653) 0.86 (0.79-0.90). As an example of performance, for a 10% predicted probability cut-off, sensitivity = 52.8%, specificity = 94.0%, PPV = 21.0%, NPV = 98.5%. For the model without LFTs the respective values were 43.8%, 92.8%, 15.6%, 98.1%. The Algorithm for Liver Function Investigations (ALFI) is the first model to successfully estimate the probability of all-cause mortality in patients with no apparent liver disease having LFTs in primary care. While LFTs added to the model's discrimination and sensitivity, the clinical utility of ALFI remains to be established since LFTs did not improve an already high NPV for short term mortality and only modestly improved a very low PPV.

In vivo liver visualizations with magnetic particle imaging based on the calibration measurement approach

NASA Astrophysics Data System (ADS)

Dieckhoff, J.; Kaul, M. G.; Mummert, T.; Jung, C.; Salamon, J.; Adam, G.; Knopp, T.; Ludwig, F.; Balceris, C.; Ittrich, H.

2017-05-01

Magnetic particle imaging (MPI) facilitates the rapid determination of 3D in vivo magnetic nanoparticle distributions. In this work, liver MPI following intravenous injections of ferucarbotran (Resovist®) was studied. The image reconstruction was based on a calibration measurement, the so called system function. The application of an enhanced system function sample reflecting the particle mobility and aggregation status of ferucarbotran resulted in significantly improved image reconstructions. The finding was supported by characterizations of different ferucarbotran compositions with the magnetorelaxometry and magnetic particle spectroscopy technique. For instance, similar results were obtained between ferucarbotran embedded in freeze-dried mannitol sugar and liver tissue harvested after a ferucarbotran injection. In addition, the combination of multiple shifted measurement patches for a joint reconstruction of the MPI data enlarged the field of view and increased the covering of liver MPI on magnetic resonance images noticeably.

In vivo liver visualizations with magnetic particle imaging based on the calibration measurement approach.

PubMed

Dieckhoff, J; Kaul, M G; Mummert, T; Jung, C; Salamon, J; Adam, G; Knopp, T; Ludwig, F; Balceris, C; Ittrich, H

2017-05-07

Magnetic particle imaging (MPI) facilitates the rapid determination of 3D in vivo magnetic nanoparticle distributions. In this work, liver MPI following intravenous injections of ferucarbotran (Resovist ® ) was studied. The image reconstruction was based on a calibration measurement, the so called system function. The application of an enhanced system function sample reflecting the particle mobility and aggregation status of ferucarbotran resulted in significantly improved image reconstructions. The finding was supported by characterizations of different ferucarbotran compositions with the magnetorelaxometry and magnetic particle spectroscopy technique. For instance, similar results were obtained between ferucarbotran embedded in freeze-dried mannitol sugar and liver tissue harvested after a ferucarbotran injection. In addition, the combination of multiple shifted measurement patches for a joint reconstruction of the MPI data enlarged the field of view and increased the covering of liver MPI on magnetic resonance images noticeably.

[Studying the hepatoprotector effect of bemithyl on a model of chronic toxic liver damage].

PubMed

Oskovityĭ, S V; Bezborodkina, N N; Zarubina, I V; Mironova, O P; Kudrivtsev, B N; Shulenin, S N

2006-01-01

A prophylactic and therapeutic introduction of the synthetic adaptogen bemithyl (2-ethylthiobensimidasole hydrobromide) produces a hepatoprotector effect in rats with experimental cirrhosis. The drug exhibits an anticytolytic activity, restores liver participation in the pigment exchange, and normalizes the function of the microsomal oxidation system responsible for the metabolism of xenobiotics. The treatment with bemithyl also leads to a certain improvement of a histologic picture of the damaged liver and to a decrease in the degree of fibrosis. The drug is also capable of increasing the activity of the antioxidant system and inhibiting the process of lipid peroxidation of proteins and lipids in the liver.

Using ultrasonography to monitor liver blood flow for liver transplant from donors supported on extracorporeal membrane oxygenation.

PubMed

Zhu, Xian-Sheng; Wang, Sha-Sha; Cheng, Qi; Ye, Chuang-Wen; Huo, Feng; Li, Peng

2016-02-01

Extracorporeal membrane oxygenation (ECMO) has been used to support brain-dead donors for liver procurement. This study investigated the potential role of ultrasonographic monitoring of hepatic perfusion as an aid to improve the viability of liver transplants obtained from brain-dead donors who are supported on ECMO. A total of 40 brain-dead patients maintained on ECMO served as the study population. Hepatic blood flow was monitored using ultrasonography, and perioperative optimal perfusion was maintained by calibrating ECMO. Liver function tests were performed to assess the viability of the graft. The hepatic arterial blood flow was well maintained with no significant changes observed before and after ECMO (206 ± 32 versus 241 ± 45 mL/minute; P = 0.06). Similarly, the portal venous blood flow was also maintained throughout (451 ± 65 versus 482 ± 77 mL/minute; P = 0.09). No significant change in levels of total bilirubin, alanine transaminase, and lactic acid were reported during ECMO (P = 0.17, P = 0.08, and P = 0.09, respectively). Before the liver is procured, ultrasonographic monitoring of hepatic blood flow could be a valuable aid to improve the viability of a liver transplant by allowing for real-time calibration of ECMO perfusion in brain-dead liver donors. In our study, ultrasonographic monitoring helped prevent warm ischemic injury to the liver graft by avoiding both overperfusion and underperfusion of the liver. © 2015 American Association for the Study of Liver Diseases.

Iron-chelating effect of silymarin in patients with β-thalassemia major: A crossover randomised control trial.

PubMed

Darvishi-Khezri, Hadi; Salehifar, Ebrahim; Kosaryan, Mehrnoush; Karami, Hossein; Mahdavi, Mohammadreza; Alipour, Abbas; Aliasgharian, Aily

2018-03-01

This study aimed to determine the potential iron-chelating effects of silymarin in patients with β-thalassemia major receiving standard iron-chelation therapy. We evaluated whether addition of silymarin to standard iron-chelation therapy could improve iron burden markers and liver and cardiac function in these patients, via a placebo-controlled, crossover clinical study. Silymarin (140 mg) or placebo were administered thrice daily to all patients (n = 82) for 12 weeks, and after a 2-week washout period, patients were crossed over to the other groups. Silymarin efficacy was assessed by measuring serum iron level, ferritin level, total iron-binding capacity and liver and cardiac function on magnetic resonance imaging. Silymarin treatment resulted in a negative change in the serum iron and ferritin levels and a positive change in the total iron-binding capacity levels (treatment effect, p < .001, p = .06, and p = .05, respectively). Silymarin treatment led to positive changes in cardiac and liver function in both treatment sequences of study; however, this was not statistically significant. There was a negative change in liver iron concentration in both treatment sequences (treatment effect, p = .02). In conclusion, combined iron-chelation and silymarin therapy was effective for improving the iron-burden status in patients with β-thalassemia major. Copyright © 2017 John Wiley & Sons, Ltd.

Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis.

PubMed

Philips, Cyriac Abby; Phadke, Nikhil; Ganesan, Karthik; Ranade, Shatakshi; Augustine, Philip

2018-06-21

Alcohol-induced intestinal dysbiosis is central to the development of the severe alcoholic liver disease. We present the first study to compare outcomes in patients of severe alcoholic hepatitis (SAH) on nutritional therapy, corticosteroids, pentoxifylline, and healthy donor fecal transplantation (FMT) and discuss distinct microbial community and microbiome metabolic functional changes after FMT. Out of 1271 liver disease patients, 809 (63.7%) were diagnosed to have the alcoholic liver disease, of which 51 patients (8 treated with corticosteroids, 17 with nutritional support only, 10 with pentoxifylline, 16 receiving FMT) were included. Clinical, biochemical parameters, liver disease, and alcoholic hepatitis severity scores at baseline and mortality at the end of 1 and 3 months were analyzed between groups. Stool microbiota (SM) analysis was performed for healthy controls (HC) and respective recipients after FMT. All the patients were male. The proportions of patients surviving at the end of 1 and 3 months in the steroids, nutrition, pentoxifylline, and FMT group were 63%, 47%, 40% and 75% [p = 0.179] and 38%, 29%, 30%, and 75% [p = 0.036], respectively. When compared with FMT, relative risk and hazard ratios for death were higher in all the other groups. Following FMT, distinct and beneficial modulation of SM and pathways of dysregulated metabolism, infections, inflammation, and oxidative stress in SAH patients were noted in tandem with improved clinical outcomes. Healthy donor FMT for SAH improves survival beyond what is offered by current therapies and can function as a cost-effective bridge to liver transplant (LT) or for improving transplant-free survival. Larger studies and randomized trials are unmet needs.

Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study.

PubMed

Gerth, Hans U; Pohlen, Michele; Thölking, Gerold; Pavenstädt, Hermann; Brand, Marcus; Wilms, Christian; Hüsing-Kabar, Anna; Görlich, Dennis; Kabar, Iyad; Schmidt, Hartmut H J

2017-01-01

The primary therapeutic goals in the treatment of liver injury are to support liver regeneration or bridge the gap to liver transplantation (LT). Molecular adsorbent recirculating system (MARS) therapy has shown beneficial effects for specific symptoms of liver failure; however, general survival advantages have not yet been demonstrated. We studied the effects of MARS therapy compared to standard medical treatment (SMT) in two patient cohorts: in patients with an acute liver injury and in those with graft dysfunction (GD). We report on our experience over a 6.5-year period with 73 patients treated with SMT or with SMT and MARS (MARS group). In total, 53 patients suffered from acute liver injury in their native liver without a preexisting liver disease (SMT: n = 31, MARS: n = 22), and 20 patients showed a severe GD after LT (SMT: n = 10, MARS: n = 10). The entire cohort was predominantly characterized by hemodynamically and respiratorily stable patients with a low hepatic encephalopathy (HE) grade and a model of end-stage liver disease (MELD) score of 20.57 (MARS) or 22.51 (SMT, p = 0.555). Within the MARS group, the median number of extracorporeal therapy sessions was four (range = 3-5 sessions). Independent of the underlying etiology, MARS improved the patients' bilirubin values in the short term compared to SMT alone. In patients with acute liver injury, this response was sustained even after the end of MARS therapy. By contrast, the majority of patients with GD and an initial response to MARS therapy experienced worsened hyperbilirubinemia. No differences in 28-day mortality were observed with respect to acute liver injury (MARS 5.3% (95% CI: 0-15.3); SMT 3.3% (95% CI: 0-9.8), p = 0.754) or GD (MARS 20.0% (95% CI: 0-44.7), SMT 11.1% (95% CI: 0-31.7), p = 0.478). Although it did not improve 28-day mortality, MARS therapy improved the short-term response in patients with acute liver injury as well as in those with GD. In cases of acute hepatic injury, the use of MARS therapy resulted in the sustained stabilization of liver function and improved liver regeneration. A short-term response to MARS may predict the future course of the disease.

Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study

PubMed Central

Thölking, Gerold; Pavenstädt, Hermann; Brand, Marcus; Wilms, Christian; Hüsing-Kabar, Anna; Görlich, Dennis; Kabar, Iyad; Schmidt, Hartmut H. J.

2017-01-01

Background The primary therapeutic goals in the treatment of liver injury are to support liver regeneration or bridge the gap to liver transplantation (LT). Molecular adsorbent recirculating system (MARS) therapy has shown beneficial effects for specific symptoms of liver failure; however, general survival advantages have not yet been demonstrated. Aim We studied the effects of MARS therapy compared to standard medical treatment (SMT) in two patient cohorts: in patients with an acute liver injury and in those with graft dysfunction (GD). Methods We report on our experience over a 6.5-year period with 73 patients treated with SMT or with SMT and MARS (MARS group). In total, 53 patients suffered from acute liver injury in their native liver without a preexisting liver disease (SMT: n = 31, MARS: n = 22), and 20 patients showed a severe GD after LT (SMT: n = 10, MARS: n = 10). Results The entire cohort was predominantly characterized by hemodynamically and respiratorily stable patients with a low hepatic encephalopathy (HE) grade and a model of end-stage liver disease (MELD) score of 20.57 (MARS) or 22.51 (SMT, p = 0.555). Within the MARS group, the median number of extracorporeal therapy sessions was four (range = 3–5 sessions). Independent of the underlying etiology, MARS improved the patients’ bilirubin values in the short term compared to SMT alone. In patients with acute liver injury, this response was sustained even after the end of MARS therapy. By contrast, the majority of patients with GD and an initial response to MARS therapy experienced worsened hyperbilirubinemia. No differences in 28-day mortality were observed with respect to acute liver injury (MARS 5.3% (95% CI: 0–15.3); SMT 3.3% (95% CI: 0–9.8), p = 0.754) or GD (MARS 20.0% (95% CI: 0–44.7), SMT 11.1% (95% CI: 0–31.7), p = 0.478). Conclusions Although it did not improve 28-day mortality, MARS therapy improved the short-term response in patients with acute liver injury as well as in those with GD. In cases of acute hepatic injury, the use of MARS therapy resulted in the sustained stabilization of liver function and improved liver regeneration. A short-term response to MARS may predict the future course of the disease. PMID:28403210

Rapid generation of functional hepatocyte-like cells from human adipose-derived stem cells.

PubMed

Fu, Yanli; Deng, Jie; Jiang, Qingyuan; Wang, Yuan; Zhang, Yujing; Yao, Yunqi; Cheng, Fuyi; Chen, Xiaolei; Xu, Fen; Huang, Meijuan; Yang, Yang; Zhang, Shuang; Yu, Dechao; Zhao, Robert Chunhua; Wei, Yuquan; Deng, Hongxin

2016-08-05

Liver disease is a major cause of death worldwide. Orthotropic liver transplantation (OLT) represents the only effective treatment for patients with liver failure, but the increasing demand for organs is unfortunately so great that its application is limited. Hepatocyte transplantation is a promising alternative to OLT for the treatment of some liver-based metabolic disorders or acute liver failure. Unfortunately, the lack of donor livers also makes it difficult to obtain enough viable hepatocytes for hepatocyte-based therapies. Currently, a fundamental solution to this key problem is still lacking. Here we show a novel non-transgenic protocol that facilitates the rapid generation of functional induced hepatocytes (iHeps) from human adipose-derived stem cells (hADSCs), providing a source of available cells for autologous hepatocytes to treat liver disease. We used collagenase digestion to isolate hADSCs. The surface marker was detected by flow cytometry. The multipotential differentiation potency was detected by induction into adipocytes, osteocytes, and chondrocytes. Passage 3-7 hADSCs were induced into iHeps using an induction culture system composed of small molecule compounds and cell factors. Primary cultured hADSCs presented a fusiform or polygon appearance that became fibroblast-like after passage 3. More than 95 % of the cells expressed the mesenchymal cell markers CD29, CD44, CD166, CD105, and CD90. hADSCs possessed multipotential differentiation towards adipocytes, osteocytes, and chondrocytes. We rapidly induced hADSCs into iHeps within 10 days in vitro; the cellular morphology changed from fusiform to close-connected cubiform, which was similar to hepatocytes. After induction, most of the iHeps co-expressed albumin and alpha-1 antitrypsin; they also expressed mature hepatocyte special genes and achieved the basic functions of hepatocyte. Moreover, iHep transplantation could improve the liver function of acute liver-injured NPG mice and prolong life. We isolated highly purified hADSCs and rapidly induced them into functional hepatocyte-like cells within 10 days. These results provide a source of available cells for autologous hepatocytes to treat liver disease.

Impact of Sofosbuvir-Based Regimens for the Treatment of Hepatitis C After Liver Transplant on Renal Function: Results of a Canadian National Retrospective Study.

PubMed

Faisal, Nabiha; Bilodeau, Marc; Aljudaibi, Bandar; Hirch, Geri; Yoshida, Eric M; Hussaini, Trana; Ghali, Maged P; Congly, Stephen E; Ma, Mang M; Lilly, Leslie B

2018-04-04

We assessed the impact of sofosbuvir-based regimens on renal function in liver transplant recipients with recurrent hepatitis C virus and the role of renal function on the efficacy and safety of these regimens. In an expanded pan-Canadian cohort, 180 liver transplant recipients were treated with sofosbuvir-based regimens for hepatitis C virus recurrence from January 2014 to May 2015. Mean age was 58 ± 6.85 years, and 50% had F3/4 fibrosis. Patients were stratified into 4 groups based on baseline estimated glomerular filtration rate (calculated by the Modification of Diet in Renal Disease formula): < 30, 30 to 45, 46 to 60, and > 60 mL/min/173 m2. The primary outcome was posttreatment changes in renal function from baseline. Secondary outcomes included sustained virologic response at 12 weeks posttreatment and anemia-related and serious adverse events. Posttreatment renal function was improved in most patients (58%). Renal function declined in 22% of patients, which was more marked in those with estimated glomerular filtration rate < 30 mL/min/173 m2, advanced cirrhosis (P = .05), and aggressive hepatitis C virus/fibrosing cholestatic hepatitis (P < .05). High rates (80%-88%) of sustained virologic response at 12 weeks posttreatment were seen across all renal function strata. Cirrhotic patients with glomerular filtration rates < 30 mL/min/173 m2 had sustained virologic response rates at 12 weeks posttreatment comparable to the overall patient group. Rates of anemia-related adverse events and transfusion requirements increased across decreasing estimated glomerular filtration rate groups, with notably more occurrences with ribavirin-based regimens. Sofosbuvir-based regimens improved overall renal function in liver transplant recipients, with sustained virologic response, suggesting an association of subclinical hepatitis C virus-related renal disease. Sustained virologic response rates at 12 weeks posttreatment (80%-88%) were comparable regardless of baseline renal function but lower in cirrhosis.

A review of drug-induced liver injury databases.

PubMed

Luo, Guangwen; Shen, Yiting; Yang, Lizhu; Lu, Aiping; Xiang, Zheng

2017-09-01

Drug-induced liver injuries have been a major focus of current research in drug development, and are also one of the major reasons for the failure and withdrawal of drugs in development. Drug-induced liver injuries have been systematically recorded in many public databases, which have become valuable resources in this field. In this study, we provide an overview of these databases, including the liver injury-specific databases LiverTox, LTKB, Open TG-GATEs, LTMap and Hepatox, and the general databases, T3DB, DrugBank, DITOP, DART, CTD and HSDB. The features and limitations of these databases are summarized and discussed in detail. Apart from their powerful functions, we believe that these databases can be improved in several ways: by providing the data about the molecular targets involved in liver toxicity, by incorporating information regarding liver injuries caused by drug interactions, and by regularly updating the data.

Long-term and short-term effects of hemodialysis on liver function evaluated using the galactose single-point test.

PubMed

Hou, Yi-Chou; Liu, Wen-Chih; Liao, Min-Tser; Lu, Kuo-Cheng; Lo, Lan; Pan, Heng-Chih; Wu, Chia-Chao; Hu, Oliver Yoa-Pu; Tang, Hung-Shang

2014-01-01

The galactose single-point (GSP) test assesses functioning liver mass by measuring the galactose concentration in the blood 1 hour after its administration. The purpose of this study was to investigate the impact of hemodialysis (HD) on short-term and long-term liver function by use of GSP test. Seventy-four patients on maintenance HD (46 males and 28 females, 60.38 ± 11.86 years) with a mean time on HD of 60.77 ± 48.31 months were studied. The GSP values were compared in two groups: (1) before and after single session HD, and (2) after one year of maintenance HD. Among the 74 HD patient, only the post-HD Cr levels and years on dialysis were significantly correlated with GSP values (r = 0.280, P < 0.05 and r = -0.240, P < 0.05, resp.). 14 of 74 patients were selected for GSP evaluation before and after a single HD session, and the hepatic clearance of galactose was similar (pre-HD 410 ± 254 g/mL, post-HD 439 ± 298 g/mL, P = 0.49). GSP values decreased from 420.20 ± 175.26 g/mL to 383.40 ± 153.97 g/mL after 1 year maintenance HD in other 15 patients (mean difference: 19.00 ± 37.66 g/mL, P < 0.05). Patients on maintenance HD for several years may experience improvement of their liver function. However, a single HD session does not affect liver function significantly as assessed by the GSP test. Since the metabolism of galactose is dependent on liver blood flow and hepatic functional mass, further studies are needed.

Donor Indocyanine Green Clearance Test Predicts Graft Quality and Early Graft Prognosis After Liver Transplantation.

PubMed

Tang, Yunhua; Han, Ming; Chen, Maogen; Wang, Xiaoping; Ji, Fei; Zhao, Qiang; Zhang, Zhiheng; Ju, Weiqiang; Wang, Dongping; Guo, Zhiyong; He, Xiaoshun

2017-11-01

Transplantation centers have given much attention to donor availability. However, no reliable quantitative methods have been employed to accurately assess graft quality before transplantation. Here, we report that the indocyanine green (ICG) clearance test is a valuable index for liver grafts. We performed the ICG clearance test on 90 brain-dead donors within 6 h before organ procurement between March 2015 and November 2016. We also analyzed the relationship between graft liver function and early graft survival after liver transplantation (LT). Our results suggest that the ICG retention rate at 15 min (ICGR15) of donors before procurement was independently associated with 3-month graft survival after LT. The best donor ICGR15 cutoff value was 11.0%/min, and we observed a significant increase in 3-month graft failure among patients with a donor ICGR15 above this value. On the other hand, a donor ICGR15 value of ≤ 11.0%/min could be used as an early assessment index of graft quality because it provides additional information to the transplant surgeon or organ procurement organization members who must maintain or improve organ function to adapt the LT. An ICG clearance test before liver procurement might be an effective quantitative method to predict graft availability and improve early graft prognosis after LT.

Liver transplant modulates gut microbial dysbiosis and cognitive function in cirrhosis.

PubMed

Bajaj, Jasmohan S; Fagan, Andrew; Sikaroodi, Masoumeh; White, Melanie B; Sterling, Richard K; Gilles, HoChong; Heuman, Douglas; Stravitz, Richard T; Matherly, Scott C; Siddiqui, Mohammed S; Puri, Puneet; Sanyal, Arun J; Luketic, Velimir; John, Binu; Fuchs, Michael; Ahluwalia, Vishwadeep; Gillevet, Patrick M

2017-07-01

Liver transplantation (LT) improves daily function and cognition in patients with cirrhosis, but a subset of patients can remain impaired. Unfavorable microbiota or dysbiosis is observed in patients with cirrhosis, but the effect of LT on microbial composition, especially with poor post-LT cognition, is unclear. The aims were to determine the effect of LT on gut microbiota and to determine whether gut microbiota are associated with cognitive dysfunction after LT. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Cognition (Psychometric Hepatic Encephalopathy score [PHES]), health-related quality of life (HRQOL), and stool microbiota (multitagged sequencing for diversity and taxa) tests were performed at both visits. Persistent cognitive impairment was defined as a stable/worsening PHES. Both pre-/post-LT data were compared with age-matched healthy controls. We enrolled 45 patients (56 ± 7 years, Model for End-Stage Liver Disease score 26 ± 8). They received LT 6 ± 3 months after enrollment and were re-evaluated 7 ± 2 months after LT with a stable course. A significantly improved HRQOL, PHES, with increase in microbial diversity, increase in autochthonous, and decrease in potentially pathogenic taxa were seen after LT compared with baseline. However, there was continued dysbiosis and HRQOL/cognitive impairment after LT compared with controls in 29% who did not improve PHES after LT. In these, Proteobacteria relative abundance was significantly higher and Firmicutes were lower after LT, whereas the reverse occurred in the group that improved. Delta PHES was negatively correlated with delta Proteobacteria and positively with delta Firmicutes. In conclusion, LT improves gut microbiota diversity and dysbiosis compared with pre-LT baseline but residual dysbiosis remains compared with controls. There is cognitive and HRQOL enhancement in general after LT, but a higher Proteobacteria relative abundance change is associated with posttransplant cognitive impairment. Liver Transplantation 23 907-914 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

Recurrent Acute Liver Failure Because of Acute Hepatitis Induced by Organic Solvents: A Case Report.

PubMed

Ito, Daisuke; Tanaka, Tomohiro; Akamatsu, Nobuhisa; Ito, Kyoji; Hasegawa, Kiyoshi; Sakamoto, Yoshihiro; Nakagawa, Hayato; Fujinaga, Hidetaka; Kokudo, Norihiro

2016-01-01

The authors present a case of recurrent acute liver failure because of occupational exposure to organic solvents. A 35-year-old man with a 3-week history of worsening jaundice and flu-like symptoms was admitted to our hospital. Viral hepatitis serology and autoimmune factors were negative. The authors considered liver transplantation, but the patient's liver function spontaneously recovered. Liver biopsy revealed massive infiltration of neutrophils, but the cause of the acute hepatitis was not identified. Four months after discharge, the patient's liver function worsened again. The authors considered the possibility of antinuclear antibody-negative autoimmune hepatitis and initiated steroid treatment, which was effective. Four months after discharge, the patient was admitted for repeated liver injury. The authors started him on steroid pulse therapy, but this time it was not effective. Just before the first admission, he had started his own construction company where he was highly exposed to organic solvents, and thus the authors considered organic solvent-induced hepatitis. Although urine test results for organic solvents were negative, a second liver biopsy revealed severe infiltration of neutrophils, compatible with toxic hepatitis. Again, his liver function spontaneously improved. Based on the pathology and detailed clinical course, including the patient's high exposure to organic solvents since just before the first admission, and the spontaneous recovery of his liver damage in the absence of the exposure, he was diagnosed with toxic hepatitis. The authors strongly advised him to avoid organic solvents. Since then, he has been in good health without recurrence. This is the first report of recurrent acute liver failure because of exposure to organic solvents, which was eventually diagnosed through a meticulous medical history and successfully recovered by avoiding the causative agents. In acute liver failure with an undetermined etiology, clinicians should rule out organic solvent-induced hepatitis.

Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function.

PubMed

Larson-Meyer, D Enette; Newcomer, Bradley R; Heilbronn, Leonie K; Volaufova, Julia; Smith, Steven R; Alfonso, Anthony J; Lefevre, Michael; Rood, Jennifer C; Williamson, Donald A; Ravussin, Eric

2008-06-01

Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures. Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m(2)) were randomized to "control (CO)" = 100% energy requirements; "CR" = 25%; "caloric restriction and increased structured exercise (CR+EX)"= 12.5% CR + 12.5% increase in energy expenditure through exercise; or "low-calorie diet (LCD)" = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood. At baseline, increased liver lipid content (by MRS) correlated (P < 0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation. CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD.

Effect of 6-Month Calorie Restriction and Exercise on Serum and Liver Lipids and Markers of Liver Function

PubMed Central

Larson-Meyer, D. Enette; Newcomer, Bradley R.; Heilbronn, Leonie K.; Volaufova, Julia; Smith, Steven R.; Alfonso, Anthony J.; Lefevre, Michael; Rood, Jennifer C.; Williamson, Donald A.; Ravussin, Eric

2009-01-01

objective Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures. Methods and Procedures Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m2) were randomized to “control (CO)” = 100% energy requirements; “CR” = 25%; “caloric restriction and increased structured exercise (CR+EX)”= 12.5% CR + 12.5% increase in energy expenditure through exercise; or “low-calorie diet (LCD)” = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood. Results At baseline, increased liver lipid content (by MRS) correlated (P < 0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation. Discussion CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD. PMID:18421281

Preliminary profiling of microRNA in the normal and regenerating liver of Chiloscyllium plagiosum.

PubMed

Cheng, Dandan; Chen, Yanna; Lu, Conger; Qian, Yuezhong; Lv, Zhengbing

2017-12-01

Liver is a vital organ present in animals for detoxification, protein synthesis, digestion and other functions and its powerful regenerative capacity is well known. C. plagiosum is an abundant fish that is representative of the cartilaginous class in the southeast coastal region of China and its liver accounts for >70% of the fish's visceral weight and contains many bioactive substances. MicroRNAs (microRNAs) play important roles in a wide range of biological processes in eukaryotes, including cell proliferation, differentiation, apoptosis. However, microRNAs in response to liver regeneration has not been well studied. This study aimed to identify the microRNAs that participate in liver regeneration and other liver-related diseases and to improve our understanding of the mechanisms of liver regeneration in sharks. To this end, normal and regenerating liver tissues from C. plagiosum were harvested 0, 3, 6, 12 and 24h after partial hepatectomy (pH) and were sequenced using the Illumina/Solexa platform. In total, 309 known microRNAs and 590 novel microRNAs were identified in C. plagiosum. There were many microRNAs differentially expressed in the normal and regenerating livers between time points. Using target prediction and GO analysis, most of the differentially expressed microRNAs were assigned to functional categories that may be involved in regulating liver regeneration, such as cell proliferation, differentiation and apoptosis. The microRNA expression profile of liver regeneration will pave the way for the development of effective strategies to fight against liver disease and other related disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Hepatic overexpression of steroid sulfatase ameliorates mouse models of obesity and type 2 diabetes through sex-specific mechanisms.

PubMed

Jiang, Mengxi; He, Jinhan; Kucera, Heidi; Gaikwad, Nilesh W; Zhang, Bin; Xu, Meishu; O'Doherty, Robert M; Selcer, Kyle W; Xie, Wen

2014-03-21

The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this report, we first showed that the liver expression of Sts was induced in both the high fat diet (HFD) and ob/ob models of obesity and type 2 diabetes and during the fed to fasting transition. In defining the functional relevance of STS induction in metabolic disease, we showed that overexpression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity by converting biologically inactive estrogen sulfates to active estrogens and consequently improved the metabolic functions, whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue and skeletal muscle as well as a pattern of skeletal muscle gene expression that favors energy expenditure. The metabolic benefit in male STS transgenic mice was retained after castration. Treatment with the STS substrate estrone sulfate also improved metabolic functions in both the HFD and ob/ob models. Our results have uncovered a novel function of STS in energy metabolism and type 2 diabetes. Liver-specific STS induction or estrogen/estrogen sulfate delivery may represent a novel approach to manage metabolic syndrome.

Liver enzyme abnormalities in taking traditional herbal medicine in Korea: A retrospective large sample cohort study of musculoskeletal disorder patients.

PubMed

Lee, Jinho; Shin, Joon-Shik; Kim, Me-Riong; Byun, Jang-Hoon; Lee, Seung-Yeol; Shin, Ye-Sle; Kim, Hyejin; Byung Park, Ki; Shin, Byung-Cheul; Lee, Myeong Soo; Ha, In-Hyuk

2015-07-01

The objective of this study is to report the incidence of liver injury from herbal medicine in musculoskeletal disease patients as large-scale studies are scarce. Considering that herbal medicine is frequently used in patients irrespective of liver function in Korea, we investigated the prevalence of liver injury by liver function test results in musculoskeletal disease patients. Of 32675 inpatients taking herbal medicine at 7 locations of a Korean medicine hospital between 2005 and 2013, we screened for liver injury in 6894 patients with liver function tests (LFTs) at admission and discharge. LFTs included t-bilirubin, AST, ALT, and ALP. Liver injury at discharge was assessed by LFT result classifications at admission (liver injury, liver function abnormality, and normal liver function). In analyses for risk factors of liver injury at discharge, we adjusted for age, sex, length of stay, conventional medicine intake, HBs antigen/antibody, and liver function at admission. A total 354 patients (prevalence 5.1%) had liver injury at admission, and 217 (3.1%) at discharge. Of the 354 patients with liver injury at admission, only 9 showed a clinically significant increase after herbal medicine intake, and 225 returned to within normal range or showed significant liver function recovery. Out of 4769 patients with normal liver function at admission, 27 (0.6%) had liver injury at discharge. In multivariate analyses for risk factors, younger age, liver function abnormality at admission, and HBs antigen positive were associated with injury at discharge. The prevalence of liver injury in patients with normal liver function taking herbal medicine for musculoskeletal disease was low, and herbal medicine did not exacerbate liver injury in most patients with injury prior to intake. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Changes in nutritional status after liver transplantation.

PubMed

Giusto, Michela; Lattanzi, Barbara; Di Gregorio, Vincenza; Giannelli, Valerio; Lucidi, Cristina; Merli, Manuela

2014-08-21

Chronic liver disease has an important effect on nutritional status, and malnourishment is almost universally present in patients with end-stage liver disease who undergo liver transplantation. During recent decades, a trend has been reported that shows an increase in number of patients with end-stage liver disease and obesity in developed countries. The importance of carefully assessing the nutritional status during the work-up of patients who are candidates for liver replacement is widely recognised. Cirrhotic patients with depleted lean body mass (sarcopenia) and fat deposits have an increased surgical risk; malnutrition may further impact morbidity, mortality and costs in the post-transplantation setting. After transplantation and liver function is restored, many metabolic alterations are corrected, dietary intake is progressively normalised, and lifestyle changes may improve physical activity. Few studies have examined the modifications in body composition that occur in liver recipients. During the first 12 mo, the fat mass progressively increases in those patients who had previously depleted body mass, and the muscle mass recovery is subtle and non-significant by the end of the first year. In some patients, unregulated weight gain may lead to obesity and may promote metabolic disorders in the long term. Careful monitoring of nutritional changes will help identify the patients who are at risk for malnutrition or over-weight after liver transplantation. Physical and nutritional interventions must be investigated to evaluate their potential beneficial effect on body composition and muscle function after liver transplantation.

Ciprofloxacin and statin interaction: a cautionary tale of rhabdomyolysis.

PubMed

Goldie, Fraser Charles; Brogan, Amy; Boyle, James Graham

2016-07-28

A 62-year-old woman presented to hospital, on general practitioner (GP) advice, with a 15-day history of slowly progressing muscle weakness. Results showed newly deranged liver function and creatine kinase (CK) of >24 000. Prior medical history includes previous myocardial infarction and recurrent urinary tract infection. 4 days prior to symptom onset, the patient developed typical urinary tract infection symptoms, treated with ciprofloxacin. The patient had been taking simvastatin (40 mg nocte) for 13 years and had never previously taken ciprofloxacin. Initial management included intravenous crystalloid fluids and discontinuation of simvastatin. CK level fell, liver function slowly improved and renal function remained stable. Muscle weakness improved and the patient became independently able to perform activities of daily living. While the interactions between statins and other antibiotics are well documented, the interaction between statins and ciprofloxacin is less so. The consequences of this interaction can have potentially serious outcomes. 2016 BMJ Publishing Group Ltd.

Arginine-glycine-aspartic acid-polyethylene glycol-polyamidoamine dendrimer conjugate improves liver-cell aggregation and function in 3-D spheroid culture.

PubMed

Chen, Zhanfei; Lian, Fen; Wang, Xiaoqian; Chen, Yanling; Tang, Nanhong

The polyamidoamine (PAMAM) dendrimer, a type of macromolecule material, has been used in spheroidal cell culture and drug delivery in recent years. However, PAMAM is not involved in the study of hepatic cell-spheroid culture or its biological activity, particularly in detoxification function. Here, we constructed a PAMAM-dendrimer conjugate decorated by an integrin ligand: arginine-glycine-aspartic acid (RGD) peptide. Our studies demonstrate that RGD-polyethylene glycol (PEG)-PAMAM conjugates can promote singly floating hepatic cells to aggregate together in a sphere-like growth with a weak reactive oxygen species. Moreover, RGD-PEG-PAMAM conjugates can activate the AKT-MAPK pathway in hepatic cells to promote cell proliferation and improve basic function and ammonia metabolism. Together, our data support the hepatocyte sphere treated by RGD-PEG-PAMAM conjugates as a potential source of hepatic cells for a biological artificial liver system.

Safety of Direct-Acting Antiviral Therapy Regarding Renal Function in Post-Liver Transplant Patients Infected with Hepatitis C Virus and a 100% 12-Week Sustained Virologic Response-A Single-Center Study.

PubMed

Peschel, G; Moleda, L; Baier, L; Selgrad, M; Schmid, S; Scherer, M N; Müller, M; Weigand, K

2018-06-01

Patients after liver transplantation (LT) with hepatitis C virus (HCV) infection often suffer from renal or hepatic impairment. Treating patients after LT with direct-acting antivirals (DAA) might result in decreasing renal function due to interaction of DAA and immunosuppressive therapy. In this single-center study we analyzed clinical parameters of 18 HCV-infected patients treated with DAA therapy after LT. The primary end points were change of renal function (glomerular filtration rate) and sustained virologic response 12 weeks after therapy (SVR12). For secondary end points, we investigated the influence of DAA therapy on transaminases, bilirubin, international normalized ratio, noninvasive fibrosis measurement, and Model for End-Stage Liver Disease (MELD) score. Five out of 18 patients treated with DAA suffered from renal impairment stage 2, and 7 patients of renal impairment stage 3. Renal function at SVR12 was not influenced by preexisting renal impairment (P > .5), type of immunosuppressant (P > .5), or type of DAA regimen (P > .5). All patients reached SVR12. The levels of transaminases and bilirubin declined rapidly, as expected. Ten out of 18 patients already suffered from cirrhosis or liver fibrosis >F3 according to noninvasive measurement before initiation of treatment. Single-point acoustic radiation force impulse imaging improved in 9 patients (P = .012). In 7 patients, MELD score improved owing to the decrease of bilirubin levels. In 6 patients it worsened. DAA therapy in LT patients was effective and safe in this single-center real-life cohort. Renal function was not influenced by the administered drug combinations, even in patients with preexisting renal impairment. Copyright © 2018. Published by Elsevier Inc.

Perfusion enhanced polydimethylsiloxane based scaffold cell culturing system for multi-well drug screening platform.

PubMed

Tania, Marshella; Hsu, Myat Noe; Png, Si Ning; Leo, Hwa Liang; Toh, Guoyang William; Birgersson, Erik

2014-01-01

Conventional two-dimensional cultures in monolayer and sandwich configuration have been used as a model for in vitro drug testing. However, these culture configurations do not present the actual in vivo liver cytoarchitecture for the hepatocytes cultures and thus they may compromise the cells liver-specific functions and their cuboidal morphology over longer term culture. In this study, we present a three-dimensional polydimethylsiloxane (PDMS) scaffold with interconnected spherical macropores for the culturing of rat liver cells (hepatocytes). The scaffolds were integrated into our perfusion enhanced bioreactor to improve the nutrients and gas supply for cell cultures. The liver-specific functions of the cell culture were assessed by their albumin and urea production, and the changes in the cell morphology were tracked by immunofluorescence staining over 9 days of culture period. N-Acetyl-Para-Amino-Phenol (acetaminophen) was used as drug model to investigate the response of cells to drug in our scaffold-bioreactor system. Our experimental results revealed that the perfusion enhanced PDMS-based scaffold system provides a more conducive microenvironment with better cell-to-cell contacts among the hepatocytes that maintains the culture specific enzymatic functions and their cuboidal morphology during the culturing period. The numerical simulation results further showed improved oxygen distribution within the culturing chamber with the scaffold providing an additional function of shielding the cell cultures from the potentially detrimental fluid induced shear stresses. In conclusion, this study could serve a crucial role as a platform for future preclinical hepatotoxicity testing. © 2014 American Institute of Chemical Engineers.

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group.

PubMed

Neuberger, James M; Bechstein, Wolf O; Kuypers, Dirk R J; Burra, Patrizia; Citterio, Franco; De Geest, Sabina; Duvoux, Christophe; Jardine, Alan G; Kamar, Nassim; Krämer, Bernhard K; Metselaar, Herold J; Nevens, Frederik; Pirenne, Jacques; Rodríguez-Perálvarez, Manuel L; Samuel, Didier; Schneeberger, Stefan; Serón, Daniel; Trunečka, Pavel; Tisone, Giuseppe; van Gelder, Teun

2017-04-01

Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.

Synthesis, characterization and liver targeting evaluation of self-assembled hyaluronic acid nanoparticles functionalized with glycyrrhetinic acid.

PubMed

Wang, Xiaodan; Gu, Xiangqin; Wang, Huimin; Sun, Yujiao; Wu, Haiyang; Mao, Shirui

2017-01-01

Recently, polymeric materials with multiple functions have drawn great attention as the carrier for drug delivery system design. In this study, a series of multifunctional drug delivery carriers, hyaluronic acid (HA)-glycyrrhetinic acid (GA) succinate (HSG) copolymers were synthesized via hydroxyl group modification of hyaluronic acid. It was shown that the HSG nanoparticles had sub-spherical shape, and the particle size was in the range of 152.6-260.7nm depending on GA graft ratio. HSG nanoparticles presented good short term and dilution stability. MTT assay demonstrated all the copolymers presented no significant cytotoxicity. In vivo imaging analysis suggested HSG nanoparticles had superior liver targeting efficiency and the liver targeting capacity was GA graft ratio dependent. The accumulation of DiR (a lipophilic, NIR fluorescent cyanine dye)-loaded HSG-6, HSG-12, and HSG-20 nanoparticles in liver was 1.8-, 2.1-, and 2.9-fold higher than that of free DiR. The binding site of GA on HA may influence liver targeting efficiency. These results indicated that HSG copolymers based nanoparticles are potential drug carrier for improved liver targeting. Copyright © 2016 Elsevier B.V. All rights reserved.

The Role of Celiac Disease in Severity of Liver Disorders and Effect of a Gluten Free Diet on Diseases Improvement

PubMed Central

Rostami-Nejad, Mohammad; Haldane, Thea; AlDulaimi, David; Alavian, Seyed Moayed; Zali, Mohammad Reza; Rostami, Kamran

2013-01-01

Context Celiac disease (CD) is defined as a permanent intolerance to ingested gluten. The intolerance to gluten results in immune-mediated damage of small intestine mucosa manifested by villous atrophy and crypt hyperplasia. These abnormalities resolve with initiationa gluten-free diet. Evidence Acquisition PubMed, Ovid, and Google were searched for full text articles published between 1963 and 2012. The associated keywords were used, and papers described particularly the impact of celiac disease on severity of liver disorder were identified. Results Recently evidence has emerged revealingthat celiac disease not only is associated with small intestine abnormalities and malabsorption, but is also a multisystem disorder affecting other systems outside gastrointestinal tract, including musculo-skeletal, cardiovascular and nervous systems. Some correlations have been assumed between celiac and liver diseases. In particular, celiac disease is associated with changes in liver biochemistry and linked to alter the prognosis of other disorders. This review will concentrate on the effect of celiac disease and gluten-free diets on the severity of liver disorders. Conclusions Although GFD effect on the progression of CD associated liver diseases is not well defined, it seems that GFD improves liver function tests in patients with a hypertransaminasemia. PMID:24348636

Improved rat liver decellularization by arterial perfusion under oscillating pressure conditions.

PubMed

Struecker, Benjamin; Butter, Antje; Hillebrandt, Karl; Polenz, Dietrich; Reutzel-Selke, Anja; Tang, Peter; Lippert, Steffen; Leder, Anne; Rohn, Susanne; Geisel, Dominik; Denecke, Timm; Aliyev, Khalid; Jöhrens, Korinna; Raschzok, Nathanael; Neuhaus, Peter; Pratschke, Johann; Sauer, Igor M

2017-02-01

One approach of regenerative medicine to generate functional hepatic tissue in vitro is decellularization and recellularization, and several protocols for the decellularization of livers of different species have been published. This appears to be the first report on rat liver decellularization by perfusion under oscillating pressure conditions, intending to optimize microperfusion and minimize damage to the ECM. Four decellularization protocols were compared: perfusion via the portal vein (PV) or the hepatic artery (HA), with (+P) or without (-P) oscillating pressure conditions. All rat livers (n = 24) were perfused with 1% Triton X-100 and 1% sodium dodecyl sulphate, each for 90 min with a perfusion rate of 5 ml/min. Perfusion decellularization was observed macroscopically and the decellularized liver matrices were analysed by histology and biochemical analyses (e.g. levels of DNA, glycosaminoglycans and hepatocyte growth factor). Livers decellularized via the hepatic artery and under oscillating pressure showed a more homogeneous decellularization and less remaining DNA, compared with the livers of the other experimental groups. The novel decellularization method described is effective, quick (3 h) and gentle to the extracellular matrix and thus represents an improvement of existing methodology. Copyright © 2014 John Wiley & Sons, Ltd. Copyright © 2014 John Wiley & Sons, Ltd.

Open-Porous Hydroxyapatite Scaffolds for Three-Dimensional Culture of Human Adult Liver Cells

PubMed Central

Schmelzer, Eva; Over, Patrick; Nettleship, Ian; Gerlach, Joerg C.

2016-01-01

Liver cell culture within three-dimensional structures provides an improved culture system for various applications in basic research, pharmacological screening, and implantable or extracorporeal liver support. Biodegradable calcium-based scaffolds in such systems could enhance liver cell functionality by providing endothelial and hepatic cell support through locally elevated calcium levels, increased surface area for cell attachment, and allowing three-dimensional tissue restructuring. Open-porous hydroxyapatite scaffolds were fabricated and seeded with primary adult human liver cells, which were embedded within or without gels of extracellular matrix protein collagen-1 or hyaluronan. Metabolic functions were assessed after 5, 15, and 28 days. Longer-term cultures exhibited highest cell numbers and liver specific gene expression when cultured on hydroxyapatite scaffolds in collagen-1. Endothelial gene expression was induced in cells cultured on scaffolds without extracellular matrix proteins. Hydroxyapatite induced gene expression for cytokeratin-19 when cells were cultured in collagen-1 gel while culture in hyaluronan increased cytokeratin-19 gene expression independent of the use of scaffold in long-term culture. The implementation of hydroxyapatite composites with extracellular matrices affected liver cell cultures and cell differentiation depending on the type of matrix protein and the presence of a scaffold. The hydroxyapatite scaffolds enable scale-up of hepatic three-dimensional culture models for regenerative medicine applications. PMID:27403430

Hepatic (Liver) Function Panel

MedlinePlus

... Educators Search English Español Blood Test: Hepatic (Liver) Function Panel KidsHealth / For Parents / Blood Test: Hepatic (Liver) ... kidneys ) is working. What Is a Hepatic (Liver) Function Panel? A liver function panel is a blood ...

Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury.

PubMed

Carvalho, Adriana B; Quintanilha, Luiz Fernando; Dias, Juliana V; Paredes, Bruno D; Mannheimer, Elida G; Carvalho, Felipe G; Asensi, Karina D; Gutfilen, Bianca; Fonseca, Lea Mirian B; Resende, Celia Maria C; Rezende, Guilherme F M; Takiya, Christina M; de Carvalho, Antonio Carlos Campos; Goldenberg, Regina C S

2008-05-01

The objective of our study was to evaluate the therapeutic potential of bone marrow mesenchymal stromal cells (MSC) in a rat model of severe chronic liver injury. Fourteen female Wistar rats were fed exclusively an alcoholic liquid diet and received intraperitoneal injections of carbon tetrachloride every other day during 15 weeks. After this period, eight animals (MSC group) had 1 x 10(7) cells injected into the portal vein while six animals (placebo group) received vehicle. Blood analysis was performed to evaluate alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin before cell therapy and 1 and 2 months after cell or placebo infusion. Fibrosis was evaluated before and 1 month after cell or placebo injection by liver biopsies. Two months after cell delivery, animals were sacrificed and histological analysis of the livers was performed. Fibrosis was quantified by histomorphometry. Biopsies obtained before cell infusion showed intense collagen deposition and septa interconnecting regenerative nodules. One month after cell injection, this result was unaltered and differences in fibrosis quantification were not found between MSC and placebo groups. ALT and AST returned to normal values 2 weeks after cell or placebo infusion, without significant differences between experimental groups. Two months after cell or placebo injection, albumin had also returned to normal values and histological results were maintained, again without differences between MSC and placebo groups. Therefore, under our experimental conditions, MSC were unable to reduce fibrosis or improve liver function in a rat model of severe chronic liver injury.

Impact of brain death on ischemia/reperfusion injury in liver transplantation.

PubMed

Dziodzio, Tomasz; Biebl, Matthias; Pratschke, Johann

2014-04-01

In liver transplantation, the ischemia/reperfusion injury (IRI) is influenced by factors related to graft quality, organ procurement and the transplant procedure itself. However, in brain-dead donors, the process of death itself also thoroughly affects organ damage through breakdown of the autonomous nervous system and subsequent massive cytokine release. This review highlights the actual knowledge on these proinflammatory effects of brain death on IRI in liver transplantation. Brain death affects IRI either through hemodynamical or molecular effects with proinflammatory activation. Immunological effects are mainly mediated through Kupffer cell activation, leading to TNF-α and TLR4 amplification. Proinflammatory cytokines such as interleukin (IL)-6, IL-10, TNF-β and MIP-1α are released, together with activation of the innate immune system via natural killer cells and natural killer T cells, which promote organ damage and activation of fibrosis. Preprocurement treatment regimens attempt to hamper inflammatory response by the application of methylprednisolone or thymoglobulin to the donor. Selective P-selectin antagonism resulted in improved function in marginal liver grafts. Inhaled nitric oxide was found to reduce apoptosis in liver grafts. Other medications like the immunosuppressant tacrolimus produced conflicting results regarding organ protection. Furthermore, improved organ storage after procurement - such as machine perfusion - can diminish effects of IRI in a clinical setting. Brain death plays a fundamental role in the regulation of molecular markers triggering inflammation and IRI-related tissue damage in liver transplants. Although several treatment options have reached clinical application, to date, the effects of brain death during donor conditioning and organ procurement remain relevant for organ function and survival.

Two-stage liver transplantation using auxiliary laparoscopically harvested grafts in adults: Emphasizing the concept of "hypersmall graft nursing".

PubMed

Scatton, Olivier; Cauchy, François; Conti, Filomena; Perdigao, Fabiano; Massault, Pierre Philippe; Goumard, Claire; Soubrane, Olivier

2016-11-01

Living donor liver transplantation is limited by the donor's risk in case of right liver donation and by the risk of small-for-size syndrome on the recipient in case of left lobe transplantation. This study aimed at evaluating the feasibility and results of two-stage liver transplantation using auxiliary hyper small grafts harvested laparoscopically and discussing relevant technical insights and issues that still need to be overcome. Retrospective analysis involving two patients operated at a tertiary referral center. The recipients underwent left lateral sectionectomy and then auxillary liver transplantation using laparoscopically harvested left lateral section. The native right liver was transiently left in place to sustain the initially small functional graft functional during its hypertrophy. No donor experienced postoperative complication. After 7days, the hypertrophy rate was 112% (105-120). Doppler assessments during the first two postoperative weeks showed progressive portal vein inflow decrease in the right native livers and portal vein inflow increase in the grafts. Liver biopsies on postoperative day 7 showed no lesion of overperfusion. No recipient experienced liver failure or small-for-size syndrome. Second stage hepatectomy of the native liver was undertaken in one patient. In the other patient, biliary stenosis on postoperative day 30 precluded second stage hepatectomy. This patient required retransplantation after one year. The current strategy increases donor safety and may allow increasing the pool of available grafts. Refinements in the management of the native right liver are however required to improve the feasibility rate of this strategy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

[The effectiveness of the spa and health resort-based treatment with the application of Essentuki-type drinking mineral waters for the management of non-alcoholic fatty liver disease in the patients presenting with type 2 diabetes mellitus].

PubMed

Efimenko, N V; Kaĭsinova, A S; Fedorova, T E; Botvineva, L A

2015-01-01

The objective of the present study was to estimate the effectiveness of the spa and health resort-based treatment of non-alcoholic fatty liver disease in 40 patients at the mean age of 48,8 ± 5.7 years suffering from type 2 diabetes mellitus. All of them received combined therapy including the application of potable Essentuki-Novaya mineral water (20 patients) or Essentuki No 4 water (20 patients). This therapeutic modality resulted in positive dynamics of clinical symptoms of the disease, the functional liver tests, and parameters of intra-hepatic hemodynamics, lipid peroxidation homeostasis, and the hormonal status. It is concluded that the spa and health resort-based treatment with the application of local drinking Essentuki-type mineral waters for the management of non-alcoholic fatty liver disease in the patients presenting with type 2 diabetes mellitus leads to the improvement of the main functions of the liver, stabilizes carbohydrate and lipid metabolism, and prevents progression of the pathological process.

Polyethylene glycol rinse solution: An effective way to prevent ischemia-reperfusion injury

PubMed Central

Zaouali, Mohamed Amine; Bejaoui, Mohamed; Calvo, Maria; Folch-Puy, Emma; Pantazi, Eirini; Pasut, Gianfranco; Rimola, Antoni; Ben Abdennebi, Hassen; Adam, René; Roselló-Catafau, Joan

2014-01-01

AIM: To test whether a new rinse solution containing polyethylene glycol 35 (PEG-35) could prevent ischemia-reperfusion injury (IRI) in liver grafts. METHODS: Sprague-Dawley rat livers were stored in University of Wisconsin preservation solution and then washed with different rinse solutions (Ringer’s lactate solution and a new rinse solution enriched with PEG-35 at either 1 or 5 g/L) before ex vivo perfusion with Krebs-Heinseleit buffer solution. We assessed the following: liver injury (transaminase levels), mitochondrial damage (glutamate dehydrogenase activity), liver function (bile output and vascular resistance), oxidative stress (malondialdehyde), nitric oxide, liver autophagy (Beclin-1 and LCB3) and cytoskeleton integrity (filament and globular actin fraction); as well as levels of metalloproteinases (MMP2 and MMP9), adenosine monophosphate-activated protein kinase (AMPK), heat shock protein 70 (HSP70) and heme oxygenase 1 (HO-1). RESULTS: When we used the PEG-35 rinse solution, reduced hepatic injury and improved liver function were noted after reperfusion. The PEG-35 rinse solution prevented oxidative stress, mitochondrial damage, and liver autophagy. Further, it increased the expression of cytoprotective heat shock proteins such as HO-1 and HSP70, activated AMPK, and contributed to the restoration of cytoskeleton integrity after IRI. CONCLUSION: Using the rinse solution containing PEG-35 was effective for decreasing liver graft vulnerability to IRI. PMID:25473175

Spatially resolved assessment of hepatic function using 99mTc-IDA SPECT

PubMed Central

Wang, Hesheng; Cao, Yue

2013-01-01

Purpose: 99mTc-iminodiacetic acid (IDA) hepatobiliary imaging is usually quantified for hepatic function on the entire liver or regions of interest (ROIs) in the liver. The authors presented a method to estimate the hepatic extraction fraction (HEF) voxel-by-voxel from single-photon emission computed tomography (SPECT)/CT with a 99mTc-labeled IDA agent of mebrofenin and evaluated the spatially resolved HEF measurements with an independent physiological measurement. Methods: Fourteen patients with intrahepatic cancers were treated with radiation therapy (RT) and imaged by 99mTc-mebrofenin SPECT before and 1 month after RT. The dynamic SPECT volumes were with a resolution of 3.9 × 3.9 × 2.5 mm3. Throughout the whole liver with approximate 50 000 voxels, voxelwise HEF quantifications were estimated and compared between using arterial input function (AIF) from the heart and using vascular input function (VIF) from the spleen. The correlation between mean of the HEFs over the nontumor liver tissue and the overall liver function measured by Indocyanine green clearance half-time (T1/2) was assessed. Variation of the voxelwise estimation was evaluated in ROIs drawn in relatively homogeneous regions of the livers. The authors also examined effects of the time range parameter on the voxelwise HEF quantification. Results: Mean of the HEFs over the liver estimated using AIF significantly correlated with the physiological measurement T1/2 (r = 0.52, p = 0.0004), and the correlation was greatly improved by using VIF (r = 0.79, p < 0.0001). The parameter of time range for the retention phase did not lead to a significant difference in the means of the HEFs in the ROIs. Using VIF and a retention phase time range of 7–30 min, the relative variation of the voxelwise HEF in the ROIs was 10% ± 6% of respective mean HEF. Conclusions: The voxelwise HEF derived from 99mTc-IDA SPECT by the deconvolution analysis is feasible to assess the spatial distribution of hepatic function in the liver. PMID:24007177

Effects of endurance and endurance-strength exercise on biochemical parameters of liver function in women with abdominal obesity.

PubMed

Skrypnik, Damian; Ratajczak, Marzena; Karolkiewicz, Joanna; Mądry, Edyta; Pupek-Musialik, Danuta; Hansdorfer-Korzon, Rita; Walkowiak, Jarosław; Jakubowski, Hieronim; Bogdański, Paweł

2016-05-01

Obesity is a risk factor of nonalcoholic fatty liver disease. Although the standard therapy for obesity involves physical exercise, well-planned studies of the changes in liver function in response to different exercise intensities in obese subjects are scarce. The aim of the present study was to examine a question of how does exercise mode affect the liver function. 44 women with abdominal obesity were randomized into two exercise groups: endurance (group A) and endurance-strength (group B). Women in each group exercised for 60min 3 times/week for a 3-month period. Markers of liver function: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltranspeptidase (GGT), alkaline phosphatase (ALP) activities, and bilirubin levels were quantified. We found significant differences in ALT (p<0.01) and AST (p<0.05) activities between group A and B after training exercise. Blood ALT and AST tended to decrease in group B, increase in group A. Significant reduction in serum GGT level after exercise in both groups was observed (p<0.001, group A; p<0.01, group B). Neither endurance nor endurance-strength exercise led to changes in serum ALP activity and total or direct bilirubin level. However, endurance-strength training resulted in significant decreases in serum indirect bilirubin (p<0.05). Strong positive correlations between serum indirect bilirubin and body mass (r=0.615; p=0.0085) and BMI (r=0.576; p=0.0154) were found after endurance-strength exercise (group B). The mode of exercise does matter: endurance-strength exercise led to a greater improvement, compared to endurance exercise, in the liver function in women with abdominal obesity. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Protective effects of dietary avocado oil on impaired electron transport chain function and exacerbated oxidative stress in liver mitochondria from diabetic rats.

PubMed

Ortiz-Avila, Omar; Gallegos-Corona, Marco Alonso; Sánchez-Briones, Luis Alberto; Calderón-Cortés, Elizabeth; Montoya-Pérez, Rocío; Rodriguez-Orozco, Alain R; Campos-García, Jesús; Saavedra-Molina, Alfredo; Mejía-Zepeda, Ricardo; Cortés-Rojo, Christian

2015-08-01

Electron transport chain (ETC) dysfunction, excessive ROS generation and lipid peroxidation are hallmarks of mitochondrial injury in the diabetic liver, with these alterations also playing a role in the development of non-alcoholic fatty liver disease (NAFLD). Enhanced mitochondrial sensitivity to lipid peroxidation during diabetes has been also associated to augmented content of C22:6 in membrane phospholipids. Thus, we aimed to test whether avocado oil, a rich source of C18:1 and antioxidants, attenuates the deleterious effects of diabetes on oxidative status of liver mitochondria by decreasing unsaturation of acyl chains of membrane lipids and/or by improving ETC functionality and decreasing ROS generation. Streptozocin-induced diabetes elicited a noticeable increase in the content of C22:6, leading to augmented mitochondrial peroxidizability index and higher levels of lipid peroxidation. Mitochondrial respiration and complex I activity were impaired in diabetic rats with a concomitant increase in ROS generation using a complex I substrate. This was associated to a more oxidized state of glutathione, All these alterations were prevented by avocado oil except by the changes in mitochondrial fatty acid composition. Avocado oil did not prevented hyperglycemia and polyphagia although did normalized hyperlipidemia. Neither diabetes nor avocado oil induced steatosis. These results suggest that avocado oil improves mitochondrial ETC function by attenuating the deleterious effects of oxidative stress in the liver of diabetic rats independently of a hypoglycemic effect or by modifying the fatty acid composition of mitochondrial membranes. These findings might have also significant implications in the progression of NAFLD in experimental models of steatosis.

Adenoviral bcl-2 transfer improves survival and early graft function after ischemia and reperfusion in rat liver transplantation.

PubMed

Rentsch, Markus; Kienle, Klaus; Mueller, Thomas; Vogel, Mandy; Jauch, Karl Walter; Püllmann, Kerstin; Obed, Aiman; Schlitt, Hans J; Beham, Alexander

2005-11-27

Primary graft dysfunction due to ischemia and reperfusion injury represents a major problem in liver transplantation. The related cell stress may induce apoptosis, which can be suppressed by bcl-2. The purpose of the study was to investigate the effect of adenoviral bcl-2 gene transfer on early graft function and survival in rat liver transplantation. An adenoviral construct that transfers bcl-2 under the control of a tetracycline inducible promoter was generated (advTetOn bcl-2) and used with a second adenovirus that transfers the repressor protein (advCMV Rep). Forty-eight hours before explantation, donor rats were treated with advTetOn bcl-2/ advCMV Rep (n=7) and doxycyclin, with the control adenoviral construct advCMV GFP (n=8) or with doxycyclin alone (n=8). Liver transplantation was performed following 16 hours of cold storage (UW). Bcl-2 expression and intrahepatic apoptosis was assessed. Bile flow was monitored 90 min posttransplantation. The endpoint for survival was 7 days. Bcl-2 was expressed in hepatocytes and sinusoidal lining cells. This was associated with a significant reduction of apoptotic sinusoidal lining cells and hepatocytes after 24 hours and 7 days. Bile production was significantly higher following bcl-2 pretreatment. Furthermore, bcl-2 transfer resulted in significantly improved survival (100% vs. 50% both control groups). Adenoviral bcl-2 transfer results in protein expression in hepatocytes and sinusoidal lining cells resulting in early graft function and survival enhancement after prolonged ischemia and reperfusion injury. The inhibition of apoptosis in the context of liver transplantation might be a reasonable approach in the treatment of graft dysfunction.

Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice

PubMed Central

Silva-Filho, Saulo Euclides; Cardia, Gabriel Fernando Esteves; Cremer, Edivaldo; Bersani-Amado, Ciomar Aparecida

2017-01-01

High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP. PMID:28717379

Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice.

PubMed

Uchida, Nancy Sayuri; Silva-Filho, Saulo Euclides; Cardia, Gabriel Fernando Esteves; Cremer, Edivaldo; Silva-Comar, Francielli Maria de Souza; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

2017-01-01

High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase ( γ GT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γ GT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP.

Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea.

PubMed

Kheirandish-Gozal, Leila; Sans Capdevila, Oscar; Kheirandish, Ebrahim; Gozal, David

2008-01-01

Fatty liver disease (FLD) is a highly prevalent condition in obese (Ob) children, who are at increased risk for obstructive sleep apnea (OSA). However, the contribution of OSA to FLD remains unknown. Prospective study. Polysomnographic evaluation and assessment of plasma levels of insulin, glucose, and lipids, and liver function tests. A total of 518 consecutive snoring children 4 to 17 years of age who were being evaluated for habitual snoring and suspected OSA. A total of 376 children had body mass index z score of < 1.20 (non-Ob children), 3 children (<1%) had elevated serum aminotransferase (LFT) levels, and 248 had OSA (65.9%). Among the 142 overweight/Ob children, 46 had elevated LFT levels (32.4%); of these children, 42 had OSA (91.3%). In contrast, OSA was present in only 71.8% of Ob children without elevated LFT level (p < 0.01). Insulin resistance and hyperlipidemia were more likely to occur in children with FLD. Furthermore, FLD was improved after treatment of OSA in 32 of 42 Ob children (p < 0.0001). Increased liver enzyme levels are frequently found in Ob snoring children, particularly among those with OSA and/or metabolic dysfunction. Effective treatment of OSA results in improved liver function test results in the vast majority of these patients.

Endurance exercise in a rat model of metabolic syndrome.

PubMed

Cameron, Isabelle; Alam, Mohammad Ashraful; Wang, Jianxiong; Brown, Lindsay

2012-11-01

We have measured the responses to endurance exercise training on body composition and glucose regulation, as well as cardiovascular and liver structure and function in rats fed a high carbohydrate and high fat (HCHF) diet as a model of human metabolic syndrome. Male Wistar rats (9-10 weeks old) were randomly allocated into corn starch (CS) or HCHF diet groups for 16 weeks; half of each group were exercised on a treadmill for 20, 25, and then 30 min/day, 5 days/week, during the last 8 weeks of the protocol. Metabolic, cardiovascular, and liver parameters were monitored. The HCHF diet induced symptoms of metabolic syndrome, including obesity, dyslipidemia, impaired glucose tolerance, and increased systolic blood pressure associated with the development of cardiovascular remodeling and nonalcoholic steatohepatitis. Exercise in HCHF rats decreased body mass, abdominal fat pads and circumference, blood glucose concentrations, plasma lipid profiles, systolic blood pressure, left ventricular diastolic stiffness, collagen deposition and inflammatory cell infiltration in the left ventricle, improved aortic contractile and relaxation responses, and decreased liver mass and hepatic fat accumulation. This study demonstrates that endurance exercise is effective in this rat model of diet-induced metabolic syndrome in improving body composition and glucose regulation, as well as cardiovascular and liver structure and function.

Reducing Liver Fat by Low Carbohydrate Caloric Restriction Targets Hepatic Glucose Production in Non-Diabetic Obese Adults with Non-Alcoholic Fatty Liver Disease.

PubMed

Yu, Haoyong; Jia, Weiping; Guo, ZengKui

2014-09-01

Non-alcoholic fatty liver disease (NAFLD) impairs liver functions, the organ responsible for the regulation of endogenous glucose production and thus plays a key role in glycemic homeostasis. Therefore, interventions designed to normalize liver fat content are needed to improve glucose metabolism in patients affected by NAFLD such as obesity. this investigation is designed to determine the effects of caloric restriction on hepatic and peripheral glucose metabolism in obese humans with NAFLD. eight non-diabetic obese adults were restricted for daily energy intake (800 kcal) and low carbohydrate (<10%) for 8 weeks. Body compositions, liver fat and hepatic glucose production (HGP) and peripheral glucose disposal before and after the intervention were determined. the caloric restriction reduced liver fat content by 2/3 (p = 0.004). Abdominal subcutaneous and visceral fat, body weight, BMI, waist circumference and fasting plasma triglyceride and free fatty acid concentrations all significantly decreased (p < 0.05). The suppression of post-load HGP was improved by 22% (p = 0.002) whereas glucose disposal was not affected (p = 0.3). Fasting glucose remained unchanged and the changes in the 2-hour plasma glucose and insulin concentration were modest and statistically insignificant (p > 0.05). Liver fat is the only independent variable highly correlated to HGP after the removal of confounders. NAFLD impairs HGP but not peripheral glucose disposal; low carbohydrate caloric restriction effectively lowers liver fat which appears to directly correct the HGP impairment.

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

PubMed Central

Jiang, Shu-Jun; Li, Wen

2013-01-01

Abstract Hepatic stimulator substance (HSS) has been suggested to protect liver cells from various toxins. However, the precise role of HSS in hepatic ischemia–reperfusion (I/R) injury remains unknown. This study aims to elucidate whether overexpression of HSS could attenuate hepatic ischemia–reperfusion injury and its possible mechanisms. Both in vivo hepatic I/R injury in mice and in vitro hypoxia–reoxygenation (H/R) in a cell model were used to evaluate the effect of HSS protection after adenoviral gene transfer. Moreover, a possible mitochondrial mechanism of HSS protection was investigated. Efficient transfer of the HSS gene into liver inhibited hepatic I/R injury in mice, as evidenced by improvement in liver function tests, the preservation of hepatic morphology, and a reduction in hepatocyte apoptosis. HSS overexpression also inhibited H/R-induced cell death, as detected by cell viability and cell apoptosis assays. The underlying mechanism of this hepatic protection might involve the attenuation of mitochondrial dysfunction and mitochondrial-dependent cell apoptosis, as shown by the good preservation of mitochondrial ultrastructure, mitochondrial membrane potential, and the inhibition of cytochrome c leakage and caspase activity. Moreover, the suppression of H/R-induced mitochondrial ROS production and the maintenance of mitochondrial respiratory chain complex activities may participate in this mechanism. This new function of HSS expands the possibility of its application for the prevention of I/R injury, such as hepatic resection and liver transplantation in clinical practice. PMID:23461564

A Case of Left Renal Vein Ligation in a Patient with Solitary Left Kidney Undergoing Liver Transplantation to Control Splenorenal Shunt and Improve Portal Venous Flow.

PubMed

Martino, Rodrigo B; Júnior, Eserval Rocha; Manuel, Valdano; Rocha-Santos, Vinicius; D'Albuquerque, Luis Augusto C; Andraus, Wellington

2017-10-11

BACKGROUND Adequate portal venous flow is required for successful liver transplantation. Reduced venous flow and blood flow 'steal' by collateral vessels are a concern, and when there is a prominent splenorenal shunt present, ligation of the left renal vein has been recommended to improve portal venous blood flow. CASE REPORT A 51-year-old man who had undergone right nephrectomy in childhood required liver transplantation for liver cirrhosis and hepatocellular carcinoma due to hepatitis C virus (HCV) infection. The patient had no other comorbidity and no history of hepatorenal syndrome. At transplantation surgery, portal venous flow was poor and did not improve with ligation of shunt veins, but ligation of the left renal vein improved portal venous flow. On the first and fifth postoperative days, the patient was treated with basiliximab, a chimeric monoclonal antibody to the IL-2 receptor, and methylprednisolone. The calcineurin inhibitor, tacrolimus, was introduced on the fifth postoperative day. On the sixteenth postoperative day, renal color Doppler ultrasound showed normal left renal parenchyma; hepatic Doppler ultrasound showed good portal vein flow and preserved hepatic parenchyma in the liver transplant. CONCLUSIONS This case report has shown that in a patient with a single left kidney, left renal vein ligation is feasible and safe in a patient with no other risk factors for renal impairment following liver transplantation. Modification of postoperative immunosuppression to avoid calcineurin inhibitors in the very early postoperative phase may be important in promoting good recovery of renal function and to avoid the need for postoperative renal dialysis.

Protective effect of aqueous extract of Feronia elephantum correa leaves on thioacetamide induced liver necrosis in diabetic rats

PubMed Central

Sharma, Prashant; Bodhankar, Subhash L; Thakurdesai, Prasad A

2012-01-01

Objective To evalueate hepatoprotective effects Feronia elephantum (F. elephantum) correa against thioacetamide (TA) induced liver necrosis in diabetic rats. Methods Male wistar rats were made diabetic with alloxan (160 mg/kg) on day 0 of the study. They were intoxicated with hepatotoxicant (thioacetamide, 300 mg/kg, ip) on day 9 of study to produce liver necrosis. Effects of 7 day daily once administration (day 2 to day 9) of EF (400 and 800 mg/kg, po) were evaluated on necorosis of liver in terms of mortality, liver volume, liver weight, serum aspartate aminotransferase (AST) and serum alanine transaminase (ALT), and histopathology of liver sections (for signs of necorosis and inflammation) on day-9 of the study. Separate groups of rats with treated only with alloxan (DA control), thioacetamide (TA control) and both (TA+DA control) were maintained. Results FE significantly lowered the mortality rate and showed improvement in liver function parameters in TA-induced diabetic rats without change in liver weight, volume and serum glucose levels. Conclusions FE showed promising activity against TA-induced liver necorsis in diabetic rats and so might be useful for prevention of liver complications in DM. PMID:23569996

Antifibrotic effect of total flavonoids of Astmgali Radix on dimethylnitrosamine-induced liver cirrhosis in rats.

PubMed

Cheng, Yang; Mai, Jing-Yin; Wang, Mei-Feng; Chen, Gao-Feng; Ping, Jian

2017-01-01

To study the effect of total flavonoids of Astmgali Radix (TFA) on liver cirrhosis induced with dimethylnitrosamine (DMN) in rats, and the effect on peroxisome proliferator-activated receptor γ (PPARγ), uncoupling protein 2 (UCP2) and farnesoid X receptor (FXR). Fifty-three Sprague-Dawley rats were randomly divided into a control group (10 rats) and a DMN group (43 rats). Rats in the DMN group were given DMN for 4 weeks and divided randomly into a model group (14 rats), a low-dosage TFA group (14 rats) and a high-dosage TFA group (15 rats) in the 3rd week. Rats were given TFA for 4 weeks at the dosage of 15 and 30 mg/kg in the low- and high-TFA groups, respectively. At the end of the experiment blood and liver samples were collected. Serum liver function and liver tissue hydroxyproline content were determined. hematoxylin-eosin (HE), Sirus red and immunohistochemical stainings of collagen I, smooth muscle actin (α-SMA) was conducted in paraffinembedded liver tissue slices. Real time polymerase chain reaction (PCR) was adopted to determine PPARγ, UCP2 and FXR mRNA levels. Western blot was adopted to determine protein levels of collagen I, α-SMA, PPARγ, UCP2 and FXR. Compared with the model group, TFA increased the ratio of liver/body weight (low-TFA group P<0.05, high-TFA group P<0.01), improved liver biochemical indices (P<0.01 for ALT, AST, GGT in both groups, P<0.05 for albumin and TBil in the high-TFA group) and reduced liver tissue hydroxproline content (P<0.01 in both groups) in treatment groups significantly. HE staining showed that TFA alleviated liver pathological changes markedly and Sirus red staining showed that TFA reduced collagen deposition, alleviated formation and extent of liver pseudolobule. Collagen I and α-SMA immunohistochemical staining showed that staining area and extent markedly decreased in TFA groups compared with the model group. TFA could increase PPARγ, it regulated target UCP2, and FXR levels significantly compared with the model group (in the low-TFA group all P<0.05, in the high group all P<0.01). TFA could improve liver function, alleviate liver pathological changes, and reduce collagen deposition and formation of liver pseudolobule in rats with liver cirrhosis. The antifibrotic effect of TFA was through regulating PPARγ signal pathway and the interaction with FXR.

New physiologically-relevant liver tissue model based on hierarchically cocultured primary rat hepatocytes with liver endothelial cells.

PubMed

Xiao, Wenjin; Perry, Guillaume; Komori, Kikuo; Sakai, Yasuyuki

2015-11-01

To develop an in vitro liver tissue equivalent, hepatocytes should be cocultured with liver non-parenchymal cells to mimic the in vivo physiological microenvironments. In this work, we describe a physiologically-relevant liver tissue model by hierarchically organizing layers of primary rat hepatocytes and human liver sinusoidal endothelial cells (TMNK-1) on an oxygen-permeable polydimethylsiloxane (PDMS) membrane, which facilitates direct oxygenation by diffusion through the membrane. This in vivo-mimicking hierarchical coculture was obtained by simply proceeding the overlay of TMNK-1 cells on the hepatocyte layer re-formed on the collagen immobilized PDMS membranes. The comparison of hepatic functionalities was achieved between coculture and sandwich culture with Matrigel, in the presence and absence of direct oxygenation. A complete double-layered structure of functional liver cells with vertical contact between hepatocytes and TMNK-1 was successfully constructed in the coculture with direct oxygen supply and was well-maintained for 14 days. The hepatocytes in this hierarchical culture exhibited improved survival, functional bile canaliculi formation, cellular level polarization and maintenance of metabolic activities including Cyp1A1/2 activity and albumin production. By contrast, the two cell populations formed discontinuous monolayers on the same surfaces in the non-oxygen-permeable cultures. These results demonstrate that (i) the direct oxygenation through the PDMS membranes enables very simple formation of a hierarchical structure consisting of a hepatocyte layer and a layer of TMNK-1 and (ii) we may include other non-parenchymal cells in this format easily, which can be widely applicable to other epithelial organs.

Stiffness of hyaluronic acid gels containing liver extracellular matrix supports human hepatocyte function and alters cell morphology.

PubMed

Deegan, Daniel B; Zimmerman, Cynthia; Skardal, Aleksander; Atala, Anthony; Shupe, Thomas D

2015-03-01

Tissue engineering and cell based liver therapies have utilized primary hepatocytes with limited success due to the failure of hepatocytes to maintain their phenotype in vitro. In order to overcome this challenge, hyaluronic acid (HA) cell culture substrates were formulated to closely mimic the composition and stiffness of the normal liver cellular microenvironment. The stiffness of the substrate was modulated by adjusting HA hydrogel crosslinking. Additionally, the repertoire of bioactive molecules within the HA substrate was bolstered by supplementation with normal liver extracellular matrix (ECM). Primary human hepatocyte viability and phenotype were determined over a narrow physiologically relevant range of substrate stiffnesses from 600 to 4600Pa in both the presence and absence of liver ECM. Cell attachment, viability, and organization of the actin cytoskeleton improved with increased stiffness up to 4600Pa. These differences were not evident in earlier time points or substrates containing only HA. However, gene expression for the hepatocyte markers hepatocyte nuclear factor 4 alpha (HNF4α) and albumin significantly decreased on the 4600Pa stiffness at day 7 indicating that cells may not have maintained their phenotype long-term at this stiffness. Function, as measured by albumin secretion, varied with both stiffness and time in culture and peaked at day 7 at the 1200Pa stiffness, slightly below the stiffness of normal liver ECM at 3000Pa. Overall, gel stiffness affected primary human hepatocyte cell adhesion, functional marker expression, and morphological characteristics dependent on both the presence of liver ECM in gel substrates and time in culture. Copyright © 2015 Elsevier Ltd. All rights reserved.

Human Hepatocyte Growth Factor (hHGF)-Modified Hepatic Oval Cells Improve Liver Transplant Survival

PubMed Central

Li, Li; Ran, Jiang-Hua; Li, Xue-Hua; Liu, Zhi-Heng; Liu, Gui-Jie; Gao, Yan-Chao; Zhang, Xue-Li; Sun, Hiu-Dong

2012-01-01

Despite progress in the field of immunosuppression, acute rejection is still a common postoperative complication following liver transplantation. This study aims to investigate the capacity of the human hepatocyte growth factor (hHGF) in modifying hepatic oval cells (HOCs) administered simultaneously with orthotopic liver transplantation as a means of improving graft survival. HOCs were activated and isolated using a modified 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) model in male Lewis rats. A HOC line stably expressing the HGF gene was established following stable transfection of the pBLAST2-hHGF plasmid. Our results demonstrated that hHGF-modified HOCs could efficiently differentiate into hepatocytes and bile duct epithelial cells in vitro. Administration of HOCs at the time of liver transplantation induced a wider distribution of SRY-positive donor cells in liver tissues. Administration of hHGF-HOC at the time of transplantation remarkably prolonged the median survival time and improved liver function for recipients compared to these parameters in the other treatment groups (P<0.05). Moreover, hHGF-HOC administration at the time of liver transplantation significantly suppressed elevation of interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) levels while increasing the production of IL-10 and TGF-β1 (P<0.05). HOC or hHGF-HOC administration promoted cell proliferation, reduced cell apoptosis, and decreased liver allograft rejection rates. Furthermore, hHGF-modified HOCs more efficiently reduced acute allograft rejection (P<0.05 versus HOC transplantation only). Our results indicate that the combination of hHGF-modified HOCs with liver transplantation decreased host anti-graft immune responses resulting in a reduction of allograft rejection rates and prolonging graft survival in recipient rats. This suggests that HOC-based cell transplantation therapies can be developed as a means of treating severe liver injuries. PMID:23028627

Dynamic PET of human liver inflammation: impact of kinetic modeling with optimization-derived dual-blood input function.

PubMed

Wang, Guobao; Corwin, Michael T; Olson, Kristin A; Badawi, Ramsey D; Sarkar, Souvik

2018-05-30

The hallmark of nonalcoholic steatohepatitis is hepatocellular inflammation and injury in the setting of hepatic steatosis. Recent work has indicated that dynamic 18F-FDG PET with kinetic modeling has the potential to assess hepatic inflammation noninvasively, while static FDG-PET did not show a promise. Because the liver has dual blood supplies, kinetic modeling of dynamic liver PET data is challenging in human studies. The objective of this study is to evaluate and identify a dual-input kinetic modeling approach for dynamic FDG-PET of human liver inflammation. Fourteen human patients with nonalcoholic fatty liver disease were included in the study. Each patient underwent one-hour dynamic FDG-PET/CT scan and had liver biopsy within six weeks. Three models were tested for kinetic analysis: traditional two-tissue compartmental model with an image-derived single-blood input function (SBIF), model with population-based dual-blood input function (DBIF), and modified model with optimization-derived DBIF through a joint estimation framework. The three models were compared using Akaike information criterion (AIC), F test and histopathologic inflammation reference. The results showed that the optimization-derived DBIF model improved the fitting of liver time activity curves and achieved lower AIC values and higher F values than the SBIF and population-based DBIF models in all patients. The optimization-derived model significantly increased FDG K1 estimates by 101% and 27% as compared with traditional SBIF and population-based DBIF. K1 by the optimization-derived model was significantly associated with histopathologic grades of liver inflammation while the other two models did not provide a statistical significance. In conclusion, modeling of DBIF is critical for kinetic analysis of dynamic liver FDG-PET data in human studies. The optimization-derived DBIF model is more appropriate than SBIF and population-based DBIF for dynamic FDG-PET of liver inflammation. © 2018 Institute of Physics and Engineering in Medicine.

Hepatic Regeneration and Reno-Protection by Fish oil, Nigella sativa Oil and Combined Fish Oil/Nigella sativa Volatiles in CCl4 Treated Rats.

PubMed

Al-Okbi, Sahar Y; Mohamed, Doha A; Hamed, Thanaa E; Edris, Amr E; Fouda, Karem

2018-03-01

The aim of the present research was to investigate the effect of fish oil, crude Nigella sative oil and combined fish oil/Nigella sative volatile oil as hepato-regenerative and renal protective supplements. The oils were administered as emulsions to rat model with liver injury induced by CCl 4 . Plasma activities of transaminases (AST and ALT) were evaluated as liver function indicators, while plasma creatinine and urea and creatinine clearance were determined as markers of kidney function. Plasma malondialdehyde (MDA), nitrite (NO) and tumor necrosis factor-α (TNF-α) were estimated to assess the exposure to oxidative stress and subsequent inflammation. Liver fat was extracted and their fatty acids´ methyl esters were determined using gas chromatography. Results showed that plasma activities of AST and ALT were significantly higher in CCl 4 control group compared to control healthy group. Plasma levels of creatinine and urea increased significantly in CCl 4 control, while creatinine clearance was reduced significantly in the same group. All rat treated groups given the three oil emulsions showed improvement in liver function pointing to the initiation of liver regeneration. The combination of fish oil/Nigella sative volatiles showed the most promising regenerative activity. Oxidative stress and inflammation which were increased significantly in CCl 4 control group showed improvement on administration of the three different oil emulsions. Fatty acids methyl ester of liver fat revealed that rats treated with fish oil/Nigella sative volatile oil presented the highest content of unsaturated fatty acids (45.52% ± 0.81) while fish oil showed the highest saturated fatty acids (53.28% ± 1.68). Conclusion; Oral administration of oil emulsions of native fish oil, Nigella sative crude oil and combined fish oil/Nigella sative volatile oil reduced liver and kidney injury in rat model of CCl 4 through exerting anti-inflammatory and antioxidant activity. Fish oil/Nigella sative volatile oil emulsion was the most promising hepato-regenerative and reno-protective formula among the different groups.

A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma.

PubMed

Siegel, Abby B; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J; Hansen, Ryan J; Gustafson, Daniel L; Flaig, Thomas W; Tsai, Wei Yann; Wu, David P H; Lee, Valerie; Greenlee, Heather

2014-01-01

To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.

Possible autoimmune hepatitis induced after chronic active Epstein-Barr virus infection.

PubMed

Wada, Yoshiko; Sato, Chikako; Tomita, Kyoko; Ishii-Aso, Rika; Haga, Hiroaki; Okumoto, Kazuo; Nishise, Yuko; Watanabe, Hisayoshi; Saito, Takafumi; Ueno, Yoshiyuki

2014-02-01

Chronic active Epstein-Barr virus infection (CAEBV) can be manifested in a variety of systemic conditions, including interstitial pneumonia, malignant lymphoma, and coronary aneurysm. Sometimes it may be associated with hepatic failure, although the mechanism underlying CAEBV-related hepatotoxicity remains unclear. We encountered a case of autoimmune hepatitis (AIH) associated with CAEBV. A 61-year-old male was referred to our hospital because of abnormal liver enzyme levels after initial diagnosis of CAEBV had been made by laboratory tests and liver biopsy. On admission, positivity for anti-nuclear antibody was evident, and examination of the liver biopsy specimen showed findings compatible with AIH. Steroid administration was initiated, and the liver function parameters subsequently improved. Although phenotypic changes in liver biopsy specimens are rare in this condition, the present case could provide clues to the possible pathogenesis of AIH.

Preliminary study on liver function changes after trisectionectomy with versus without prior portal vein embolization.

PubMed

Malinowski, Maciej; Lock, Johan Friso; Seehofer, Daniel; Gebauer, Bernhard; Schulz, Antje; Demirel, Lina; Bednarsch, Jan; Stary, Victoria; Neuhaus, Peter; Stockmann, Martin

2016-09-01

Post-hepatectomy liver failure (PHLF) is the major risk factor for mortality after hepatectomy. Preoperative planning of the future liver remnant volume reduces PHLF rates; however, future liver remnant function (FLR-F) might have an even stronger predictive value. In this preliminary study, we used a new method to calculate FLR-F by the LiMAx test and computer tomography-assisted volumetric-analysis to visualize liver function changes after portal vein embolization (PVE) before extended hepatectomy. The subjects included patients undergoing extended right hepatectomy either directly (NO-PVE group) or after PVE (PVE group). Computed tomography (CT) scan and liver function tests (LiMAx) were done before PVE and preoperatively. FLR-F was calculated and correlated with the postoperative liver function. There were 12 patients in the NO-PVE group and 19 patients in the PVE group. FLR-F and postoperative liver function correlated significantly in both groups (p = 0.036, p = 0.011), although postoperative liver function was slightly overestimated, at 32 and 45 µg/kg/min, in the NO-PVE and PVE groups, respectively. LiMAx value did not change after PVE. Volume-function analysis using LiMAx and CT scan enables us to reliably predict early postoperative liver function. Global enzymatic liver function measured by the LiMAx test did not change after PVE, confirming that liver function distribution in the liver stays constant after PVE. An overestimation of FLR-F is needed to compensate for the intraoperative liver injury that occurs in patients undergoing extended hepatectomy.

[Effects of bemethyl, ethomersol, and yakton on the liver regeneration after partial hepatectomy].

PubMed

Gaĭvoronskaia, V V; Okovityĭ, S V; Shustov, E B; Smirnov, A V

2000-01-01

It is experimentally demonstrated for the first time that the new drugs bemithyl, etomerzol, and yakton are capable of accelerating the process of liver regeneration following partial hepatectomy. The drugs produce a hasty gain in the mass of liver, increase in the content of nucleic acids and glycogen, and improve the functional state, as manifested by a decrease in the blood bilirubin and a reduction in the hexenal sleep duration. Bemithyl, etomerzol, and yakton produce a positive effect upon the liver morphology and the intracellular regeneration process. The repair activity of the new drugs exceeds that of a combination of the well-known regeneration stimulants riboxin and potassium orotate, representing derivatives of purine and pyrimidine bases.

An Oxygenated and Transportable Machine Perfusion System Fully Rescues Liver Grafts Exposed to Lethal Ischemic Damage in a Pig Model of DCD Liver Transplantation.

PubMed

Compagnon, Philippe; Levesque, Eric; Hentati, Hassen; Disabato, Mara; Calderaro, Julien; Feray, Cyrille; Corlu, Anne; Cohen, José Laurent; Ben Mosbah, Ismail; Azoulay, Daniel

2017-07-01

Control of warm ischemia (WI) lesions that occur with donation after circulatory death (DCD) would significantly increase the donor pool for liver transplantation. We aimed to determine whether a novel, oxygenated and hypothermic machine perfusion device (HMP Airdrive system) improves the quality of livers derived from DCDs using a large animal model. Cardiac arrest was induced in female large white pigs by intravenous injection of potassium chloride. After 60 minutes of WI, livers were flushed in situ with histidine-tryptophan-ketoglutarate and subsequently preserved either by simple cold storage (WI-SCS group) or HMP (WI-HMP group) using Belzer-MPS solution. Liver grafts procured from heart-beating donors and preserved by SCS served as controls. After 4 hours of preservation, all livers were transplanted. All recipients in WI-SCS group died within 6 hours after transplantation. In contrast, the HMP device fully protected the liver against lethal ischemia/reperfusion injury, allowing 100% survival rate. A postreperfusion syndrome was observed in all animals of the WI-SCS group but none of the control or WI-HMP groups. After reperfusion, HMP-preserved livers functioned better and showed less hepatocellular and endothelial cell injury, in agreement with better-preserved liver histology relative to WI-SCS group. In addition to improved energy metabolism, this protective effect was associated with an attenuation of inflammatory response, oxidative load, endoplasmic reticulum stress, mitochondrial damage, and apoptosis. This study demonstrates for the first time the efficacy of the HMP Airdrive system to protect liver grafts from lethal ischemic damage before transplantation in a clinically relevant DCD model.

17β-Estradiol protects the liver against cold ischemia/reperfusion injury through the Akt kinase pathway.

PubMed

Yang, Xiaohua; Qin, Lei; Liu, Jianxia; Tian, Liping; Qian, Haixin

2012-12-01

Hepatic ischemia-reperfusion (IR) injury occurs during liver resection and transplantation. Recent studies have shown that 17β-estradiol (E2) can protect the heart and liver against warm IR. The present study focused on the cytoprotective effects of E2 on cold IR injury to the liver. Sprague-Dawley male rats were randomly divided into three groups: sham, IR, and IR plus E2. The model of rat orthotopic liver transplantation was used. The rats in the IR plus E2 group were intraperitoneally injected with E2 (100 μg/kg/d) for 7 d before surgery. The sham and IR group received the same quantity of saline. The donor livers were then orthotopically transplanted into rats after cold ischemia preservation for 4 h at 4°C lactated Ringer's solution. After 6 h reperfusion, liver function, bile flow volume, hepatocyte apoptosis, and activation of Akt, glycogen synthase kinase-3β, and Bcl-2-associated death promoter were assessed. The survival rate of the rats was also investigated. The administration of E2 significantly prolonged the survival of liver grafts by improving liver function and decreasing hepatocyte apoptosis. Rats undergoing E2 demonstrated a greater level activation of Akt in the liver compared with the IR group. In addition, E2 also inhibited the activities of glycogen synthase kinase-3β, Bcl-2-associated death promoter, and caspase-3-induced by IR injury. E2 pretreatment attenuated the hepatocellular damage caused by hepatic cold IR injury through the Akt pathway. Estrogen therapy might be important in clinical settings associated with cold IR injury during liver transplantation. Copyright © 2012 Elsevier Inc. All rights reserved.

Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model

PubMed Central

Elswefy, Sahar E; Rashed, Laila A; Younis, Nahla N; Shaheen, Mohamed A; Ghanim, Amal MH

2016-01-01

Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 106 cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA. PMID:26811102

Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model.

PubMed

Mohamed, Hoda E; Elswefy, Sahar E; Rashed, Laila A; Younis, Nahla N; Shaheen, Mohamed A; Ghanim, Amal M H

2016-03-01

Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA. © 2016 by the Society for Experimental Biology and Medicine.

A novel subcutaneous site of islet transplantation superior to the liver.

PubMed

Yasunami, Yohichi; Nakafusa, Yuki; Nitta, Naoyoshi; Nakamura, Masafumi; Goto, Masafumi; Ono, Junko; Taniguchi, Masaru

2018-03-08

Islet transplantation is an attractive treatment for patients with insulin-dependent diabetes mellitus, and currently the liver is the favored transplantation site. However, an alternative site is desirable because of the low efficiency of hepatic transplantation, requiring 2-3 donors for a single recipient, and because the transplanted islets cannot be accessed or retrieved. We developed a novel procedure of islet transplantation to the inguinal subcutaneous white adipose tissue (ISWAT) of mice and described functional and morphological characteristics of transplanted syngeneic islets. Also, it was determined whether islet allograft rejection in the ISWAT can be prevented by immunosuppressive agents. Furthermore, it was examined whether human islets function when grafted in this particular site of immune-deficient mice. In this site, transplanted islets are engrafted as clusters and function to reverse STZ-induced diabetes in mice. Importantly, transplanted islets can be visualized by CT and are easily retrievable, and allograft rejection is preventable by blockade of co-stimulatory signals. Of much importance, the efficiency of islet transplantation in this site is superior to the liver, in which hyperglycemia of diabetic recipient mice is ameliorated after transplantation of 200 syngeneic islets (the islet number yielded from 1 mouse pancreas) to the ISWAT but not to the liver. Furthermore, human islets transplanted in this particular site function to reverse diabetes in immune-deficient mice. Thus, the ISWAT is superior to the liver as the site of islet transplantation, which may lead to improved outcome of clinical islet transplantation.

Clamp-crushing vs. radiofrequency-assisted liver resection:changes in liver function tests.

PubMed

Palibrk, Ivan; Milicic, Biljana; Stojiljkovic, Ljuba; Manojlovic, Nebojsa; Dugalic, Vladimir; Bumbasirevic, Vesna; Kalezic, Nevena; Zuvela, Marinko; Milicevic, Miroslav

2012-05-01

Liver resection is the gold standard in managing patients with metastatic or primary liver cancer. The aim of our study was to compare the traditional clamp-crushing technique to the radiofrequency- assisted liver resection technique in terms of postoperative liver function. Liver function was evaluated preoperatively and on postoperative days 3 and 7. Liver synthetic function parameters (serum albumin level, prothrombin time and international normalized ratio), markers of hepatic injury and necrosis (serum alanine aminotransferase, aspartate aminotransferase and total bilirubin level) and microsomal activity (quantitative lidocaine test) were compared. Forty three patients completed the study (14 had clamp-crushing and 29 had radiofrequency assisted liver resection). The groups did not differ in demographic characteristics, pre-operative liver function, operative time and perioperative transfusion rate. In postoperative period, there were similar changes in monitored parameters in both groups except albumin levels, that were higher in radiofrequency-assisted liver resection group (p=0.047). Both, traditional clamp-crushing technique and radiofrequency assisted liver resection technique, result in similar postoperative changes of most monitored liver function parameters.

A Role for the Liver in Parturition and Preterm Birth.

PubMed

Mawson, Anthony R

Neither the mechanisms of parturition nor the pathogenesis of preterm birth are well understood. Poor nutritional status has been suspected as a major causal factor, since vitamin A concentrations are low in preterm infants. However, even large enteral doses of vitamin A from birth fail to increase plasma concentrations of vitamin A or improve outcomes in preterm and/or extremely low birthweight infants. These findings suggest an underlying impairment in the secretion of vitamin A from the liver, where about 80% of the vitamin is stored. Vitamin A accumulates in the liver and breast during pregnancy in preparation for lactation. While essential in low concentration for multiple biological functions, vitamin A in higher concentration can be pro-oxidant, mutagenic, teratogenic and cytotoxic, acting as a highly surface-active, membrane-seeking and destabilizing compound. Regarding the mechanism of parturition, it is conjectured that by nine months of gestation the hepatic accumulation of vitamin A (retinol) from the liver is such that mobilization and secretion are impaired to the point where stored vitamin A compounds in the form of retinyl esters and retinoic acid begin to spill or leak into the circulation, resulting in amniotic membrane destabilization and the initiation of parturition. If, however, the accumulation and spillage of stored retinoids reaches a critical threshold prior to nine months, e.g., due to cholestatic liver disease, which is common in mothers of preterm infants, the increased retinyl esters and/or retinoic acid rupture the fetal membranes, inducing preterm birth and its complications, including retinopathy, necrotizing enterocolitis and bronchopulmonary dysplasia. Subject to testing, the model suggests that measures taken prior to and during pregnancy to improve liver function could reduce the risk of adverse birth outcomes, including preterm birth.

A Role for the Liver in Parturition and Preterm Birth

PubMed Central

Mawson, Anthony R.

2016-01-01

Neither the mechanisms of parturition nor the pathogenesis of preterm birth are well understood. Poor nutritional status has been suspected as a major causal factor, since vitamin A concentrations are low in preterm infants. However, even large enteral doses of vitamin A from birth fail to increase plasma concentrations of vitamin A or improve outcomes in preterm and/or extremely low birthweight infants. These findings suggest an underlying impairment in the secretion of vitamin A from the liver, where about 80% of the vitamin is stored. Vitamin A accumulates in the liver and breast during pregnancy in preparation for lactation. While essential in low concentration for multiple biological functions, vitamin A in higher concentration can be pro-oxidant, mutagenic, teratogenic and cytotoxic, acting as a highly surface-active, membrane-seeking and destabilizing compound. Regarding the mechanism of parturition, it is conjectured that by nine months of gestation the hepatic accumulation of vitamin A (retinol) from the liver is such that mobilization and secretion are impaired to the point where stored vitamin A compounds in the form of retinyl esters and retinoic acid begin to spill or leak into the circulation, resulting in amniotic membrane destabilization and the initiation of parturition. If, however, the accumulation and spillage of stored retinoids reaches a critical threshold prior to nine months, e.g., due to cholestatic liver disease, which is common in mothers of preterm infants, the increased retinyl esters and/or retinoic acid rupture the fetal membranes, inducing preterm birth and its complications, including retinopathy, necrotizing enterocolitis and bronchopulmonary dysplasia. Subject to testing, the model suggests that measures taken prior to and during pregnancy to improve liver function could reduce the risk of adverse birth outcomes, including preterm birth. PMID:27595011

Factors influencing long-term quality of life and depression in German liver transplant recipients: a single-centre cross-sectional study.

PubMed

Zahn, Alexandra; Seubert, Lisa; Jünger, Jana; Schellberg, Dieter; Weiss, Karl Heinz; Schemmer, Peter; Stremmel, Wolfgang; Sauer, Peter; Gotthardt, Daniel Nils

2013-06-26

Health-related quality of life (HRQOL) following orthotopic liver transplantation (OLT) has become increasingly important. Therefore, we aimed to identify factors affecting HRQOL after OLT. This cross-sectional, single-centre study surveyed 281 OLT patients. Survey tools included the Short Form (SF-36) Health Survey, the Patient Health Questionnaire 9 (PHQ9), and a self-designed employment questionnaire. Patient medical records were reviewed. Participants included 187 men (mean age at OLT: 50 [± 11; 13-69] years). Primary indications for OLT were viral hepatitis (28%), alcoholic liver disease (35%), cholestatic liver disease (11%), and others (26%). Follow-up ranged from 2 to 136 months. Clinical factors associated with improved HRQOL were age ≤ 45 years at OLT and current MELD score <=≤ 13. Time after OLT and indication for transplantation affected SF-36 HRQOL. SF-36 physical component summary scales plateaued at 3-years post-OLT and then stabilized. For the SF-36 HRQOL, scores were the lowest in all domains for OLT recipients transplanted for chronic viral hepatitis and for unemployed patients, whereas sex and number of transplantations showed no significant differences. The PHQ9 results showed that depression was significantly more frequent among patients with current MELD score ≥ 13 or impaired liver function and those transplanted for chronic viral hepatitis or unemployed patients. Age and sex did not influence PHQ9 results. Medical and psychosocial support is crucial for long-term HRQOL after OLT. Developing multidisciplinary interventions to address issues such as employment, age, MELD score, and liver function may improve long-term HRQOL in these patients.

Transgenic expression of omega-3 PUFA synthesis genes improves zebrafish survival during Vibrio vulnificus infection.

PubMed

Cheng, Chih-Lun; Huang, Shin-Jie; Wu, Chih-Lu; Gong, Hong-Yi; Ken, Chuian-Fu; Hu, Shao-Yang; Wu, Jen-Leih

2015-11-17

Highly desaturated n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are synthesized by desaturases and elongase. They exert hepatoprotective effects to prevent alcoholic fatty liver syndrome or cholestatic liver injury. However, it is unclear how n-3 PUFAs improve immune function in liver. Vibrio vulnificus, a gram-negative bacterial pathogen, causes high mortality of aquaculture fishes upon infection. Humans can become infected with V. vulnificus through open wounds or by eating raw seafood, and such infections may result in systemic septicemia. Moreover, patients with liver diseases are vulnerable to infection, and are more likely than healthy persons to present with liver inflammation following infection. This study quantified n-3 PUFAs and their anti-bacterial effects in Fadsd6 and Elvol5a transgenic zebrafish. Two transgenic zebrafish strains with strong liver specific expression of Fadsd6 and Elvol5a (driven by the zebrafish Fabp10 promoter) were established using the Tol2 system. Synthesis of n-3 PUFAs in these strains were increased by 2.5-fold as compared to wild type (Wt) fish. The survival rate in 24 h following challenge with V. vulnificus was 20 % in Wt, but 70 % in the transgenic strains. In addition, the bacteria counts in transgenic fish strains were significantly decreased. The expression levels of pro-inflammatory genes, such as TNF-α, IL-1β, and NF-κB, were suppressed between 9 and 12 h after challenge. This study confirms the anti-bacterial function of n-3 PUFAs in a transgenic zebrafish model. Fadsd6 and Elvol5a transgenic zebrafish are more resistant to V. vulnificus infection, and enhance survival by diminishing the attendant inflammatory response.

Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise.

PubMed

Uddin, Golam Mezbah; Youngson, Neil A; Doyle, Bronte M; Sinclair, David A; Morris, Margaret J

2017-11-08

Maternal overnutrition increases the risk of long-term metabolic dysfunction in offspring. Exercise improves metabolism partly by upregulating mitochondrial biogenesis or function, via increased levels of nicotinamide adenine dinucleotide (NAD + ). We have shown that the NAD + precursor, nicotinamide mononucleotide (NMN) can reverse some of the negative consequences of high fat diet (HFD) consumption. To investigate whether NMN can impact developmentally-set metabolic deficits, we compared treadmill exercise and NMN injection in offspring of obese mothers. Five week old lean and obese female C57BL6/J mice were mated with chow fed males. Female offspring weaned onto HFD were given treadmill exercise for 9 weeks, or NMN injection daily for 18 days. Maternal obesity programmed increased adiposity and liver triglycerides, with decreased glucose tolerance, liver NAD + levels and citrate synthase activity in offspring. Both interventions reduced adiposity, and showed a modest improvement in glucose tolerance and improved markers of mitochondrial function. NMN appeared to have stronger effects on liver fat catabolism (Hadh) and synthesis (Fasn) than exercise. The interventions appeared to exert the most global benefit in mice that were most metabolically challenged (HFD-consuming offspring of obese mothers). This work encourages further study to confirm the suitability of NMN for use in reversing metabolic dysfunction linked to programming by maternal obesity.

High intensity intermittent exercise improves cardiac structure and function and reduces liver fat in patients with type 2 diabetes: a randomised controlled trial.

PubMed

Cassidy, Sophie; Thoma, Christian; Hallsworth, Kate; Parikh, Jehill; Hollingsworth, Kieren G; Taylor, Roy; Jakovljevic, Djordje G; Trenell, Michael I

2016-01-01

Cardiac disease remains the leading cause of mortality in type 2 diabetes, yet few strategies to target cardiac dysfunction have been developed. This randomised controlled trial aimed to investigate high intensity intermittent training (HIIT) as a potential therapy to improve cardiac structure and function in type 2 diabetes. The impact of HIIT on liver fat and metabolic control was also investigated. Using an online random allocation sequence, 28 patients with type 2 diabetes (metformin and diet controlled) were randomised to 12 weeks of HIIT (n = 14) or standard care (n = 14). Cardiac structure and function were measured by 3.0 T MRI and tagging. Liver fat was determined by 1H-magnetic resonance spectroscopy and glucose control by an OGTT. MRI analysis was performed by an observer blinded to group allocation. All study procedures took place in Newcastle upon Tyne, UK. Five patients did not complete the study and were therefore excluded from analysis: this left 12 HIIT and 11 control patients for the intention-to-treat analysis. Compared with controls, HIIT improved cardiac structure (left ventricular wall mass 104 ± 17 g to 116 ± 20 g vs. 107 ± 25 g to 105 ± 25 g, p < 0.05) and systolic function (stroke volume 76 ± 16 ml to 87 ± 19 ml vs. 79 ± 14 ml to 75 ± 15 ml, p < 0.01). Early diastolic filling rates increased (241 ± 84 ml/s to 299 ± 89 ml/s vs. 250 ± 44 ml/s to 251 ± 47 ml/s, p < 0.05) and peak torsion decreased (8.1 ± 1.8° to 6.9 ± 1.6° vs. 7.1 ± 2.2° to 7.6 ± 1.9°, p < 0.05) in the treatment group. Following HIIT, there was a 39% relative reduction in liver fat (p < 0.05) and a reduction in HbA1c (7.1 ± 1.0% [54.5 mmol/mol] to 6.8 ± 0.9% [51.3 mmol/mol] vs. 7.2 ± 0.5% [54.9 mmol/mol] to 7.4 ± 0.7% [57.0 mmol/mol], p < 0.05). Changes in liver fat correlated with changes in HbA1c (r = 0.70, p < 0.000) and 2 h glucose (r = 0.57, p < 0.004). No adverse events were recorded. This is the first study to demonstrate improvements in cardiac structure and function, along with the greatest reduction in liver fat, to be recorded following an exercise intervention in type 2 diabetes. HIIT should be considered by clinical care teams as a therapy to improve cardiometabolic risk in patients with type 2 diabetes. www.isrctn.com 78698481 FUNDING: : Medical Research Council.

Liver transplantation for metastatic liver malignancies.

PubMed

Foss, Aksel; Lerut, Jan P

2014-06-01

Liver transplantation is a validated treatment of primary hepatobiliary tumours. Over the last decade, a renewed interest for liver transplantation as a curative treatment of colorectal liver metastasis (CR-LM) and neuro-endocrine metastasis (NET-LM) has developed. The ELTR and UNOS analyses showed that liver transplantation may offer excellent disease-free survival (ranging from 30 to 77%) in case of NET-LM, on the condition that stringent selection criteria are implemented. The interest for liver transplantation in the treatment of CR-LM has been fostered by the Norwegian SECA study. Five-year A 5-year survival rate of 60% could be reached. Despite the high recurrence rate (90%), one-third of patients were disease free following pulmonary surgery for metastases. Liver transplantation will take a more prominent place in the therapeutic algorithm of CR-LM and NET-LM. Larger experiences are necessary to improve knowledge about tumour biology and to refine selection criteria. A multimodal approach adding neo and adjuvant medical treatment to the transplant procedure will be key to bring this oncologic transplant project into the clinical arena. The preserved liver function in these patients will allow a more deliberate access to split liver and living donation for these indications.

Comparative Proteomic Analysis of Human Liver Tissue and Isolated Hepatocytes with a Focus on Proteins Determining Drug Exposure.

PubMed

Vildhede, Anna; Wiśniewski, Jacek R; Norén, Agneta; Karlgren, Maria; Artursson, Per

2015-08-07

Freshly isolated human hepatocytes are considered the gold standard for in vitro studies of liver functions, including drug transport, metabolism, and toxicity. For accurate predictions of the in vivo outcome, the isolated hepatocytes should reflect the phenotype of their in vivo counterpart, i.e., hepatocytes in human liver tissue. Here, we quantified and compared the membrane proteomes of freshly isolated hepatocytes and human liver tissue using a label-free shotgun proteomics approach. A total of 5144 unique proteins were identified, spanning over 6 orders of magnitude in abundance. There was a good global correlation in protein abundance. However, the expression of many plasma membrane proteins was lower in the isolated hepatocytes than in the liver tissue. This included transport proteins that determine hepatocyte exposure to many drugs and endogenous compounds. Pathway analysis of the differentially expressed proteins confirmed that hepatocytes are exposed to oxidative stress during isolation and suggested that plasma membrane proteins were degraded via the protein ubiquitination pathway. Finally, using pitavastatin as an example, we show how protein quantifications can improve in vitro predictions of in vivo liver clearance. We tentatively conclude that our data set will be a useful resource for improved hepatocyte predictions of the in vivo outcome.

Recellularization of Rat Liver Scaffolds by Human Liver Stem Cells

PubMed Central

Navarro-Tableros, Victor; Herrera Sanchez, Maria Beatriz; Figliolini, Federico; Romagnoli, Renato; Tetta, Ciro

2015-01-01

In the present study, rat liver acellular scaffolds were used as biological support to guide the differentiation of human liver stem-like cells (HLSC) to hepatocytes. Once recellularized, the scaffolds were maintained for 21 days in different culture conditions to evaluate hepatocyte differentiation. HLSC lost the embryonic markers (alpha-fetoprotein, nestin, nanog, sox2, Musashi1, Oct 3/4, and pax2), increased the expression of albumin, and acquired the expression of lactate dehydrogenase and three subtypes of cytochrome P450. The presence of urea nitrogen in the culture medium confirmed their metabolic activity. In addition, cells attached to tubular remnant matrix structures expressed cytokeratin 19, CD31, and vimentin. The rat extracellular matrix (ECM) provides not only a favorable environment for differentiation of HLSC in functional hepatocytes (hepatocyte like) but also promoted the generation of some epithelial-like and endothelial-like cells. When fibroblast growth factor–epidermal growth factor or HLSC-derived conditioned medium was added to the perfusate, an improvement of survival rate was observed. The conditioned medium from HLSC potentiated also the metabolic activity of hepatocyte-like cells repopulating the acellular liver. In conclusion, HLSC have the potential, in association with the natural ECM, to generate in vitro a functional “humanized liver-like tissue.” PMID:25794768

Defective adaptive thermogenesis contributes to metabolic syndrome and liver steatosis in obese mice.

PubMed

Poekes, Laurence; Legry, Vanessa; Schakman, Olivier; Detrembleur, Christine; Bol, Anne; Horsmans, Yves; Farrell, Geoffrey C; Leclercq, Isabelle A

2017-02-01

Fatty liver diseases are complications of the metabolic syndrome associated with obesity, insulin resistance and low grade inflammation. Our aim was to uncover mechanisms contributing to hepatic complications in this setting. We used foz/foz mice prone to obesity, insulin resistance and progressive fibrosing non-alcoholic steatohepatitis (NASH). Foz/foz mice are hyperphagic but wild-type (WT)-matched calorie intake failed to protect against obesity, adipose inflammation and glucose intolerance. Obese foz/foz mice had similar physical activity level but reduced energy expenditure. Thermogenic adaptation to high-fat diet (HFD) or to cold exposure was severely impaired in foz/foz mice compared with HFD-fed WT littermates due to lower sympathetic tone in their brown adipose tissue (BAT). Intermittent cold exposure (ICE) restored BAT function and thereby improved glucose tolerance, decreased fat mass and liver steatosis. We conclude that failure of BAT adaptation drives the metabolic complications of obesity in foz/foz mice, including development of liver steatosis. Induction of endogenous BAT function had a significant therapeutic impact on obesity, glucose tolerance and liver complications and is a potential new avenue for therapy of non-alcoholic fatty liver disease (NAFLD). © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Levels and interactions of plasma xanthine oxidase, catalase and liver function parameters in Nigerian children with Plasmodium falciparum infection.

PubMed

Iwalokun, B A; Bamiro, S B; Ogunledun, A

2006-12-01

Elevated plasma levels of xanthine oxidase and liver function parameters have been associated with inflammatory events in several human diseases. While xanthine oxidase provides in vitro protection against malaria, its pathophysiological functions in vivo and interactions with liver function parameters remain unclear. This study examined the interactions and plasma levels of xanthine oxidase (XO) and uric acid (UA), catalase (CAT) and liver function parameters GOT, GPT and bilirubin in asymptomatic (n=20), uncomplicated (n=32), and severe (n=18) falciparum malaria children aged 3-13 years. Compared to age-matched control (n=16), significant (p<0.05) elevation in xanthine oxidase by 100-550%, uric acid by 15.4-153.8%, GOT and GPT by 22.1-102.2%, and total bilirubin by 2.3-86% according to parasitaemia (geometric mean parasite density (GMPD)=850-87100 parasites/microL) was observed in the malarial children. Further comparison with control revealed higher CAT level (16.2+/-0.5 vs 14.6+/-0.4 U/L; p<0.05) lacking significant (p>0.05) correlation with XO, but lower CAT level (13.4-5.4 U/L) with improved correlations (r=-0.53 to -0.91; p<0.05) with XO among the asymptomatic and symptomatic malaria children studied. 75% of control, 45% of asymptomatic, 21.9% of uncomplicated, and none of severe malaria children had Hb level>11.0 g/dL. Multivariate analyses further revealed significant (p<0.05) correlations between liver function parameters and xanthine oxidase (r=0.57-0.64) only in the severe malaria group. We conclude that elevated levels of XO and liver enzymes are biochemical features of Plasmodium falciparum parasitaemia in Nigerian children, with both parameters interacting differently to modulate the catalase response in asymptomatic and symptomatic falciparum malaria.

Functional restoration of cirrhotic liver after partial hepatectomy in the rat.

PubMed

Hashimoto, Masaji; Watanabe, Goro

2005-01-01

Although cirrhosis is the terminal stage of various liver diseases, thanks to recent advances one might eliminate some causes of liver damage. Liver has a potent regeneration capacity. It is important to evaluate the regenerating cirrhotic liver after partial hepatectomy, morphologically and functionally, in the long term. We evaluated the functional capacity of the rat liver rendered cirrhotic by orally administered thioacetamide, and examined the correlation between morphological and functional restoration after 2/3 hepatectomy in comparison with hepatectomized normal rats and sham-operated cirrhotic rats. Morphological restoration was evaluated by remnant liver weight, proliferating cell nuclear antigen labeling index, and fibrosis ratio. Functional restoration was evaluated by the indocyanine green disappearance rate and aminopyrine clearance. Cirrhotic rats were functionally deteriorated in comparison with the normal rats. Morphological restoration in cirrhotic rats was delayed in comparison with normal rats. Functional restoration after 2/3 hepatectomy was advanced in comparison with morphological restoration. In comparison with sham-operated cirrhotic rats, functional restoration of the cirrhotic liver was accelerated by partial hepatectomy. In cirrhotic rats, functional restoration of the liver after 2/3 hepatectomy was advanced in comparison with morphological restoration. Partial hepatectomy seemed to promote functional restoration of the cirrhotic liver.

[Isoflavone genistein-8-c-glycoside prevents the oxidative damages in structure and function of rat liver microsomal membranes].

PubMed

Zavodnik, L B

2003-01-01

Bioflavonoids (polyhydroxyphenols) are ubiquitous components of plants, fruits and vegetables; these compounds are efficient scavengers of free oxygen radicals and peroxides. The aim of this study was to investigate the antioxidant and radioprotective effects of genistein-8-C-glicoside (G8CG), an isoflavone, isolated from the flowers of Lipinus luteusl L. G8CG prevents dose-dependently the destruction of the cytochrome P-450 and its conversion to an inactive form cytochrome P-420, inhibits membrane lipid peroxidation and membrane SH-group oxidation in isolated rat liver microsomal membranes under tert-butylhydroperoxide-induced oxidative stress. Single whole-body gamma-irradiation (1 Gy) of rats results in blood plasma and liver microsomal membrane lipid peroxidation, impairments of microsomal membrane structure and function. Rat treatment with G8CG (75 mg/kg) developed the clear protective effect, stabilized membrane structure and improved the parameters of the monooxygenase function. We can conclude that G8CG can be used as antioxidant and radioprotective agent.

Construction of bioengineered hepatic tissue derived from human umbilical cord mesenchymal stem cells via aggregation culture in porcine decellularized liver scaffolds.

PubMed

Li, Yi; Wu, Qiong; Wang, Yujia; Li, Li; Chen, Fei; Shi, Yujun; Bao, Ji; Bu, Hong

2017-01-01

An individualized, tissue-engineered liver suitable for transplanting into a patient with liver disease would be of great benefit to the patient and the healthcare system. The tissue-engineered liver would possess the functions of the original healthy organ. Two fields of study, (i) using decellularized tissue as cell scaffolding, and (ii) stem cell differentiation into functional cells, are coming together to make this concept feasible. The decellularized liver scaffolds (DLS) can interact with cells to promote cell differentiation and signal transduction and three-dimensional (3D) stem cell aggregations can maintain the phenotypes and improve functions of stem cells after differentiation by undergoing cell-cell contact. Although the effects of DLS and stem cell aggregation culture have been intensively studied, few observations about the interaction between the two have been achieved. We established a method that combines the use of decellularized liver scaffolds and aggregation culture of MSCs (3D-DLS) and explored the effects of the two on hepatic differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) in bioengineered hepatic tissue. A higher percentage of albumin-producing cells, higher levels of liver-specific transcripts, higher urea cycle-related transcripts, and lower levels of stem cell-specific transcripts were observed in the 3D-DLS group when compared to that of hUC-MSCs in monolayer culture (2D), aggregation culture (3D), monolayer on DLS culture (2D-DLS). The gene arrays also indicated that 3D-DLS induced the differentiation from the hUC-MSC phenotype to the PHH phenotype. Liver-specific proteins albumin, CK-18, and glycogen storage were highly positive in the 3D-DLS group. Albumin secretion and ammonia conversion to urea were more effective with a higher cell survival rate in the 3D-DLS group for 14 days. This DLS and aggregation combination culture system provides a novel method to improve hepatic differentiation, maintain phenotype of hepatocyte-like cells and sustain survival for 14 days in vitro. This is a promising strategy to use to construct bioengineered hepatic tissue. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Selenite-Releasing Bone Mineral Nanoparticles Retard Bone Tumor Growth and Improve Healthy Tissue Functions In Vivo.

PubMed

Wang, Yanhua; Hao, Hang; Liu, Haoming; Wang, Yifan; Li, Yan; Yang, Gaojie; Ma, Jun; Mao, Chuanbin; Zhang, Shengmin

2015-08-26

Selenite-doped bone mineral nanoparticles can retard the growth of osteosarcoma in a nude mice model, through sustained release of selenite ions. The selenite ions released from the nanoparticles through a degradation-mediated fashion inhibit tumor metastasis. Blood routine analysis indicates that selenite ions can also improve the functions of liver, kidney, and heart. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Randomised clinical trial: the effects of a multispecies probiotic vs. placebo on innate immune function, bacterial translocation and gut permeability in patients with cirrhosis.

PubMed

Horvath, A; Leber, B; Schmerboeck, B; Tawdrous, M; Zettel, G; Hartl, A; Madl, T; Stryeck, S; Fuchs, D; Lemesch, S; Douschan, P; Krones, E; Spindelboeck, W; Durchschein, F; Rainer, F; Zollner, G; Stauber, R E; Fickert, P; Stiegler, P; Stadlbauer, V

2016-11-01

Probiotics may correct intestinal dysbiosis and proinflammatory conditions in patients with liver cirrhosis. To test the effects of a multispecies probiotic on innate immune function, bacterial translocation and gut permeability. In a randomised, double blind, placebo-controlled study, stable cirrhotic out-patients either received a daily dose of a probiotic powder containing eight different bacterial strains (Ecologic Barrier, Winclove, Amsterdam, The Netherlands) (n = 44) or a placebo (n = 36) for 6 months and were followed up for another 6 months. We found a significant but subclinical increase in neutrophil resting burst (2.6-3.2%, P = 0.0134) and neopterin levels (7.7-8.4 nmol/L, P = 0.001) with probiotics but not with placebo. Probiotic supplementation did not have a significant influence on neutrophil phagocytosis, endotoxin load, gut permeability or inflammatory markers. Ten severe infections occurred in total; one during intervention in the placebo group, and five and four after the intervention has ended in the probiotic and placebo group, respectively. Liver function showed some improvement with probiotics but not with placebo. Probiotic supplementation significantly increased serum neopterin levels and the production of reactive oxygen species by neutrophils. These findings might explain the beneficial effects of probiotics on immune function. Furthermore, probiotic supplementation may be a well-tolerated method to maintain or even improve liver function in stable cirrhosis. However, its influence on gut barrier function and bacterial translocation in cirrhotic patients is minimal. © 2016 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.

Multipotent cells from the human third molar: feasibility of cell-based therapy for liver disease.

PubMed

Ikeda, Etsuko; Yagi, Kiyohito; Kojima, Midori; Yagyuu, Takahiro; Ohshima, Akira; Sobajima, Satoshi; Tadokoro, Mika; Katsube, Yoshihiro; Isoda, Katsuhiro; Kondoh, Masuo; Kawase, Masaya; Go, Masahiro J; Adachi, Hisashi; Yokota, Yukiharu; Kirita, Tadaaki; Ohgushi, Hajime

2008-05-01

Adult stem cells have been reported to exist in various tissues. The isolation of high-quality human stem cells that can be used for regeneration of fatal deseases from accessible resources is an important advance in stem cell research. In the present study, we identified a novel stem cell, which we named tooth germ progenitor cells (TGPCs), from discarded third molar, commonly called as wisdom teeth. We demonstrated the characterization and distinctiveness of the TGPCs, and found that TGPCs showed high proliferation activity and capability to differentiate in vitro into cells of three germ layers including osteoblasts, neural cells, and hepatocytes. TGPCs were examined by the transplantation into a carbon tetrachloride (CCl4)-treated liver injured rat to determine whether this novel cell source might be useful for cell-based therapy to treat liver diseases. The successful engraftment of the TGPCs was demonstrated by PKH26 fluorescence in the recipient's rat as to liver at 4 weeks after transplantation. The TGPCs prevented the progression of liver fibrosis in the liver of CCl4-treated rats and contributed to the restoration of liver function, as assessed by the measurement of hepatic serum markers aspartate aminotransferase and alanine aminotransferase. Furthermore, the liver functions, observed by the levels of serum bilirubin and albumin, appeared to be improved following transplantation of TGPCs. These findings suggest that multipotent TGPCs are one of the candidates for cell-based therapy to treat liver diseases and offer unprecedented opportunities for developing therapies in treating tissue repair and regeneration.

Chlorogenic acid protects D-galactose-induced liver and kidney injury via antioxidation and anti-inflammation effects in mice.

PubMed

Feng, Yan; Yu, Ying-Hua; Wang, Shu-Ting; Ren, Jing; Camer, Danielle; Hua, Yu-Zhou; Zhang, Qian; Huang, Jie; Xue, Dan-Lu; Zhang, Xiao-Fei; Huang, Xu-Feng; Liu, Yi

2016-01-01

Oxidative stress and inflammation are implicated in the aging process and its related hepatic and renal function decline. Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in the human diet. Recently, CGA has shown in vivo and in vitro antioxidant properties. The current study investigates the effects of protective effects of chlorogenic acid (CGA) on D-galactose-induced liver and kidney injury. Hepatic and renal injuries were induced in a mouse model by subcutaneously injection of D-galactose (D-gal; 100 mg/kg) once a day for 8 consecutive weeks and orally administered simultaneously with CGA included in the food (200 mg/kg of diet). The liver and renal functions were examined. Histological analyses of liver and kidney were done by haematoxylin and eosin staining. The oxidative stress markers and pro-inflammatory cytokines in the liver and the kidney were measured. Results CGA significantly reduced the serum aminotransferase, serum creatinine (SCr) and blood urea nitrogen (BUN) levels in D-gal mice (p <0.05). CGA also restored superoxide dismutase, catalase, and malondialdehyde levels and decreased glutathione content in the liver and kidney in D-gal mice (p <0.05). Improvements in liver and kidney were also noted in histopathological studies. CGA reduced tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) protein levels in the liver and kidney in D-gal mice (p <0.05). These findings suggest that CGA attenuates D-gal-induced chronic liver and kidney injury and that this protection may be due to its antioxidative and anti-inflammatory activities.

Morphofunctional Changes After Sleeve Gastrectomy and Very Low Calorie Diet in an Animal Model of Non-Alcoholic Fatty Liver Disease.

PubMed

Talavera-Urquijo, Eider; Rodríguez-Navarro, Sarai; Beisani, Marc; Salcedo-Allende, Maria Teresa; Chakkur, Aisha; Arús-Avilés, Marc; Cremades, Manel; Augustin, Salvador; Martell, María; Balibrea, José M

2018-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is found in 70% of obese people. The evidence available to date suggests that bariatric surgery could be an effective treatment by reducing weight and also by improving metabolic complications in the long term. This work aimed to compare, in a diet-induced NAFLD animal model, the effect of both sleeve gastrectomy (SG) and very-low calorie diet (VLCD). Thirty-five Wistar rats were divided into control rats (n = 7) and obese rats fed a high-fat diet (HFD). After 10 weeks, the obese rats were subdivided into four groups: HFD (n = 7), VLCD (n = 7), and rats submitted to either a sham operation (n = 7) or SG (n = 7). Both liver tissue and blood samples were processed to evaluate steatosis and NASH changes in histology (Oil Red, Sirius Red and H&E); presence of endothelial damage (CD31, Moesin/p-Moesin, Akt/p-Akt, eNOS/p-eNOS), oxidative stress (iNOS) and fibrosis (αSMA, Col1, PDGF, VEGF) proteins in liver tissue; and inflammatory (IL6, IL10, MCP-1, IL17α, TNFα), liver biochemical function, and hormonal (leptin, ghrelin, visfatin and insulin) alterations in plasma. Both VLCD and SG improved histology, but only SG induced a significant weight loss, improved endothelial damage, and a decreased cardiovascular risk by reducing insulin resistance (IR), leptin, total cholesterol, and triglyceride levels. There were no relevant variations in the inflammatory and fibrosis markers. Our study suggests a slight superiority of SG over VLCD by improving not only the histology but also the IR and cardiovascular risk markers related to NAFLD.

Survival Benefits of Small Anatomical Resection of the Liver for Patients with Hepatocellular Carcinoma and Impaired Liver Function, Based on New-Era Imaging Studies.

PubMed

Sakoda, Masahiko; Ueno, Shinichi; Iino, Satoshi; Hiwatashi, Kiyokazu; Minami, Koji; Kawasaki, Yota; Kurahara, Hiroshi; Mataki, Yuko; Maemura, Kosei; Shinchi, Hiroyuki; Natsugoe, Shoji

2016-01-01

It has been reported that anatomical resection of the liver may be preferred for primary hepatocellular carcinoma (HCC), and is at least recommended for systematic removal of a segment confined by tumor-bearing portal tributaries. However, nonanatomical resection (NAR) is often selected because of the patient's background, impairment of liver function, and tumor factors. The aims of the present study were to retrospectively compare the recurrence-free survival (RFS) rates for cases of partial resection (PR) and for small anatomical resection (SAR), which is regarded as NAR for primary HCC with impaired liver function. So-called NAR was performed for a primary and solitary (≤ 5cm) HCC in 47 patients; the patients were classified into PR (n=25) and SAR (n=22) groups. Clinicopathological factors, survival data, and recurrence patterns were compared between groups. There were no significant differences in the preoperative characteristics between the two groups. Operative time was significantly longer in the SAR group than in the PR group. There was no significant difference in the postoperative morbidity and tumor pathological characteristics between the two groups. The RFS of the SAR group was significantly better than those of the PR group. Although there was no significant difference in the pattern of recurrence between the two groups, the rate of intrahepatic recurrence in the same segment as the initial tumor tended to be higher in the PR group than in the SAR group. Multivariate analysis revealed that only the PR operative procedure was significant independent risk factor for poorer RFS. Compared with PR, SAR effectively improves the rate of RFS after surgery for a primary and solitary HCC with impaired liver function.

The prognostic value of functional and anatomical parameters for the selection of patients receiving yttrium-90 microspheres for the treatment of liver cancer

NASA Astrophysics Data System (ADS)

Mesoloras, Geraldine

Yttrium-90 (90Y) microsphere therapy is being utilized as a treatment option for patients with primary and metastatic liver cancer due to its ability to target tumors within the liver. The success of this treatment is dependent on many factors, including the extent and type of disease and the nature of prior treatments received. Metabolic activity, as determined by PET imaging, may correlate with the number of viable cancer cells and reflect changes in viable cancer cell volume. However, contouring of PET images by hand is labor intensive and introduces an element of irreproducibility into the determination of functional target/tumor volume (FTV). A computer-assisted method to aid in the automatic contouring of FTV has the potential to substantially improve treatment individualization and outcome assessment. Commercial software to determine FTV in FDG-avid primary and metastatic liver tumors has been evaluated and optimized. Volumes determined using the automated technique were compared to those from manually drawn contours identified using the same cutoff in the standard uptake value (SUV). The reproducibility of FTV is improved through the introduction of an optimal threshold value determined from phantom experiments. Application of the optimal threshold value from the phantom experiments to patient scans was in good agreement with hand-drawn determinations of the FTV. It is concluded that computer-assisted contouring of the FTV for primary and metastatic liver tumors improves reproducibility and increases accuracy, especially when combined with the selection of an optimal SUV threshold determined from phantom experiments. A method to link the pre-treatment assessment of functional (PET based) and anatomical (CT based) parameters to post-treatment survival and time to progression was evaluated in 22 patients with colorectal cancer liver metastases treated using 90Y microspheres and chemotherapy. The values for pre-treatment parameters that were the best predictors of response were determined for FTV, anatomical tumor volume, total lesion glycolysis, and the tumor marker, CEA. Of the parameters considered, the best predictors of response were found to be pre-treatment FTV ≤153 cm3, ATV ≤163 cm3, TLG ≤144 g in the chemo-SIRT treated field, and CEA ≤11.6 ng/mL.

Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice.

PubMed

Peng, Yuan; Chen, Qian; Yang, Tao; Tao, Yanyan; Lu, Xiong; Liu, Chenghai

2014-03-01

Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and D-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phenanthroline treatment groups. The Serum liver function parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assayed with the commercial kit. The inflammation and scaffold structure in liver were stained with hematoxylin and eosin and silver staining respectively. The LSECs and sub-endothelial basement membrane were observed with the scanning and transmission electronic microscope. The protein expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in liver were analyzed with Western blotting. Expression of von Willebrand factor (vWF) was investigated with immunofluorescence staining. The lipid peroxidation indicators including antisuperoxideanion (ASAFR), hydroxyl free radical (·OH), superoxide dismutase (SOD), malondialdehyde and glutathione S-transferase (GST) were determined with kits, and matrix metalloproteinase-2 and 9 (MMP-2/9) activities in liver were analyzed with gelatin zymography and in situ fluorescent zymography respectively. The model mice had much higher serum levels of ALT and AST than the normal mice. Compared to that in the normal control, more severe liver inflammation and hepatocyte apoptosis, worse hepatic lipid peroxidation demonstrated by the increased ASAFR, ·OH and MDA, but decreased SOD and GST, increased MMP-2/9 activities and VCAM-1, ICAM-1 and vWF expressions, which revealed obvious LSEC injury and scaffold structure broken, were shown in the model control. Compared with the model group, CMCS and 1,10-phenanthroline significantly improved serum ALT/AST, attenuated hepatic inflammation and improved peroxidative injury in liver, decreased MMP-2/9 activities in liver tissue, improved integration of scaffold structure, and decreased protein expression of VCAM-1 and ICAM-1. CMCS could protect LSECs from injury and maintain the microvasculature integration in acute injured liver of mice induced by LPS/D-GalN. Its action mechanism was associated with the down-regulation of MMP-2/9 activities and inhibition of peroxidation in injured liver.

Thrombocytopenia after liver transplantation: Should we care?

PubMed Central

Takahashi, Kazuhiro; Nagai, Shunji; Safwan, Mohamed; Liang, Chen; Ohkohchi, Nobuhiro

2018-01-01

Transient thrombocytopenia is a common phenomenon after liver transplantation. After liver transplantation (LT), platelet count decreases and reaches a nadir on postoperative days 3-5, with an average reduction in platelet counts of 60%; platelet count recovers to preoperative levels approximately two weeks after LT. The putative mechanisms include haemodilution, decreased platelet production, increased sequestration, medications, infections, thrombosis, or combination of these processes. However, the precise mechanisms remain unclear. The role of platelets in liver transplantation has been highlighted in recent years, and particular attention has been given to their effects beyond hemostasis and thrombosis. Previous studies have demonstrated that perioperative thrombocytopenia causes poor graft regeneration, increases the incidence of postoperative morbidity, and deteriorates the graft and decreases patient survival in both the short and long term after liver transplantation. Platelet therapies to increase perioperative platelet counts, such as thrombopoietin, thrombopoietin receptor agonist, platelet transfusion, splenectomy, and intravenous immunoglobulin treatment might have a potential for improving graft survival, however clinical trials are lacking. Further studies are warranted to detect direct evidence on whether thrombocytopenia is the cause or result of poor-graft function and postoperative complications, and to determine who needs platelet therapies in order to prevent postoperative complications and thus improve post-transplant outcomes. PMID:29632420

Microbiota, a key player in alcoholic liver disease.

PubMed

Cassard, Anne-Marie; Ciocan, Dragos

2017-12-22

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. Only 20% of heavy alcohol consumers develop alcoholic liver cirrhosis. The intestinal microbiota (IM) has been recently identified as a key player in the severity of liver injury in ALD. Common features of ALD include a decrease of gut epithelial tight junction protein expression, mucin production, and antimicrobial peptide levels. This disruption of the gut barrier, which is a prerequisite for ALD, leads to the passage of bacterial products into the blood stream (endotoxemia). Moreover, metabolites produced by bacteria, such as short chain fatty acids, volatile organic compounds (VOS), and bile acids (BA), are involved in ALD pathology. Probiotic treatment, IM transplantation, or the consumption of dietary fiber, such as pectin, which all alter the ratio of bacterial species, have been shown to improve liver injury in animal models of ALD and to be associated with an improvement in gut barrier function. Although the connections between the microbiota and the host in ALD are well established, the underlying mechanisms are still an active area of research. Targeting the microbiome through the use of prebiotic, probiotic, and postbiotic modalities could be an attractive new approach to manage ALD.

Preoperative selection of patients with colorectal cancer liver metastasis for hepatic resection

PubMed Central

Mattar, Rafif E; Al-alem, Faisal; Simoneau, Eve; Hassanain, Mazen

2016-01-01

Surgical resection of colorectal liver metastases (CRLM) has a well-documented improvement in survival. To benefit from this intervention, proper selection of patients who would be adequate surgical candidates becomes vital. A combination of imaging techniques may be utilized in the detection of the lesions. The criteria for resection are continuously evolving; currently, the requirements that need be met to undergo resection of CRLM are: the anticipation of attaining a negative margin (R0 resection), whilst maintaining an adequate functioning future liver remnant. The timing of hepatectomy in regards to resection of the primary remains controversial; before, after, or simultaneously. This depends mainly on the tumor burden and symptoms from the primary tumor. The role of chemotherapy differs according to the resectability of the liver lesion(s); no evidence of improved survival was shown in patients with resectable disease who received preoperative chemotherapy. Presence of extrahepatic disease in itself is no longer considered a reason to preclude patients from resection of their CRLM, providing limited extra-hepatic disease, although this currently is an area of active investigations. In conclusion, we review the indications, the adequate selection of patients and perioperative factors to be considered for resection of colorectal liver metastasis. PMID:26811608

Portal vein embolization for induction of selective hepatic hypertrophy prior to major hepatectomy: rationale, techniques, outcomes and future directions

PubMed Central

Li, David; Madoff, David C.

2016-01-01

The ability to modulate the future liver remnant (FLR) is a key component of modern oncologic hepatobiliary surgery practice and has extended surgical candidacy for patients who may have been previously thought unable to survive liver resection. Multiple techniques have been developed to augment the FLR including portal vein embolization (PVE), associating liver partition and portal vein ligation (ALPPS), and the recently reported transhepatic liver venous deprivation (LVD). PVE is a well-established means to improve the safety of liver resection by redirecting blood flow to the FLR in an effort to selectively hypertrophy and ultimately improve functional reserve of the FLR. This article discusses the current practice of PVE with focus on summarizing the large number of published reports from which outcomes based practices have been developed. Both technical aspects of PVE including volumetry, approaches, and embolization agents; and clinical aspects of PVE including data supporting indications, and its role in conjunction with chemotherapy and transarterial embolization will be highlighted. PVE remains an important aspect of oncologic care; in large part due to the substantial foundation of information available demonstrating its clear clinical benefit for hepatic resection candidates with small anticipated FLRs. PMID:28154774

Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function.

PubMed

Elinav, Eran; Ali, Mohammad; Bruck, Rafi; Brazowski, Eli; Phillips, Adam; Shapira, Yami; Katz, Meirav; Solomon, Gila; Halpern, Zamir; Gertler, Arieh

2009-01-01

Leptin signaling is involved in T-cell polarization and is required for profibrotic function of hepatic stellate cells (HSCs). Leptin-deficient ob/ob mice do not develop liver fibrosis despite the presence of severe long-standing steatohepatitis. Here, we blocked leptin signaling with our recently generated mouse leptin antagonist (MLA), and examined the effects on chronic liver fibrosis in vivo using the chronic thioacetamide (TAA) fibrosis model, and in vitro using freshly-isolated primary HSCs. In the chronic TAA fibrosis model, leptin administration was associated with significantly enhanced liver disease and a 100% 5-week to 8-week mortality rate, while administration or coadministration of MLA markedly improved survival, attenuated liver fibrosis, and reduced interferon gamma (IFN-gamma) levels. No significant changes in weight, serum cholesterol, or triglycerides were noted. In vitro administration of rat leptin antagonist (RLA), either alone or with leptin, to rat primary HSCs reduced leptin-stimulated effects such as increased expression of alpha-smooth muscle actin (alpha-SMA), and activation of alpha1 procollagen promoter. Inhibition of leptin-enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality.

A case of lacosamide-induced hepatotoxicity.

PubMed

Sunwoo, Jun-Sang; Byun, Jung-Ick; Lee, Sang Kun

2015-06-01

Lacosamide is a novel antiepileptic drug that acts mainly via the selective enhancement of slow inactivation of voltage-gated sodium channels. It has been reported that lacosamide is effective and generally tolerable as an adjuvant treatment in patients with partial seizures. There are few reports regarding liver damage caused by lacosamide. We describe a case of a patient with drug-resistant epilepsy who developed symptomatic hepatotoxicity after lacosamide administration. A 22-year-old female with a 2-year history of temporal lobe epilepsy was admitted to our hospital because of nausea, dizziness, and abnormal liver function tests. Lacosamide was added for further seizure control 9 days before the current presentation. Her liver enzymes were markedly increased: aspartate aminotransferase, 635 U/L; alanine aminotransferase, 697 U/L. Lacosamide was ceased immediately, whereas other medications (zonisamide, clobazam, and tianeptine) were not withdrawn. The level of liver enzymes improved significantly within a few days, and a diagnosis of lacosamide-induced hepatitis was made based on the obvious temporal relationship. This case report demonstrates that hepatotoxicity may develop in association with lacosamide therapy. Liver function tests should be prompted in patients with symptoms suggestive of adverse effects after the initiation of lacosamide. Further research is required to identify predisposing factors of lacosamideinduced hepatotoxicity.

Care standards for non-alcoholic fatty liver disease in the United Kingdom 2016: a cross-sectional survey.

PubMed

Sheridan, David A; Aithal, Guru; Alazawi, William; Allison, Michael; Anstee, Quentin; Cobbold, Jeremy; Khan, Shahid; Fowell, Andrew; McPherson, Stuart; Newsome, Philip N; Oben, Jude; Tomlinson, Jeremy; Tsochatzis, Emmanouil

2017-10-01

Guidelines for the assessment of non-alcoholic fatty liver disease (NAFLD) have been published in 2016 by National Institute for Health and Care Excellence and European Associations for the study of the Liver-European Association for the study of Diabetes-European Association for the study of Obesity. Prior to publication of these guidelines, we performed a cross-sectional survey of gastroenterologists and hepatologists regarding NAFLD diagnosis and management. An online survey was circulated to members of British Association for the Study of the Liver and British Society of Gastroenterology between February 2016 and May 2016. 175 gastroenterologists/hepatologists responded, 116 completing the survey, representing 84 UK centres. 22% had local NAFLD guidelines. 45% received >300 referrals per year from primary care for investigation of abnormal liver function tests (LFTs). Clinical assessment tended to be performed in secondary rather than primary care including body mass index (82% vs 26%) and non-invasive liver screen (86% vs 32%) and ultrasound (81% vs 37%). Widely used tools for non-invasive fibrosis risk stratification were aspartate transaminase (AST)/alanine transaminase (ALT) ratio (53%), Fibroscan (50%) and NAFLD fibrosis score (41%). 78% considered liver biopsy in selected cases. 50% recommended 10% weight loss target as first-line treatment. Delivery of lifestyle interventions was mostly handed back to primary care (56%). A minority have direct access to community weight management services (22%). Follow-up was favoured by F3/4 fibrosis (72.9%), and high-risk non-invasive fibrosis tests (51%). Discharge was favoured by simple steatosis at biopsy (30%), and low-risk non-invasive scores (25%). The survey highlights areas for improvement of service provision for NAFLD assessment including improved recognition of non-alcoholic steatohepatitis in people with type 2 diabetes, streamlining abnormal LFT referral pathways, defining non-invasive liver fibrosis assessment tools, use of liver biopsy, managing metabolic syndrome features and improved access to lifestyle interventions.

Liver Function Tests

MedlinePlus

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Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications

PubMed Central

Ponziani, Francesca Romana; Gerardi, Viviana; Pecere, Silvia; D’Aversa, Francesca; Lopetuso, Loris; Zocco, Maria Assunta; Pompili, Maurizio; Gasbarrini, Antonio

2015-01-01

Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial “fingerprint”, characterized by the reduced ratio of “good” to “potentially pathogenic” bacteria has recently been outlined, and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover, in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), and, portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic, immune-modulating and anti-inflammatory activity, a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE, and also to prevent the development of SBP, to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality, triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease. PMID:26604640

Ex vivo adenoviral gene transfer of constitutively activated STAT3 reduces post-transplant liver injury and promotes regeneration in a 20% rat partial liver transplant model.

PubMed

Huda, Kamrul A S M; Guo, Lei; Haga, Sanae; Murata, Hiroshi; Ogino, Tetsuya; Fukai, Moto; Yagi, Takahito; Iwagaki, Hiromi; Tanaka, Noriaki; Ozaki, Michitaka

2006-05-01

Signal transducer and activator of transcription-3 (STAT3) is one of the most important transcription factors for liver regeneration. This study was designed to examine the effects of constitutively activated STAT3 (STAT3-C) on post-transplant liver injury and regeneration in a rat 20% partial liver transplant (PLTx) model by ex vivo adenoviral gene transfer. Adenovirus encoding the STAT3-C gene was introduced intraportally into liver grafts and clamped for 30 min during cold preservation. After orthotopic PLTx, liver graft/body weights and serum biochemistry were monitored, and both a histological study and DNA binding assay were performed. STAT3-C protein expression and its binding to DNA in the liver graft were confirmed by Western blotting and electrophoretic mobility shift assay (EMSA), respectively. This treatment modality promoted post-Tx liver regeneration effectively and rapidly. The serum levels of alanine aminotransferase/aspartate aminotransferase (AST/ALT) and bilirubin decreased in rats with STAT3-C. However, albumin (a marker of liver function) did not. Ex vivo gene transfer of STAT3-C to liver grafts reduced post-Tx injury and promoted liver regeneration. Thus, the activation of STAT3 in the liver graft may be a potentially effective clinical strategy for improving the outcome of small-for-size liver transplantation.

Long-term hepatotoxicity of polyethylene-glycol functionalized multi-walled carbon nanotubes in mice

NASA Astrophysics Data System (ADS)

Zhang, Danying; Deng, Xiaoyong; Ji, Zongfei; Shen, Xizhong; Dong, Ling; Wu, Minghong; Gu, Taoying; Liu, Yuanfang

2010-04-01

The toxicity of polyethylene-glycol functionalized (PEGylated) multi-walled carbon nanotubes (MWCNTs) and non-PEGylated MWCNTs in vivo was evaluated and compared. Mice were exposed to MWCNTs by intravenous injection. The activity level of glutathione, superoxide dismutase and gene expression in liver, as well as some biochemical parameters and the tumor necrosis factor alpha level in blood were measured over 2 months. The pathological and electron micrographic observations of liver evidently indicate that the damage caused by non-PEGylated MWCNTs is slightly more severe than that of PEGylated MWCNTs, which means that PEGylation can partly, but not substantially, improve the in vivo biocompatibility of MWCNTs.

Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction.

PubMed

La Mura, Vincenzo; Pasarín, Marcos; Meireles, Cintia Z; Miquel, Rosa; Rodríguez-Vilarrupla, Aina; Hide, Diana; Gracia-Sancho, Jorge; García-Pagán, Juan Carlos; Bosch, Jaime; Abraldes, Juan G

2013-03-01

Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis. The present study explores liver vascular abnormalities and the effects of statins in a rat model of endotoxemia. For this purpose, lipopolysaccharide (LPS) or saline was given to: (1) rats treated with placebo; (2) rats treated with simvastatin (25 mg/kg, orally), given at 3 and 23 hours after LPS/saline challenge; (3) rats treated with simvastatin (25 mg/kg/24 h, orally) from 3 days before LPS/saline injection. Livers were isolated and perfused and sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine. The phosphorylated endothelial nitric oxide synthase (PeNOS)/endothelial nitric oxide synthase (eNOS) ratio was measured as a marker of eNOS activation. LPS administration induced an increase in baseline portal perfusion pressure and a decrease in vasodilation to acetylcholine (sinusoidal endothelial dysfunction). This was associated with reduced eNOS phosphorylation and liver inflammation. Simvastatin after LPS challenge did not prevent the increase in baseline portal perfusion pressure, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine and reduced liver inflammation. Both protocols of treatment restored a physiologic PeNOS/eNOS ratio. LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia. Copyright © 2012 American Association for the Study of Liver Diseases.

Hyperammoniemic coma in a patient with ureterosigmoidostomy and normal liver function.

PubMed

Van Laethem, J L; Gay, F; Franck, N; Van Gossum, A

1992-11-01

Hyperammoniemic encephalopathy has been reported after ureterosigmoidostomy. Its development is related to a problem of bacterial overgrowth and, most often, is favored by the presence of an underlying liver dysfunction. We report the case of a 43-year-old woman with a ureterosigmoidostomy done 28 years earlier who developed hyperammoniemic coma induced by an acute rectocolitis and in the absence of any detectable liver dysfunction. Neither administration of Lactilol and neomycin nor rectal tube drainage were effective; systemic antimicrobial therapy effective against the urease-producing gram-negative bacilli was required and led to a decrease in serum ammonia levels and a dramatic clinical improvement.

Tenofovir-based rescue therapy for advanced liver disease in 6 patients coinfected with HIV and hepatitis B virus and receiving lamivudine.

PubMed

Gutiérrez, Sonia; Guillemi, Silvia; Jahnke, Natalie; Montessori, Valentina; Harrigan, P Richard; Montaner, Julio S G

2008-02-01

We summarize the clinical history and laboratory results following the introduction of tenofovir among 6 patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) who presented with severe liver disease while receiving lamivudine-based highly active antiretroviral therapy. In all cases, the introduction of tenofovir led to a sustained undetectable HBV and HIV loads, with marked clinical and laboratory improvement in liver function. We provide supporting evidence for the role of tenofovir in the management of advanced HBV infection in HIV-positive patients after the development of lamivudine resistance.

Enzymatic liver function capacity correlates with disease severity of patients with liver cirrhosis: a study with the LiMAx test.

PubMed

Malinowski, Maciej; Jara, Maximilian; Lüttgert, Katja; Orr, James; Lock, Johan Friso; Schott, Eckart; Stockmann, Martin

2014-12-01

Assessment and quantification of actual liver function is crucial in patients with chronic liver disease to monitor disease progression and predict individual prognosis. Mathematical models, such as model for end-stage liver disease, are used for risk stratification of patients with chronic liver disease but do not include parameters that reflect the actual functional state of the liver. We aimed to evaluate the potential of a (13)C-based liver function test as a stratification tool by comparison with other liver function tests and clinical parameters in a large sample of healthy controls and cirrhotic patients. We applied maximum liver function capacity (LiMAx) to evaluate actual liver function in 347 patients with cirrhosis and in 86 controls. LiMAx showed strong negative correlation with Child-Pugh Score (r = -0.707; p < 0.001), MELD (r = -0.686; p < 0.001) and liver function tests. LiMAx was lower in patients with liver cirrhosis compared to healthy controls [99 (57-160) µg/kg/h vs. 412 (365-479) µg/kg/h, p < 0.001] and differed among Child-Pugh classes [a: 181 (144-227) µg/kg/h, b: 96 (62-132) µg/kg/h and c: 52 (37-81) µg/kg/h; p < 0.001]. When stratified patients according to disease severity, LiMAx results were not different between cirrhotic patients and cirrhotic patients with transjugular intrahepatic portosystemic shunt. LiMAx appears to provide reliable information on remnant enzymatic liver function in chronic liver disease and allows graduation of disease severity.

Regulation of mitochondrial trifunctional protein modulates nonalcoholic fatty liver disease in mice

PubMed Central

Nassir, Fatiha; Arndt, Justin J.; Johnson, Sarah A.

2018-01-01

Mitochondrial trifunctional protein (MTP) plays a critical role in the oxidation of long-chain fatty acids. We previously reported that aging mice (>9 months old) heterozygous for an MTP defect (MTP+/−) develop nonalcoholic fatty liver disease (NAFLD). We tested whether a high-fat diet (HFD) accelerates NAFLD in young MTP+/−mice, and whether overexpression of the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin 3 (SIRT3) deacetylates MTP and improves mitochondrial function and NAFLD. Three-month-old WT and MTP+/− mice were fed HFD (60% cal fat) for 16 weeks and livers were assessed for fatty acid oxidation (FAO) and NAFLD. Compared with WT, MTP+/− mice displayed reduced hepatic SIRT3 levels and reduced FAO, with increased hepatic steatosis and the inflammatory marker CD68. Hepatic overexpression of SIRT3 in HFD-fed MTP+/− mice increased hepatic MTP protein levels at the posttranscriptional level. Immunoprecipitation of MTP from liver mitochondria followed by Western blot with acetyl-lysine antibody showed higher acetylation of MTP in MTP+/− compared with WT mice. Overexpression of SIRT3 in MTP+/− mice significantly reduced the acetylation of MTP compared with β-galactosidase controls, increased mitochondrial FAO, and reduced hepatic steatosis, CD68, and serum ALT levels. Taken together, our data indicate that deacetylation of MTP by SIRT3 improves mitochondrial function and rescues NAFLD in MTP+/− mice. PMID:29581157

In vivo bioavailability of polyphenols from grape by-product extracts, and effect on lipemia of normocholesterolemic Wistar rats.

PubMed

Olivero-David, Raul; Ruiz-Roso, Maria Belen; Caporaso, Nicola; Perez-Olleros, Lourdes; De Las Heras, Natalia; Lahera, Vicente; Ruiz-Roso, Baltasar

2018-04-24

The direct use of phenolic extracts from grape by-products can be useful to formulate functional food to improve consumers' health. The use of phenolic extracts instead of pure polyphenols as an ingredient is relevant in this context. The current work studied the bioavailability and absorption of polyphenols from grape by-product extracts and their health effect on cholesterolemia, by adding the extract (GE) to Wistar rats diet (50 g/kg) in vivo. GE caused the appearance of (+)-catechin, myricetin and quercetic acid in plasma and liver. (+)-Catechin was the most abundant compound, with 6 μg/mL in plasma and 0.7 μg/mg protein in liver, while no phenolic compounds were detected in plasma or liver in the control group. Similarly, 3,4-hydroxyphenylacetic (DOPAC), a major product of polyphenol digestion, was detected in the plasma, liver and urine of the GE-group only. GE-group had significantly lower cholesterol level and lower total cholesterol/HDL ratio in plasma. Total bile acid (TBA) content significantly increased in faecal matter after 24 h administration of the GE-enriched diet. Grape extract polyphenols are partially bioavailable and showed improvement in lipid metabolism. Thus, the results suggest that GE is promising as a functional ingredient in the prevention of hypercholesterolemia. This article is protected by copyright. All rights reserved.

Comparison of the therapeutic effectiveness of human CD34+ and rat bone marrow mesenchymal stem cells on improvement of experimental liver fibrosis in Wistar rats

PubMed Central

Sayyed, Hayam G; Osama, Amany; Idriss, Naglaa K; Sabry, Dina; Abdelrhim, Azza S; Bakry, Rania

2016-01-01

Background and objective: Human umbilical cord blood (UCB) cells and bone marrow mesenchymal stem cells (BM-MSCs) have numerous advantages as grafts for cell transplantation. We hypothesized differing impacts of human UCB cells and rat BM-MSCs on reversal of hepatic injury and revival of liver function in carbon tetrachloride (CCl4)-induced liver fibrosis. Methods: Forty rats were divided into 4 groups; control group, CCl4 group, CCl4/CD34+ group and CCl4/BM-MSCs group. Blood samples were driven from rats at 4, 8 and 12 weeks to measure serum concentration of albumin and alanine aminotransferase (ALT). Quantitative expression of collagen Iα, TGF-β, α-SMA, albumin, MMP-2, MMP-9 and TNF-α were assessed by polymerase chain reaction. Histopathological examination of the liver tissue was performed. GFP labeled cells were detected in groups injected with stem cells. Results: Regarding liver function, CD34+ were more efficient than BM-MSCs in elevating albumin (P<0.05) and reducing ALT (P<0.05) concentrations. Concerning gene expression, CD34+ were more effective than BM-MSCs in reducing gene expressions of collagen Iα (P<0.01), TGF-β1 (P<0.01) and α-SMA (P<0.01). Both CD34+ and BM-MSCs have the same efficacy in reducing TNF-α (P<0.001 and P<0.01, respectively). Furthermore, CD34+ were more valuable than BM-MSCs in increasing gene expression of albumin (P<0.05) and MMP-9 (P<0.01). Conclusion: Taken together; human UCB CD34+ stem cells were more efficient in improvement of experimental liver injury than BM-MSCs. This study highlighted an important role of human UCB CD34+ stem cells in liver fibrosis therapy. PMID:27785340

Choline supplementation protects against liver damage by normalizing cholesterol metabolism in Pemt/Ldlr knockout mice fed a high-fat diet.

PubMed

Al Rajabi, Ala; Castro, Gabriela S F; da Silva, Robin P; Nelson, Randy C; Thiesen, Aducio; Vannucchi, Helio; Vine, Donna F; Proctor, Spencer D; Field, Catherine J; Curtis, Jonathan M; Jacobs, René L

2014-03-01

Dietary choline is required for proper structure and dynamics of cell membranes, lipoprotein synthesis, and methyl-group metabolism. In mammals, choline is synthesized via phosphatidylethanolamine N-methyltransferase (Pemt), which converts phosphatidylethanolamine to phosphatidylcholine. Pemt(-/-) mice have impaired VLDL secretion and developed fatty liver when fed a high-fat (HF) diet. Because of the reduction in plasma lipids, Pemt(-/-)/low-density lipoprotein receptor knockout (Ldlr(-/-)) mice are protected from atherosclerosis. The goal of this study was to investigate the importance of dietary choline in the metabolic phenotype of Pemt(-/-)/Ldlr(-/-) male mice. At 10-12 wk of age, Pemt(+/+)/Ldlr(-/-) (HF(+/+)) and half of the Pemt(-/-)/Ldlr(-/-) (HF(-/-)) mice were fed an HF diet with normal (1.3 g/kg) choline. The remaining Pemt(-/-)/Ldlr(-/-) mice were fed an HF diet supplemented (5 g/kg) with choline (HFCS(-/-) mice). The HF diet contained 60% of calories from fat and 1% cholesterol, and the mice were fed for 16 d. HF(-/-) mice lost weight and developed hepatomegaly, steatohepatitis, and liver damage. Hepatic concentrations of free cholesterol, cholesterol-esters, and triglyceride (TG) were elevated by 30%, 1.1-fold and 3.1-fold, respectively, in HF(-/-) compared with HF(+/+) mice. Choline supplementation normalized hepatic cholesterol, but not TG, and dramatically improved liver function. The expression of genes involved in cholesterol transport and esterification increased by 50% to 5.6-fold in HF(-/-) mice when compared with HF(+/+) mice. Markers of macrophages, oxidative stress, and fibrosis were elevated in the HF(-/-) mice. Choline supplementation normalized the expression of these genes. In conclusion, HF(-/-) mice develop liver failure associated with altered cholesterol metabolism when fed an HF/normal choline diet. Choline supplementation normalized cholesterol metabolism, which was sufficient to prevent nonalcoholic steatohepatitis development and improve liver function. Our data suggest that choline can promote liver health by maintaining cholesterol homeostasis.

Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure.

PubMed

Wang, Kun; Li, Yuwen; Zhu, Tiantian; Zhang, Yongting; Li, Wenting; Lin, Wenyu; Li, Jun; Zhu, Chuanlong

2017-07-05

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has emerged as a novel therapy for acute liver failure (ALF). However, the homing efficiency of BMSCs to the injured liver sites appears to be poor. In this study, we aimed to determine if overexpression of c-Met in BMSCs could promote the homing ability of BMSCs to rat livers affected by ALF. Overexpression of c-Met in BMSCs (c-Met-BMSCs) was attained by transfection of naive BMSCs with the lenti-c-Met-GFP. The impact of transplanted c-Met-BMSCs on both homing and repair of ALF was evaluated and compared with lenti-GFP empty vector transfected BMSCs (control BMSCs). After cells were transfected with the lenti-c-Met-GFP vector, the BMSCs displayed very high expression of c-Met protein as demonstrated by Western blot. In addition, in vitro transwell migration assays showed that the migration ability of c-Met-BMSCs was significantly increased in comparison with that of control BMSCs (P < 0.05), and was dependent on hepatocyte growth factor (HGF). Furthermore, rats with ALF that received transplanted c-Met-BMSCs showed significantly improved homing ability to the injured liver; this was accompanied by elevated survival rates and liver function in the ALF rats. Parallel pathological examination further confirmed that transplantation of c-Met-BMSCs ameliorated liver injury with reduced hepatic activity index (HAI) scores, and that the effects of c-Met-BMSCs were more profound than those of control BMSCs. Overexpression of c-Met promotes the homing of BMSCs to injured hepatic sites in a rat model of ALF, thereby improving the efficacy of BMSC therapy for ALF repair.

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation

PubMed Central

Hey, Penelope; Lokan, Julie; Johnson, Paul; Gow, Paul

2017-01-01

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease. PMID:28951512

Consumption of Goats’ Milk Protects Mice From Carbon Tetrachloride-Induced Acute Hepatic Injury and Improves the Associated Gut Microbiota Imbalance

PubMed Central

Zhang, Jiachao; Wang, Zhaoxia; Huo, Dongxue; Shao, Yuyu

2018-01-01

Drugs used to treat liver diseases have serious side effects; it is important to search for safe functional foods with hepatoprotective functions and few side effects. In this study, potential hepatoprotective effects of goats’ milk and cows’ milk on mice with CCl4-induced acute hepatic injury were evaluated. We also elucidated the role of goats’ and cows’ milk on the regulation of CCl4-induced gut microbiota imbalance. In mice with liver damage induced by CCl4, administration of goats’ milk for 7 days prior to injection of CCl4 had beneficial effects on the indicators of liver damage within 1 day: the area of liver necrosis was small; activity of alanine transaminase (ALT) and aspartate transaminase (AST) and expression of the genes CYP2E1 and TNF-α were lower than that of model group of mice. By 7 days after CCl4 injection, there were no significant differences in liver damage indicators (ALT, AST, malondialdehyde, superoxide dismutase, and glutathione) between the goats’ milk group, which continued to receive goats’ milk, and the untreated control group of mice showing that goats’ milk continued to protect against liver damage. Throughout the entire experiment, the community of gut microbes from mice in the goats’ milk treatment was more similar to the untreated control group than to the cows’ milk group and the model group, indicating that intake of goats’ milk prior and post-CCl4 injection effectively prevented and alleviated the intestinal microbial disorder that caused by CCl4 in mice. Our research suggests that goats’ milk could be developed as a potential functional food to prevent/protect against liver injury. PMID:29867999

Biliary drainage strategy of unresectable malignant hilar strictures by computed tomography volumetry.

PubMed

Takahashi, Ei; Fukasawa, Mitsuharu; Sato, Tadashi; Takano, Shinichi; Kadokura, Makoto; Shindo, Hiroko; Yokota, Yudai; Enomoto, Nobuyuki

2015-04-28

To identify criteria for predicting successful drainage of unresectable malignant hilar biliary strictures (UMHBS) because no ideal strategy currently exists. We examined 78 patients with UMHBS who underwent biliary drainage. Drainage was considered effective when the serum bilirubin level decreased by ≥ 50% from the value before stent placement within 2 wk after drainage, without additional intervention. Complications that occurred within 7 d after stent placement were considered as early complications. Before drainage, the liver volume of each section (lateral and medial sections of the left liver and anterior and posterior sections of the right liver) was measured using computed tomography (CT) volumetry. Drained liver volume was calculated based on the volume of each liver section and the type of bile duct stricture (according to the Bismuth classification). Tumor volume, which was calculated by using CT volumetry, was excluded from the volume of each section. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff values for drained liver volume. In addition, factors associated with the effectiveness of drainage and early complications were evaluated. Multivariate analysis showed that drained liver volume [odds ratio (OR) = 2.92, 95%CI: 1.648-5.197; P < 0.001] and impaired liver function (with decompensated liver cirrhosis) (OR = 0.06, 95%CI: 0.009-0.426; P = 0.005) were independent factors contributing to the effectiveness of drainage. ROC analysis for effective drainage showed cutoff values of 33% of liver volume for patients with preserved liver function (with normal liver or compensated liver cirrhosis) and 50% for patients with impaired liver function (with decompensated liver cirrhosis). The sensitivity and specificity of these cutoff values were 82% and 80% for preserved liver function, and 100% and 67% for impaired liver function, respectively. Among patients who met these criteria, the rate of effective drainage among those with preserved liver function and impaired liver function was 90% and 80%, respectively. The rates of effective drainage in both groups were significantly higher than in those who did not fulfill these criteria (P < 0.001 and P = 0.02, respectively). Drainage-associated cholangitis occurred in 9 patients (12%). A smaller drained liver volume was associated with drainage-associated cholangitis (P < 0.01). Liver volume drainage ≥ 33% in patients with preserved liver function and ≥ 50% in patients with impaired liver function correlates with effective biliary drainage in UMHBS.

High Efficient Differentiation of Functional Hepatocytes from Porcine Induced Pluripotent Stem Cells

PubMed Central

Ao, Ying; Mich-Basso, Jocelyn Danielle; Lin, Bo; Yang, Lei

2014-01-01

Hepatocyte transplantation is considered to be a promising therapy for patients with liver diseases. Induced pluripotent stem cells (iPSCs) provide an unlimited source for the generation of functional hepatocytes. In this study, we generated iPSCs from porcine ear fibroblasts (PEFs) by overexpressing Sox2, Klf4, Oct4, and c-Myc (SKOM), and developed a novel strategy for the efficient differentiation of hepatocyte-like cells from porcine iPSCs by following the processes of early liver development. The differentiated cells displayed the phenotypes of hepatocytes, exhibited classic hepatocyte-associated bio-functions, such as LDL uptake, glycogen storage and urea secretion, as well as possessed the metabolic activities of cytochrome P-450 (CYP) 3A and 2C. Furthermore, we compared the hepatocyte differentiation efficacy of our protocol with another published method, and the results demonstrated that our differentiation strategy could significantly improve the generation of morphological and functional hepatocyte-like cells from porcine iPSCs. In conclusion, this study establishes an efficient method for in vitro generation of functional hepatocytes from porcine iPSCs, which could represent a promising cell source for preclinical testing of cell-based therapeutics for liver failure and for pharmacological applications. PMID:24949734

Effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells on microcirculation and energy metabolism following liver transplantation

PubMed Central

Yang, Liu; Shen, Zhong-Yang; Wang, Rao-Rao; Yin, Ming-Li; Zheng, Wei-Ping; Wu, Bin; Liu, Tao; Song, Hong-Li

2017-01-01

AIM To investigate the effects of heme oxygenase-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation (RLT) in a rat model. METHODS BMMSCs were isolated and cultured in vitro using an adherent method, and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs. A rat acute rejection model following 50% RLT was established using a two-cuff technique. Recipients were divided into three groups based on the treatment received: normal saline (NS), BMMSCs and HO-1/BMMSCs. Liver function was examined at six time points. The levels of endothelin-1 (ET-1), endothelial nitric-oxide synthase (eNOS), inducible nitric-oxide synthase (iNOS), nitric oxide (NO), and hyaluronic acid (HA) were detected using an enzyme-linked immunosorbent assay. The portal vein pressure (PVP) was detected by Power Lab ML880. The expressions of ET-1, iNOS, eNOS, and von Willebrand factor (vWF) protein in the transplanted liver were detected using immunohistochemistry and Western blotting. ATPase in the transplanted liver was detected by chemical colorimetry, and the ultrastructural changes were observed under a transmission electron microscope. RESULTS HO-1/BMMSCs could alleviate the pathological changes and rejection activity index of the transplanted liver, and improve the liver function of rats following 50% RLT, with statistically significant differences compared with those of the NS group and BMMSCs group (P < 0.05). In term of the microcirculation of hepatic sinusoids: The PVP on POD7 decreased significantly in the HO-1/BMMSCs and BMMSCs groups compared with that of the NS group (P < 0.01); HO-1/BMMSCs could inhibit the expressions of ET-1 and iNOS, increase the expressions of eNOS and inhibit amounts of NO production, and maintain the equilibrium of ET-1/NO (P < 0.05); and HO-1/BMMSCs increased the expression of vWF in hepatic sinusoidal endothelial cells (SECs), and promoted the degradation of HA, compared with those of the NS group and BMMSCs group (P < 0.05). In term of the energy metabolism of the transplanted liver, HO-1/BMMSCs repaired the damaged mitochondria, and improved the activity of mitochondrial aspartate aminotransferase (ASTm) and ATPase, compared with the other two groups (P <0.05). CONCLUSION HO-1/BMMSCs can improve the microcirculation of hepatic sinusoids significantly, and recover the energy metabolism of damaged hepatocytes in rats following RLT, thus protecting the transplanted liver. PMID:28596681

A fourth dimension in decision making in hepatology.

PubMed

Ilan, Yaron

2010-12-01

Today, the assessment of liver function in patients suffering from acute or chronic liver disease is based on liver biopsy and blood tests including synthetic function, liver enzymes and viral load, most of which provide only circumstantial evidence as to the degree of hepatic impairment. Most of these tests lack the degree of sensitivity to be useful for follow-up of these patients at the frequency that is needed for decision making in clinical hepatology. Accurate assessment of liver function is essential to determine both short- and long-term prognosis, and for making decisions about liver and non-liver surgery, TIPS, chemoembolization or radiofrequency ablation in patients with chronic liver disease. Liver function tests can serve as the basis for accurate decision-making regarding the need for liver transplantation in the setting of acute failure or in patients with chronic liver disease. The liver metabolic breath test relies on measuring exhaled (13) C tagged methacetin, which is metabolized only by the liver. Measuring this liver-specific substrate by means of molecular correlation spectroscopy is a rapid, non-invasive method for assessing liver function at the point-of-care. The (13) C methacetin breath test (MBT) is a powerful tool to aid clinical hepatologists in bedside decision-making. Our recent findings regarding the ability of point-of-care (13) C MBT to assess the hepatic functional reserve in patients with acute and chronic liver disease are reviewed along with suggested treatment algorithms for common liver disorders. © 2010 The Japan Society of Hepatology.

Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives.

PubMed

Jin, Tianru; Weng, Jianping

2016-09-01

GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed "degradation" products of GLP-1 without involving canonic GLP-1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed "degradation" products of GLP-1 in the liver and elsewhere, including GLP-128-36 and GLP-132-36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1-based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation. Copyright © 2016 the American Physiological Society.

Liver function tests

MedlinePlus

Liver function tests are common tests that are used to see how well the liver is working. Tests include: ... E, Bowne WB, Bluth MH. Evaluation of liver function. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Liver Function Tests

MedlinePlus

... food, store energy, and remove poisons. Liver function tests are blood tests that check to see how well your liver ... hepatitis and cirrhosis. You may have liver function tests as part of a regular checkup. Or you ...

Delivery of the bioactive gas hydrogen sulfide during cold preservation of rat liver: effects on hepatic function in an ex vivo model.

PubMed

Balaban, Cecilia L; Rodriguez, Joaquín V; Guibert, Edgardo E

2011-05-01

The insults sustained by transplanted livers (hepatectomy, hypothermic preservation, and normothermic reperfusion) could compromise hepatic function. Hydrogen sulfide (H₂S) is a physiologic gaseous signaling molecule, like nitric oxide (NO) and carbon monoxide (CO). We examined the effect of diallyl disulfide as a H₂S donor during hypothermic preservation and reperfusion on intrahepatic resistance (IVR), lactate dehydrogenase (LDH) release, bile production, oxygen consumption, bromosulfophthalein (BSP) depuration and histology in an isolated perfused rat liver model (IPRL), after 48 h of hypothermic storage (4 °C) in University of Wisconsin solution (UW, Viaspan). Livers were retrieved from male Wistar rats. Three experimental groups were analyzed: Control group (CON): IPRL was performed after surgery; UW: IPRL was performed in livers preserved (48 h-4 °C) in UW; and UWS: IPRL was performed in livers preserved (48 h-4 °C) in UW in the presence of 3.4 mM diallyl disulfide. Hypothermic preservation injuries were manifested at reperfusion by a slight increment in IHR and LDH release compared with the control group. Also, bile production for the control group (1.32 µL/min/g of liver) seemed to be diminished after preservation by 73% in UW and 69% in UW H₂S group at the end of normothermic reperfusion. Liver samples analyzed by hematoxylin/eosin clearly showed the deleterious effect of cold storage process, partially reversed (dilated sinusoids and vacuolization attenuation) by the addition of a H₂S delivery compound to the preservation solution. Hepatic clearance (HC) of BSP was affected by cold storage of livers, but there were no noticeable differences between livers preserved with or without diallyl disulfide. Meanwhile, livers preserved in the presence of H₂S donor showed an enhanced capacity for BSP uptake (k(A) CON = 0.29 min⁻¹; k(A) UW = 0.29 min⁻¹ ; k(A) UWS = 0.36 min ⁻¹). In summary, our animal model suggests that hepatic hypothermic preservation for transplantation affects liver function and hepatic depuration of BSP, and implies that the inclusion of an H₂S donor during hypothermic preservation could improve standard methods of preparing livers for transplant. © 2011, Copyright the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice.

PubMed

Yu, Hongwei; Li, Man; Tint, G Stephen; Chen, Jianliang; Xu, Guorong; Patel, Shailendra B

2007-04-04

Targeted disruption of the murine 3beta-hydroxysterol-Delta7-reductase gene (Dhcr7), an animal model of Smith-Lemli-Opitz syndrome, leads to loss of cholesterol synthesis and neonatal death that can be partially rescued by transgenic replacement of DHCR7 expression in brain during embryogenesis. To gain further insight into the role of non-brain tissue cholesterol deficiency in the pathophysiology, we tested whether the lethal phenotype could be abrogated by selective transgenic complementation with DHCR7 expression in the liver. We generated mice that carried a liver-specific human DHCR7 transgene whose expression was driven by the human apolipoprotein E (ApoE) promoter and its associated liver-specific enhancer. These mice were then crossed with Dhcr7+/- mutants to generate Dhcr7-/- mice bearing a human DHCR7 transgene. Robust hepatic transgene expression resulted in significant improvement of cholesterol homeostasis with cholesterol concentrations increasing to 80~90 % of normal levels in liver and lung. Significantly, cholesterol deficiency in brain was not altered. Although late gestational lung sacculation defect reported previously was significantly improved, there was no parallel increase in postnatal survival in the transgenic mutant mice. The reconstitution of DHCR7 function selectively in liver induced a significant improvement of cholesterol homeostasis in non-brain tissues, but failed to rescue the neonatal lethality of Dhcr7 null mice. These results provided further evidence that CNS defects caused by Dhcr7 null likely play a major role in the lethal pathogenesis of Dhcr7-/- mice, with the peripheral organs contributing the morbidity.

A Review of Organ Transplantation: Heart, Lung, Kidney, Liver, and Simultaneous Liver-Kidney.

PubMed

Scheuher, Cynthia

2016-01-01

Heart, lung, kidney, liver, and simultaneous liver-kidney transplants share many features. They all follow the same 7-step process, the same 3 immunosuppressant medications, and the same reason for organ transplantation. Organs are transplanted because of organ failure. The similarities end there. Each organ has its unique causes for failure. Each organ also has its own set of criteria that must be met prior to transplantation. Simultaneous liver-kidney transplant criteria vary per transplant center but are similar in nature. Both the criteria required and the 7-step process are described by the United Network of Organ Sharing, which is a private, nonprofit organization, under contract with the US Department of Health and Human Services. Its function is to increase the number of transplants, improve survival rates after transplantation, promote safe transplant practices, and endorse efficiency. The purpose of this article is to review the reasons transplant is needed, specifically heart, lung, kidney, liver, and simultaneous liver-kidney, and a brief overview of the transplant process including criteria used, contraindications, and medications prescribed.

Encephalopathy in an infant with infantile spasms: possible role of valproate toxicity

PubMed Central

Sivathanu, Shobhana; Sampath, Sowmya; Veerasamy, Madhubala; Sunderkumar, Satheeshkumar

2014-01-01

An infant presented with global developmental delay and infantile spasms. EEG was suggestive of hypsarrhythmia. She was started on sodium valproate, clonazepam and adrenocorticotropic hormone injection. After an initial improvement the child developed vomiting, altered sensorium and increase in frequency of seizures suggestive of encephalopathy. Valproate-induced hyperammonaemia or hepatic encephalopathy was considered and the drug was withheld following which there was a dramatic improvement. Paradoxically, the liver function tests and serum ammonia were normal. However, a complete reversal of encephalopathy, on withdrawal of the drug, strongly suggested an adverse drug reaction (ADR) due to valproic acid. Marginal elevation of serum valproic acid prompted us to use the Naranjo ADR probability score to confirm the diagnosis. This case highlights the fact that valproate toxicity can manifest with normal liver function and serum ammonia levels. This is the youngest reported case with this rare form of valproate-induced encephalopathy. PMID:24810446

A Phase I Dose-Finding Study of Silybin Phosphatidylcholine (Milk Thistle) in Patients With Advanced Hepatocellular Carcinoma

PubMed Central

Siegel, Abby B.; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S.; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.; Flaig, Thomas W.; Tsai, Wei Yann; Wu, David P. H.; Lee, Valerie; Greenlee, Heather

2013-01-01

Purpose To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Experimental Design Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Results Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Conclusion Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests. PMID:23757319

Comparison of purple carrot juice and β-carotene in a high-carbohydrate, high-fat diet-fed rat model of the metabolic syndrome.

PubMed

Poudyal, Hemant; Panchal, Sunil; Brown, Lindsay

2010-11-01

Anthocyanins, phenolic acids and carotenoids are the predominant phytochemicals present in purple carrots. These phytochemicals could be useful in treatment of the metabolic syndrome since anthocyanins improve dyslipidaemia, glucose tolerance, hypertension and insulin resistance; the phenolic acids may also protect against CVD and β-carotene may protect against oxidative processes. In the present study, we have compared the ability of purple carrot juice and β-carotene to reverse the structural and functional changes in rats fed a high-carbohydrate, high-fat diet as a model of the metabolic syndrome induced by diet. Cardiac structure and function were defined by histology, echocardiography and in isolated hearts and blood vessels; liver structure and function, oxidative stress and inflammation were defined by histology and plasma markers. High-carbohydrate, high-fat diet-fed rats developed hypertension, cardiac fibrosis, increased cardiac stiffness, endothelial dysfunction, impaired glucose tolerance, increased abdominal fat deposition, altered plasma lipid profile, liver fibrosis and increased plasma liver enzymes together with increased plasma markers of oxidative stress and inflammation as well as increased inflammatory cell infiltration. Purple carrot juice attenuated or reversed all changes while β-carotene did not reduce oxidative stress, cardiac stiffness or hepatic fat deposition. As the juice itself contained low concentrations of carotenoids, it is likely that the anthocyanins are responsible for the antioxidant and anti-inflammatory properties of purple carrot juice to improve glucose tolerance as well as cardiovascular and hepatic structure and function.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Unkelbach, J; Perko, Z; Wolfgang, J

Purpose: Stereotactic body radiotherapy (SBRT) has become an established treatment option for liver cancer. For patients with large tumors, the prescription dose is often limited by constraints on the mean liver dose, leading to tumor recurrence. In this work, we demonstrate that spatiotemporal fractionation schemes, ie delivering distinct dose distributions in different fractions, may allow for a 10% increase in biologically effective dose (BED) in the tumor compared to current practice where each fraction delivers the same dose distribution. Methods: We consider rotation therapy delivered with x-ray beams. Treatment plan optimization is performed using objective functions evaluated for the cumulativemore » BED delivered at the end of treatment. This allows for simultaneously optimizing multiple distinct treatment plans for different fractions. Results: The treatment that optimally exploits fractionation effects is designed such that each fraction delivers a similar dose bath to the uninvolved liver while delivering high single fraction doses to complementary parts of the target volume. Thereby, partial hypofractionation in the tumor is achieved along with near uniform fractionation in the surrounding liver - leading to an improvement in the therapeutic ratio. The benefit of such spatiotemporal fractionation schemes depends on tumor geometry and location as well as the number of fractions. For 5-fraction treatments (allowing for 5 distinct dose distributions) an improvement in the order of 10% is observed. Conclusion: Delivering distinct dose distributions in different fractions, purely motivated by fractionation effects rather than geometric changes, may improve the therapeutic ratio. For treatment sites where the prescriptions dose is limited by mean dose constraints in the surrounding organ, such as liver cancer, this approach may facilitate biological dose escalation and improved cure rates.« less

Vitex agnus-castus L. (Verbenaceae) Improves the Liver Lipid Metabolism and Redox State of Ovariectomized Rats.

PubMed

Moreno, Franciele Neves; Campos-Shimada, Lilian Brites; da Costa, Silvio Claudio; Garcia, Rosângela Fernandes; Cecchini, Alessandra Lourenço; Natali, Maria Raquel Marçal; Vitoriano, Adriana de Souza; Ishii-Iwamoto, Emy Luiza; Salgueiro-Pagadigorria, Clairce Luzia

2015-01-01

Vitex agnus-castus (VAC) is a plant that has recently been used to treat the symptoms of menopause, by its actions on the central nervous system. However, little is known about its actions on disturbances in lipid metabolism and nonalcoholic fat liver disease (NAFLD), frequently associated with menopause. Ovariectomized (OVX) rats exhibit increased adiposity and NAFLD 13 weeks after ovary removal and were used as animal models of estrogen deficiency. The rats were treated with crude extract (CE) and a butanolic fraction of VAC (ButF) and displayed the beneficial effects of a reduction in the adiposity index and a complete reversion of NAFLD. NAFLD reversion was accompanied by a general improvement in the liver redox status. The activities of some antioxidant enzymes were restored and the mitochondrial hydrogen peroxide production was significantly reduced in animals treated with CE and the ButF. It can be concluded that the CE and ButF from Vitex agnus-castus were effective in preventing NAFLD and oxidative stress, which are frequent causes of abnormal liver functions in the postmenopausal period.

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

PubMed Central

Aigner, Elmar; Weiss, Günter; Datz, Christian

2015-01-01

Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications. PMID:25729473

Vitex agnus-castus L. (Verbenaceae) Improves the Liver Lipid Metabolism and Redox State of Ovariectomized Rats

PubMed Central

Moreno, Franciele Neves; Campos-Shimada, Lilian Brites; da Costa, Silvio Claudio; Garcia, Rosângela Fernandes; Cecchini, Alessandra Lourenço; Natali, Maria Raquel Marçal; Vitoriano, Adriana de Souza; Ishii-Iwamoto, Emy Luiza; Salgueiro-Pagadigorria, Clairce Luzia

2015-01-01

Vitex agnus-castus (VAC) is a plant that has recently been used to treat the symptoms of menopause, by its actions on the central nervous system. However, little is known about its actions on disturbances in lipid metabolism and nonalcoholic fat liver disease (NAFLD), frequently associated with menopause. Ovariectomized (OVX) rats exhibit increased adiposity and NAFLD 13 weeks after ovary removal and were used as animal models of estrogen deficiency. The rats were treated with crude extract (CE) and a butanolic fraction of VAC (ButF) and displayed the beneficial effects of a reduction in the adiposity index and a complete reversion of NAFLD. NAFLD reversion was accompanied by a general improvement in the liver redox status. The activities of some antioxidant enzymes were restored and the mitochondrial hydrogen peroxide production was significantly reduced in animals treated with CE and the ButF. It can be concluded that the CE and ButF from Vitex agnus-castus were effective in preventing NAFLD and oxidative stress, which are frequent causes of abnormal liver functions in the postmenopausal period. PMID:25954315

Insulin protects against hepatic damage postburn.

PubMed

Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

2011-01-01

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.

Insulin Protects against Hepatic Damage Postburn

PubMed Central

Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

2011-01-01

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509

Effects of N-Acetylcysteine Addition to University of Wisconsin Solution on the Rate of Ischemia-Reperfusion Injury in Adult Orthotopic Liver Transplant.

PubMed

Aliakbarian, Mohsen; Nikeghbalian, Saman; Ghaffaripour, Sina; Bahreini, Amin; Shafiee, Mohammad; Rashidi, Mohammad; Rajabnejad, Yaser

2017-08-01

One of the main concerns in liver transplant is the prolonged ischemia time, which may lead to primary graft nonfunction or delayed function. N-acetylcysteine is known as a hepato-protective agent in different studies, which may improve human hepatocyte viability in steatotic donor livers. This study investigated whether N-acetylcysteine can decrease the rate of ischemia-reperfusion syndrome and improve short-term outcome in liver transplant recipients. This was a double-blind, randomized, control clinical trial of 115 patients. Between April 2012 and January 2013, patients with orthotopic liver transplant were randomly divided into 2 groups; in 49 cases N-acetylcysteine was added to University of Wisconsin solution as the preservative liquid (experimental group), and in 66 cases standard University of Wisconsin solution was used (control group). We compared postreperfusion hypotension, inotrope requirement before and after portal reperfusion, intermittent arterial blood gas analysis and potassium measurement, pathological review of transplanted liver, in-hospital complications, morbidity, and mortality. There was no significant difference between the groups regarding time to hepatic artery reperfusion, hospital stay, vascular complications, inotrope requirement before and after portal declamping, and blood gas analysis. Hypotension after portal reperfusion was significantly more common in experimental group compared with control group (P = .005). Retransplant and in-hospital mortality were comparable between the groups. Preservation of the liver inside Univer-sity of Wisconsin solution plus N-acetylcysteine did not change the rate of ischemia reperfusion injury and short-term outcome in liver transplant recipients.

Assessment of hepatoprotective and nephroprotective potential of withaferin A on bromobenzene-induced injury in Swiss albino mice: possible involvement of mitochondrial dysfunction and inflammation.

PubMed

Vedi, Mahima; Sabina, Evan Prince

2016-10-01

Bromobenzene is a well-known environmental toxin which causes liver and kidney damage through CYP450-mediated bio-activation to generate reactive metabolites and, consequently, oxidative stress. The present study aimed to evaluate the possible protective role of withaferin A against bromobenzene-induced liver and kidney damage in mice. Withaferin A (10 mg/kg) was administered orally to the mice for 8 days before intragastric intubation of bromobenzene (10 mmol/kg). As results of this experiment, the levels of liver and kidney functional markers, lipid peroxidation, and cytokines (TNF-α and IL-1β) presented an increase and there was a decrease in anti-oxidant activity in the bromobenzene-treated group of mice. Pre-treatment with withaferin A not only significantly decreased the levels of liver and kidney functional markers and cytokines but also reduced oxidative stress, as evidenced by improved anti-oxidant status. In addition, the mitochondrial dysfunction shown through the decrease in the activities of mitochondrial enzymes and imbalance in the Bax/Bcl-2 expression in the livers and kidneys of bromobenzene-treated mice was effectively prevented by pre-administration of withaferin A. These results validated our conviction that bromobenzene caused liver and kidney damage via mitochondrial pathway and withaferin A provided significant protection against it. Thus, withaferin A may have possible usage in clinical liver and kidney diseases in which oxidative stress and mitochondrial dysfunction may be existent.

Orthotopic liver transplantation in an adult with cholesterol ester storage disease.

PubMed

Ambler, Graeme K; Hoare, Matthew; Brais, Rebecca; Shaw, Ashley; Butler, Andrew; Flynn, Paul; Deegan, Patrick; Griffiths, William J H

2013-01-01

Cholesterol ester storage disease (CESD) is a rare autosomal recessive lipid storage disorder associated with mutations of the gene encoding lysosomal acid lipase, manifestations of which include chronic liver disease and early atherosclerosis. Although normally presenting in childhood, severity is variable and the condition can occasionally remain undetected until middle age. Typical presentation is with asymptomatic hepatosplenomegaly and hyperlipidaemia, though the condition is probably underdiagnosed. Treatment is supportive and may include attention to cardiovascular risk factors. Phase I/II trials of enzyme replacement therapy are ongoing, but this approach remains experimental. We present the case of a 42-year-old woman diagnosed with CESD in childhood who ran an indolent course until re-presentation with cirrhotic hydrothorax. She underwent orthotopic liver transplantation but required re-transplantation for hepatic artery thrombosis. She remains well with excellent graft function 2 years later. Although atherosclerosis was apparent at assessment, and may have contributed to hepatic artery thrombosis, partial correction of the metabolic defect and restoration of liver function by transplantation together with ongoing medical therapy should permit reasonable survival over the longer term from both a liver and a vascular perspective. This is the first reported case of orthotopic liver transplantation for CESD in an adult, which was the only available option to improve survival. The case highlights the importance of monitoring patients with CESD through adulthood and suggests that liver replacement at a later stage may yet be indicated and remain of benefit.

Correlation between the mechanical and histological properties of liver tissue.

PubMed

Yarpuzlu, Berkay; Ayyildiz, Mehmet; Tok, Olgu Enis; Aktas, Ranan Gulhan; Basdogan, Cagatay

2014-01-01

In order to gain further insight into the mechanisms of tissue damage during the progression of liver diseases as well as the liver preservation for transplantation, an improved understanding of the relation between the mechanical and histological properties of liver is necessary. We suggest that this relation can only be established truly if the changes in the states of those properties are investigated dynamically as a function of post mortem time. In this regard, we first perform mechanical characterization experiments on three bovine livers to investigate the changes in gross mechanical properties (stiffness, viscosity, and fracture toughness) for the preservation periods of 5, 11, 17, 29, 41 and 53h after harvesting. Then, the histological examination is performed on the samples taken from the same livers to investigate the changes in apoptotic cell count, collagen accumulation, sinusoidal dilatation, and glycogen deposition as a function of the same preservation periods. Finally, the correlation between the mechanical and histological properties is investigated via the Spearman's Rank-Order Correlation method. The results of our study show that stiffness, viscosity, and fracture toughness of bovine liver increase as the preservation period is increased. These macroscopic changes are very strongly correlated with the increase in collagen accumulation and decrease in deposited glycogen level at the microscopic level. Also, we observe that the largest changes in mechanical and histological properties occur after the first 11-17h of preservation. © 2013 Elsevier Ltd. All rights reserved.

Liver function testing with nuclear medicine techniques is coming of age.

PubMed

Bennink, Roelof J; Tulchinsky, Mark; de Graaf, Wilmar; Kadry, Zakiyah; van Gulik, Thomas M

2012-03-01

Liver function is a broad term, as the organ participates in a multitude of different physiological and biochemical processes, including metabolic, synthetic, and detoxifying functions. However, it is the function of the hepatocyte that is central to sustaining normal life and dealing with disease states. When the liver begins to fail in severely ill patients, it forecasts a terminal outcome. However, unlike the glomerular filtration rate which clearly quantifies the key renal function, at most practice sites, there is no clinically available quantitative test for liver function. Although it is commonplace to assess indirect evidence of that function (by measuring blood levels of its end products and by-products) and to detect an acute injury (by following rising transaminases), a widely available test that would directly measure hepatocellular function is lacking. This article reviews current knowledge on liver function studies and focuses on those nuclear medicine tests available to study the whole liver and regional liver function. The clinical application driving these tests, prediction of remnant liver function after partial hepatectomy for primary liver malignancy or metastatic disease, is addressed here in detail. The test was recently validated for this specific application and was shown to be better than the current standard of practice (computed tomography volumetry), particularly in patients with hepatic comorbidities like cirrhosis, steatosis, or cholestasis. Furthermore, early assessment of regional liver function increase after preoperative portal vein embolization becomes possible with this technology. The limiting factor to a wider acceptance of this test is based on the lack of clinical software that would allow calculation of liver function parameters. This article provides information that enables a clinical nuclear medicine facility to provide this test using readily available equipment. Furthermore, it addresses emerging clinical applications that are under investigation. Copyright © 2012 Elsevier Inc. All rights reserved.

[Effects of resolving phlegm method on fibrinolytic status in non-alcoholic steatohepatitis patients of phlegm and blood-stasis syndrome].

PubMed

Chen, Li; Jiang, Yang-Kun; Cai, Yan-Bo

2006-12-01

To observe the effect of resolving phlegm method (RPM) on fibrinolytic status in non-alcoholic steatohepatitis (NASH) patients of phlegm blood-stasis (PBS) syndrome type. Sixty-two patients were randomly assigned to 2 groups, namely the treated group (n = 34) treated with Chinese herbs for resolving phlegm and dampness, smoothing liver and gallbladder, promoting blood circulation and removing blood stasis (composition: Indigo Naturalis 10 g, Alumen 3 g, Semen Cassiae 15 g, Fructus Crataegi 15 g, vinegar prepared Radix Bupleuri 10 g, Radix Curcumae 10 g, Radix Salviae Miltiorrhizae 12 g, Herba Lycopi 12 g, talc 12 g and Radix Glycyrrhizae 2 g), one dose twice per day orally, and the control group (n = 28) with ursodeoxycholic acid tablet (UAT) 150 mg three times per day. The treatment course for both groups was 12 weeks. Liver function (ALT, AST, ALP), insulin resistance (IR) index represented by homeostasis model-IR (HOMA-IR) and insulin (Ins), levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1), as well as main symptoms and physical signs were assessed before and after treatment. (1) Compared with those before treatment, levels of ALT, AST, HOMA-IR, t-PA, PAl-1 and main symptoms were all improved in the treated group (P < 0.05 or P < 0.01); (2) There was significant difference in ALP, HOMA-IR, t-PA and PAI-1 between the treated group and the control group (P < 0.05 or P < 0.01); (3) The improvement in liver function related indexes in the control group was mainly the level of ALT, t-PA (P < 0.01), and also shown on HOMA-IR, Ins and PAI-1. RPM could effectively improve liver function and fibrinolytic status. Its effect was better than that of UAT.

A bioartificial liver to treat severe acute liver failure.

PubMed Central

Rozga, J; Podesta, L; LePage, E; Morsiani, E; Moscioni, A D; Hoffman, A; Sher, L; Villamil, F; Woolf, G; McGrath, M

1994-01-01

OBJECTIVE: To test the safety and efficacy of a bioartificial liver support system in patients with severe acute liver failure. SUMMARY BACKGROUND DATA: The authors developed a bioartificial liver using porcine hepatocytes. The system was tested in vitro and shown to have differentiated liver functions (cytochrome P450 activity, synthesis of liver-specific proteins, bilirubin synthesis, and conjugation). When tested in vivo in experimental animals with liver failure, it gave substantial metabolic and hemodynamic support. METHODS: Seven patients with severe acute liver failure received a double lumen catheter in the saphenous vein; blood was removed, plasma was separated and perfused through a cartridge containing 4 to 6 x 10(9) porcine hepatocytes, and plasma and blood cells were reconstituted and reinfused. Each treatment lasted 6 to 7 hours. RESULTS: All patients tolerated the procedure(s) well, with neurologic improvement, decreased intracranial pressure (23.0 +/- 2.3 to 7.8 +/- 1.7 mm Hg; p < 0.005) associated with an increase in cerebral perfusion pressure, decreased plasma ammonia (163.3 +/- 21.3 to 112.2 +/- 9.8 microMoles/L; p < 0.01), and increased encephalopathy index (0.60 +/- 0.17 to 1.24 +/- 0.22; p < 0.03). All patients survived, had a liver transplant, and were discharged from the hospital. CONCLUSIONS: This bioartificial liver is safe and serves as an effective "bridge" to liver transplant in some patients. Images Figure 2. Figure 3. PMID:8185403

Hemorrhage-induced hepatic injury and hypoperfusion can be prevented by direct peritoneal resuscitation.

PubMed

Hurt, Ryan T; Zakaria, El Rasheid; Matheson, Paul J; Cobb, Mahoney E; Parker, John R; Garrison, R Neal

2009-04-01

Crystalloid fluid resuscitation after hemorrhagic shock (HS) that restores/maintains central hemodynamics often culminates in multi-system organ failure and death due to persistent/progressive splanchnic hypoperfusion and end-organ damage. Adjunctive direct peritoneal resuscitation (DPR) using peritoneal dialysis solution reverses HS-induced splanchnic hypoperfusion and improves survival. We examined HS-mediated hepatic perfusion (galactose clearance), tissue injury (histopathology), and dysfunction (liver enzymes). Anesthetized rats were randomly assigned (n = 8/group): (1) sham (no HS); (2) HS (40% mean arterial pressure for 60 min) plus conventional i.v. fluid resuscitation (CR; shed blood + 2 volumes saline); (3) HS + CR + 30 mL intraperitoneal (IP) DPR; or (4) HS + CR + 30 mL IP saline. Hemodynamics and hepatic blood flow were measured for 2 h after CR completion. In duplicate animals, liver and splanchnic tissues were harvested for histopathology (blinded, graded), hepatocellular function (liver enzymes), and tissue edema (wet-dry ratio). Group 2 decreased liver blood flow, caused liver injuries (focal to submassive necrosis, zones 2 and 3) and tissue edema, and elevated liver enzymes (alanine aminotransferase (ALT), 149 +/- 28 microg/mL and aspartate aminotransferase (AST), 234 +/- 24 microg/mL; p < 0.05) compared to group 1 (73 +/- 9 and 119 +/- 10 microg/mL, respectively). Minimal/no injuries were observed in group 3; enzymes were normalized (ALT 89 +/- 9 microg/mL and AST 150 +/- 17 microg/mL), and tissue edema was similar to sham. CR from HS restored and maintained central hemodynamics but did not restore or maintain liver perfusion and was associated with significant hepatocellular injury and dysfunction. DPR added to conventional resuscitation (blood and crystalloid) restored and maintained liver perfusion, prevented hepatocellular injury and edema, and preserved liver function.

Patterns and Predictors of Sexual Function After Liver Donation: the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL)

PubMed Central

DiMartini, AF.; Dew, MA.; Butt, Z.; Simpson, MA.; Ladner, DP.; Smith, AR.; Hill-Callahan, P.; Gillespie, BW.

2015-01-01

Although sexual functioning is an important facet of living donor quality of life, it has not received extensive evaluation in this population. Using data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, we examined donor sexual functioning across the donation process from the predonation evaluation to 3 months and 1 year postdonation. Donors (n=208) and a comparison group of non-donors (n=155) completed self-reported surveys with specific questions on sexual desire, satisfaction, orgasm, and (for men) erectile function. Across the three time points, donor sexual functioning was lower at the evaluation phase and 3 months postdonation than at one year postdonation. In the early recovery period, abdominal pain was associated with difficulty reaching orgasm (OR = 3.98, 95% CI 1.30–12.16), concerns over appearance with lower sexual desire (OR = 4.14, 95% CI 1.02–16.79), and not feeling back to normal was associated with dissatisfaction with sexual life (OR 3.58, 95% CI 1.43–8.99). Efforts to educate donors before the surgery and prepare them for the early recovery phase may improve recovery and reduce distress regarding sexual functioning. PMID:25779554

Estimation of contrast agent bolus arrival delays for improved reproducibility of liver DCE MRI

NASA Astrophysics Data System (ADS)

Chouhan, Manil D.; Bainbridge, Alan; Atkinson, David; Punwani, Shonit; Mookerjee, Rajeshwar P.; Lythgoe, Mark F.; Taylor, Stuart A.

2016-10-01

Delays between contrast agent (CA) arrival at the site of vascular input function (VIF) sampling and the tissue of interest affect dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling. We investigate effects of altering VIF CA bolus arrival delays on liver DCE MRI perfusion parameters, propose an alternative approach to estimating delays and evaluate reproducibility. Thirteen healthy volunteers (28.7  ±  1.9 years, seven males) underwent liver DCE MRI using dual-input single compartment modelling, with reproducibility (n  =  9) measured at 7 days. Effects of VIF CA bolus arrival delays were assessed for arterial and portal venous input functions. Delays were pre-estimated using linear regression, with restricted free modelling around the pre-estimated delay. Perfusion parameters and 7 days reproducibility were compared using this method, freely modelled delays and no delays using one-way ANOVA. Reproducibility was assessed using Bland-Altman analysis of agreement. Maximum percent change relative to parameters obtained using zero delays, were  -31% for portal venous (PV) perfusion, +43% for total liver blood flow (TLBF), +3247% for hepatic arterial (HA) fraction, +150% for mean transit time and  -10% for distribution volume. Differences were demonstrated between the 3 methods for PV perfusion (p  =  0.0085) and HA fraction (p  <  0.0001), but not other parameters. Improved mean differences and Bland-Altman 95% Limits-of-Agreement for reproducibility of PV perfusion (9.3 ml/min/100 g, ±506.1 ml/min/100 g) and TLBF (43.8 ml/min/100 g, ±586.7 ml/min/100 g) were demonstrated using pre-estimated delays with constrained free modelling. CA bolus arrival delays cause profound differences in liver DCE MRI quantification. Pre-estimation of delays with constrained free modelling improved 7 days reproducibility of perfusion parameters in volunteers.

Durability of virologic response, risk of de novo hepatocellular carcinoma, liver function and stiffness two years after treatment with Ombitasvir/Paritaprevir/Ritonavir ±Dasabuvir ±Ribavirin in the AMBER, real-world experience study.

PubMed

Flisiak, Robert; Janczewska, Ewa; Łucejko, Mariusz; Karpińska, Ewa; Zarębska-Michaluk, Dorota; Nazzal, Khalil; Bolewska, Beata; Białkowska, Jolanta; Berak, Hanna; Fleischer-Stępniewska, Katarzyna; Tomasiewicz, Krzysztof; Karwowska, Kornelia; Simon, Krzysztof; Piekarska, Anna; Tronina, Olga; Tuchendler, Ewelina; Garlicki, Aleksander

2018-06-11

We followed for 2 years patients treated with Direct Acting Agents (DAA) to assess long-term durability of virologic response, improvement of liver function, reduction of liver stiffness (LS), and risk of hepatocellular carcinoma (HCC).The study included patients from 16 hepatologic centers involved in the AMBER, investigators initiated study on treatment of chronic hepatitis C patients within a programme preceding EU registration of Ombitasvir/Paritaprevir/ritonavir±Dasabuvir±Ribavirin. A total of 204 patients among 209 from the primary study were enrolled; 200 with available testing at 2 years follow-up (2yFU) with undetectable HCV RNA (198 responders and 2 non-responders retreated). During 2yFU 4 patients died, 17 had hepatic decompensation and 3 needed liver transplantation. De novo hepatocellular carcinoma was diagnosed in 4 and its recurrence in 3 patients. Significant decreases in bilirubin, MELD, Child-Pugh scores and liver stiffness, and increases in albumin level were observed during 2yFU. Strengths of the study were a fixed period of post treatment follow-up, prospective character of the study and high proportion of available patients from the primary study. The major weaknesses was lack of a comparative arm and relatively insufficient number of patients for subsets analysis. In conclusion, two-years follow-up confirmed durability of virologic response after treatment of HCV infection with Ombitasvir/Paritaprevir/ritonavir±Dasabuvir±Ribavirin. It was accompanied by significant improvement of major measures of hepatic function and reduction of hepatic stiffness. Successful therapy did not prevent hepatic decompensation, HCC or death in cirrhotics, that support the need for longer than 2-year monitoring for possible disease progression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

[Contraception and pregnancy after liver transplantation: an update overview].

PubMed

Parolin, Mônica Beatriz; Coelho, Júlio Cezar Uili; Urbanetz, Almir Antônio; Pampuch, Melina

2009-01-01

Successful liver transplantation not only treats the underlying liver disease but also restores libido and fertility in female recipients. Although reports of successful pregnancy after liver transplantation continue to increase, these pregnancies are considered of high-risk because they are associated with increase maternofetal morbidity. A MEDLINE search (1978-2007) was conducted using the terms 'liver transplantation', 'pregnancy', 'immunosuppressive agents', 'sexual function'. Reviews, retrospective series, long-term clinical follow-up of case series and original articles containing basic scientific observations were included. Although no formal guidelines have been established there are some 'golden rules' to improve the probability of favorable maternal and fetal outcome. Most transplant centers recommend to delay pregnancy for at least 1-year after transplantation. The recipient should be on a stable immunosuppression regimen, with good graft function and no evidence of renal dysfunction or uncontrolled arterial hypertension. Considering the increased incidence of prematurity, low birth weight, hypertension and preeclampsia reported during pregnancy post-LT, these high-risk patients should be managed by a multidisciplinary team, including an obstetrician specialized in high-risk pregnancies. Carefully monitoring of immunosuppressive drugs serum level is prudent to avoid graft rejection episodes and drugs with teratogenic potential should be discontinued. Breastfeeding is usually not recommended. Successful pregnancies are the rule after liver transplantation. A carefully monitoring by an experience multidisciplinary team increases the chances of favorable maternofetal outcome.

Application of a proteomic approach to identify proteins associated with primary graft non-function after liver transplantation.

PubMed

Kornasiewicz, Oskar; Bojarczuk, Kamil; Bugajski, Marek; Golab, Jakub; Krawczyk, Marek

2012-10-01

Primary graft non-function (PNF) is a rare, life-threatening complication of liver transplantation. Increasing use of extended criteria donor pools and high-risk recipients seem to influence the incidence of PNF. Primary failure is associated with high patient morbidity and inferior graft survival. The only available treatment for PNF is emergency hepatic retransplantation, which is also correlated with significant morbidity and mortality. Therefore, researchers are working to identify risk factors of diagnostic value to prevent PNF. The current study attempted to explore liver proteomic patterns in patients with PNF. Using two-dimensional gel electrophoresis and liquid chromatography-mass spectrometry (LC-MS), we compared liver protein homogenates from 3 patients with PNF to those obtained from 6 healthy liver samples to identify potential new biomarkers of PNF. Our comparisons revealed 21 proteins with differential expression (13 upregulated and 8 downregulated). Most of these proteins are involved in energy metabolism, lipid metabolism, peptide cleavage, cell differentiation, and apoptosis. Although none of these proteins appeared more than once in separate analyses, this preliminary study shows that two-dimensional gel electrophoresis and LC-MS may allow identification of characteristic proteins to be used as biomarkers of a life-threatening complication of liver transplantation. Larger-scale analyses could improve patient care by finding suitable prognostic and therapeutic options. These data represent the first global proteomic approach to study PNF.

Manual exchange transfusion for severe imported falciparum malaria: a retrospective study.

PubMed

Lin, Jinfeng; Huang, Xiaoying; Qin, Gang; Zhang, Suyan; Sun, Weiwei; Wang, Yadong; Ren, Ke; Xu, Junxian; Han, Xudong

2018-01-16

This study was designed to evaluate the efficacy of exchange transfusion in patients with severe imported falciparum malaria. Twelve patients who met the diagnostic criteria for severe malaria were treated with exchange transfusion 14 times according to a conventional anti-malarial treatment. This study evaluated the efficacy of exchange transfusion for severe imported falciparum malaria. Clinical data of severe imported falciparum malaria patients admitted to the intensive care unit (ICU) of Nantong Third People's Hospital from January 2007 to December 2016 were investigated in this retrospective study. Patients were divided into the intervention group, which received exchange transfusion, and the control group. This study assessed parasite clearance and outcomes of the two groups, and levels of erythrocytes, haemoglobin, platelets, coagulation, liver function, lactate, C-reactive protein, and procalcitonin, before and after exchange transfusion in the intervention group. There was no significant difference in the severity of admitted patients. Exchange transfusion was successfully applied 14 times in the intervention group. Differences in the levels of erythrocytes, haemoglobin and platelets did not reach statistical significance. Exchange transfusion improved coagulation, liver function, lactic acid, C-reactive protein, and procalcitonin. No differences were observed in parasite clearance, ICU and hospital length of stay, in-hospital mortality, and costs of hospitalization between the two groups. Exchange transfusion as adjunctive therapy for severe malaria was observed to be safe in this setting. Exchange transfusion can improve liver function and coagulation and reduce inflammation, but it failed to improve parasite clearance and the outcomes of severe imported falciparum malaria in this case series.

Ursodeoxycholic acid for cystic fibrosis-related liver disease.

PubMed

Cheng, Katharine; Ashby, Deborah; Smyth, Rosalind L

2014-12-15

Abnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. To analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis. We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also contacted drug companies.Date of the most recent search of the Group's trials register: 29 May 2014. Randomised controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis. Two authors independently assessed trial eligibility and quality. Ten trials have been identified, of which three trials involving 118 participants were included; the dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30 participants from two trials. Improvement in biliary excretion was reported in only one trial and no significant change after treatment was shown. There were no data available for analysis for long-term outcomes such as death or need for liver transplantation. There are few trials assessing the effectiveness of ursodeoxycholic acid. There is insufficient evidence to justify its routine use in cystic fibrosis.

Acute Kidney Injury after Liver Transplantation.

PubMed

Durand, François; Francoz, Claire; Asrani, Sumeet K; Khemichian, Saro; Pham, Thomas A; Sung, Randall S; Genyk, Yuri S; Nadim, Mitra K

2018-05-29

Since the implementation of the MELD score-based allocation system, the number of transplant candidates with impaired renal function has increased. The aims of this review are to present new insights in the definitions and predisposing factors that result in acute kidney injury (AKI), and to propose guidelines for the prevention and treatment of post liver transplantation (LT) AKI. This review is based on both systematic review of relevant literature and expert opinion. Pretransplant AKI is associated with posttransplant morbidity, including prolonged post LT AKI which then predisposes to posttransplant chronic kidney disease (CKD). Prevention of posttransplant AKI is essential in the improvement of long term outcomes. Accurate assessment of baseline kidney function at evaluation is necessary, taking into account that serum creatinine overestimates glomerular filtration rate (GFR). New diagnostic criteria for AKI have been integrated with traditional approaches in patients with cirrhosis to potentially identify AKI earlier and improve outcomes. Delayed introduction or complete elimination of calcineurin inhibitors during the first weeks post LT in patients with early posttransplant AKI may improve GFR in high risk patients but with higher rates of rejection and more adverse events. Biomarkers may in the future provide diagnostic information such as etiology of AKI, and prognostic information on renal recovery post-LT, and potentially impact the decision for simultaneous liver-kidney transplantation. Overall, more attention should be paid to pretransplant and early posttransplant AKI to reduce the burden of late CKD.

High intensity focused ultrasound ablation for patients with inoperable liver cancer.

PubMed

Chen, Lianyu; Wang, Kun; Chen, Zhen; Meng, Zhiqiang; Chen, Hao; Gao, Huifeng; Wang, Peng; Zhu, Huili; Lin, Junhua; Liu, Luming

2015-01-01

To analyses the feasibility and efficacy of high intensity focused ultrasound (HIFU) treatment in patients with inoperable liver cancer. 187 patients were treated with HIFU, of all these patients 116 cases were Primary Liver Cancer (PLC) and 71 cases were Metastatic Liver Cancer (MLC). According to some parameters, such as clinical symptoms, the basis of main organs functional tests, imaging examinations, and progression-free survival (PFS) time to assess the safety and efficacy of HIFU in the treatment of liver cancer. 55 patients (29.4%) achieved CR and 73 patients (39.0%) achieved PR, 32 patients (17.1%) had responses of SD, and 27 patients (14.4%) were PD, respectively. Response rates were 90.5% (32 CR + 6 PR/42) in left lobe cancer and 64.1% (22 CR + 62 PR/131) in right lobe cancer. The median PFS for those CR case was 7 months, of PLC was 8 months, of MLC was 5 months. HIFU is effective and feasible in the treatment of liver cancer. It offer a significant noninvasive therapy for local treatment of liver cancer. For those right lobe liver cancers or with poor ultrasonic window, increasing treatment time or repeated treatment may improve the efficiency of HIFU ablation.

Liver‐Directed Human Amniotic Epithelial Cell Transplantation Improves Systemic Disease Phenotype in Hurler Syndrome Mouse Model

PubMed Central

Rodriguez, Natalie S.; Yanuaria, Lisa; Parducho, Kevin Murphy R.; Garcia, Irving M.; Varghese, Bino A.; Grubbs, Brendan H.

2017-01-01

Abstract Mucopolysaccharidosis type 1 (MPS1) is an inherited lysosomal storage disorder caused by a deficiency in the glycosaminoglycan (GAG)‐degrading enzyme α‐l‐iduronidase (IDUA). In affected patients, the systemic accumulation of GAGs results in skeletal dysplasia, neurological degeneration, multiple organ dysfunction, and early death. Current therapies, including enzyme replacement and bone marrow transplant, improve life expectancy but the benefits to skeletal and neurological phenotypes are limited. In this study, we tested the therapeutic efficacy of liver‐directed transplantation of a placental stem cell, which possesses multilineage differentiation potential, low immunogenicity, and high lysosomal enzyme activity. Unfractionated human amniotic epithelial cells (hAECs) were transplanted directly into the liver of immunodeficient Idua knockout mouse neonates. The hAECs engraftment was immunohistochemically confirmed with anti‐human mitochondria staining. Enzyme activity assays indicated that hAECs transplantation restored IDUA function in the liver and significantly decreased urinary GAG excretion. Histochemical and micro‐computed tomography analyses revealed reduced GAG deposition in the phalanges joints and composition/morphology improvement of cranial and facial bones. Neurological assessment in the hAEC treated mice showed significant improvement of sensorimotor coordination in the hAEC treated mice compared to untreated mice. Results confirm that partial liver cell replacement with placental stem cells can provide long‐term (>20 weeks) and systemic restoration of enzyme function, and lead to significant phenotypic improvement in the MPS1 mouse model. This preclinical data indicate that liver‐directed placental stem cell transplantation may improve skeletal and neurological phenotypes of MPS1 patients. Stem Cells Translational Medicine 2017;6:1583–1594 PMID:28585336

Improvement of the complex medical treatment for the patients wіth chronic biliary pancreatitis.

PubMed

Babinets, L S; Kytsai, K Yu; Kotsaba, Yu Ya; Halabitska, I M; Melnyk, N A; Semenova, I V; Zemlyak, O S

The most common reason of chronic pancreatitis is liver and bile ducts disease: functional disorders, chronic cholecystitis, cholelithiasis and cholecystectomy in medical history. All these changes are associated with the colloidal structure of bile, increased lithogenicity, gallstones formation, Oddi's sphincter dysfunction, dysmotility and inflammation in the bile ducts. to study the effectiveness of using medicine Liveria IC (metadoxine) in standard therapy as well as effect on spectrum of blood serum lipids and structural condition of liver (stiffness) and pancreas in patients with chronic biliary pancreatitis combined with obesity. 115 patients suffering from chronic biliary pancreatitis and obesity were the subjects of the study. They were compared to etiological factor socioeconomic conditions and nutrition (regular food 5 times a day without aggressive food (fatty, spicy, sour, fried products)). Also the effect of the alcohol factor was excluded. The obtained decrease in stiffness of the liver and pancreas indicates an improvement of their structural state. Using medication LiveriaIC (metadoxine) as the part of the complex therapy for the patients who are suffering from CBP combined with obesity gives some improvement of the lipid profile indices and the structural condition of liver and pancreas (according to the data of SWE) (р<0.05).

Dynamic gadoxetate-enhanced MRI for the assessment of total and segmental liver function and volume in primary sclerosing cholangitis.

PubMed

Nilsson, Henrik; Blomqvist, Lennart; Douglas, Lena; Nordell, Anders; Jacobsson, Hans; Hagen, Karin; Bergquist, Annika; Jonas, Eduard

2014-04-01

To evaluate dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) for the assessment of global and segmental liver volume and function in patients with primary sclerosing cholangitis (PSC), and to explore the heterogeneous distribution of liver function in this patient group. Twelve patients with primary sclerosing cholangitis (PSC) and 20 healthy volunteers were examined using DHCE-MRI with Gd-EOB-DTPA. Segmental and total liver volume were calculated, and functional parameters (hepatic extraction fraction [HEF], input relative blood-flow [irBF], and mean transit time [MTT]) were calculated in each liver voxel using deconvolutional analysis. In each study subject, and incongruence score (IS) was constructed to describe the mismatch between segmental function and volume. Among patients, the liver function parameters were correlated to bile duct obstruction and to established scoring models for liver disease. Liver function was significantly more heterogeneously distributed in the patient group (IS 1.0 versus 0.4). There were significant correlations between biliary obstruction and segmental functional parameters (HEF rho -0.24; irBF rho -0.45), and the Mayo risk score correlated significantly with the total liver extraction capacity of Gd-EOB-DTPA (rho -0.85). The study demonstrates a new method to quantify total and segmental liver function using DHCE-MRI in patients with PSC. Copyright © 2013 Wiley Periodicals, Inc.

Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia.

PubMed

Ward, C; Lucas, M; Piris, J; Collier, J; Chapel, H

2008-09-01

Patients with common variable immunodeficiency disorders are monitored for liver function test abnormalities. A proportion of patients develop deranged liver function and some also develop hepatomegaly. We investigated the prevalence of abnormalities and types of liver disease, aiming to identify those at risk and determine outcomes. The local primary immunodeficiency database was searched for patients with a common variable immunodeficiency disorder and abnormal liver function and/or a liver biopsy. Patterns of liver dysfunction were determined and biopsies reviewed. A total of 47 of 108 patients had deranged liver function, most commonly raised alkaline phosphatase levels. Twenty-three patients had liver biopsies. Nodular regenerative hyperplasia was found in 13 of 16 with unexplained pathology. These patients were more likely to have other disease-related complications of common variable immunodeficiency disorders, in particular non-coeliac (gluten insensitive) lymphocytic enteropathy. However, five had no symptoms of liver disease and only one died of liver complications. Nodular regenerative hyperplasia is a common complication of common variable immunodeficiency disorders but was rarely complicated by portal hypertension.

Sulforaphane-rich broccoli sprout extract improves hepatic abnormalities in male subjects

PubMed Central

Kikuchi, Masahiro; Ushida, Yusuke; Shiozawa, Hirokazu; Umeda, Rumiko; Tsuruya, Kota; Aoki, Yudai; Suganuma, Hiroyuki; Nishizaki, Yasuhiro

2015-01-01

AIM: To evaluate effects of dietary supplementation of sulforaphane (SF)-rich broccoli sprout (BS) extract on hepatic abnormalities in Japanese male participants. METHODS: In a randomized, placebo-controlled, double blind trial, male participants with fatty liver received either BS capsules containing glucoraphanin [GR; a precursor of SF (n = 24)] or placebo (n = 28) for 2 mo. Liver function markers, serum levels of aspartate and alanine aminotransferases (AST and ALT, respectively) and γ-glutamyl transpeptidase (γ-GTP) and an oxidative stress marker, urinary levels of 8-hydroxydeoxyguanosine (8-OHdG), were measured and compared in participants before and after the trial period. In an animal model, chronic liver failure was induced in Sprague-Dawley rats by successive intraperitoneal injection with N-nitrosodimethylamine (NDMA) for 4 wk. Concomitantly, rats received AIN-76 diets supplemented with or without BS extract. Thereafter, rats were sacrificed, and their sera and livers were collected to measure serum liver function markers and hepatic levels of thiobarbituric acid reactive substances (TBARS) levels and hepatic glutathione S-transferase (GST) activity, a prototypical phase 2 antioxidant enzyme. RESULTS: Dietary supplementation with BS extract containing SF precursor GR for 2 mo significantly decreased serum levels of liver function markers, ALT [median (interquartile range), before: 54.0 (34.5-79.0) vs after supplementation: 48.5 (33.3-65.3) IU/L, P < 0.05] and γ-GTP [before: 51.5 (40.8-91.3) vs after: 50.0 (37.8-85.3) IU/L, P < 0.05], as well as the alkali phosphatase activity. Placebo showed no significant effects on the markers. The urinary level of 8-OHdG, an established oxidative stress marker, was significantly reduced in participants who had received BS capsules but not the placebo [before: 6.66 (5.51-9.03) vs after: 5.49 (4.89-6.66) ng/mg-creatinine, P < 0.05]. The reduction of urinary 8-OHdG was significantly correlated with decreased levels of both ALT and γ-GTP [∆8-OHdG and ∆ALT: Spearman r (r) 0.514 and P = 0.012, ∆8-OHdG and ∆γ-GTP: r = 0.496 and P = 0.016]. Intake of BS extract prevented NDMA-induced chronic liver failure in rats, which was attributable to the suppression of the increase in TBARS through induction of hepatic phase 2 antioxidant enzymes including hepatic GST (86.6 ± 95.2 vs 107.8 ± 7.7 IU/g, P < 0.01). CONCLUSION: Dietary supplementation with BS extract containing the SF precursor GR is likely to be highly effective in improving liver function through reduction of oxidative stress. PMID:26604653

Future remnant liver function as predictive factor for the hypertrophy response after portal vein embolization.

PubMed

Cieslak, Kasia P; Huisman, Floor; Bais, Thomas; Bennink, Roelof J; van Lienden, Krijn P; Verheij, Joanne; Besselink, Marc G; Busch, Olivier R C; van Gulik, Thomas M

2017-07-01

Preoperative portal vein embolization is widely used to increase the future remnant liver. Identification of nonresponders to portal vein embolization is essential because these patients may benefit from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which induces a more powerful hypertrophy response. 99m Tc-mebrofenin hepatobiliary scintigraphy is a quantitative method for assessment of future remnant liver function with a calculated cutoff value for the prediction of postoperative liver failure. The aim of this study was to analyze future remnant liver function before portal vein embolization to predict sufficient functional hypertrophy response after portal vein embolization. Sixty-three patients who underwent preoperative portal vein embolization and computed tomography imaging were included. Hepatobiliary scintigraphy was performed to determine pre-portal vein embolization and post-portal vein embolization future remnant liver function. Receiver operator characteristic analysis of pre-portal vein embolization future remnant liver function was performed to identify patients who would meet the post-portal vein embolization cutoff value for sufficient function (ie, 2.7%/min/m 2 ). Mean pre-portal vein embolization future remnant liver function was 1.80% ± 0.45%/min/m 2 and increased to 2.89% ± 0.97%/min/m 2 post-portal vein embolization. Receiver operator characteristic analysis in 33 patients who did not receive chemotherapy revealed that a pre-portal vein embolization future remnant liver function of ≥1.72%/min/m 2 was able to identify patients who would meet the safe future remnant liver function cutoff value 3 weeks after portal vein embolization (area under the curve = 0.820). The predictive value was less pronounced in 30 patients treated with neoadjuvant chemotherapy (area under the curve = 0.618). A total of 45 of 63 patients underwent liver resection, of whom 5 of 45 developed postoperative liver failure; 4 of 5 patients had a post-portal vein embolization future remnant liver function below the cutoff value for safe resection. When selecting patients for portal vein embolization, future remnant liver function assessed with hepatobiliary scintigraphy can be used as a predictor of insufficient functional hypertrophy after portal vein embolization, especially in nonchemotherapy patients. These patients are potential candidates for ALPPS. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of liver volume and liver function on posthepatectomy liver failure after portal vein embolization- A multivariable cohort analysis.

PubMed

Alizai, Patrick H; Haelsig, Annabel; Bruners, Philipp; Ulmer, Florian; Klink, Christian D; Dejong, Cornelis H C; Neumann, Ulf P; Schmeding, Maximilian

2018-01-01

Liver failure remains a life-threatening complication after liver resection, and is difficult to predict preoperatively. This retrospective cohort study evaluated different preoperative factors in regard to their impact on posthepatectomy liver failure (PHLF) after extended liver resection and previous portal vein embolization (PVE). Patient characteristics, liver function and liver volumes of patients undergoing PVE and subsequent liver resection were analyzed. Liver function was determined by the LiMAx test (enzymatic capacity of cytochrome P450 1A2). Factors associated with the primary end point PHLF (according to ISGLS definition) were identified through multivariable analysis. Secondary end points were 30-day mortality and morbidity. 95 patients received PVE, of which 64 patients underwent major liver resection. PHLF occurred in 7 patients (11%). Calculated postoperative liver function was significantly lower in patients with PHLF than in patients without PHLF (67 vs. 109 μg/kg/h; p = 0.01). Other factors associated with PHLF by univariable analysis were age, future liver remnant, MELD score, ASA score, renal insufficiency and heart insufficiency. By multivariable analysis, future liver remnant was the only factor significantly associated with PHLF (p = 0.03). Mortality and morbidity rates were 4.7% and 29.7% respectively. Future liver remnant is the only preoperative factor with a significant impact on PHLF. Assessment of preoperative liver function may additionally help identify patients at risk for PHLF.

Liver Function in Patients With Nonalcoholic Fatty Liver Disease Randomized to Roux-en-Y Gastric Bypass Versus Sleeve Gastrectomy: A Secondary Analysis of a Randomized Clinical Trial.

PubMed

Kalinowski, Piotr; Paluszkiewicz, Rafał; Ziarkiewicz-Wróblewska, Bogna; Wróblewski, Tadeusz; Remiszewski, Piotr; Grodzicki, Mariusz; Krawczyk, Marek

2017-11-01

The aim of the study was to compare the influence of sleeve gastrectomy (SG) versus Roux-en-Y gastric bypass (RYGB) on liver function in bariatric patients with non-alcoholic fatty liver disease (NAFLD) in a randomized clinical trial (NCT01806506). Rapid weight loss and malabsorption after bariatric surgery in patients with NAFLD or steatohepatitis (NASH) may impair liver function. Sixty-six morbidly obese patients randomized to SG or RYGB were included in a secondary outcome analysis. Intraoperative liver biopsies were categorized with NAFLD Activity Score (NAS) and liver function tests were done before surgery and after 1, 6 and 12 months. NASH was present in 54.5% RYGB and 51.5% SG patients (P > 0.05). At 12 months excess weight loss was 68.7 ± 19.7% after SG and 62.8 ± 18.5% after RYGB (P > 0.05). At 1 month international normalized ratio (INR) increased after RYGB (0.98 ± 0.05 vs 1.14 ± 0.11; P < 0.05) and SG (0.99 ± 0.06 vs 1.04 ± 0.06; P < 0.05), RYGB induced significantly greater increase in INR in the whole group and NASH patients than SG. After RYGB albumin decreased at 1 month (41.2 ± 2.7 vs 39.0 ± 3.2 g/L; P < 0.05). At 12 months, INR and albumin returned to baseline. At 12 months in NASH group, SG induced significant improvement in aspartate aminotransferase (32.4 ± 17.4 vs 21.5 ± 6.9U/L), alanine aminotransferase (39.9 ± 28.6U/L vs 23.8 ± 14.1U/L), gamma-glutamyl transpeptidase (34.3 ± 16.6 vs 24.5 ± 16.8U/L), and lactate dehydrogenase (510.8 ± 33 vs 292.4 ± 29). Variables predictive of INR change after 1 month included operation type, NAS ≥ 5, bilirubin, body mass index, hemoglobin A1C, and dyslipidemia. Patients with NASH undergoing RYGB are more susceptible to early transient deterioration of liver function than after SG.

A phase II, randomized, controlled trial of S-adenosylmethionine in reducing serum alpha-fetoprotein (AFP) in patients with hepatitis C cirrhosis and elevated AFP

PubMed Central

Morgan, Timothy R.; Osann, Kathryn; Bottiglieri, Teodoro; Pimstone, Neville; Hoefs, John C.; Hu, Ke-Qin; Hassanein, Tarek; Boyer, Thomas D.; Kong, Lorene; Chen, Wen-Pin; Richmond, Ellen; Gonzalez, Rachel; Rodriguez, Luz M.; Meyskens, Frank L.

2015-01-01

In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC while administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum AFP level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 grams/day, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. 110 subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury, or markers of oxidative stress or antioxidant potential. PMID:26130251

Analysis of the liver functional reserve of patients with advanced hepatocellular carcinoma undergoing sorafenib treatment: Prospects for regorafenib therapy.

PubMed

Terashima, Takeshi; Yamashita, Tatsuya; Sunagozaka, Hajime; Arai, Kuniaki; Kawaguchi, Kazunori; Kitamura, Kazuya; Yamashita, Taro; Sakai, Yoshio; Mizukoshi, Eishiro; Honda, Masao; Kaneko, Shuichi

2018-05-29

This study aimed to investigate liver functional reserves during sorafenib treatment for advanced hepatocellular carcinoma (HCC), to identify predictive factors for maintaining them, and to analyze the proportion of candidates for regorafenib, which has been proven to improve patients' outcomes in the RESORCE trial. We retrospectively investigated Child-Pugh scores during and after sorafenib treatment and evaluated their effects on second-line treatment and outcomes of 125 patients with advanced HCC. Pretreatment Child-Pugh A was maintained in 59/90 (65.6%) patients and pretreatment Child-Pugh B was improved to Child-Pugh A in 10/35 (28.6%) patients when sorafenib ceased. A Child-Pugh score = 5 and aspartate amino transferase <40 IU/L before treatment were contributing factors; vascular invasion and cessation of sorafenib due to gastrointestinal or liver-related adverse effects were reverse predictive factors for Child-Pugh A when sorafenib treatment ceased. Significantly more patients with Child-Pugh A when sorafenib treatment ceased received subsequent therapy and achieved better outcomes compared with patients with Child-Pugh B. When sorafenib treatment failed, 45/125 patients (36.0%) fulfilled key inclusion criteria of the RESORCE trial as follows: Child-Pugh A, Eastern Cooperative Oncology Group performance status 0 or 1, tumor progression revealed by imaging, and treatment with ≥400 mg sorafenib for at least 20 of the last 28 days before treatment failure in 56.8%, 84.8%, 73.6%, and 68.0% of patients, respectively. A comprehensive understanding and management of dynamic changes in liver functional reserve during sorafenib treatment contributed to the efficacy of subsequent therapy (e.g. regorafenib) and to better outcomes for patients with advanced HCC. © 2018 The Japan Society of Hepatology.

Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis.

PubMed

Moratalla, Alba; Gómez-Hurtado, Isabel; Moya-Pérez, Ángela; Zapater, Pedro; Peiró, Gloria; González-Navajas, José M; Gómez Del Pulgar, Eva Maria; Such, José; Sanz, Yolanda; Francés, Rubén

2016-02-01

Intestinal homeostasis plays an important role in bacteria-derived complications in cirrhosis. Intestinal lymphocytes are responsible for immune effector functions and can be modulated by certain probiotics. We evaluate the interaction between Bifidobacterium pseudocatenulatum CECT7765 and intestinal lymphocytes in mice with cirrhosis. Cirrhosis was induced by intragastrical administration of carbon tetrachloride in Balb/C mice. One week prior to laparotomy, animals received B. pseudocatenulatum CECT7765 (10(7), 10(9) or 10(10) cfu/daily) or placebo. Chemokine receptor and cytokine expression were evaluated in intestinal lymphocytes. Gut permeability was studied by FITC-LPS recovery in vivo. Luminal antigens, inflammation and functional markers were evaluated in liver samples. Bifidobacterium pseudocatenulatum CECT7765 decreased the expression of pro-inflammatory chemokine receptors CCR6, CCR9, CXCR3 and CXCR6 in intestinal lymphocytes from cirrhotic mice in a concentration-dependent manner. The bifidobacterial strain induced a shift towards an anti-inflammatory cytokine profile in this cell subset. B. pseudocatenulatum CECT7765-induced inflammatory modulation was TLR2-mediated, as in vitro TLR2 blockade inhibited the reduction of TNF-alpha and its receptors and the increase of IL-10 and IL-10 receptor secretion. The recovery rate of administered fluorescence-labelled endotoxin was significantly and dose-dependently lowered with the bifidobacterial strain. The reduced intestinal permeability was associated with a decreased burden of bacterial antigens in the liver of mice treated with B. pseudocatenulatum CECT7765. Liver function and inflammation were improved with the use of the bifidobacterial strain at the highest dose tested (10(10) cfu). Bifidobacterium pseudocatenulatum CECT7765 improves gut homeostasis and prevents gut-derived complications in experimental chronic liver disease.

Imaging of pharmacokinetic rates of indocyanine green in mouse liver with a hybrid fluorescence molecular tomography/x-ray computed tomography system.

PubMed

Zhang, Guanglei; Liu, Fei; Zhang, Bin; He, Yun; Luo, Jianwen; Bai, Jing

2013-04-01

Pharmacokinetic rates have the potential to provide quantitative physiological and pathological information for biological studies and drug development. Fluorescence molecular tomography (FMT) is an attractive imaging tool for three-dimensionally resolving fluorophore distribution in small animals. In this letter, pharmacokinetic rates of indocyanine green (ICG) in mouse liver are imaged with a hybrid FMT and x-ray computed tomography (XCT) system. A recently developed FMT method using structural priors from an XCT system is adopted to improve the quality of FMT reconstruction. In the in vivo experiments, images of uptake and excretion rates of ICG in mouse liver are obtained, which can be used to quantitatively evaluate liver function. The accuracy of the results is validated by a fiber-based fluorescence measurement system.

Activity of essential phospholipids (EPL) from soybean in liver diseases.

PubMed

Gundermann, Karl-Josef; Kuenker, Ann; Kuntz, Erwin; Droździk, Marek

2011-01-01

Essential phospholipids (EPL) contain a highly purified extract of polyenylphosphatidylcholine (PPC) molecules from soybean. The main active ingredient is 1,2-dilinoleoylphosphatidylcholine (DLPC), which differentiates it from other phospholipids, lecithins, or extracts from other sources. Although EPLis widely used in liver diseases of various origins, its mode of action and pharmacological and clinical evidence of its efficacy have not yet been concisely reviewed. This paper critically summarizes experimental and clinical results. With regard to in-vitro and animal tests, EPL influenced membrane-dependent cellular functions and showed anti-oxidant, anti-inflammatory, anti-fibrotic, apoptosis-modulating, regenerative, membrane-repairing and -protective, cell-signaling and receptor-influencing, as well as lipid-regulating effects in intoxication models with chemicals or drugs. Clinical studies, primarily from European and Asian countries, have shown improvement in subjective symptoms; clinical, biochemical and imaging findings; and histology in liver indications such as fatty liver of different origin, drug hepatotoxicity, and adjuvant in chronic viral hepatitis and hepatic coma. The available studies characterize EPL as evidence-based medicine, although further long-term controlled clinical trials are required to precisely determine its benefit for alleviating symptoms, improving well-being, inducing histological changes and slowing the progression of liver disease. EPL-related relevant side effects were not observed.

Postoperative pain management of liver transplantation in cystic fibrosis: Is it time to start US-guided neuraxial blocks?

PubMed

Piazza, M; Martucci, G; Arcadipane, A

2016-01-01

Cystic fibrosis (CF) is the most common life-limiting genetic disease in Caucasians. Declining lung function is the principal cause of death, but liver involvement can lead to the need for liver transplantation. General anesthesia has detrimental effects on pulmonary function, increasing perioperative morbidity and mortality in CF patients. Regional anesthetic techniques improve outcomes by reducing anesthetic drugs and administration of opioids, and hastening extubation, awakening, and restarting respiratory of physiotherapy. There is a growing evidence that thoracic epidural anesthesia is feasible in pediatric patients. Concerns about coagulopathy and immunosuppression have limited its use in liver transplantation. Ultrasonography is becoming an adjunct tool in neuraxial blocks, allowing faster and easier recognition of the epidural space, and reducing vertebral touch and number of attempts. In pediatric patients, it is still debated whether anesthesia has detrimental effects on cognitive development. Efforts to make regional techniques easier and safer by ultrasonography are ongoing. We report the first case of continuous thoracic epidural analgesia after pediatric liver transplantation in a 10-year-old boy affected with CF with macronodular cirrhosis. Despite a challenging coagulation profile, the echo-assisted procedure was safely performed and allowed extubation in the odds ratio, postoperative awakening and comfort, and quick resumption of respiratory physiotherapy.

[Parenteral S-adenosylmethionine compared to placebos in the treatment of alcoholic liver diseases].

PubMed

Diaz Belmont, A; Dominguez Henkel, R; Uribe Ancira, F

1996-01-01

The improvements in the knowledge of the action of ethanol over the hepatic cell, its direct action over the cell, and the intracytoplasmatic structures membranes, point out the possibilities of use of sulfo-adenosil-L-metionina (SAMe); as an util drug inn the treatment of the altered metilation reactions, that take place in those membranes, facilitating their physiological functions. The primary end point in this study was to demonstrate the therapeutic worth os SAMe, by parenteral route in 45 patients with alcoholic liver disease, which were determined by clinical laboratory and hepatic function test, label qith 32 points or more of the discriminatory function index. Divided into two groups, placebo-SAMe, randomized, double blind. As well as total plasmatic and reduced glutation and lipoperoxidation index, indirect form as malondehaldehyde. Were determined at the first visit anf after 8 and 15 days of treatment. Comparing the results of both groups there were a significative favorable results for the group treatment with SAMe and this confirms the utility of this drug in the treatment of patients with alcoholic liver disease with a discriminatory function index (Maddrey index), of 32 points or more.

Congenital hypothyroidism in a kitten resulting in decreased IGF-I concentration and abnormal liver function tests.

PubMed

Quante, Saskia; Fracassi, Federico; Gorgas, Daniela; Kircher, Patrick R; Boretti, Felicitas S; Ohlerth, Stefanie; Reusch, Claudia E

2010-06-01

A 7-month-old male kitten was presented with chronic constipation and retarded growth. Clinical examination revealed disproportional dwarfism with mild skeletal abnormalities and a palpable thyroid gland. The presumptive diagnosis of congenital hypothyroidism was confirmed by low serum total thyroxine (tT(4)) concentration prior to and after the administration of thyroid stimulation hormone (TSH), increased endogenous TSH concentration and abnormal thyroid scintigraphic scan. The kitten had abnormal liver function tests and decreased insulin-like growth factor 1 (IGF-1) concentration, both of which returned to normal in correspondence with an improvement of the clinical signs after 6 weeks of thyroxine therapy. Congenital hypothyroidism is a rare disease that may present with considerable variation in clinical manifestation. In cases in which clinical signs are ambiguous, disorders such as portosystemic shunt and hyposomatotropism have to be taken into account as differential diagnosis. As hypothyroidism may be associated with abnormal liver function tests and low IGF-1 concentrations, test results have to be interpreted carefully. Copyright 2010 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Molecular pathogenesis and clinical consequences of iron overload in liver cirrhosis.

PubMed

Sikorska, Katarzyna; Bernat, Agnieszka; Wroblewska, Anna

2016-10-01

The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.

Prediction of postoperative outcome after hepatectomy with a new bedside test for maximal liver function capacity.

PubMed

Stockmann, Martin; Lock, Johan F; Riecke, Björn; Heyne, Karsten; Martus, Peter; Fricke, Michael; Lehmann, Sina; Niehues, Stefan M; Schwabe, Michael; Lemke, Arne-Jörn; Neuhaus, Peter

2009-07-01

To validate the LiMAx test, a new bedside test for the determination of maximal liver function capacity based on C-methacetin kinetics. To investigate the diagnostic performance of different liver function tests and scores including the LiMAx test for the prediction of postoperative outcome after hepatectomy. Liver failure is a major cause of mortality after hepatectomy. Preoperative prediction of residual liver function has been limited so far. Sixty-four patients undergoing hepatectomy were analyzed in a prospective observational study. Volumetric analysis of the liver was carried out using preoperative computed tomography and intraoperative measurements. Perioperative factors associated with morbidity and mortality were analyzed. Cutoff values of the LiMAx test were evaluated by receiver operating characteristic. Residual LiMAx demonstrated an excellent linear correlation with residual liver volume (r = 0.94, P < 0.001) after hepatectomy. The multivariate analysis revealed LiMAx on postoperative day 1 as the only predictor of liver failure (P = 0.003) and mortality (P = 0.004). AUROC for the prediction of liver failure and liver failure related death by the LiMAx test was both 0.99. Preoperative volume/function analysis combining CT volumetry and LiMAx allowed an accurate calculation of the remnant liver function capacity prior to surgery (r = 0.85, P < 0.001). Residual liver function is the major factor influencing the outcome of patients after hepatectomy and can be predicted preoperatively by a combination of LiMAx and CT volumetry.

The Role of Akt in Chronic Liver Disease and Liver Regeneration.

PubMed

Morales-Ruiz, Manuel; Santel, Ansgar; Ribera, Jordi; Jiménez, Wladimiro

2017-02-01

The liver is continuously exposed to diverse insults, which may culminate in pathological processes causing liver disease. An effective therapeutic strategy for chronic liver disease should control the causal factors of the disease and stimulate functional liver regeneration. Preclinical studies have shown that interventions aimed at maintaining Akt activity in a dysfunctional liver meet most of the criteria. Although the central function of Akt is cell survival, other cellular aspects such as glucose uptake, glycogen synthesis, cell-cycle progression, and lipid metabolism have been shown to be prominent functions of Akt in the context of hepatic physiology. In this review, the authors describe the benefits of the Akt signaling pathway, emphasizing its importance in coordinating proper cellular growth and differentiation during liver regeneration, hepatic function, and liver disease. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Quality of life following liver transplantation: a comparative study between Familial Amyloid Neuropathy and liver disease patients

PubMed Central

2009-01-01

Background It has been demonstrated in many studies that quality of life can be improved after liver transplantation in patients with liver disease. Nevertherless quality of life improvement in specific groups of transplantated patients such as those with Familial Amyloid Polineuropathy hasn't yet been explored. The present study aimed to compare the change in quality of life following liver transplantation between patients with Familial Amyloid Polineuropathy (FAP) and patients with liver disease. Results Patient's mental quality of life showed an improvement in all liver disease patients, and a worsening in FAP patients, resulting in a significant difference between the two groups. Regarding physical quality of life, although a similar improvement was seen in both groups, FAP patients had significantly less improvement than the sub-group of decompensated liver disease (Child-Pugh B and C). Conclusion It is concluded that liver transplantation has a less beneficial impact in FAP patient's physical quality of life, probably because they are not so much disabled by their disease at the moment of liver transplantation. The lesser improvement in mental quality of life of FAP patients may be due to their particular psychological profile and greater expectations towards transplantation. PMID:19604387

Overexpression of the long noncoding RNA TUG1 protects against cold-induced injury of mouse livers by inhibiting apoptosis and inflammation.

PubMed

Su, Song; Liu, Jiang; He, Kai; Zhang, Mengyu; Feng, Chunhong; Peng, Fangyi; Li, Bo; Xia, Xianming

2016-04-01

Hepatic injury provoked by cold storage is a major problem affecting liver transplantation, as exposure to cold induces apoptosis in hepatic tissues. Long noncoding RNAs (lncRNAs) are increasingly understood to regulate apoptosis, but the contribution of lncRNAs to cold-induced liver injury remains unknown. Using RNA-seq, we determined the differential lncRNA expression profile in mouse livers after cold storage and found that expression of the lncRNA TUG1 was significantly down-regulated. Overexpression of TUG1 attenuated cold-induced apoptosis in mouse hepatocytes and liver sinusoidal endothelial cells LSECs, in part by blocking mitochondrial apoptosis and endoplasmic reticulum (ER) stress pathways. Moreover, TUG1 attenuated apoptosis, inflammation, and oxidative stress in vivo in livers subjected to cold storage. Overexpression of TUG1 also improved hepatocyte function and prolonged hepatic graft survival rates in mice. These results suggest that the lncRNA TUG1 exerts a protective effect against cold-induced liver damage by inhibiting apoptosis in mice, and suggests a potential role for TUG1 as a target for the prevention of cold-induced liver damage in liver transplantation. RNA-seq data are available from GEO using accession number GSE76609. © 2016 Federation of European Biochemical Societies.

Evaluation of gastric emptying function in clinical practice.

PubMed

Poitras, P; Picard, M; Déry, R; Giguère, A; Picard, D; Morais, J; Plourde, V; Boivin, M

1997-11-01

In this retrospective analysis, we compared different methods to evaluate gastric emptying function, aiming to improve the sensitivity and the clinical availability of our diagnostic testing. In the first study, we compared, in 72 patients clinically suspected of gastroparesis, the emptying of a meal containing two solid nutrients with different disintegration rates: 111In-labeled scrambled eggs and 99Tc-labeled liver cubes. Gastric emptying of 111In-labeled egg was delayed in 12 of our patients and the evacuation of the 99Tc-labeled liver was prolonged in 19 patients. The choice of the nutrient was not important for the identification of diabetic gastroparesis (43% vs 57%; NS), but it was determinant in the case of patients suspected of idiopathic gastroparesis (12% were positive with the egg and 25% with the liver; P < 0.05). In the second study, we compared two different diagnostic methods in 46 patients: a simple radiological detection of the gastric emptying of radiopaque pellets, and the scintigraphic emptying of a solid meal containing 99Tc-labeled liver cubes. Both tests correlated perfectly in 78% of our patients. In 15% of the population (six of these seven patients were diabetics suspected of gastroparesis) the scintigraphic method was normal, while the evacuation of radiopaque pellets was delayed. For clinical purposes, we therefore propose: (1) the scintigraphic method should use liver rather than egg as a radiolabeled tracer in order to improve the sensitivity of the test for detection of gastroparesis; and (2) the radiological detection of radiopaque markers is a reliable and convenient method for the detection of gastroparesis in clinical practice. It is possibly more sensitive than scintigraphy.

Statistical quality control charts for liver transplant process indicators: evaluation of a single-center experience.

PubMed

Varona, M A; Soriano, A; Aguirre-Jaime, A; Barrera, M A; Medina, M L; Bañon, N; Mendez, S; Lopez, E; Portero, J; Dominguez, D; Gonzalez, A

2012-01-01

Liver transplantation, the best option for many end-stage liver diseases, is indicated in more candidates than the donor availability. In this situation, this demanding treatment must achieve excellence, accessibility and patient satisfaction to be ethical, scientific, and efficient. The current consensus of quality measurements promoted by the Sociedad Española de Trasplante Hepático (SETH) seeks to depict criteria, indicators, and standards for liver transplantation in Spain. According to this recommendation, the Canary Islands liver program has studied its experience. We separated the 411 cadaveric transplants performed in the last 15 years into 2 groups: The first 100 and the other 311. The 8 criteria of SETH 2010 were correctly fulfilled. In most indicators, the outcomes were favorable, with an actuarial survivals at 1, 3, 5, and 10 years of 84%, 79%, 76%, and 65%, respectively; excellent results in retransplant rates (early 0.56% and long-term 5.9%), primary nonfunction rate (0.43%), waiting list mortality (13.34%), and patient satisfaction (91.5%). On the other hand, some indicators of mortality were worse as perioperative, postoperative, and early mortality with normal graft function and reoperation rate. After the analyses of the series with statistical quality control charts, we observed an improvement in all indicators, even in the apparently worst, early mortality with normal graft functions in a stable program. Such results helped us to discover specific areas to improve the program. The application of the quality measurement, as SETH consensus recommends, has shown in our study that despite being a consuming time process, it is a useful tool. Copyright © 2012 Elsevier Inc. All rights reserved.

Novel synergic antidiabetic effects of Astragalus polysaccharides combined with Crataegus flavonoids via improvement of islet function and liver metabolism.

PubMed

Cui, Kai; Zhang, Shaobo; Jiang, Xin; Xie, Weidong

2016-06-01

The present study investigated the synergic effects and potential mechanisms of action of Astragalus polysaccharides (APS) combined with Crataegus flavonoids (CF) in the treatment of type 1 diabetes. Diabetes was induced by intraperitoneal injection of 100 mg/kg streptozotocin in mice. Normal and untreated diabetic control mice were used, and CF‑treated (200 mg/kg/day), APS‑treated (200 mg/kg/day), APS + CF (AC)‑treated (200 mg/kg/day of each) and metformin‑treated (200 mg/kg/day) diabetic mice were orally administrated the appropriate therapeutic agent for 4 weeks. The results demonstrated that AC treatment significantly reduced the fasting blood glucose, food and water intake in the diabetic mice. The AC group demonstrated increased serum insulin levels and islet cell function was restored. Furthermore, the AC‑treated mice demonstrated significant increases in the protein expression levels of pancreatic and duodenal homeobox‑1 and phosphorylated adenosine 5'‑monophosphate‑activated protein kinase in the pancreatic and liver tissue samples, respectively. In addition, AC significantly increased the mRNA expression levels of neurogenin 3, v‑maf musculoaponeurotic fibrosarcoma oncogene family, protein A and insulin, and simultaneously decreased the expressions of interleukin 6, tumor necrosis factor‑α and chemokine (C‑C motif) ligand 2 in the pancreatic islet cells of diabetic mice. The anti‑inflammatory activity of APS and the islet‑restoring effect of CF may contribute to the improvement of islet function. AC exerted greater antidiabetic effects compared with APS or CF treatments alone. These results indicated that AC treatment had a synergic antidiabetic effect, which may involve improvements in islet function and liver metabolism. These effects of AC may facilitate the treatment of type 1 or 2 diabetes, as these patients frequently experience impaired islet function and disordered extrapancreatic metabolism.

Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

PubMed

Sato, Ken; Gosho, Masahiko; Yamamoto, Takaya; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Nakade, Yukiomi; Ito, Kiyoaki; Fukuzawa, Yoshitaka; Yoneda, Masashi

2015-01-01

Vitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH. PubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis. According to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment. Vitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH. Copyright © 2015 Elsevier Inc. All rights reserved.

Toll-Like Receptor 4 Stimulation before or after Streptococcus pneumoniae Induced Sepsis Improves Survival and Is Dependent on T-Cells

PubMed Central

Martin, Edward N.; Scheld, W. Michael

2014-01-01

Introduction Endotoxin tolerance improves outcomes from gram negative sepsis but the underlying mechanism is not known. We determined if endotoxin tolerance before or after pneumococcal sepsis improved survival and the role of lymphocytes in this protection. Methods Mice received lipopolysaccharide (LPS) or vehicle before or after a lethal dose of Streptococcus pneumoniae. Survival, quantitative bacteriology, liver function, and cytokine concentrations were measured. We confirmed the necessity of Toll-like receptor 4 (TLR4) for endotoxin tolerance using C3H/HeN (TLR4 replete) and C3H/HeJ (TLR4 deficient) mice. The role of complement was investigated through A/J mice deficient in C5 complement. CBA/CaHN-Btkxid//J mice with dysfunctional B cells and Rag-1 knockout (KO) mice deficient in T and B cells delineated the role of lymphocytes. Results Endotoxin tolerance improved survival from pneumococcal sepsis in mice with TLR4 that received LPS pretreatment or posttreatment. Survival was associated with reduced bacterial burden and serum cytokine concentrations. Death was associated with abnormal liver function and blood glucose concentrations. Endotoxin tolerance improved survival in A/J and CBA/CaHN-Btkxid//J mice but not Rag-1 KO mice. Conclusions TLR4 stimulation before or after S. pneumoniae infection improved survival and was dependent on T-cells but did not require an intact complement cascade or functional B cells. PMID:24465843

Can apricot kernels fatty acids delay the atrophied hepatocytes from progression to fibrosis in dimethylnitrosamine (DMN)-induced liver injury in rats?

PubMed

Abdel-Rahman, Manal K

2011-07-07

The present study was aimed to analyze the chemical composition of ground apricot kernel (GAK) and examine its effect on hepatic fibrosis in vivo induced by dimethylnitrosamine (DMN) in rats. Hepatic fibrosis was induced by intraperitoneal injections of 10 mg/kg DMN for 3 consecutive days each week over a period of 4 wk. The rats were randomly assigned to five groups of nine rats each: the negative control group (NC), the hepatic fibrosis group (PC), hepatic fibrosis supplemented with GAK (0.5 mg/kg/BW/rat), hepatic fibrosis supplemented with GAK (1 mg/kg/BW/rat) and hepatic fibrosis supplemented with GAK (1.5 mg/kg/BW/rat). Rats were killed, blood was collected and livers were excised for biochemical measurements and histological examination. Results indicate that the diet supplemented with GAK led to improving liver function, lipid peroxides, and liver CAT, SOD and GSH. These results were confirmed by liver histology. Hierarchically high levels f GAK (1.5 mg/kg/BW/rat) gave the best results compared to other tested levels. This study demonstrates that GAK administration specifically (1.5 mg/kg/BW/rat) can effectively improve liver fibrosis caused by DMN, and may be used as a therapeutic option and preventive measure against hepatic fibrosis. Furthermore, a human trial would be applied specially GAK is a part of Egyptian diet. The act of why high amounts of GAK was improved biochemical values compared to low or moderate levels tested in this study may be due to increase levels of oleic acid and other polyphenols in apricot kernels.

Can apricot kernels fatty acids delay the atrophied hepatocytes from progression to fibrosis in dimethylnitrosamine (DMN)-induced liver injury in rats?

PubMed Central

2011-01-01

Background and aims The present study was aimed to analyze the chemical composition of ground apricot kernel (GAK) and examine its effect on hepatic fibrosis in vivo induced by dimethylnitrosamine (DMN) in rats. Methods and results Hepatic fibrosis was induced by intraperitoneal injections of 10 mg/kg DMN for 3 consecutive days each week over a period of 4 wk. The rats were randomly assigned to five groups of nine rats each: the negative control group (NC), the hepatic fibrosis group (PC), hepatic fibrosis supplemented with GAK (0.5 mg/kg/BW/rat), hepatic fibrosis supplemented with GAK (1 mg/kg/BW/rat) and hepatic fibrosis supplemented with GAK (1.5 mg/kg/BW/rat). Rats were killed, blood was collected and livers were excised for biochemical measurements and histological examination. Results indicate that the diet supplemented with GAK led to improving liver function, lipid peroxides, and liver CAT, SOD and GSH. These results were confirmed by liver histology. Hierarchically high levels f GAK (1.5 mg/kg/BW/rat) gave the best results compared to other tested levels. Conclusion This study demonstrates that GAK administration specifically (1.5 mg/kg/BW/rat) can effectively improve liver fibrosis caused by DMN, and may be used as a therapeutic option and preventive measure against hepatic fibrosis. Furthermore, a human trial would be applied specially GAK is a part of Egyptian diet. The act of why high amounts of GAK was improved biochemical values compared to low or moderate levels tested in this study may be due to increase levels of oleic acid and other polyphenols in apricot kernels PMID:21736706

Graft selection strategy in adult-to-adult living donor liver transplantation: When both hemiliver grafts meet volumetric criteria.

PubMed

Kurihara, Takeshi; Yoshizumi, Tomoharu; Yoshida, Yoshihiro; Ikegami, Toru; Itoh, Shinji; Harimoto, Norifumi; Ninomiya, Mizuki; Uchiyama, Hideaki; Okabe, Hirohisa; Kimura, Koichi; Kawanaka, Hirofumi; Shirabe, Ken; Maehara, Yoshihiko

2016-07-01

To ensure donor safety in living donor liver transplantation (LDLT), the left and caudate lobe (LL) is the preferred graft choice. However, patient prognosis may still be poor even if graft volume (GV) selection criteria are met. Our aim was to evaluate the effects of right lobe (RL) donation when the LL graft selection criteria are met. Consecutive donors (n = 135) with preoperative LL graft volumetric GV/standard liver volume (SLV) of ≥35% and RL remnant of ≥35% were retrospectively studied. Patients were divided into 2 groups: LL graft and RL graft. Recipient's body surface area (BSA), Model for End-Stage Liver Disease (MELD) score, and the donor's age were higher in the RL group. The donor's BSA and preoperative volumetric GV/SLV of the LL graft were smaller in the RL group. The predicted score (calculated using data for graft size, donor age, MELD score, and the presence of portosystemic shunt, which correlated well with graft function and with 6-month graft survival) of the RL group, was significantly lower if the LL graft were used, but using the actual RL graft improved the score equal to that of the LL group. Six-month and 12-month graft survival rates did not differ between the 2 groups. In patients with a poor prognosis, a larger RL graft improved the predicted score and survival was equal to that of patients who received LL grafts. In conclusion, graft selection by GV, donor age, and recipient MELD score improves outcomes in LDLT. Liver Transplantation 22 914-922 2016 AASLD. © 2016 American Association for the Study of Liver Diseases.

New Developments in Hepatorenal Syndrome.

PubMed

Mindikoglu, Ayse L; Pappas, Stephen C

2018-02-01

Hepatorenal syndrome (HRS) continues to be one of the major complications of decompensated cirrhosis, leading to death in the absence of liver transplantation. Challenges in precisely evaluating renal function in the patient with cirrhosis remain because of the limitations of serum creatinine (Cr) alone in estimating glomerular filtration rate (GFR); current GFR estimating models appear to underestimate renal dysfunction. Newer models incorporating renal biomarkers, such as the Cr-Cystatin C GFR Equation for Cirrhosis appear to estimate measured GFR more accurately. A major change in the diagnostic criteria for HRS based on dynamic serial changes in serum Cr that regard HRS type 1 as a special form of acute kidney injury promises the possibility of earlier identification of renal dysfunction in patients with cirrhosis. The diagnostic criteria of HRS still include the exclusion of other causes of kidney injury. Renal biomarkers have been disappointing in assisting with the differentiation of HRS from prerenal azotemia and other kidney disorders. Serum metabolomic profiling may be a more powerful tool to assess renal dysfunction, although the practical clinical significance of this remains unclear. As a result of the difficulties of assessing renal function in cirrhosis and the varying HRS diagnostic criteria and the rigor with which they are applied, the precise incidence and prevalence of HRS is unknown, but it is likely that HRS occurs more commonly than expected. The pathophysiology of HRS is rooted firmly in the setting of progressive reduction in renal blood flow as a result of portal hypertension and splanchnic vasodilation. Progressive marked renal cortical ischemia in patients with cirrhosis parallels the evolution of diuretic-sensitive ascites to diuretic-refractory ascites and HRS, a recognized continuum of renal dysfunction in cirrhosis. Alterations in nitrous oxide production, both increased and decreased, may play a major role in the pathophysiology of this evolution. The inflammatory cascade, triggered by bacterial translocation and endotoxemia, increasingly recognized as important in the manifestation of acute-on-chronic liver failure, also may play a significant role in the pathophysiology of HRS. The mainstay of treatment remains vasopressor therapy with albumin in an attempt to reverse splanchnic vasodilation and improve renal blood flow. Several meta-analyses have confirmed the value of vasopressors, chiefly terlipressin and noradrenaline, in improving renal function and reversing HRS type 1. Other interventions such as renal replacement therapy, transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Liver transplantation remains the definitive treatment for HRS. The frequency of simultaneous liver-kidney transplantation has increased dramatically in the Model for End-stage Liver Disease era, with changes in organ allocation policies. This has resulted in a more urgent need to predict native kidney recovery from HRS after liver transplantation alone, to avoid unnecessary simultaneous liver-kidney transplantation. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

TH-A-9A-04: Incorporating Liver Functionality in Radiation Therapy Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, V; Epelman, M; Feng, M

2014-06-15

Purpose: Liver SBRT patients have both variable pretreatment liver function (e.g., due to degree of cirrhosis and/or prior treatments) and sensitivity to radiation, leading to high variability in potential liver toxicity with similar doses. This work aims to explicitly incorporate liver perfusion into treatment planning to redistribute dose to preserve well-functioning areas without compromising target coverage. Methods: Voxel-based liver perfusion, a measure of functionality, was computed from dynamic contrast-enhanced MRI. Two optimization models with different cost functions subject to the same dose constraints (e.g., minimum target EUD and maximum critical structure EUDs) were compared. The cost functions minimized were EUDmore » (standard model) and functionality-weighted EUD (functional model) to the liver. The resulting treatment plans delivering the same target EUD were compared with respect to their DVHs, their dose wash difference, the average dose delivered to voxels of a particular perfusion level, and change in number of high-/low-functioning voxels receiving a particular dose. Two-dimensional synthetic and three-dimensional clinical examples were studied. Results: The DVHs of all structures of plans from each model were comparable. In contrast, in plans obtained with the functional model, the average dose delivered to high-/low-functioning voxels was lower/higher than in plans obtained with its standard counterpart. The number of high-/low-functioning voxels receiving high/low dose was lower in the plans that considered perfusion in the cost function than in the plans that did not. Redistribution of dose can be observed in the dose wash differences. Conclusion: Liver perfusion can be used during treatment planning potentially to minimize the risk of toxicity during liver SBRT, resulting in better global liver function. The functional model redistributes dose in the standard model from higher to lower functioning voxels, while achieving the same target EUD and satisfying dose limits to critical structures. This project is funded by MCubed and grant R01-CA132834.« less

The anti-fibrotic effect of liver growth factor is associated with decreased intrahepatic levels of matrix metalloproteinases 2 and 9 and transforming growth factor beta 1 in bile duct-ligated rats.

PubMed

Díaz-Gil, Juan J; García-Monzón, Carmelo; Rúa, Carmen; Martín-Sanz, Paloma; Cereceda, Rosa M; Miquilena-Colina, María E; Machín, Celia; Fernández-Martínez, Amalia; García-Cañero, Rarael

2008-05-01

Liver growth factor (LGF), a mitogen for liver cells, behaves as an anti-fibrotic agent even in extrahepatic sites, but its mechanistic basis is unknown. We aimed to determine the intrahepatic expression pattern of key modulators of liver fibrosis in bile duct-ligated rats (BDL) after injection of LGF. BDL rats received either LGF (4.5 microg/ratXdose, two doses/week, at time 0 or 2 or 5w after operation, depending on the group (BDL+LGF groups, n=20) or saline (BDL+S groups, n=20). Groups were compared in terms of fibrosis (histomorphometry), liver function (aminopyrine breath test), matrix metalloproteinases MMP-2 and MMP-9, transforming growth factor beta 1 (TGF-beta1) and liver endoglin content (Western blotting), and serum tissue inhibitor of metalloproteinases 1 (TIMP-1) levels (ELISA). In BDL+LGF rats, the fibrotic index was significantly lower at 5w, p=0.006, and at 8w, p=0.04, than in BDL+S rats. Liver function values in BDL+LGF rats were higher than those obtained in BDL+S rats (80% at 5w and 79% at 8w, versus 38% and 29%, p<0.01, taking healthy controls as 100%). Notably, in BDL+LGF rats the intrahepatic expression levels of both MMPs were lower at 2w (MMP-2, p=0.03; MMP-9, p=0.05) and 5w (MMP-2, p=0.05, MMP-9, p=0.04). In addition, the hepatic TGF-beta1 level in BDL+LGF rats was lower at 2w (36%, p=0.008), 5w (50%) and 8wk (37%), whereas intrahepatic endoglin expression remained constant in all BDL rats studied. LGF ameliorates liver fibrosis and improves liver function in BDL rats. The LGF-induced anti-fibrotic effect is associated with a decreased hepatic level of MMP-2, MMP-9 and TGF-beta1 in fibrotic rats.

CXCR3+CD4+ T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury.

PubMed

Zhai, Yuan; Shen, Xiu-da; Hancock, Wayne W; Gao, Feng; Qiao, Bo; Lassman, Charles; Belperio, John A; Strieter, Robert M; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W

2006-05-15

Ischemia-reperfusion injury (IRI), an innate immune-dominated inflammatory response, develops in the absence of exogenous Ags. The recently highlighted role of T cells in IRI raises a question as to how T lymphocytes interact with the innate immune system and function with no Ag stimulation. This study dissected the mechanism of innate immune-induced T cell recruitment and activation in rat syngeneic orthotopic liver transplantation (OLT) model. Liver IRI was induced after cold storage (24-36 h) at 4 degrees C in University of Wisconsin solution. Gene products contributing to IRI were identified by cDNA microarray at 4-h posttransplant. IRI triggered increased intrahepatic expression of CXCL10, along with CXCL9 and 11. The significance of CXCR3 ligand induction was documented by the ability of neutralizing anti-CXCR3 Ab treatment to ameliorate hepatocellular damage and improve 14-day survival of 30-h cold-stored OLTs (95 vs 40% in controls; p < 0.01). Immunohistology analysis confirmed reduced CXCR3+ and CD4+ T cell infiltration in OLTs after treatment. Interestingly, anti-CXCR3 Ab did not suppress innate immune activation in the liver, as evidenced by increased levels of IL-1beta, IL-6, inducible NO synthase, and multiple neutrophil/monokine-targeted chemokine programs. In conclusion, this study demonstrates a novel mechanism of T cell recruitment and function in the absence of exogenous Ag stimulation. By documenting that the execution of innate immune function requires CXCR3+CD4+ T cells, it highlights the critical role of CXCR3 chemokine biology for the continuum of innate to adaptive immunity in the pathophysiology of liver IRI.

Cultured Mycelium Cordyceps sinensis allevi¬ates CCl4-induced liver inflammation and fibrosis in mice by activating hepatic natural killer cells.

PubMed

Peng, Yuan; Huang, Kai; Shen, Li; Tao, Yan-yan; Liu, Cheng-hai

2016-02-01

Recent evidence shows that cultured mycelium Cordyceps sinensis (CMCS) effectively protects against liver fibrosis in mice. Here, we investigated whether the anti-fibrotic action of CMCS was related to its regulation of the activity of hepatic natural killer (NK) cells in CCl4-treated mice. C57BL/6 mice were injected with 10% CCl4 (2 mL/kg, ip) 3 times per week for 4 weeks, and received CMCS (120 mg·kg(-1)·d(-1), ig) during this period. In another part of experiments, the mice were also injected with an NK cell-deleting antibody ASGM-1 (20 μg, ip) 5 times in the first 3 weeks. After the mice were sacrificed, serum liver function, and liver inflammation, hydroxyproline content and collagen deposition were assessed. The numbers of hepatic NK cells and expression of NKG2D (activation receptor of NK cells) on isolated liver lymphocytes were analyzed using flow cytometry. Desmin expression and cell apoptosis in liver tissues were studied using desmin staining and TUNEL assay, respectively. The levels of α-SMA, TGF-β, RAE-1δ and RAE-1ε in liver tissues were determined by RT-qPCR. In CCl4-treated mice, CMCS administration significantly improved liver function, attenuated liver inflammation and fibrosis, and increased the numbers of hepatic NK cells and expression level of NKG2D on hepatic NK cells. Furthermore, CMCS administration significantly decreased desmin expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Injection with NK cell-deleting ASGM-1 not only diminished the numbers of hepatic NK cells, but also greatly accelerated liver inflammation and fibrosis in CCl4-treated mice. In CCl4-treated mice with NK cell depletion, CMCS administration decelerated the rate of liver fibrosis development, and mildly upregulated the numbers of hepatic NK cells but without changing NKG2D expression. CMCS alleviates CCl4-induced liver inflammation and fibrosis via promoting activation of hepatic NK cells. CMCS partially reverses ASGM-1-induced depletion of hepatic NK cells.

Comparative factor analysis of the effect of postoperative peripheral parenteral nutrition on recovery of right lobe liver donors.

PubMed

Hsieh, Chia-En; Lin, Kuo-Hua; Lin, Chia-Cheng; Hwu, Yueh-Juen; Lin, Ping-Yi; Lin, Hui-Chuan; Ko, Chih-Jan; Wang, Su-Han; Chen, Yao-Li

2015-04-01

Intensive nutritional support can reduce the catabolic response, improve protein synthesis, and promote liver regeneration. This study examined whether postoperative peripheral parenteral nutrition may improve recovery and reduce the length of hospital stay in right lobe liver donors. In this retrospective study, we enrolled liver donors with residual liver volume < 50%. Donors were classified into 2 groups: donors who received (n = 44) or did not receive (n = 40) postoperative peripheral parenteral nutrition. Liver function tests included alanine aminotransferase and total bilirubin levels, and postoperative complications included pleural effusion, atelectasis, and wound complications. Hospital length of stay was included as a potential risk factor for the evaluation of the effect of postoperative peripheral parenteral nutrition on recovery of right lobe liver donors. Male sex (β, 22.04; 95% confidence interval: 6.22 - 37.86) was a significant predictor of changes in postoperative alanine aminotransferase level. Male sex (β, 0.045; 95% confidence interval: 0.16 - 37.86) and receipt of peripheral parenteral nutrition (β, -0.045; 95% confidence interval: -0.72 - 0.17) were significant predictors of changes in total bilirubin level. Postoperative atelectasis (P < .001), pleural effusion (P < .011), and total complications (P = .015) had significantly lower incidence in the peripheral parenteral nutrition than control group. Multivariate logistic regression showed that recipients of peripheral parenteral nutrition (odds ratio, 0.161; 95% confidence interval: 0.043 - 0.598) and age (odds ratio, 0.870; 95% confidence interval: 0.782 - 0.968) were significant preoperative risk factors for postoperative complications. Postoperative peripheral parenteral nutrition is associated with a lower incidence of pleural effusion and atelectasis, a more rapid recovery of hyperbilirubinemia, and shorter length of stay in right lobe liver donors.

Combination of vildagliptin and rosiglitazone ameliorates nonalcoholic fatty liver disease in C57BL/6 mice.

PubMed

Mookkan, Jeyamurugan; De, Soumita; Shetty, Pranesha; Kulkarni, Nagaraj M; Devisingh, Vijayaraj; Jaji, Mallikarjun S; Lakshmi, Vinitha P; Chaudhary, Shilpee; Kulathingal, Jayanarayan; Rajesh, Navin B; Narayanan, Shridhar

2014-01-01

To evaluate the effect of vildagliptin alone and in combination with metformin or rosiglitazone on murine hepatic steatosis in diet-induced nonalcoholic fatty liver disease (NAFLD). Male C57BL/6 mice were fed with high fat diet (60 Kcal %) and fructose (40%) in drinking water for 60 days to induce NAFLD. After the induction period, animals were divided into different groups and treated with vildagliptin (10 mg/kg), metformin (350 mg/kg), rosiglitazone (10 mg/kg), vildagliptin (10 mg/kg) + metformin (350 mg/kg), or vildagliptin (10 mg/kg) + rosiglitazone (10 mg/kg) orally for 28 days. Following parameters were measured: body weight, food intake, plasma glucose, triglyceride (TG), total cholesterol, liver function tests, and liver TG. Liver histopathology was also examined. Oral administration of vildagliptin and rosiglitazone in combination showed a significant reduction in fasting plasma glucose, hepatic steatosis, and liver TGs. While other treatments showed less or no improvement in the measured parameters. These preliminary results demonstrate that administration of vildagliptin in combination with rosiglitazone could be a promising therapeutic strategy for the treatment of NAFLD.

Marine collagen peptides protect against early alcoholic liver injury in rats.

PubMed

Lin, Bing; Zhang, Feng; Yu, Yongchao; Jiang, Qinghao; Zhang, Zhaofeng; Wang, Junbo; Li, Yong

2012-04-01

Marine collagen peptides (MCP) have been reported to exhibit antioxidative activity, which is the common property of numerous hepatoprotective agents. Previous studies have shown that MCP have biological functions including anti-hypertension, anti-ulcer, anti-skin ageing and extending the life span. However, its role in alcoholic liver injury remains unknown. The present study aimed to investigate the effects of MCP on early alcoholic liver injury in rats. Rats were administered with alcohol at a dose of 6 g/kg body weight intragastrically per d to induce early liver injury, which was then evaluated by serum markers and histopathological examination. Treatment with MCP could reverse the increased level of serum aminotransferase and reduce hepatic histological damage. In addition, MCP attenuated the alteration in serum superoxide dismutase and malondialdehyde levels. MCP also counteracted the increased levels of total cholesterol and TAG. However, no significant difference was observed in the contents of alcohol dehydrogenase both in liver and serum protein of rats. These findings suggest that MCP have a protective effect on early alcoholic liver injury in rats by their antioxidative activity and improving lipid metabolism.

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation.

PubMed

Hey, Penelope; Lokan, Julie; Johnson, Paul; Gow, Paul

2017-09-25

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Hepatitis A complicated with acute renal failure and high hepatocyte growth factor: A case report.

PubMed

Oe, Shinji; Shibata, Michihiko; Miyagawa, Koichiro; Honma, Yuichi; Hiura, Masaaki; Abe, Shintaro; Harada, Masaru

2015-08-28

A 58-year-old man was admitted to our hospital. Laboratory data showed severe liver injury and that the patient was positive for immunoglobulin M anti-hepatitis A virus (HAV) antibodies. He was also complicated with severe renal dysfunction and had an extremely high level of serum hepatocyte growth factor (HGF). Therefore, he was diagnosed with severe acute liver failure with acute renal failure (ARF) caused by HAV infection. Prognosis was expected to be poor because of complications by ARF and high serum HGF. However, liver and renal functions both improved rapidly without intensive treatment, and he was subsequently discharged from our hospital on the 21(st) hospital day. Although complication with ARF and high levels of serum HGF are both important factors predicting poor prognosis in acute liver failure patients, the present case achieved a favorable outcome. Endogenous HGF might play an important role as a regenerative effector in injured livers and kidneys.

Impairment of Host Liver Repopulation by Transplanted Hepatocytes in Aged Rats and the Release by Short-Term Growth Hormone Treatment.

PubMed

Stock, Peggy; Bielohuby, Maximilian; Staege, Martin S; Hsu, Mei-Ju; Bidlingmaier, Martin; Christ, Bruno

2017-03-01

Hepatocyte transplantation is an alternative to whole liver transplantation. Yet, efficient liver repopulation by transplanted hepatocytes is low in livers of old animals. This restraint might be because of the poor proliferative capacity of aged donor hepatocytes or the regenerative impairment of the recipient livers. The age-dependent liver repopulation by transplanted wild-type hepatocytes was investigated in juvenile and senescent rats deficient in dipeptidyl-peptidase IV. Repopulation was quantified by flow cytometry and histochemical estimation of dipeptidyl-peptidase IV enzyme activity of donor cells in the negative host liver. As a potential pathway involved, expression of cell cycle proteins was assessed. Irrespective of the age of the donor hepatocytes, large cell clusters appeared in juvenile, but only small clusters in senescent host livers. Because juvenile and senescent donor hepatocytes were likewise functional, host-derived factor(s) impaired senescent host liver repopulation. Growth hormone levels were significantly higher in juvenile than in senescent rats, suggesting that growth hormone might promote host liver repopulation. Indeed, short-term treatment with growth hormone augmented senescent host liver repopulation involving the growth hormone-mediated release of the transcriptional blockade of genes associated with cell cycle progression. Short-term growth hormone substitution might improve liver repopulation by transplanted hepatocytes, thus augmenting the therapeutic benefit of clinical hepatocyte transplantation in older patients. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Liver Function Assessment Using Technetium 99m-Galactosyl Single-Photon Emission Computed Tomography/CT Fusion Imaging: A Prospective Trial.

PubMed

Okabayashi, Takehiro; Shima, Yasuo; Morita, Sojiro; Shimada, Yasuhiro; Sumiyoshi, Tatsuaki; Sui, Kenta; Iwata, Jun; Iiyama, Tatsuo

2017-12-01

The prediction of postoperative liver function remains a largely subjective practice based on CT volumetric analysis. However, future liver volume after a hepatectomy is not the only factor that contributes to postoperative liver function and outcomes. In this prospective trial, 185 consecutive patients who underwent liver operations between 2014 and 2015 were studied. Volumetric and functional rates of remnant liver were measured using technetium 99m-galactosyl human serum albumin single-photon emission computed tomography/CT fusion imaging to evaluate post-hepatectomy remnant liver function. Remnant indocyanine green clearance rate using galactosyl (KGSA) (KGSA × functional rate) was used to predict future remnant liver function. Hepatectomy was considered safe for patients with remnant KGSA values ≥0.05, and the primary end point was to determine the accuracy and reliability of this criteria. The prediction of the 90-day major complication and mortality rates was assessed. Median hospital stay was 9 days and median ICU stay was 1 day, with only 1 in-hospital death (90-day mortality rate 0.5%). Overall morbidity rate evaluated according to the Clavien-Dindo classification was 9%. For post-hepatectomy liver failure definitions, the International Study Group of Liver Surgery definition was fulfilled in 14 patients (8%), with the majority being grade B (50%), compared with 2 patients (1%) fulfilling the "50-50" criteria, and 0 patients (0%) fulfilling the Peak Bili >7 criteria. Results of this study showed that remnant KGSA provided information that allowed us to predict remnant liver function. This information will be important for surgeons when deciding on a treatment plan for patients with liver diseases. (ClinicalTrials.gov ID: NCT02013895). Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Antrodia Cinnamomea Reduces Carbon Tetrachloride-induced Hepatotoxicity In Male Wister Rats.

PubMed

Shih, Yung-Luen; Wu, Ming-Fang; Lee, Ching-Hsiao; Yeh, Ming-Yang; Chou, Jason; Liu, Jia-You; Lu, Hsu-Feng; Huang, Yi-Ping; Liao, Nien-Chieh; Chung, Jing-Gung

2017-01-01

Antrodia cinnamomea is found with polysaccharides, lipids, vitamins, fibers and ash (minerals) and is well known in Taiwan as a traditional Chinese medicine. Its biological activities have been reported to have anti-inflammatory, anti-fatigue, anti-tumor and immunomodulatory effects, but its protective effects on liver function are still unclear. We determined if Antrodia cinnamomea was hepatoprotective against carbon tetrachloride (CCl 4 ) toxicity in Wistar rats. Six groups were used in the study: 1) control (no induction by CCl 4 ); 2) negative control (CCl 4 -induction and no treatment); 3) positive control (silymarin treatment); 4) groups 4-6 were treated with CC1 4 and different concentrations (350 mg/kg, 1,400 mg/kg, 3,150 mg/kg) of Antrodia cinnamomea. Blood and liver samples of rats were harvested and then detected by biochemical and tissue histochemical analysis. Activity of the antioxidative enzymes glutathione peroxidase, superoxide dismutase and catalase in the liver were also monitored. Only the high-dose treatment was able to decrease serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels and improve liver function. High and medium doses increased total liver protein and reduced hydroxyproline. It was also observed that the high dose treatment reduced lipid peroxidation. Liver sections of CC1 4 treated animals receiving Antrodia cinnamomea showed less fibrosis compared to the CCl 4 control group. This finding suggested that Antrodia cinnamomea can either enhance liver recovering from CCl 4 damage or attenuate CCl 4 toxicity in rats. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Acetaminophen (Paracetamol) induced acute liver failure - A social problem in an era of increasing tendency to self-treatment.

PubMed

Wróblewski, Tadeusz; Kobryń, Konrad; Kozieł, Sławomir; Ołdakowska-Jedynak, Urszula; Pinkas, Jarosław; Danielewicz, Roman; Ziarkiewicz-Wróblewska, Bogna; Krawczyk, Marek

2015-01-01

The widespread availability of medication without prescription, so-called over the counter (OTC), and the rapid development of health consciousness of Poles is associated with broad access to medical information in the mass media. This causes patients to recognize their own disease, cancel doctor's appointments, and begin self-treatment. This time and money-saving behavior, often signaled by pain, usually leads to the treatment of symptoms alone, without seeking the cause of the disease.The aim of the study was to present life-threatening paracetamol poisoning, and the treatment of acute liver failure. In 2002-2014, 35 patients were hospitalized due to acute paracetamol poisoning: 17 female and 18 male patients aged between 17-59 (mean 32.3 years). Patients were treated in the surgical intensive care unit, where their parameters of liver and renal function were continuously monitored. If there was no improvement in the liver function, patients underwent albumin dialysis with the Prometheus system and were qualified for liver transplantation (LTx). 26 patients were treated pharmacologically and 7 out of 9 patients who underwent LTx were dialyzed. Overall, 11 patients had 26 albumin dialysis in total; 4 patients died - 1 post-transplant and 3 pre-transplant. Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

Assessment of functional liver reserve: old and new in 99mTc-sulfur colloid scintigraphy.

PubMed

Matesan, Manuela M; Bowen, Stephen R; Chapman, Tobias R; Miyaoka, Robert S; Velez, James W; Wanner, Michele F; Nyflot, Matthew J; Apisarnthanarax, Smith; Vesselle, Hubert J

2017-07-01

A semiquantitative assessment of hepatic reticuloendothelial system function using colloidal particles scintigraphy has been proposed previously as a surrogate for liver function evaluation. In this article, we present an updated method for the overall assessment of technetium-99m (Tc)-sulfur colloid (SC) biodistribution that combines information from planar and attenuation-corrected Tc-SC single-photon emission computed tomography (SPECT) images. The imaging protocol described here was developed as an easy-to-implement method to assess overall and regional liver function changes associated with chronic liver disease. Thirty patients with chronic liver disease and primary liver cancers underwent Tc-SC whole-body planar imaging and upper-abdomen SPECT/computed tomography (CT) imaging before external beam radiation therapy. Liver plus spleen and bone marrow counts as a fraction of whole-body total counts were calculated from SC planar imaging. Attenuation correction Tc-SC images were rigidly coregistered with treatment planning CT images that contained liver and spleen regions-of-interest. Ratios of total liver counts to total spleen counts were obtained from the aligned Tc-SC SPECT and CT images, and were subsequently used to separate liver plus spleen counts obtained on the planar images. This hybrid SPECT/CT and planar scintigraphy approach yielded an updated estimation of whole-body SC distribution. These biodistribution estimates were compared with historical data for reference. Statistical associations of Tc-SC biodistribution to liver function parameters and liver disease scoring systems (Child-Pugh) were evaluated by Spearman rank correlation. Percentages of Tc-SC uptake ranged from 19.3 to 77.3% for the liver; 3.4 to 40.7% for the spleen; and 19.0 to 56.7% for the bone marrow. Spearman's correlation coefficient showed a significant statistical association between Child-Pugh score and bone marrow uptake at 0.55 (P≤0.05), liver uptake at 0.71 (P≤0.001), spleen uptake at 0.56 (P≤0.05), and spleen plus bone marrow uptake at 0.71 (P≤0.001). There was also a good correlation of SC uptake percentages with individual quantitative liver function components such as albumin and total bilirubin, and qualitative liver function components (varices, portal hypertension, ascites). For albumin: r=0.64 (P<0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P<0.001) compared with splenic uptake percentage, and r=0.45 (P≤0.05) compared with bone marrow uptake percentage. We describe a novel liver function quantitative assessment method that combines whole-body planar images and SPECT/CT attenuation-corrected images of Tc-SC distribution. Attenuation-corrected SC images provide valuable regional liver function information, which is a unique feature compared with other imaging methods available. The results of our study indicate that the Tc-SC uptake by the liver, spleen, and bone marrow correlates with liver function parameters in patients with diffuse liver disease and the correlation with liver disease severity is slightly better for liver uptake percentages than for individual values of bone marrow and spleen uptake percentages.

Zebrafish: An Important Tool for Liver Disease Research

PubMed Central

Goessling, Wolfram; Sadler, Kirsten C.

2016-01-01

As the incidence of hepatobiliary diseases increases, we must improve our understanding of the molecular, cellular, and physiological factors that contribute to the pathogenesis of liver disease. Animal models help us identify disease mechanisms that might be targeted therapeutically. Zebrafish (Danio rerio) have traditionally been used to study embryonic development but are also important to the study of liver disease. Zebrafish embryos develop rapidly; all of their digestive organs are mature in larvae by 5 days of age. At this stage, they can develop hepatobiliary diseases caused by developmental defects or toxin- or ethanol-induced injury and manifest premalignant changes within weeks. Zebrafish are similar to humans in hepatic cellular composition, function, signaling, and response to injury as well as the cellular processes that mediate liver diseases. Genes are highly conserved between humans and zebrafish, making them a useful system to study the basic mechanisms of liver disease. We can perform genetic screens to identify novel genes involved in specific disease processes and chemical screens to identify pathways and compounds that act on specific processes. We review how studies of zebrafish have advanced our understanding of inherited and acquired liver diseases as well as liver cancer and regeneration. PMID:26319012

Intestinal ischemic preconditioning reduces liver ischemia reperfusion injury in rats

PubMed Central

XUE, TONG-MIN; TAO, LI-DE; ZHANG, JIE; ZHANG, PEI-JIAN; LIU, XIA; CHEN, GUO-FENG; ZHU, YI-JIA

2016-01-01

The aim of the current study was to investigate whether intestinal ischemic preconditioning (IP) reduces damage to the liver during hepatic ischemia reperfusion (IR). Sprague Dawley rats were used to model liver IR injury, and were divided into the sham operation group (SO), IR group and IP group. The results indicated that IR significantly increased Bax, caspase 3 and NF-κBp65 expression levels, with reduced expression of Bcl-2 compared with the IP group. Compared with the IR group, the levels of AST, ALT, MPO, MDA, TNF-α and IL-1 were significantly reduced in the IP group. Immunohistochemistry for Bcl-2 and Bax indicated that Bcl-2 expression in the IP group was significantly increased compared with the IR group. In addition, IP reduced Bax expression compared with the IR group. The average liver injury was worsened in the IR group and improved in the IP group, as indicated by the morphological evaluation of liver tissues. The present study suggested that IP may alleviates apoptosis, reduce the release of pro-inflammatory cytokines, ameloriate reductions in liver function and reduce liver tissue injury. To conclude, IP provided protection against hepatic IR injury. PMID:26821057

Effects of aspirin and enoxaparin in a rat model of liver fibrosis.

PubMed

Li, Chen-Jie; Yang, Zhi-Hui; Shi, Xiao-Liu; Liu, De-Liang

2017-09-21

To examine the effects of aspirin and enoxaparin on liver function, coagulation index and histopathology in a rat model of liver fibrosis. METHODS Forty-five male Sprague-Dawley rats were randomly divided into the control group (n = 5) and model group (n = 40). Thioacetamide (TAA) was used to induce liver fibrosis in the model group. TAA-induced fibrotic rats received TAA continuously (n = 9), TAA + low-dose aspirin (n = 9), TAA + high-dose aspirin (n = 9) or TAA + enoxaparin (n = 9) for 4 wk. All rats were euthanized after 4 wk, and both hematoxylin-eosin and Masson staining were performed to observe pathological changes in liver tissue. Liver fibrosis was assessed according to the METAVIR score. Compared with untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the low-dose aspirin, high-dose aspirin and enoxaparin treated groups, especially in the high-dose aspirin treated group. Alanine aminotransferase and total bilirubin were higher, albumin was lower and both prothrombin time and international normalized ratio were prolonged in the four treatment groups compared to controls. No significant differences among the four groups were observed. Aspirin and enoxaparin can alleviate liver fibrosis in this rat model.

[Definition of surgical degree of freedom by functional anatomy in liver resection surgery].

PubMed

Kraus, T W; Golling, M; Klar, E

2001-07-01

Liver resections have developed to very complex and differentiated operations, clearly adapted to individual anatomical and physiological conditions. In parallel, perioperative morbidity has been dramatically reduced. Intraoperative strict consideration of various details of hepatic anatomy, particularly of functional liver anatomy, has proved to be of particular importance when liver surgery reaches indication and technical limits. The term "functional anatomy" stands for a form of hepatic substructurization, which is primarily based on the existence of hemodynamically independent regions of liver parenchyma. A selection of some of the most important details and facts of functional liver anatomy and secondary derived guidelines for surgical strategy and technique is presented in an overview, with special focus on liver resection.

Liver Function Assessment by Magnetic Resonance Imaging.

PubMed

Ünal, Emre; Akata, Deniz; Karcaaltincaba, Musturay

2016-12-01

Liver function assessment by hepatocyte-specific contrast-enhanced magnetic resonance imaging is becoming a new biomarker. Liver function can be assessed by T1 mapping (reduction rate) and signal intensity measurement (relative enhancement ratio) before and after GD-EOB-DTPA (gadoxetic acid) administration, as alternative to Tc-99m galactosyl serum albumin scintigraphy, 99m Tc-labeled mebrofenin scintigraphy, and indocyanine green clearance test. Magnetic resonance imaging assessment of liver function can enable diagnosis of cirrhosis, nonalcoholic fatty liver disease associated fibrosis and steatohepatitis, primary sclerosing cholangitis, toxic hepatitis, and chemotherapy and radiotherapy-related changes, which may be only visible on hepatobiliary phase images. Simple visual assessment of signal intensity at hepatobiliary phase images is important for the diagnosis of different patterns of liver dysfunction including diffuse, lobar, segmental, and subsegmental forms. Furthermore, preoperative assessment of liver function is feasible before oncologic hepatic surgery, which may be important to prevent posthepatectomy liver failure and to estimate future remnant volume. Functional magnetic resonance cholangiography obtained by T1-weighted images at hepatobiliary phase can allow diagnosis of acalculous cholecystitis, biliary leakage, bile reflux to the stomach, sphincter of oddi dysfunction, and lesions with communication to biliary tree. Functional information can be easily obtained when Gd-EOB-DTPA is used for liver magnetic resonance imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of physical and psychological factors on health-related quality of life in adult patients with liver cirrhosis: a systematic review protocol.

PubMed

Polis, Suzanne; Fernandez, Ritin

2015-01-01

What is the impact of physical and psychological factors on health-related quality of life in adult patients diagnosed with liver cirrhosis? All chronic liver diseases stimulate a degree of repetitive hepatocyte injury that alters the normal liver architecture and ends in cirrhosis.Liver cirrhosis and hepatocellular carcinoma secondary to livercirrhosis are a major public health burden, reporting increasing mortality and morbidity both in Australia and globally.The four leading causes of cirrhosis include harmful alcohol consumption, viral hepatitis B and C and metabolic syndromes related to non-alcoholic fatty liver disease and obesity.A cirrhotic liver is characterized by the presence of regenerative nodules surrounded by fibrous bands that inhibit the passing of molecules between blood and functional units of liver hepatocytes, leading to liver dysfunction.Additionally, the presence of fibrous bands disrupts the normal vascular architecture, increasing resistance within the liver sinusoids and contributing to increased portal vein pressure.The early stages of cirrhosis are referred to as compensated liver disease with no reported symptoms or evidence of impaired liver function.However, the signs and symptoms of liver failure, as well as the mortality rate, increase as the severity of cirrhosis increases.Transition from compensated to decompensated cirrhosis is marked by one or more physiological changes. The physiological changes include increased portal vein pressure, impaired synthetic function, electrolyte imbalance and malnourishment.These physiological changes trigger the development of physical signs and symptoms and impact on the psychological wellbeing of the individual living with cirrhosis. The physical signs and symptoms include esophageal varices, ascites, hepatic encephalopathy, jaundice, irregular sleep patterns, muscle cramps, pruritus, fatigue, impaired mobility, breathlessness, abdominal discomfort, gastrointestinal symptoms, change of body image and pitting edema.Psychological symptoms include stress, depression and anxiety.Living with liver cirrhosis has a marked impact on the quality of life of the individual. Health-related quality of life (HRQOL) is the individual's perception of their physical, cognitive, emotional and social functioning.Studies report that physical and psychological factors affect the quality of life of patients with cirrhosis which can be problematic and debilitating.There is strong evidence which indicates that disease severity is associated with an impairment of the patient's HRQOL.For example, gross ascites causes abdominal discomfort, breathlessness, increased stress and anxiety related to body image, immobility and an increased likelihood of falls. In addition, the management of ascites involves frequent invasive procedures, an increase in pill burden and implementation of dietary restrictions, all of which impact on HRQOL.Despite the clear relationship between HRQOL and severity of disease, there has been no systematic review undertaken to determine the physical, psychological and physiological factors that affect the HRQOL of patients with liver cirrhosis. This systematic review will therefore identify the best available evidence related to the impact of physical, psychological and physiological factors on the health-related quality of life of adult patients with liver cirrhosis. The results of the review will increase clinicians' knowledge and highlight areas of clinical management that may require additional strategies and treatment plans to improve symptom relief and HRQOL.

Non-invasive assessment of the liver using imaging

NASA Astrophysics Data System (ADS)

Thorling Thompson, Camilla; Wang, Haolu; Liu, Xin; Liang, Xiaowen; Crawford, Darrell H.; Roberts, Michael S.

2016-12-01

Chronic liver disease causes 2,000 deaths in Australia per year and early diagnosis is crucial to avoid progression to cirrhosis and end stage liver disease. There is no ideal method to evaluate liver function. Blood tests and liver biopsies provide spot examinations and are unable to track changes in function quickly. Therefore better techniques are needed. Non-invasive imaging has the potential to extract increased information over a large sampling area, continuously tracking dynamic changes in liver function. This project aimed to study the ability of three imaging techniques, multiphoton and fluorescence lifetime imaging microscopy, infrared thermography and photoacoustic imaging, in measuring liver function. Collagen deposition was obvious in multiphoton and fluorescence lifetime imaging in fibrosis and cirrhosis and comparable to conventional histology. Infrared thermography revealed a significantly increased liver temperature in hepatocellular carcinoma. In addition, multiphoton and fluorescence lifetime imaging and photoacoustic imaging could both track uptake and excretion of indocyanine green in rat liver. These results prove that non-invasive imaging can extract crucial information about the liver continuously over time and has the potential to be translated into clinic in the assessment of liver disease.

Glucomannan or Glucomannan Plus Spirulina-Enriched Squid-Surimi Diets Reduce Histological Damage to Liver and Heart in Zucker fa/fa Rats Fed a Cholesterol-Enriched and Non-Cholesterol-Enriched Atherogenic Diet.

PubMed

Vázquez-Velasco, Miguel; González-Torres, Laura; García-Fernández, Rosa A; Méndez, María Teresa; Bastida, Sara; Benedí, Juana; González-Muñoz, María José; Sánchez-Muniz, Francisco J

2017-06-01

Glucomannan-enriched squid surimi improves cholesterolemia and liver antioxidant status. The effect of squid surimi enriched with glucomannan or glucomannan plus spirulina on liver and heart structures and cell damage markers was tested in fa/fa rats fed highly saturated-hyper-energetic diets. Animals were fed 70% AIN-93M rodent diet plus six versions of 30% squid surimi for 7 weeks: control (C), glucomannan (G), and glucomannan plus spirulina (GS). The cholesterol-control (HC), cholesterol-glucomannan (HG), and cholesterol-glucomannan plus spirulina (HGS) groups were given similar diets that were enriched with 2% cholesterol and 0.4% cholic acid. G and GS diets versus C diet significantly inhibited weight gain and lowered plasma alanine aminotransferase and aspartate aminotransferase, liver steatosis, lipogranulomas, and total inflammation and alteration scores. The hypercholesterolemic agent significantly increased the harmful effects of the C diet. Liver weight, the hepatosomatic index, all damage markers, and total histological scoring rose for HC versus C (at least P < .05). The addition of glucomannan (HG vs. HC) improved these biomarkers, and non-additional effects from spirulina were observed except for the total liver alteration score. In conclusion, glucomannan and glucomannan plus spirulina blocked the highly saturated-hyper-energetic diet negative effects both with and without added cholesterol. Results suggest the usefulness of including these functional ingredients in fish products.

Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

PubMed Central

Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M.; Coelho, A.M.M.; Xerfan, M.P.; Cogliati, B.; Barbeiro, D.F.; Mazo, D.F.C.; Kubrusly, M.S.; D'Albuquerque, L.A.C.; Souza, H.P.; Carrilho, F.J.; Oliveira, C.P.

2015-01-01

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH. PMID:25714891

The role of rumen-protected choline in hepatic function and performance of transition dairy cows.

PubMed

Shahsavari, Arash; D'Occhio, Michael J; Al Jassim, Rafat

2016-07-01

High-producing dairy cows enter a period of negative energy balance during the first weeks of lactation. Energy intake is usually sufficient to cover the increase in energy requirements for fetal growth during the period before calving, but meeting the demand for energy is often difficult during the early stages of lactation. A catabolic state predominates during the transition period, leading to the mobilisation of energy reserves (NEFA and amino acids) that are utilised mainly by the liver and muscle. Increased uptake of mobilised NEFA by the liver, combined with the limited capacity of hepatocytes to either oxidise fatty acids for energy or to incorporate esterified fatty acids into VLDL results in fatty liver syndrome and ketosis. This metabolic disturbance can affect the general health, and it causes economic losses. Different nutritional strategies have been used to restrict negative effects associated with the energy challenge in transition cows. The provision of choline in the form of rumen-protected choline (RPC) can potentially improve liver function by increasing VLDL exportation from the liver. RPC increases gene expression of microsomal TAG transfer protein and APOB100 that are required for VLDL synthesis and secretion. Studies with RPC have looked at gene expression, metabolic hormones, metabolite profiles, milk production and postpartum reproduction. A reduction in liver fat and enhanced milk production has been observed with RPC supplementation. However, the effects of RPC on health and reproduction are equivocal, which could reflect the lack of sufficient dose-response studies.

Induction of three-dimensional assembly of human liver cells by simulated microgravity

NASA Technical Reports Server (NTRS)

Khaoustov, V. I.; Darlington, G. J.; Soriano, H. E.; Krishnan, B.; Risin, D.; Pellis, N. R.; Yoffe, B.

1999-01-01

The establishment of long-term cultures of functional primary human liver cells (PHLC) is formidable. Developed at NASA, the Rotary Cell Culture System (RCCS) allows the creation of the unique microgravity environment of low shear force, high-mass transfer, and 3-dimensional cell culture of dissimilar cell types. The aim of our study was to establish long-term hepatocyte cultures in simulated microgravity. PHLC were harvested from human livers by collagenase perfusion and were cultured in RCCS. PHLC aggregates were readily formed and increased up to 1 cm long. The expansion of PHLC in bioreactors was further evaluated with microcarriers and biodegradable scaffolds. While microcarriers were not conducive to formation of spheroids, PHLC cultured with biodegradable scaffolds formed aggregates up to 3 cm long. Analyses of PHLC spheroids revealed tissue-like structures composed of hepatocytes, biliary epithelial cells, and/or progenitor liver cells that were arranged as bile duct-like structures along nascent vascular sprouts. Electron microscopy revealed groups of cohesive hepatocytes surrounded by complex stromal structures and reticulin fibers, bile canaliculi with multiple microvilli, and tight cellular junctions. Albumin mRNA was expressed throughout the 60-d culture. A simulated microgravity environment is conducive to maintaining long-term cultures of functional hepatocytes. This model system will assist in developing improved protocols for autologous hepatocyte transplantation, gene therapy, and liver assist devices, and facilitate studies of liver regeneration and cell-to-cell interactions that occur in vivo.

Direct oxygen supply with polydimethylsiloxane (PDMS) membranes induces a spontaneous organization of thick heterogeneous liver tissues from rat fetal liver cells in vitro.

PubMed

Hamon, Morgan; Hanada, Sanshiro; Fujii, Teruo; Sakai, Yasuyuki

2012-01-01

Oxygen is a vital nutrient for growth and maturation of in vitro cells (e.g., adult hepatocytes). We previously demonstrated that direct oxygenation through a polydimethylsiloxane (PDMS) membrane increases the oxygen supply to cell cultures and improves hepatocyte functions. In this study, we removed limits on oxygen supply to fetal rat liver cells through the use of direct oxygenation through a PDMS membrane to investigate in vitro growth and maturation. We chose fetal liver cells because they are considered a feasible source of liver progenitor cells for regenerative medicine therapy due to their highly efficient maturation and proliferation. Cells from 17-day-old pregnant rats were cultured under 5% and 21% oxygen atmospheres. Some cells were first cultured under 5% oxygen, and then switched to a 21% oxygen atmosphere. When oxygen supply was enhanced by a PDMS membrane, the rat fetal liver cells organized into a complex tissue composed of an epithelium of hepatocytes above a mesenchyme-like tissue. The thickness of this supportive tissue was directly correlated to oxygen concentration and was thicker under 5% oxygen. When cultures were switched from 5% to 21% oxygen, lumen-containing structures were formed in the thick mesenchymal-like tissue and the albumin secretion rate increased. In addition, cells adapted their glycolytic activity to the oxygen concentrations. This system promoted the formation of a functional and organized thick tissue suitable for use in regenerative medicine.

Inducing Hepatitis C Virus Resistance After Pig Liver Transplantation-A Proof of Concept of Liver Graft Modification Using Warm Ex Vivo Perfusion.

PubMed

Goldaracena, N; Spetzler, V N; Echeverri, J; Kaths, J M; Cherepanov, V; Persson, R; Hodges, M R; Janssen, H L A; Selzner, N; Grant, D R; Feld, J J; Selzner, M

2017-04-01

Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide "proof of concept" for using NEVLP to modify and optimize liver grafts for transplantation. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Acute hepatic decompensation precipitated by pregnancy-related catabolic stress: a rare mimic of acute liver failure.

PubMed

Sinclair, Marie; Ket, Shara; Testro, Adam; Gow, Paul J; Angus, Peter W

2014-02-01

Abnormal liver function tests are common in pregnancy; however, liver failure is rare. Pregnancy is a catabolic state that can precipitate illness in patients with underlying metabolic disorders. A 19-year-old woman presented at 14 weeks of gestation with an alanine transaminase of 2,252 international units/L (less than 30), an international normalized ratio of 6.9 (0.9-1.2), and an ammonia of 58 micromole/L (11-51 micromole/L). No cause was identified on routine investigations including liver biopsy. Biochemical and clinical deterioration prompted investigation for a metabolic disorder. Urinary orotic acid was elevated, consistent with the urea cycle disorder type 1 citrullinemia. Appropriate management (arginine supplementation and dietary protein restriction) led to rapid improvement and later delivery of a healthy neonate. This is an unusual presentation that reminds us of the importance of considering metabolic disorders during the catabolic stress of pregnancy.

High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.

PubMed

Larsen, Fin Stolze; Schmidt, Lars Ebbe; Bernsmeier, Christine; Rasmussen, Allan; Isoniemi, Helena; Patel, Vishal C; Triantafyllou, Evangelos; Bernal, William; Auzinger, Georg; Shawcross, Debbie; Eefsen, Martin; Bjerring, Peter Nissen; Clemmesen, Jens Otto; Hockerstedt, Krister; Frederiksen, Hans-Jørgen; Hansen, Bent Adel; Antoniades, Charalambos G; Wendon, Julia

2016-01-01

Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters. In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken. For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (p<0.001). Treatment with HVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Medium-chain TAG improve energy metabolism and mitochondrial biogenesis in the liver of intra-uterine growth-retarded and normal-birth-weight weanling piglets.

PubMed

Zhang, Hao; Li, Yue; Hou, Xiang; Zhang, Lili; Wang, Tian

2016-05-01

We previously reported that medium-chain TAG (MCT) could alleviate hepatic oxidative damage in weanling piglets with intra-uterine growth retardation (IUGR). There is a relationship between oxidative status and energy metabolism, a process involved in substrate availability and glucose flux. Therefore, the aim of this study was to investigate the effects of IUGR and MCT on hepatic energy metabolism and mitochondrial function in weanling piglets. Twenty-four IUGR piglets and twenty-four normal-birth-weight (NBW) piglets were fed a diet of either soyabean oil (SO) or MCT from 21 d of postnatal age to 49 d of postnatal age. Then, the piglets' biochemical parameters and gene expressions related to energy metabolism and mitochondrial function were determined (n 4). Compared with NBW, IUGR decreased the ATP contents and succinate oxidation rates in the liver of piglets, and reduced hepatic mitochondrial citrate synthase (CS) activity (P<0·05). IUGR piglets exhibited reductions in hepatic mitochondrial DNA (mtDNA) contents and gene expressions related to mitochondrial biogenesis compared with NBW piglets (P<0·05). The MCT diet increased plasma ghrelin concentration and hepatic CS and succinate dehydrogenase activities, but decreased hepatic pyruvate kinase activity compared with the SO diet (P<0·05). The MCT-fed piglets showed improved mtDNA contents and PPARγ coactivator-1α expression in the liver (P<0·05). The MCT diet alleviated decreased mRNA abundance of the hepatic PPARα induced by IUGR (P<0·05). It can therefore be postulated that MCT may have beneficial effects in improving energy metabolism and mitochondrial function in weanling piglets.

Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mice.

PubMed

Singh, Dhirendra Pratap; Singh, Jagdeep; Boparai, Ravneet Kaur; Zhu, JianHua; Mantri, Shrikant; Khare, Pragyanshu; Khardori, Romesh; Kondepudi, Kanthi Kiran; Chopra, Kanwaljit; Bishnoi, Mahendra

2017-09-01

High fat diet (HFD)-induced alterations in gut microbiota and resultant 'leaky gut' phenomenon promotes metabolic endotoxemia, ectopic fat deposition, and low-grade systemic inflammation. Here we evaluated the effects of a combination of green tea extract (GTE) with isomalto-oligosaccharide (IMOs) on HFD-induced alterations in mice. Male Swiss albino mice were fed with HFD (58% fat kcal) for 12 weeks. Systemic adiposity, gut derangement parameters and V3-V4 region based 16S rRNA metagenomic sequencing, ectopic fat deposition, liver metabolome analysis, systemic and tissue inflammation, and energy homeostasis markers along with gene expression analysis in multiple tissues were done in mice supplemented with GTE, IMOs or their combination. The combination of GTE and IMOs effectively prevented HFD-induced adiposity and lipid accumulation in liver and muscle while normalizing fasting blood glucose, insulin, glucagon, and leptin levels. Co-administration of GTE with IMOs effectively modulated liver metabolome associated with lipid metabolism. It also prevented leaky gut phenotype and HFD-induced increase in circulating lipopolysaccharides and pro-inflammatory cytokines (e.g. resistin, TNF-α, and IL-1β) and reduction in anti-inflammatory cytokines (e.g. adiponectin and IL-6). Gene expression analysis across multiple tissues further supported these functional outcomes. Most importantly, this combination improved beneficial gut microbiota (Lactobacillus sp., Bifidobacteria, Akkermansia muciniphila, Roseburia spp.) abundances, restored Firmicutes/Bacteriodetes and improved Prevotella/Bacteroides proportions. In particular, a combination of these two agents has shown improved beneficial effects on multiple parameters studied. Data presented herein suggests that strategically chosen food components might be highly effective in the prevention of HFD-induced alterations and may further be developed as functional foods. Copyright © 2017 Elsevier Ltd. All rights reserved.

The protective role of quercetin and arginine on gold nanoparticles induced hepatotoxicity in rats.

PubMed

Abdelhalim, Mohamed Anwar K; Moussa, Sherif A Abdelmottaleb; Qaid, Huda Abdo Yahya

2018-01-01

The aim of the study was to confirm the hepatotoxicity induced by small-sized gold nanoparticles (GNPs) and evaluate the role of quercetin (Qur) and arginine (Arg) against hepatotoxicity caused by GNPs. Twenty-five healthy male Wistar-Kyoto rats were used. GNPs were administered intraperitoneally to these rats at the dose of 50 μL for seven consecutive days. The role of Qur and Arg antioxidants against toxicity induced by GNPs was detected through the measurement of serum liver function and oxidative stress biomarkers in the liver tissues. Coadministration of Qur and Arg along with GNPs significantly induced dramatic alterations in the biochemical parameters. Levels of malondialdehyde, gamma-glutamyl transferase, alanine aminotransferase, alkaline phosphatase, and total protein increased significantly in the GNPs injected group than in the control group, while reduced glutathione was greatly reduced in the GNPs group than in the control group. It also significantly decreased liver enzymes and the oxidative stress, therefore improving the liver damage and hepatotoxicity induced by GNPs. This study demonstrated that Qur and Arg antioxidants effectively improved the hepatic oxidative damage induced by GNPs. It also substantiates the application of Qur and Arg as protecting stand-in against GNPs' hepatotoxicity.

A practice-changing culture method relying on shaking substantially increases mitochondrial energy metabolism and functionality of human liver cell lines.

PubMed

Adam, Aziza A A; van der Mark, Vincent A; Donkers, Joanne M; Wildenberg, Manon E; Oude Elferink, Ronald P J; Chamuleau, Robert A F M; Hoekstra, Ruurdtje

2018-01-01

Practice-changing culturing techniques of hepatocytes are highly required to increase their differentiation. Previously, we found that human liver cell lines HepaRG and C3A acquire higher functionality and increased mitochondrial biogenesis when cultured in the AMC-Bioartificial liver (BAL). Dynamic medium flow (DMF) is one of the major contributors to this stimulatory effect. Recently, we found that DMF-culturing by shaking of HepaRG monolayers resulted in higher mitochondrial biogenesis. Here we further investigated the effect of DMF-culturing on energy metabolism and hepatic functionality of HepaRG and C3A monolayers. HepaRG and C3A DMF-monolayers were incubated with orbital shaking at 60 rpm during the differentiation phase, while control monolayers were maintained statically. Subsequently, energy metabolism and hepatic functionality were compared between static and DMF-cultures. DMF-culturing of HepaRG cells substantially increased hepatic differentiation; transcript levels of hepatic structural genes and hepatic transcription regulators were increased up to 15-fold (Cytochrome P450 3A4) and nuclear translocation of hepatic transcription factor CEBPα was stimulated. Accordingly, hepatic functions were positively affected, including ammonia elimination, urea production, bile acid production, and CYP3A4 activity. DMF-culturing shifted energy metabolism from aerobic glycolysis towards oxidative phosphorylation, as indicated by a decline in lactate production and glucose consumption, and an increase in oxygen consumption. Similarly, DMF-culturing increased mitochondrial energy metabolism and hepatic functionality of C3A cells. In conclusion, simple shaking of monolayer cultures substantially improves mitochondrial energy metabolism and hepatic differentiation of human liver cell lines. This practice-changing culture method may prove to prolong the in-vitro maintenance of primary hepatocytes and increase hepatic differentiation of stem cells.

Anti-fibrosis effects of Huisheng oral solution in CCl4-induced hepatic fibrosis in rat.

PubMed

Li, Wenting; Wu, Yuanbo; Zhu, Chuanlong; Wang, Zheng; Gao, Rentao; Wu, Quan

2014-01-01

Some gradient of Huisheng oral solution (HOS) has been reported to have anti-fibrosis activity. This study was designed to investigate whether HOS could inhibit liver fibrosis and to elucidate its molecular mechanism of action. Hepatic fibrosis model in rat was induced by subcutaneous injection of CCl4. Rats in the treatment group were administrated with HOS intragastrically. Hematoxylin and eosin (H and E) staining and Masson's trichrome staining were used to examine the changes in liver pathology. Levels of ALT, AST, LDH, hyaluronic acid (HA) and laminin (LN) in serum and hydroxyproline (Hyp) in liver were detected by biochemical examination and radioimmunoassay, respectively. The expression and distribution of Smad3, TGF-β1, α-SMA and TIMP-1 were observed and the active TGF-β1 was tested. Our data demonstrated that HOS alleviated CCl4-induced collagen deposition in liver tissue, improved liver condition and liver function in rats. HOS also significantly reduced the expression and distribution of Smad3, TGF-β1, α-SMA and TIMP-1 as well as decreased active TGF-β1. This study revealed that HOS attenuates the development of liver fibrosis through suppressing the TGF-β1 pathway. It provides us a new approach to treatment of liver fibrosis.

Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model.

PubMed

Tautenhahn, Hans-Michael; Brückner, Sandra; Uder, Christiane; Erler, Silvio; Hempel, Madlen; von Bergen, Martin; Brach, Janine; Winkler, Sandra; Pankow, Franziska; Gittel, Claudia; Baunack, Manja; Lange, Undine; Broschewitz, Johannes; Dollinger, Matthias; Bartels, Michael; Pietsch, Uta; Amann, Kerstin; Christ, Bruno

2017-06-01

In patients, acute kidney injury (AKI) is often due to haemodynamic impairment associated with hepatic decompensation following extended liver surgery. Mesenchymal stem cells (MSCs) supported tissue protection in a variety of acute and chronic diseases, and might hence ameliorate AKI induced by extended liver resection. Here, 70% liver resection was performed in male pigs. MSCs were infused through a central venous catheter and haemodynamic parameters as well as markers of acute kidney damage were monitored under intensive care conditions for 24 h post-surgery. Cytokine profiles were established to anticipate the MSCs' potential mode of action. After extended liver resection, hyperdynamic circulation, associated with hyponatraemia, hyperkalaemia, an increase in serum aldosterone and low urine production developed. These signs of hepatorenal dysfunction and haemodynamic impairment were corrected by MSC treatment. MSCs elevated PDGF levels in the serum, possibly contributing to circulatory homeostasis. Another 14 cytokines were increased in the kidney, most of which are known to support tissue regeneration. In conclusion, MSCs supported kidney and liver function after extended liver resection. They probably acted through paracrine mechanisms improving haemodynamics and tissue homeostasis. They might thus provide a promising strategy to prevent acute kidney injury in the context of post-surgery acute liver failure.

Mushroom insoluble polysaccharides prevent carbon tetrachloride-induced hepatotoxicity in rat.

PubMed

Nada, Somaia A; Omara, Enayat A; Abdel-Salam, Omar M E; Zahran, Hanan G

2010-11-01

The aim of the present study was to investigate the effect of mushroom insoluble non-starch polysaccharides (MINSP) on the carbon tetrachloride (CCl(4))-induced hepatic damage in rat. MINSP (100 and 200 mg/kg) administered daily orally for 15 days before CCl(4) (1.5 ml/kg). The effect of MINSP treatment was also examined in normal rats. Normal groups treated with MINSP showed significant decrease in serum activities of the liver enzymes, lipid peroxides and nitric oxide (NO) in the liver. Reduced glutathione (GSH) and total proteins (TP) contents in liver homogenate also increased after treatment with only MINSP for 15 days. In CCl(4)-treated rats, significant elevation in serum liver enzymes, increased lipid peroxides and NO in the liver, and depletion of hepatic-GSH level were observed. Pre-treatment with MINSP significantly ameliorated the tested parameters when compared with CCl(4)-treated group. It improved the antioxidant activity of the liver in a dose-dependent manner. Histopathological examination of hepatic tissue revealed that MINSP administration alone protected hepatocytes from the damage induced by CCl(4). MINSP are safe; it could be used as fat replacer in processing low fat diet. MINSP represents a good functional food and liver supporter for patient suffering from various liver diseases. Copyright © 2010 Elsevier Ltd. All rights reserved.

Nadolol for lithium tremor in the presence of liver damage.

PubMed

Dave, M; Langbart, M M

1994-03-01

Lithium-induced tremor classically responds to treatment with propranolol. Since it is metabolized in the liver, propranolol may not be the drug of choice in those patients who have compromised liver function or who are recovering from prior liver diseases. Another nonselective beta-adrenergic blocker, nadolol, has no hepatic biotransformation. We present here the first case report of successful treatment of lithium-induced tremor with nadolol, which was selected because the patient had compromised liver function. The patient's liver function tests remained stable with the therapy.

Human hepatocytes loaded in 3D bioprinting generate mini-liver.

PubMed

Zhong, Cheng; Xie, Hai-Yang; Zhou, Lin; Xu, Xiao; Zheng, Shu-Sen

2016-10-01

Because of an increasing discrepancy between the number of potential liver graft recipients and the number of organs available, scientists are trying to create artificial liver to mimic normal liver function and therefore, to support the patient's liver when in dysfunction. 3D printing technique meets this purpose. The present study was to test the feasibility of 3D hydrogel scaffolds for liver engineering. We fabricated 3D hydrogel scaffolds with a bioprinter. The biocompatibility of 3D hydrogel scaffolds was tested. Sixty nude mice were randomly divided into four groups, with 15 mice in each group: control, hydrogel, hydrogel with L02 (cell line HL-7702), and hydrogel with hepatocyte growth factor (HGF). Cells were cultured and deposited in scaffolds which were subsequently engrafted into livers after partial hepatectomy and radiation-induced liver damage (RILD). The engrafted tissues were examined after two weeks. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total bilirubin, CYP1A2, CYP2C9, glutathione S-transferase (a-GST), and UDP-glucuronosyl transferase (UGT-2) were compared among the groups. Hematoxylin-eosin (HE) staining and immunohistochemistry of cKit and cytokeratin 18 (CK18) of engrafted tissues were evaluated. The survival time of the mice was also compared among the four groups. 3D hydrogel scaffolds did not impact the viability of cells. The levels of ALT, AST, albumin, total bilirubin, CYP1A2, CYP2C9, a-GST and UGT-2 were significantly improved in mice engrafted with 3D scaffold loaded with L02 compared with those in control and scaffold only (P<0.05). HE staining showed clear liver tissue and immunohistochemistry of cKit and CK18 were positive in the engrafted tissue. Mice treated with 3D scaffold+L02 cells had longer survival time compared with those in control and scaffold only (P<0.05). 3D scaffold has the potential of recreating liver tissue and partial liver functions and can be used in the reconstruction of liver tissues.

Liver cirrhosis and portal hypertension in cystic fibrosis.

PubMed

Fustik, Stojka

2013-01-01

As the expected survival improves in individuals with the cystic fibrosis (CF), so they may be faced with a number of medical complications. The aim of this study was to analyze the prevalence of liver cirrhosis in our CF population as well as the clinical and genetic characteristics of these patients. All patients older than 2 years (n = 96) were screened for liver disease. Liver cirrhosis was defined by ultrasonographic findings of distinct heterogeneity of liver parenchyma and nodular liver surface and/or by liver biopsy findings. Enlarged spleen, distended portal vein and abnormal portal venous flow indicated portal hypertension. Clinical and genotype data were analyzed. Sixteen patients were found to have liver cirrhosis, three of them with portal hypertension. All patients had pancreatic insufficiency. Nutritional status expressed as standard deviation score (Z score) for weight, height, and body mass index was as follows: zW = -0.40 +/- 1.24, zH = -0.83 +/- 1.02, and BMI = 20.1 +/- 2.3. CF patients with liver cirrhosis generally had mild-to-moderate lung disease, with average FVC and FEV1 values of 97.1 +/- 16.5% of predicted and 87.9 +/- 23.5% of predicted, respectively. Genetic analysis showed high frequency of F508del mutation in the group with cirrhosis (90.6%). The prevalence of liver cirrhosis in our CF population older than 2 years was 16.6%. Patients with pancreatic insufficiency and severe CFTR mutations, especially F508del, were exposed to higher risk of developing liver cirrhosis. Liver cirrhosis has no significant impact on the pulmonary function and the nutritional status, until the end-stage liver disease.

JNK Activation of BIM Promotes Hepatic Oxidative Stress, Steatosis, and Insulin Resistance in Obesity.

PubMed

Litwak, Sara A; Pang, Lokman; Galic, Sandra; Igoillo-Esteve, Mariana; Stanley, William J; Turatsinze, Jean-Valery; Loh, Kim; Thomas, Helen E; Sharma, Arpeeta; Trepo, Eric; Moreno, Christophe; Gough, Daniel J; Eizirik, Decio L; de Haan, Judy B; Gurzov, Esteban N

2017-12-01

The members of the BCL-2 family are crucial regulators of the mitochondrial pathway of apoptosis in normal physiology and disease. Besides their role in cell death, BCL-2 proteins have been implicated in the regulation of mitochondrial oxidative phosphorylation and cellular metabolism. It remains unclear, however, whether these proteins have a physiological role in glucose homeostasis and metabolism in vivo. In this study, we report that fat accumulation in the liver increases c-Jun N-terminal kinase-dependent BCL-2 interacting mediator of cell death (BIM) expression in hepatocytes. To determine the consequences of hepatic BIM deficiency in diet-induced obesity, we generated liver-specific BIM-knockout (BLKO) mice. BLKO mice had lower hepatic lipid content, increased insulin signaling, and improved global glucose metabolism. Consistent with these findings, lipogenic and lipid uptake genes were downregulated and lipid oxidation enhanced in obese BLKO mice. Mechanistically, BIM deficiency improved mitochondrial function and decreased oxidative stress and oxidation of protein tyrosine phosphatases, and ameliorated activation of peroxisome proliferator-activated receptor γ/sterol regulatory element-binding protein 1/CD36 in hepatocytes from high fat-fed mice. Importantly, short-term knockdown of BIM rescued obese mice from insulin resistance, evidenced by reduced fat accumulation and improved insulin sensitivity. Our data indicate that BIM is an important regulator of liver dysfunction in obesity and a novel therapeutic target for restoring hepatocyte function. © 2017 by the American Diabetes Association.

The utility of uric acid assay in dogs as an indicator of functional hepatic mass.

PubMed

Hill, J M; Leisewitz, A L; Goddard, A

2011-06-01

Uric acid was used as a test for liver disease before the advent of enzymology. Three old studies criticised uric acid as a test of liver function. Uric acid, as an end-product of purine metabolism in the liver, deserved re-evaluation as a liver function test. Serum totalbile acids are widely accepted as the most reliable liver function test. This study compared the ability of serum uric acid concentration to assess liver function with that of serum pre-prandial bile acids in dogs. In addition, due to the renal excretion of uric acid the 2 assays were also compared in a renal disease group. Using a control group of healthy dogs, a group of dogs with congenital vascular liver disease, a group of dogs with non-vascular parenchymal liver diseases and a renal disease group, the ability of uric acid and pre-prandial bile acids was compared to detect reduced functional hepatic mass overall and in the vascular or parenchymal liver disease groups separately. Sensitivities, specificities and predictive value parameters were calculated for each test. The medians of uric acid concentration did not differ significantly between any of the groups, whereas pre-prandial bile acids medians were significantly higher in the liver disease groups compared with the normal and renal disease group of dogs. The sensitivity of uric acid in detecting liver disease overall was 65% while the specificity of uric acid in detecting liver disease overall was 59%. The sensitivity and specificity of uric acid in detecting congenital vascular liver disease was 68% and 59%, respectively. The sensitivity and specificity of uric acid in detecting parenchymal liver disease was 63% and 60%, respectively. The overall positive and negative predictive values for uric acid in detecting liver disease were poor and the data in this study indicated uric acid to be an unreliable test of liver function. In dogs suffering from renal compromise serum uric acid concentrations may increase into the abnormal range due to its renal route of excretion.

The influence of interferon alpha on the rat liver injured by chronic administration of carbon tetrachloride.

PubMed

Madro, Agnieszka; Słomka, Maria; Celiński, Krzysztof; Chibowski, Daniel; Czechowska, Grazyna; Kleinrok, Zdzisław; Karpińska, Agnieszka

2002-01-01

Due to their complex and not fully known etiopathogenesis as well as difficulties in treatment, chronic hepatitis and cirrhosis still remain one of the main problems of hepatologists. Nowadays, the use of IFN alpha is considered the most effective method of treatment in chronic hepatitis. Recently, a new property of IFN, i.e. its effects on the reduction of fibrosis, has been discovered. The aim of the paper was to examine the effects of IFN alpha on biochemical parameters (AlAt and AspAt activities), on the metabolic function of the liver and its morphologic picture observed under the light and electron microscope after the 3- and 6-week CCl4-induced damage. The experiments were carried out in Wistar male rats. To evaluate the liver function, the test of aminophenazone elimination in the isolated perfused rat livers was used according to Miller modified by Hafte. Additionally, AspAt and AlAt activities were determined. The liver specimens were analysed under the light and electron microscope and using immunohistochemical methods. The findings show that after the 3-week CCl4-induced liver damage, IFN alpha does not significantly affect AlAt and AspAt activities, irrespective of the dose used. IFN alpha administered after the 6-week damage significantly changes those activities when the doses used are high. It was found that carbon tetrachloride does not result in evident cirrhotic changes, however it activates Ito cells, causes focal retraction of the stroma and fibrosis. The increased number of Ito cells in Disse's space observed in immunohistochemical and ultrastructural examinations is indicative of the activation of liver fibrotic processes following CCl4 administration in both variants used. IFN alpha substantially weakens fibrogenesis of the CCl4-damaged liver which is visible in the decreased number of Ito cells and weaker expression of the stroma retraction. Moreover, IFN alpha administered to the experimental animals after the CCl4-induced injury of the liver increases aminophenazone clearance, especially when used in higher doses. Positive effects of IFN confirmed in the studies suggest that the drug may be used in patients with chronic hepatitis and early cirrhosis since it is likely not only to eliminate the virus but also to improve the liver function and reduce fibrosis.

Quality of life in patients with nonalcoholic fatty liver disease in combination with essential hypertension considering taste sensitivity to sodium chloride.

PubMed

Mashura, Hanna Y; Hanych, Taras M; Rishko, Alexander A

2016-01-01

Nonalcoholic fatty liver disease and hypertensive disease - is the most common combination of abnormalities that occur in people suffering from metabolic syndrome. Their combination not only causes concurrent damage of the liver and the heart, caused by common pathogenic beginning, and also mutually complicate the disease course of each other. The leading role in the development of nonalcoholic fatty liver disease belongs to abdominal obesity and insulin resistance, and is seen as a manifestation of liver disease in metabolic syndrome. Genetic predisposition, lifestyle, improper nutrition, including excessive use of sodium chloride, lead to excessive formation of visceral adipose tissue with development of abdominal obesity, which is a likely criterion of insulin resistance. The long course of nonalcoholic fatty liver disease in combination with essential hypertension in excessive consumption of sodium chloride may negatively affect their quality of life. The aim of the study is to find out the features of quality of life in patients with nonalcoholic fatty liver disease in combination with hypertensive disease with different taste sensitivity to sodium chloride. We have investigated the quality of life of 65 patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with different taste sensitivity to sodium chloride. Salt taste sensitivity threshold to sodium chloride is determined by the method of R. Henkin. Assessment of quality of life was performed using the Ukrainian version of the questionnaire Medical Outcomes Study Short Form 36 (MO S SF-36). Was revealed that in patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with high salt taste sensitivity threshold observed the decline in the quality of life that manifests as a decline in physical condition (especially of the physical functioning, physical role functioning and general health perceptions) and mental health (especially social functioning). Also the increased salt intake and salt appetite in patients with high salt taste sensitivity threshold were noted (p <0,05). Reducing the use of sodium chloride can be a preventive measure easier than a decrease in body weight, and one that will reduce the body weight, especially in people with nonalcoholic fatty liver disease in combination with hypertensive disease, can reduce the risk of complications and improve quality of life in patients.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levine, E.; Cook, L.T.; Grantham, J.J.

Hepatic CT findings were analyzed in 44 patients with autosomal-dominant polycystic kidney disease and were correlated with liver and renal function tests and liver, splenic, and renal CT volume measurements. CT showed many large liver cysts in 31.8% of patients, small liver cysts in 25%, and no liver cysts in 43.2%. Patients with many large cysts often showed increased liver volumes. There was no correlation between severity of liver involvement and extent of renal cystic disease as determined from urea nitrogen and creatinine levels and renal volumes. Liver function tests were normal except in two patients, one with a cholangiocarcinoma,more » which may have arisen from a cyst, and the other with an infected liver cyst and chronic active hepatitis. Accordingly, if liver function tests are abnormal, an attempt should be made to identify complications of polycystic liver disease such as tumor cyst infection, and biliary obstruction. CT is a useful method for detecting liver cysts and identifying patients at risk for these complications.« less

Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease

PubMed Central

Wang, Zhigang; Yao, Tong; Pini, Maria; Zhou, Zhanxiang; Fantuzzi, Giamila

2010-01-01

Adipose tissue dysfunction, featured by insulin resistance and/or dysregulated adipokine production, plays a central role not only in disease initiation but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Promising beneficial effects of betaine supplementation on nonalcoholic fatty liver disease (NAFLD) have been reported in both clinical investigations and experimental studies; however, data related to betaine therapy in NAFLD are still limited. In this study, we examined the effects of betaine supplementation on hepatic fat accumulation and injury in mice fed a high-fat diet and evaluated mechanisms underlying its hepatoprotective effects. Male C57BL/6 mice weighing 25 ± 0.5 (SE) g were divided into four groups (8 mice/group) and started on one of four treatments: control diet, control diet supplemented with betaine, high-fat diet, and high-fat diet supplemented with betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Our results showed that long-term high-fat feeding caused NAFLD in mice, which was manifested by excessive neutral fat accumulation in the liver and elevated plasma alanine aminotransferase levels. Betaine supplementation alleviated hepatic pathological changes, which were concomitant with attenuated insulin resistance as shown by improved homeostasis model assessment of basal insulin resistance values and glucose tolerance test, and corrected abnormal adipokine (adiponectin, resistin, and leptin) productions. Specifically, betaine supplementation enhanced insulin sensitivity in adipose tissue as shown by improved extracellular signal-regulated kinases 1/2 and protein kinase B activations. In adipocytes freshly isolated from mice fed a high-fat diet, pretreatment of betaine enhanced the insulin signaling pathway and improved adipokine productions. Further investigation using whole liver tissues revealed that betaine supplementation alleviated the high-fat diet-induced endoplasmic reticulum stress response in adipose tissue as shown by attenuated glucose-regulated protein 78/C/EBP homologous protein (CHOP) protein abundance and c-Jun NH2-terminal kinase activation. Our findings suggest that betaine might serve as a safe and efficacious therapeutic tool for NAFLD by improving adipose tissue function. PMID:20203061

[Effects of Feiji decoction for soothing the liver combined with psychotherapy on quality of life in primary lung cancer patients].

PubMed

Yao, Yilin

2012-01-01

Primary lung cancer is one of the most common malignant tumors. It causes great pain and mood disorders to patients, and significantly reduces their quality of life. The aim of the current study is to evaluate the effect of Feiji Decoction for soothing the liver combined with psychotherapy on quality of life (QoL) and physical status of patients with primary lung cancer. A total of 118 patients with primary non-small cell lung cancer were randomly divided into two groups. The 57 patients in the combined therapy group were treated with Feiji Decoction for soothing the liver and psychotherapy combined with chemotherapy, whereas the 61 patients in the control group were treated with chemotherapy only. Both groups were observed for the two treatment courses. The European Organization for Research and Treatment of Cancer QoL Questionnaire LC-43 (EORTC QLQ-LC43) was used to assess the QoL of every patient in both groups before and after treatment scales. At the same time, physical status was assessed using the Karnofsky performance status (KPS) and East Cooperative Oncology Group performance status (ECOG). The scores of physiology function, role function, emotion function, cognize function, society function, and general health in the therapy group were higher than that of the control group. The therapy group also showed better QoL results than the contol group. Significant differences were observed between the two groups (P<0.01). Meanwhile, the scores of fatigue, vomit, pain, polypnea, insomnia, anorexia, constipation, and specific manifestation of lung cancer in the therapy group were obviously lower than that of the control group; more patients were observed to be relieved. Significant differences between the two groups were observed (P<0.01). The KPS and ECOG scores of the patients were observed to have improved and stabilized in the therapy group than that of the control group; the differences were statistically significant (P<0.01). Feiji Decoction for soothing the liver combined with psychotherapy can alleviate the clinical symptoms, elevate the physical status, and improve the QOL of patients with primary lung cancer. Thus, this therapy has a good clinical therapeutic effect.

Establishment and characterization of an immortalized human hepatic stellate cell line for applications in co-culturing with immortalized human hepatocytes.

PubMed

Pan, XiaoPing; Wang, Yini; Yu, XiaoPeng; Li, JianZhou; Zhou, Ning; Du, WeiBo; Zhang, YanHong; Cao, HongCui; Zhu, DanHua; Chen, Yu; Li, LanJuan

2015-01-01

The liver-specific functions of hepatocytes are improved by co-culturing hepatocytes with primary hepatic stellate cells (HSC). However, primary HSC have a short lifespan in vitro, which is considered a major limitation for their use in various applications. This study aimed to establish immortalized human HSC using the simian virus 40 large T antigen (SV40LT) for applications in co-culturing with hepatocytes and HSC in vitro. Primary human HSC were transfected with a recombinant retrovirus containing SV40LT. The immortalized human HSC were characterized by analyzing their gene expression and functional characteristics. The liver-specific functions of hepatocytes were evaluated in a co-culture system incorporating immortalized human hepatocytes with HSC-Li cells. The immortalized HSC line, HSC-Li, was obtained after infection with a recombinant retrovirus containing SV40LT. The HSC-Li cells were longitudinally spindle-like and had numerous fat droplets in their cytoplasm as shown using electron microscopy. Hepatocyte growth factor (HGF), VEGF Receptor 1(Flt-1), collagen type Iα1 and Iα2 mRNA expression levels were observed in the HSC-Li cells by RT-PCR. Immunofluorescence staining showed that the HSC-Li cells were positive for α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-beta (PDGFR-β), vimentin, and SV40LT protein expression. The HSC-Li cells produced both HGF and transforming growth factor-beta1 (TGF-β1) in a time-dependent manner. Real-time PCR showed that albumin, CYP3A5, CYP2E1, and UGT2B7 mRNA expression generally increased in the co-culture system. The enzymatic activity of CYP1A2 under the co-culture conditions also generally increased as compared to the monoculture of immortalized human hepatocytes. We successfully established the immortalized human HSC cell line HSC-Li. It has the specific phenotypic and functional characteristics of primary human HSC, which would be a useful tool to develop anti-fibrotic therapies. Co-culturing with the HSC-Li cells improved the liver-specific functions of hepatocytes, which may be valuable and applicable for bioartificial liver systems.

[State of hepatocyte transplantation: a risk or a chance?].

PubMed

Leckel, K; Blaheta, R A; Markus, B H

2003-04-01

Over the past few years, hepatocyte transplantation has been considered as an alternative method for orthotopic liver transplantation for the treatment of various liver diseases. Beside curative approach for genetic metabolic deficiencies (familial hypercholesterolemia, hemophilia, etc.), it could be a useful tool for bridging the waiting period until an appropriate donor organ is obtained. In preclinical animal studies, hepatocytes injected intraperitoneally, intraportally or into the spleen settle down in the diseased liver. This enables genetic modification to correct inborn metabolic deficiencies and improves survival in acute liver failure. In 1992, the first clinical transplantation of isolated hepatocytes in 10 patients was performed. In 1998, Fox and coworkers described the successful transplantation of allogeneic liver cells in a child with Crigler-Najjar syndrome. Accomplished studies of Strom et al. resp. Bilir et al. of the same year proved the effectiveness of liver cell transplantation for transient treatment of acute liver failure. Prerequisite of this cell-based therapeutic strategy is a sufficient amount of highly differentiated hepatocytes, hence, a well established in-vitro cell-culture technique is necessary to yield a reproducible number of proliferating hepatocytes and to preserve the physiological cell function. This review discusses the different experimental approaches regarding the cultivation of human hepatocytes and also the use of alternative cell sources (like animal hepatocytes, immortalized cells of human origin, progenitor cells from fetal human liver/liver stem cells) for hepatocyte transplantation.

Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction.

PubMed

Cortes, Miriam; Pareja, Eugenia; García-Cañaveras, Juan C; Donato, M Teresa; Montero, Sandra; Mir, Jose; Castell, José V; Lahoz, Agustín

2014-09-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD. A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients. A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n=4). A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Effects of transarterial chemoembolization combined with antiviral therapy on HBV reactivation and liver function in HBV-related hepatocellular carcinoma patients with HBV-DNA negative.

PubMed

Wang, Kai; Jiang, Guomin; Jia, Zhongzhi; Zhu, Xiaoli; Ni, Caifang

2018-06-01

The aim of this study was to investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in primary hepatocellular carcinoma (HCC) patients with HBV-DNA negative and to evaluate the effects of TACE combined with antiviral therapy. This prospective study involved 98 patients with HBV-related and HBV-DNA negative HCC (HBV DNA < 10 copies/mL) underwent TACE procedures with serial HBV DNA tests. Patients were divided into the antiviral treatment group and the no-antiviral group. The antiviral group received entecavir antiviral therapy, and the other group received no antiviral therapy. Two groups of patients were compared in rate of HBV reactivation and liver function before and after only 1 session of TACE in average 1-month follow-up after operation. P < .05 indicated differences with a statistical significance. HBV reactivation occurred in 11 patients in the nonantiviral group (11/47, 23.4%) but only 3 patients in the antiviral group (3/51, 5.9%, P < .05). On multivariate analysis, HBeAg-positive status, number of tumors more than 3, and absence of antiviral therapy were the independent risk predictor of HBV reactivation. Liver function indicators did not differ significantly between the antiviral group and the nonantiviral group in 5 days after TACE. However, the level of alanine aminotransferase and bilirubin were raised and albumin was reduced at the HBV reactivation group compared with no HBV reactivation group (P < .05). At 1 month after TACE, liver function indicators did not differ significantly between the HBV reactivation group and without HBV reactivation group. HCC patients with HBV DNA negative still remain associated with risk of HBV reactivation after TACE. HBeAg-positive, number of tumors more than 3, and absence of antiviral therapy in HCC patients after TACE have a higher risk of HBV reactivation. Antiviral therapy can reduce the risk of reactivation, helping improve liver function after TACE.

PET guidance for liver radiofrequency ablation: an evaluation

NASA Astrophysics Data System (ADS)

Lei, Peng; Dandekar, Omkar; Mahmoud, Faaiza; Widlus, David; Malloy, Patrick; Shekhar, Raj

2007-03-01

Radiofrequency ablation (RFA) is emerging as the primary mode of treatment of unresectable malignant liver tumors. With current intraoperative imaging modalities, quick, precise, and complete localization of lesions remains a challenge for liver RFA. Fusion of intraoperative CT and preoperative PET images, which relies on PET and CT registration, can produce a new image with complementary metabolic and anatomic data and thus greatly improve the targeting accuracy. Unlike neurological images, alignment of abdominal images by combined PET/CT scanner is prone to errors as a result of large nonrigid misalignment in abdominal images. Our use of a normalized mutual information-based 3D nonrigid registration technique has proven powerful for whole-body PET and CT registration. We demonstrate here that this technique is capable of acceptable abdominal PET and CT registration as well. In five clinical cases, both qualitative and quantitative validation showed that the registration is robust and accurate. Quantitative accuracy was evaluated by comparison between the result from the algorithm and clinical experts. The accuracy of registration is much less than the allowable margin in liver RFA. Study findings show the technique's potential to enable the augmentation of intraoperative CT with preoperative PET to reduce procedure time, avoid repeating procedures, provide clinicians with complementary functional/anatomic maps, avoid omitting dispersed small lesions, and improve the accuracy of tumor targeting in liver RFA.

Improvement of Diet-induced Obesity by Ingestion of Mushroom Chitosan Prepared from Flammulina velutipes.

PubMed

Miyazawa, Noriko; Yoshimoto, Hiroaki; Kurihara, Shoichi; Hamaya, Tadao; Eguchi, Fumio

2018-02-01

The anti-obesity effects of mushroom chitosan prepared from Flammulina velutipes were investigated using an animal model with diet-induced obesity. In this study, 5-week-old imprinting control region (ICR) mice were divided into six groups of 10 mice each and fed different diets based on the MF powdered diet (standard diet) for 6 weeks: standard diet control group, high-fat diet control group (induced dietary obesity) consisting of the standard diet and 20% lard, and mushroom chitosan groups consisting of the high-fat diet with mushroom chitosan added at 100, 500, 1,000, and 2,000 mg/kg body weight. On the final day of the experiment, mean body weight was 39.1 g in the high-fat control group and 36.3 g in the 2,000 mg/kg mushroom chitosan group, compared to 35.8 g in the standard diet control group. In the mushroom chitosan groups, a dose-dependent suppression of weight gain and marked improvements in serum triglycerides, total cholesterol, LDL-cholesterol, and HDL-cholesterol were found. The mushroom chitosan groups showed fewer and smaller fat deposits in liver cells than the high-fat diet control group, and liver weight was significantly reduced. Glutamic oxaloacetic transaminase (GOT) and glutamate pyruvic transaminase (GPT), which are indices of the hepatic function, all showed dose-dependent improvement with mushroom chitosan administration. These results suggested that mushroom chitosan acts to suppress enlargement of the liver from fat deposition resulting from a high-fat diet and to restore hepatic function. The lipid content of feces showed a marked increase correlated with the mushroom chitosan dose. These findings suggest the potential use of mushroom chitosan as a functional food ingredient that contributes to the prevention or improvement of dietary obesity by inhibiting digestion and absorption of fats in the digestive tract and simultaneously promotes lipolysis in adipocytes.

Early enteral feeding in postsurgical cancer patients. Fish oil structured lipid-based polymeric formula versus a standard polymeric formula.

PubMed Central

Kenler, A S; Swails, W S; Driscoll, D F; DeMichele, S J; Daley, B; Babineau, T J; Peterson, M B; Bistrian, B R

1996-01-01

OBJECTIVES: The authors compared the safety, gastrointestinal tolerance, and clinical efficacy of feeding an enteral diet containing a fish oil/medium-chain triglyceride structured lipid (FOSL-HN) versus an isonitrogenous, isocaloric formula (O-HN) in patients undergoing major abdominal surgery for upper gastrointestinal malignancies. SUMMARY BACKGROUND DATA: Previous studies suggest that feeding with n-3 fatty acids from fish oil can alter eicosanoid and cytokine production, yielding an improved immunocompetence and a reduced inflammatory response to injury. The use of n-3 fatty acids as a structured lipid can improve long-chain fatty acid absorption. METHODS: This prospective, blinded, randomized trial was conducted in 50 adult patients who were jejunally fed either FOSL-HN or O-HN for 7 days. Serum chemistries, hematology, urinalysis, gastrointestinal complications, liver and renal function, plasma and erythrocyte fatty acid analysis, urinary prostaglandins, and outcome parameters were measured at baseline and on day 7. Comparisons were made in 18 and 17 evaluable patients based a priori on the ability to reach a tube feeding rate of 40 mL/hour. RESULTS: Patients receiving FOSL-HN experienced no untoward side effects, significant incorporation of eicosapentaenoic acid into plasma and erythrocyte phospholipids, and a 50% decline in the total number of gastrointestinal complications and infections compared with patients given O-HN. The data strongly suggest improved liver and renal function during the postoperative period in the FOSL-HN group. CONCLUSION: Early enteral feeding with FOSL-HN was safe and well tolerated. Results suggest that the use of such a formula during the postoperative period may reduce the number of infections and gastrointestinal complications per patient, as well as improve renal and liver function through modulation of urinary prostaglandin levels. Additional clinical trials to fully quantify clinical benefits and optimize nutritional support with FOSL-HN should be undertaken. Images Figure 1. Figure 2. Figure 3. PMID:8604913

LPSF/GQ-02 inhibits the development of hepatic steatosis and inflammation in a mouse model of non-alcoholic fatty liver disease (NAFLD).

PubMed

Soares e Silva, Amanda Karolina; de Oliveira Cipriano Torres, Dilênia; dos Santos Gomes, Fabiana Oliveira; dos Santos Silva, Bruna; Lima Ribeiro, Edlene; Costa Oliveira, Amanda; dos Santos, Laise Aline Martins; de Lima, Maria do Carmo Alves; Pitta, Ivan da Rocha; Peixoto, Christina Alves

2015-01-01

Non-alcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extends from simple steatosis to non-alcoholic steatohepatitis. Although the pathogenesis of NAFLD remains undefined, it is recognized that insulin resistance is present in almost all patients who develop this disease. Thiazolidinediones (TZDs) act as an insulin sensitizer and have been used in the treatment of patients with type 2 diabetes and other insulin-resistant conditions, including NAFLD. Hence, therapy of NAFLD with insulin-sensitizing drugs should ideally improve the key hepatic histological changes, while also reducing cardiometabolic and cancer risks. Controversially, TZDs are associated with the development of cardiovascular events and liver problems. Therefore, there is a need for the development of new therapeutic strategies to improve liver function in patients with chronic liver diseases. The aim of the present study was to assess the therapeutic effects of LPSF/GQ-02 on the liver of LDLR-/- mice after a high-fat diet. Eighty male mice were divided into 4 groups and two different experiments: 1-received a standard diet; 2-fed with a high-fat diet (HFD); 3-HFD+pioglitazone; 4-HFD+LPSF/GQ-02. The experiments were conducted for 10 or 12 weeks and in the last two or four weeks respectively, the drugs were administered daily by gavage. The results obtained with an NAFLD murine model indicated that LPSF/GQ-02 was effective in improving the hepatic architecture, decreasing fat accumulation, reducing the amount of collagen, decreasing inflammation by reducing IL-6, iNOS, COX-2 and F4 / 80, and increasing the protein expression of IκBα, cytoplasmic NFκB-65, eNOS and IRS-1 in mice LDLR -/-. These results suggest a direct action by LPSF/GQ-02 on the factors that affect inflammation, insulin resistance and fat accumulation in the liver of these animals. Further studies are being conducted in our laboratory to investigate the possible mechanism of action of LPSF/GQ-02 on hepatic lipid metabolism.

Unilobar Versus Bilobar Biliary Drainage: Effect on Quality of Life and Bilirubin Level Reduction

PubMed Central

Gamanagatti, Shivanand; Singh, Tejbir; Sharma, Raju; Srivastava, Deep N; Dash, Nihar Ranjan; Garg, Pramod Kumar

2016-01-01

Background: Percutaneous biliary drainage is an accepted palliative treatment for malignant biliary obstruction. Purpose: To assess the effect on quality of life (QOL) and bilirubin level reduction in patients with inoperable malignant biliary obstruction treated by unilobar or bilobar percutaneous transhepatic biliary drainage (PTBD). Materials and Methods: Over a period of 2 years, 49 patients (age range, 22–75 years) of inoperable malignant biliary obstruction were treated by PTBD. Technical and clinical success rates, QOL, patency rates, survival rates, and complications were recorded. Clinical success rates, QOL, and bilirubin reduction were compared in patients treated with complete (n = 21) versus partial (n = 28) liver parenchyma drainage. QOL before and 1 month after biliary drainage were analyzed retrospectively between these two groups. Results: Biliary drainage was successful in all 49 patients, with an overall significant reduction of the postintervention bilirubin levels (P < 0.001) resulting in overall clinical success rate of 89.97%. Clinical success rates were similar in patients treated with whole-liver drainage versus partial-liver drainage. Mean serum bilirubin level before PTBD was 19.85 mg/dl and after the procedure at 1 month was 6.02 mg/dl. The mean baseline functional score was 39.35, symptom scale score was 59.55, and global health score was 27.45. At 1 month, mean functional score was 61.25, symptom scale score was 36.0 4, and global health score was 56.33, with overall significant improvement in QOL (<0.001). There was a statistically significant difference in the improvement of the QOL scores (P = 0.002), among patients who achieved clinical success, compared with those patients who did not achieve clinical success at 1 month. We did not find any significant difference in the QOL scores in patients according to the amount of liver drained (unilateral or bilateral drainage), the type of internalization used (ring biliary or stent). Overall, minor and major complications rates were 14.3% and 8.1%, respectively. Conclusion: Percutaneous biliary drainage provides good palliation of malignant obstructive jaundice. Partial-liver drainage achieved results as good as those after complete liver drainage with significant improvements in QOL and reduction of the bilirubin level. PMID:26962281

Impact of pretransplant renal function on survival after liver transplantation.

PubMed

Gonwa, T A; Klintmalm, G B; Levy, M; Jennings, L S; Goldstein, R M; Husberg, B S

1995-02-15

To determine the effect of pretransplant liver function on survival following orthotopic liver transplantation and to quantify the effects of cyclosporine administration on long-term renal function in patients undergoing liver transplant, we performed an analysis of a prospectively maintained database. Data from 569 consecutive patients undergoing liver transplantation alone who were treated with CsA for immunosuppression were used for this study. Actuarial graft and patient survival rates were calculated using Kaplan-Meier statistics. Glomerular filtration rates, serum creatinine, and the use of various immunosuppressives were analyzed for this study. The initial analysis demonstrated that patients presenting for liver transplant with hepatorenal syndrome have a significantly decreased acturial patient survival after liver transplant at 5 years compared with patients without hepatorenal syndrome (60% vs. 68%, P < 0.03). Patients with hepatorenal syndrome recovered their renal function after liver transplant. Patients who had hepatorenal syndrome were sicker and required longer stays in the intensive care unit, longer hospitalizations, and more dialysis treatments after transplantation compared with patients who did not have hepatorenal syndrome. The incidence of end-stage renal disease after liver transplantation in patients who had hepatorenal syndrome was 7%, compared with 2% in patients who did not have hepatorenal syndrome. To more fully examine the effect of pretransplant renal function on posttransplant survival, the non-hepatorenal syndrome patients were divided into quartiles depending upon their pretransplant renal function. The patients with the lowest pretransplant renal function had the same survival as the patients with the highest pretransplant renal function. In addition, there was no increased incidence of acute or chronic rejection in any of the groups. The patients with the lower pretransplant renal function were treated with more azathioprine to maintain renal function and had a negligible decrease in glomerular filtration rate following transplant. Conversely, patients with the highest level of renal function pretransplant had a 40% decline in renal function in the first year, but maintained stable renal function up to 4 years after transplant. We conclude that pretransplant renal function other than hepato-renal syndrome has no effect on patient survival after orthotopic liver transplant. Renal function after liver transplant is stable after an initial decline, despite continued administration of CsA.(ABSTRACT TRUNCATED AT 400 WORDS)

Profiling for primary-care presentation, investigation and referral for liver cancers: evidence from a national audit.

PubMed

Hughes, Daniel L; Neal, Richard D; Lyratzopoulos, Georgios; Rubin, Greg

2016-04-01

The incidence of liver cancer across Europe is increasing. There is a lack of evidence within the current literature on the identification and investigation of liver cancer within primary care. We aimed to profile liver cancer recognition and assessment as well as the timeliness of liver cancer diagnosis from within the primary-care setting in the UK. Data were obtained from the National Audit of Cancer Diagnosis in Primary Care 2009-2010 and analysed. We calculated the patient interval, the primary-care interval and the number of prereferral consultations for liver cancer. We then compared these data with prior data on the respective indicators for other common cancers. The median patient interval was 9 days (interquartile range 0-31 days), and the median primary-care interval for liver cancer was 11 days (interquartile range 0-40 days). Of the 90 patients, 21 (23.3%) had three or more consultations with their general practitioner before specialist referral. For the three metrics (patient interval, primary-care interval and number of prereferral consultations), liver cancer has average or longer intervals when compared with other cancers. The most common symptomatic presentation of liver cancer within the primary-care setting was right upper quadrant pain (11%), followed by decompensated liver failure (9%). Of the patients, 12% were diagnosed with liver cancer on the basis of an incidental finding of an abnormal liver function test. This study provides a detailed and thorough overview of the recognition of liver cancer and the promptness of liver cancer identification in an English context, and should inform strategies for improving the timeliness of diagnosis.

Unraveling molecular mechanistic differences in liver metabolism between lean and fat lines of Pekin duck (Anas platyrhynchos domestica): a proteomic study.

PubMed

Zheng, Aijuan; Chang, Wenhuan; Hou, Shuisheng; Zhang, Shu; Cai, Huiyi; Chen, Guilan; Lou, Ruiying; Liu, Guohua

2014-02-26

Duck is one of the major poultry meat sources for human consumption. To satisfy different eating habits, lean and fat strains of Pekin ducks have been developed. The objective of this study was to determine the molecular mechanistic differences in liver metabolism between two duck strains. The liver proteome of the Pekin duck lines was compared on days 1, 14, 28, and 42 posthatching using 2-DE based proteomics. There was a different abundance of 76 proteins in the livers of the two duck lines. Fat ducks strongly expressed proteins related to pathways of glycolysis, ATP synthesis, and protein catabolism, suggesting enhanced fat deposition rather than protein retention. In contrast, highly expressed proteins in lean ducks improved protein anabolism and reduced protein catabolism, resulting in an enhancement of lean meat deposition. Along with the decrease in fat deposition, the immune system of the lean duck strain may be enhanced by enhanced expression of proteins involved in stress response, immune defense, and antioxidant functions. These results indicate that selection pressure has shaped the two duck lines differently resulting in different liver metabolic capacities. These observed variations between the two strains at the molecular level are matched with physiological changes in growth performance and meat production. This information may have beneficial impacts in areas such as genetic modification through the manipulation of target proteins or genes in specific pathways to improve the efficiency of duck meat production. The objective of this study was to unravel molecular mechanistic differences in liver metabolism between lean and fat Pekin duck (Anas platyrhynchos domestica) strains. There was a different abundance of 76 proteins in the livers of the two duck lines. Enhanced protein expression in the fat ducks related to pathways of glycolysis, ATP synthesis and protein catabolism suggesting increased fat deposition rather than protein retention. In contrast, highly expressed proteins in the lean ducks facilitated protein deposition by increasing protein anabolism and reducing protein catabolism to enhance the lean meat percentage. Along with the decrease of fat deposition, the immunity of lean duck appeared to be enhanced by increased expression of proteins involved in stress response, defense and antioxidant function. This study provides potential target proteins or genes for further functional analysis and genetic manipulation to increase the efficiency of duck meat production and help satisfy the global demand for poultry meat. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Evaluation of abnormal liver function tests.

PubMed

Agrawal, Swastik; Dhiman, Radha K; Limdi, Jimmy K

2016-04-01

Incidentally detected abnormality in liver function tests is a common situation encountered by physicians across all disciplines. Many of these patients do not have primary liver disease as most of the commonly performed markers are not specific for the liver and are affected by myriad factors unrelated to liver disease. Also, many of these tests like liver enzyme levels do not measure the function of the liver, but are markers of liver injury, which is broadly of two types: hepatocellular and cholestatic. A combination of a careful history and clinical examination along with interpretation of pattern of liver test abnormalities can often identify type and aetiology of liver disease, allowing for a targeted investigation approach. Severity of liver injury is best assessed by composite scores like the Model for End Stage Liver Disease rather than any single parameter. In this review, we discuss the interpretation of the routinely performed liver tests along with the indications and utility of quantitative tests. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

[The clinicopathological analysis of 88 patients with abnormal liver function test of unknown etiology].

PubMed

Pang, Shu-zhen; Ou, Xiao-juan; Shi, Xiao-yan; Wang, Tai-ling; Duan, Wei-jia; Jia, Ji-dong

2011-01-01

To evaluate the clinical and histological features of patients with abnormal liver tests of unknown etiology, and then to investigate the diagnosis and differential diagnosis. Patients with abnormal liver function test hospitalized and had liver biopsies during 2008 - 2009 constituted this retrospective study cohort. After excluding those patients diagnosed with hepatotropic viral hepatitis, space occupying lesions of the liver, alcoholic liver disease and obstruction of bile duct caused by stone or malignancy and AMA/AMA-M(2) positive of primary biliary cirrhosis (PBC), the clinical and histological characteristics were evaluated. Out of the 180 patients who underwent liver biopsy, 88 patients were included in the present analysis. The final diagnosis involved 15 categories of diseases, with drug-induced liver injury (DILI) [34.09% (30/88)], autoimmune liver diseases [22.73% (20/88)], and nonalcoholic fatty liver disease (NAFLD) [12.50% (11/88)] being the most common causes, following by genetic and other rare diseases. DILI, autoimmune liver disease and NAFLD were the most common causes of abnormal liver tests in these non-viral liver diseases. Some rare diseases such as hereditary metabolic liver disease also represent a considerable proportion in patients with abnormal liver function test.

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

PubMed Central

Kubo, Shoji; Takemura, Shigekazu; Tanaka, Shogo; Shinkawa, Hiroji; Nishioka, Takayoshi; Nozawa, Akinori; Kinoshita, Masahiko; Hamano, Genya; Ito, Tokuji; Urata, Yorihisa

2015-01-01

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC. PMID:26217076

Concordance of Transcriptional and Apical Benchmark Dose Levels for Conazole-Induced Liver Effects in Mice

EPA Science Inventory

ABSTRACT The ability to anchor chemical class-based gene expression changes to phenotypic lesions and to describe these changes as a function of dose and time informs mode of action determinations and improves quantitative risk assessments. Previous transcription-based microarra...

Kupffer Cell Metabolism and Function

PubMed Central

Nguyen-Lefebvre, Anh Thu; Horuzsko, Anatolij

2015-01-01

Kupffer cells are resident liver macrophages and play a critical role in maintaining liver functions. Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections. Under pathological conditions, they are activated by different components and can differentiate into M1-like (classical) or M2-like (alternative) macrophages. The metabolism of classical or alternative activated Kupffer cells will determine their functions in liver damage. Special functions and metabolism of Kupffer cells suggest that they are an attractive target for therapy of liver inflammation and related diseases, including cancer and infectious diseases. Here we review the different types of Kupffer cells and their metabolism and functions in physiological and pathological conditions. PMID:26937490

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha.

PubMed

Desai, Seema S; Tung, Jason C; Zhou, Vivian X; Grenert, James P; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M; Chang, Tammy T

2016-07-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275). © 2016 by the American Association for the Study of Liver Diseases.

Albumin Dialysis for Liver Failure: A Systematic Review.

PubMed

Tsipotis, Evangelos; Shuja, Asim; Jaber, Bertrand L

2015-09-01

Albumin dialysis is the best-studied extracorporeal nonbiologic liver support system as a bridge or destination therapy for patients with liver failure awaiting liver transplantation or recovery of liver function. We performed a systematic review to examine the efficacy and safety of 3 albumin dialysis systems (molecular adsorbent recirculating system [MARS], fractionated plasma separation, adsorption and hemodialysis [Prometheus system], and single-pass albumin dialysis) in randomized trials for supportive treatment of liver failure. PubMed, Ovid, EMBASE, Cochrane's Library, and ClinicalTrials.gov were searched. Two authors independently screened citations and extracted data on patient characteristics, quality of reports, efficacy, and safety end points. Ten trials (7 of MARS and 3 of Prometheus) were identified (620 patients). By meta-analysis, albumin dialysis achieved a net decrease in serum total bilirubin level relative to standard medical therapy of 8.0 mg/dL (95% confidence interval [CI], -10.6 to -5.4) but not in serum ammonia or bile acids. Albumin dialysis achieved an improvement in hepatic encephalopathy relative to standard medical therapy with a risk ratio of 1.55 (95% CI, 1.16-2.08) but had no effect survival with a risk ratio of 0.95 (95% CI, 0.84-1.07). Because of inconsistency in the reporting of adverse events, the safety analysis was limited but did not demonstrate major safety concerns. Use of albumin dialysis as supportive treatment for liver failure is successful at removing albumin-bound molecules, such as bilirubin and at improving hepatic encephalopathy. Additional experience is required to guide its optimal use and address safety concerns. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Clinical trial watch: reports from the AASLD Liver Meeting®, Boston, November 2014.

PubMed

Londoño, María-Carlota; Abraldes, Juan G; Altamirano, José; Decaens, Thomas; Forns, Xavier

2015-05-01

The late and fast developments in the field of viral hepatitis were highly expected in the 2014 AASLD Liver Meeting®. Several combinations using direct acting antivirals (DAAs) showed high rates of sustained virological response (∼95%). Importantly, high cure rates were also demonstrated in patients with previous treatment failures, decompensated cirrhosis and hepatitis C recurrence after transplantation, making it clear that the interferon era is over (not so clear for ribavirin, which might still have a role in difficult-to-treat populations). Importantly, sustained virological response was associated with an improvement in liver function (MELD and Child-Pugh scores) in patients with advanced liver disease. In the field of liver cirrhosis, there were relevant data assessing the optimal empirical antibiotic therapy in patients with spontaneous bacterial peritonitis and high risk of resistant bacteria, as well as studies evaluating the role of terlipressin in type I hepatorenal syndrome and in septic shock. Regarding hepatic encephalopathy, two randomized trials suggest that the manipulation of the microbioma in patients with cirrhosis may have a role in the management of this complication. Some novel data on NASH support the beneficial effect of bariatric surgery (after failure of lifestyle intervention) in morbid obese patients with such diagnosis: clinical and histological improvements after surgery were evident in most patients with sufficient follow-up. A few controlled studies focused on the treatment of severe acute alcoholic hepatitis. Finally, several studies on hepatocellular carcinoma (HCC) were presented, covering topics such as ultrasound screening in cirrhosis, cryoablation treatment of early HCC and the relevance of downstaging in patients with HCC awaiting liver transplantation. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Decision making in liver transplant selection committees: a multicenter study.

PubMed

Volk, Michael L; Biggins, Scott W; Huang, Mary Ann; Argo, Curtis K; Fontana, Robert J; Anspach, Renee R

2011-10-18

To receive a liver transplant, patients must first be placed on a waiting list-a decision made at most transplant centers by a multidisciplinary committee. The function of these committees has never been studied. To describe decision making in liver transplant committees and identify opportunities for process improvement. Observational multicenter study. 4 liver transplant centers in the United States. 68 members of liver transplant committees across the 4 centers. 63 meetings were observed, and 50 committee members were interviewed. Recorded transcripts and field notes were analyzed by using standard qualitative sociologic methods. Although the structure of the meetings varied by center, the process was uniform and primarily involved inductive reasoning to review possible reasons for patient exclusion. Patients were excluded if they were too well, too sick (in the setting of advanced liver disease), or too old or had nonhepatic comorbid conditions, substance abuse problems, or other psychosocial barriers. Dominant themes in the discussions included member angst over deciding who lived or died, a high correlation between psychosocial barriers to transplantation and the patient's socioeconomic status, and the influence of external forces on decision making. Unwritten center policies and confusion regarding advocacy versus stewardship roles were consistently identified as barriers to effective group decision making. The use of qualitative methods provides broad understanding but limits specific inferences. The 4 centers may not reflect the practices of every transplant center nationwide. The difficult decisions made by liver transplant committees are reasonably consistent and well-intentioned, but the process might be improved by having more explicit written policies and clarifying roles. This may inform resource allocation in other areas of medicine. The Greenwall Foundation and the National Institutes of Health.

Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation, Oxidative stress and Hepatic Steatosis in Patients with Nonalcoholic Fatty Liver Disease.

PubMed

Pervez, Muhammad Amjad; Khan, Dishad Ahmet; Ijaz, Aamir; Khan, Shamrez

2018-03-01

Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and is associated with increased morbidity and mortality. Currently, there is no definitive treatment for this disease. δ-Tocotrienol has potent anti-inflammatory and antioxidant properties and may reduce liver injury in NAFLD. The present study aims to evaluate the efficacy and safety of δ-tocotrienol in the treatment of NAFLD. The present study was a randomized, double-blind, placebo-controlled pilot study conducted in patients aged > 20 years, belonging to both sexes, having ultrasound-proven fatty liver disease, having a fatty liver index (FLI) of ≥ 60, and persistent elevation of alanine transaminase. A total of 71 patients were assigned to receive either oral δ-tocotrienol (n=35, 300 mg twice daily) or placebo (n=36) for 12 weeks. At the baseline and at the end of the study, clinical and biochemical parameters, including lipid profile, liver function tests, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were measured. Body mass index and FLI were calculated, and ultrasound grading of hepatic steatosis was performed. Out of 71 enrolled patients, 64 patients, 31 in the δ-tocotrienol group and 33 in the placebo group, completed the study. After 12 weeks of supplementation, δ-tocotrienol showed greater efficacy than placebo by decreasing serum aminotransferases, hs-CRP, MDA, and FLI score (p<0.001). However, it did not improve hepatic steatosis on ultrasound examination. No adverse effects were reported. δ-Tocotrienol was safe, and it effectively improved aminotransferase levels and inflammatory and oxidative stress markers in patients with NAFLD. Large-scale randomized clinical trials are warranted to further support these findings.

Physiological characterization of a mouse model of cachexia in colorectal liver metastases.

PubMed

Murphy, Kate T; Struk, Adam; Malcontenti-Wilson, Cathy; Christophi, Christopher; Lynch, Gordon S

2013-05-15

Loss of skeletal muscle mass and function (cachexia) is severe in patients with colorectal liver metastases because of the large increase in resting energy expenditure but remains understudied because of a lack of suitable preclinical models. Our aim was to characterize a novel preclinical model of cachexia in colorectal liver metastases. We tested the hypothesis that mice with colorectal liver metastases would exhibit cachexia, as evidenced by a reduction in liver-free body mass, muscle mass, and physiological impairment. Twelve-week-old male CBA mice received an intrasplenic injection of Ringer solution (sham) or murine colorectal cancer cells (MoCR) to induce colorectal liver metastases. At end-point (20-29 days), the livers of MoCR mice were infiltrated completely with metastases, and MoCR mice had reduced liver-free body mass, muscle mass, and epididymal fat mass compared with sham controls (P < 0.03). MoCR mice exhibited impaired rotarod performance and grip strength (P < 0.03). Histochemical analyses of tibialis anterior muscles from MoCR mice revealed muscle fiber atrophy and reduced oxidative enzyme activity (P < 0.001). Adipose tissue remodeling was evident in MoCR mice, with reduced adipocyte diameter and greater infiltration of nonadipocyte tissue (P < 0.05). These findings reveal the MoCR mouse model exhibits significant cachexia and is a suitable preclinical model of cachexia in colorectal liver metastases. This model should be used for identifying effective treatments for cachexia to improve quality of life and reduce mortality in patients with colorectal liver metastases.

Mapping of the circulating metabolome reveals α-ketoglutarate as a predictor of morbid obesity-associated non-alcoholic fatty liver disease.

PubMed

Rodríguez-Gallego, E; Guirro, M; Riera-Borrull, M; Hernández-Aguilera, A; Mariné-Casadó, R; Fernández-Arroyo, S; Beltrán-Debón, R; Sabench, F; Hernández, M; del Castillo, D; Menendez, J A; Camps, J; Ras, R; Arola, L; Joven, J

2015-02-01

Obesity severely affects human health, and the accompanying non-alcoholic fatty liver disease (NAFLD) is associated with high morbidity and mortality. Rapid and non-invasive methods to detect this condition may substantially improve clinical care. We used liquid and gas chromatography-quadruple time-of-flight-mass spectrometry (LC/GC-QTOF-MS) analysis in a non-targeted metabolomics approach on the plasma from morbidly obese patients undergoing bariatric surgery to gain a comprehensive measure of metabolite levels. On the basis of these findings, we developed a method (GC-QTOF-MS) for the accurate quantification of plasma α-ketoglutarate to explore its potential as a novel biomarker for the detection of NAFLD. Plasma biochemical differences were observed between patients with and without NAFLD indicating that the accumulation of lipids in hepatocytes decreased β-oxidation energy production, reduced liver function and altered glucose metabolism. The results obtained from the plasma analysis suggest pathophysiological insights that link lipid and glucose disturbances with α-ketoglutarate. Plasma α-ketoglutarate levels are significantly increased in obese patients compared with lean controls. Among obese patients, the measurement of this metabolite differentiates between those with or without NAFLD. Data from the liver were consistent with data from plasma. Clinical utility was assessed, and the results revealed that plasma α-ketoglutarate is a fair-to-good biomarker in patients (n=230). Other common laboratory liver tests used in routine application did not favourably compare. Plasma α-ketoglutarate is superior to common liver function tests in obese patients as a surrogate biomarker of NAFLD. The measurement of this biomarker may potentiate the search for a therapeutic approach, may decrease the need for liver biopsy and may be useful in the assessment of disease progression.

l-Methionine and silymarin: A comparison of prophylactic protective capabilities in acetaminophen-induced injuries of the liver, kidney and cerebral cortex.

PubMed

Onaolapo, Olakunle J; Adekola, Moses A; Azeez, Taiwo O; Salami, Karimat; Onaolapo, Adejoke Y

2017-01-01

We compared the relative protective abilities of silymarin and l-methionine pre-treatment in acetaminophen overdose injuries of the liver, kidney and cerebral cortex by assessing behaviours, antioxidant status, tissue histological changes and biochemical parameters of hepatic/renal function. Rats were divided into six groups of ten each; animals in five of these groups were pre-treated with oral distilled water, silymarin (25mg/kg) or l-methionine (2.5, 5 and 10mg/kg body weight) for 14days; and then administered intraperitoneal (i.p.) acetaminophen at 800mg/kg/day for 3days. Rats in the sixth group (normal control) received distilled water orally for 14days and then i.p. for 3days. Neurobehavioural tests were conducted 7days after last i.p treatment, and animals sacrificed on the 8th day. Plasma was assayed for biochemical markers of liver/kidney function; while sections of the liver, kidney and cerebral cortex were either homogenised for assay of antioxidant status or processed for histology. Acetaminophen overdose resulted in locomotor retardation, excessive self-grooming, working-memory impairment, anxiety, derangement of liver/kidney biochemistry, antioxidant imbalance, and histological changes in the liver, kidney and cerebral cortex. Administration of silymarin or increasing doses of l-methionine counteracted the behavioural changes, reversed biochemical indices of liver/kidney injury, and improved antioxidant activity. Silymarin and l-methionine also conferred variable degrees of tissue protection, on histology. Either silymarin or l-methionine can protect vulnerable tissues from acetaminophen overdose injury; however, each offers variable protection to different tissues. This study highlights an obstacle to seeking the 'ideal' protective agent against acetaminophen overdose. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A variational approach to liver segmentation using statistics from multiple sources

NASA Astrophysics Data System (ADS)

Zheng, Shenhai; Fang, Bin; Li, Laquan; Gao, Mingqi; Wang, Yi

2018-01-01

Medical image segmentation plays an important role in digital medical research, and therapy planning and delivery. However, the presence of noise and low contrast renders automatic liver segmentation an extremely challenging task. In this study, we focus on a variational approach to liver segmentation in computed tomography scan volumes in a semiautomatic and slice-by-slice manner. In this method, one slice is selected and its connected component liver region is determined manually to initialize the subsequent automatic segmentation process. From this guiding slice, we execute the proposed method downward to the last one and upward to the first one, respectively. A segmentation energy function is proposed by combining the statistical shape prior, global Gaussian intensity analysis, and enforced local statistical feature under the level set framework. During segmentation, the shape of the liver shape is estimated by minimization of this function. The improved Chan-Vese model is used to refine the shape to capture the long and narrow regions of the liver. The proposed method was verified on two independent public databases, the 3D-IRCADb and the SLIVER07. Among all the tested methods, our method yielded the best volumetric overlap error (VOE) of 6.5 +/- 2.8 % , the best root mean square symmetric surface distance (RMSD) of 2.1 +/- 0.8 mm, the best maximum symmetric surface distance (MSD) of 18.9 +/- 8.3 mm in 3D-IRCADb dataset, and the best average symmetric surface distance (ASD) of 0.8 +/- 0.5 mm, the best RMSD of 1.5 +/- 1.1 mm in SLIVER07 dataset, respectively. The results of the quantitative comparison show that the proposed liver segmentation method achieves competitive segmentation performance with state-of-the-art techniques.

Lack of kinin B₁ receptor potentiates leptin action in the liver.

PubMed

Fonseca, Raphael Gomes; Sales, Vicencia Micheline; Ropelle, Eduardo; Barros, Carlos Castilho; Oyama, Lila; Ihara, Silvia Saiuli Iuki; Saad, Mário Jose Abdalla; Araújo, Ronaldo Carvalho; Pesquero, João Bosco

2013-07-01

Kinins B1 and B2 receptors (B1R and B2R) are classically associated with inflammation, but our group has recently demonstrated new roles for B1R in metabolism using a knockout model (B1 (-/-)). B1 (-/-) mice display improvement on leptin and insulin sensitivity and is protected from high fat diet (HFD)-induced obesity. Here, we evaluate the hepatic effects of the B1R ablation and its role on hepatic function. Despite no expression of hepatic B1R, HFD-induced hepatic lipid accumulation was lower than in control animals. B1 (-/-) mice also presented lower hepatic lipogenesis and SCD1 protein content in the liver. When stimulated with exogenous leptin, B1 (-/-) mice exhibited increased hepatic pJAK2. Similarly, leptin signaling was enhanced in the liver of ob/ob-B1 (-/-) mice, as demonstrated by increased levels of pSTAT3 compared to ob/ob. Plasma concentrations of intercellular adhesion molecule 1, fetuin A, leukemia inhibitory factor, tissue inhibitor of metalloprotease-1, resistin, and oncostatin M were reduced in B1 (-/-). Finally, B1 (-/-) mice have increased gene expression of hepatic B2 receptor, but no difference in leptin receptor expression. Our results show that B1 (-/-) mice are protected from non-alcoholic fatty liver disease (NAFLD) after HFD treatment. Since B1R expression was not observed in the liver after HFD, we propose that the cross talk between the adipose tissue and the liver, mainly through leptin, is an important factor contributing to the observed results. Besides that, several other inflammatory mediators already correlated with NAFLD or liver function were found to be altered in our model. Taken together, our data suggest that B1R plays an important role in hepatic steatosis development.

Automatic liver contouring for radiotherapy treatment planning

NASA Astrophysics Data System (ADS)

Li, Dengwang; Liu, Li; Kapp, Daniel S.; Xing, Lei

2015-09-01

To develop automatic and efficient liver contouring software for planning 3D-CT and four-dimensional computed tomography (4D-CT) for application in clinical radiation therapy treatment planning systems. The algorithm comprises three steps for overcoming the challenge of similar intensities between the liver region and its surrounding tissues. First, the total variation model with the L1 norm (TV-L1), which has the characteristic of multi-scale decomposition and an edge-preserving property, is used for removing the surrounding muscles and tissues. Second, an improved level set model that contains both global and local energy functions is utilized to extract liver contour information sequentially. In the global energy function, the local correlation coefficient (LCC) is constructed based on the gray level co-occurrence matrix both of the initial liver region and the background region. The LCC can calculate the correlation of a pixel with the foreground and background regions, respectively. The LCC is combined with intensity distribution models to classify pixels during the evolutionary process of the level set based method. The obtained liver contour is used as the candidate liver region for the following step. In the third step, voxel-based texture characterization is employed for refining the liver region and obtaining the final liver contours. The proposed method was validated based on the planning CT images of a group of 25 patients undergoing radiation therapy treatment planning. These included ten lung cancer patients with normal appearing livers and ten patients with hepatocellular carcinoma or liver metastases. The method was also tested on abdominal 4D-CT images of a group of five patients with hepatocellular carcinoma or liver metastases. The false positive volume percentage, the false negative volume percentage, and the dice similarity coefficient between liver contours obtained by a developed algorithm and a current standard delineated by the expert group are on an average 2.15-2.57%, 2.96-3.23%, and 91.01-97.21% for the CT images with normal appearing livers, 2.28-3.62%, 3.15-4.33%, and 86.14-93.53% for the CT images with hepatocellular carcinoma or liver metastases, and 2.37-3.96%, 3.25-4.57%, and 82.23-89.44% for the 4D-CT images also with hepatocellular carcinoma or liver metastases, respectively. The proposed three-step method can achieve efficient automatic liver contouring for planning CT and 4D-CT images with follow-up treatment planning and should find widespread applications in future treatment planning systems.

Assessment of hepatic function decline after stereotactic body radiation therapy for primary liver cancer.

PubMed

Toesca, Diego A S; Osmundson, Evan C; von Eyben, Rie; Shaffer, Jenny L; Koong, Albert C; Chang, Daniel T

This study aims to determine how the albumin-bilirubin (ALBI) score compares with the Child-Pugh (CP) score for assessing liver function following stereotactic body radiation therapy (SBRT). In total, 60 patients, 40 with hepatocellular carcinoma (HCC) and 20 with cholangiocarcinoma (CCA), were treated with SBRT. Liver function panels were obtained before and at 1, 3, 6, and 12 months after SBRT. Laboratory values were censored after locoregional recurrence, further liver-directed therapies, or liver transplant. A significant decline in hepatic function occurred after SBRT for HCC patients only (P = .001 by ALBI score; P < .0001 by CP score). By converting radiation doses to biologically equivalent doses by using a standard linear quadratic model using α/β of 10, the strongest dosimetric predictor of liver function decline for HCC was the volume of normal liver irradiated by a dose of 40 Gy when assessing liver function by the ALBI score (P = .07), and the volume of normal liver irradiated by a dose of 20 Gy by using the CP score (P= .0009). For CCA patients, the volume of normal liver irradiated by a dose of 40 Gy remained the strongest dosimetric predictor when using the ALBI score (P = .002), but no dosimetric predictor was significant using the CP score. Hepatic function decline correlated with worse overall survival for HCC (by ALBI, P = .0005; by CP, P < .0001) and for CCA (by ALBI, P = NS; by CP, P = .008). ALBI score was similarly able to predict hepatic function decline compared with CP score, and both systems correlated with survival. Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

The bioimpedance analysis of a parenchyma of a liver in the conditions of its extensive resection in experiment

NASA Astrophysics Data System (ADS)

Agibalov, D. Y.; Panchenkov, D. N.; Chertyuk, V. B.; Leonov, S. D.; Astakhov, D. A.

2017-01-01

The liver failure which is result of disharmony of functionality of a liver to requirements of an organism is the main reason for unsatisfactory results of an extensive resection of a liver. However, uniform effective criterion of definition of degree of a liver failure it isn’t developed now. One of data acquisition methods about a morfo-functional condition of internals is the bioimpedance analysis (BIA) based on impedance assessment (full electric resistance) of a biological tissue. Measurements of an impedance are used in medicine and biology for the characteristic of physical properties of living tissue, studying of the changes bound to a functional state and its structural features. In experimental conditions we carried out an extensive resection of a liver on 27 white laboratory rats of the Vistar line. The comparative characteristic of data of a bioimpedansometriya in intraoperative and after the operational period with the main existing methods of assessment of a functional condition of a liver was carried out. By results of the work performed by us it is possible to claim that the bioimpedance analysis of a liver on the basis of an invasive bioimpedansometriya allows to estimate morphological features and functional activity of a liver before performance of an extensive resection of a liver. The data obtained during scientific work are experimental justification for use of an impedansometriya during complex assessment of functional reserves of a liver. Preliminary data of clinical approbation at a stage of introduction of a technique speak about rather high informational content of a bioimpedansometriya. The subsequent analysis of efficiency of the invasive bioimpedance analysis of a liver requires further accumulation of clinical data. However even at this stage the method showed the prospect for further use in clinical surgical hepathology.

Chronic DON exposure and acute LPS challenge: effects on porcine liver morphology and function.

PubMed

Renner, Lydia; Kahlert, Stefan; Tesch, Tanja; Bannert, Erik; Frahm, Jana; Barta-Böszörményi, Anikó; Kluess, Jeannette; Kersten, Susanne; Schönfeld, Peter; Rothkötter, Hermann-Josef; Dänicke, Sven

2017-08-01

The aim of the present study was to examine the role of chronic deoxynivalenol (DON) exposition on the liver morphology and function in combination with pre- and post-hepatic lipopolysaccharide (LPS) stress in young pigs fed for 4 weeks with a DON-contaminated diet (4.59 mg/kg feed). At the end of the experiment, LPS (7.5 μg/kg BW) was administered for 1 h pre-hepatically (Vena portae hepatis) or post-hepatically (Vena jugularis). Liver morphology was macroscopically checked and showed haemorrhage in all LPS groups, significantly higher relative liver weights, accompanied by marked oedema in the gallbladder wall. Histological changes were judged by a modified histology activity index (HAI). Liver HAI score was significantly increased in all LPS groups compared to placebo, primarily due to neutrophil infiltration and haemorrhage. DON feed alone was without effect on the liver HAI. Liver function was characterized by (i) hepatic biochemical markers, (ii) mitochondrial respiration and (iii) Ca 2+ accumulation capacity of isolated mitochondria. Clinical chemical parameters characterizing liver function were initially (<3 h) slightly influenced by LPS. After 3 h, bilirubin and alkaline phosphatase were increased significantly, in DON-fed, jugular-infused LPS group. Respiration and Ca 2+ accumulation capacity of isolated liver mitochondria was not impaired by chronic DON exposure, acute LPS challenge or combined treatments. DON-contaminated feed did not change macroscopy and histology of the liver, but modified the function under LPS stress. The different function was not linked to modifications of liver mitochondria.

A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro

PubMed Central

Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

2017-01-01

Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotransformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two-dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases. PMID:27959388

A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro.

PubMed

Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

2017-01-01

Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two‑dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.

Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats.

PubMed

Zafrani, Lara; Ergin, Bulent; Kapucu, Aysegul; Ince, Can

2016-12-20

The effects of blood transfusion on renal microcirculation during sepsis are unknown. This study aimed to investigate the effect of blood transfusion on renal microvascular oxygenation and renal function during sepsis-induced acute kidney injury. Twenty-seven Wistar albino rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 7), a LPS group that received fluid resuscitation (n = 7), and a LPS group that received blood transfusion (n = 7). The mean arterial blood pressure, renal blood flow, and renal microvascular oxygenation within the kidney cortex were recorded. Acute kidney injury was assessed using the serum creatinine levels, metabolic cost, and histopathological lesions. Nitrosative stress (expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS)) within the kidney was assessed by immunohistochemistry. Hemoglobin levels, pH, serum lactate levels, and liver enzymes were measured. Fluid resuscitation and blood transfusion both significantly improved the mean arterial pressure and renal blood flow after LPS infusion. Renal microvascular oxygenation, serum creatinine levels, and tubular damage significantly improved in the LPS group that received blood transfusion compared to the group that received fluids. Moreover, the renal expression of eNOS was markedly suppressed under endotoxin challenge. Blood transfusion, but not fluid resuscitation, was able to restore the renal expression of eNOS. However, there were no significant differences in lactic acidosis or liver function between the two groups. Blood transfusion significantly improved renal function in endotoxemic rats. The specific beneficial effect of blood transfusion on the kidney could have been mediated in part by the improvements in renal microvascular oxygenation and sepsis-induced endothelial dysfunction via the restoration of eNOS expression within the kidney.

4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration.

PubMed

Hayashi, Hisamitsu; Mizuno, Tadahaya; Horikawa, Reiko; Nagasaka, Hironori; Yabuki, Takashi; Takikawa, Hajime; Sugiyama, Yuichi

2012-05-01

Multidrug resistance-associated protein 2 (in humans, MRP2; in rodents, Mrp2) mediates biliary excretion of bilirubin glucuronides. Therefore, upregulation of MRP2/Mrp2 expression may improve hyperbilirubinemia. We investigated the effects of 4-phenylbutyrate (4PBA), a drug used to treat ornithine transcarbamylase deficiency (OTCD), on the cell surface expression and transport function of MRP2/Mrp2 and serum T-Bil concentration. MRP2-expressing MDCKII (MRP2-MDCKII) cells and rats were studied to explore the change induced by 4PBA treatment in the cell surface expression and transport function of MRP2/Mrp2 and its underlying mechanism. Serum and liver specimens from OTCD patients were analyzed to examine the effect of 4PBA on hepatic MRP2 expression and serum T-Bil concentration in humans. In MRP2-MDCKII cells and the rat liver, 4PBA increased the cell surface expression and transport function of MRP2/Mrp2. In patients with OTCD, hepatic MRP2 expression increased and serum T-Bil concentration decreased significantly after 4PBA treatment. In vitro studies designed to explore the mechanism underlying this drug action suggested that cell surface-resident MRP2/Mrp2 is degraded via ubiquitination-mediated targeting to the endosomal/lysosomal degradation pathway and that 4PBA inhibits the degradation of cell surface-resident MRP2/Mrp2 by reducing its susceptibility to ubiquitination. 4PBA activates MRP2/Mrp2 function through increased expression of MRP2/Mrp2 at the hepatocanalicular membrane by modulating its ubiquitination, and thereby decreases serum T-Bil concentration. 4PBA has thus therapeutic potential for improving hyperbilirubinemia. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

PubMed Central

Ma, Xuanyi; Qu, Xin; Zhu, Wei; Li, Yi-Shuan; Yuan, Suli; Zhang, Hong; Liu, Justin; Wang, Pengrui; Lai, Cheuk Sun Edwin; Zanella, Fabian; Feng, Gen-Sheng; Sheikh, Farah; Chien, Shu; Chen, Shaochen

2016-01-01

The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling. PMID:26858399

Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting.

PubMed

Ma, Xuanyi; Qu, Xin; Zhu, Wei; Li, Yi-Shuan; Yuan, Suli; Zhang, Hong; Liu, Justin; Wang, Pengrui; Lai, Cheuk Sun Edwin; Zanella, Fabian; Feng, Gen-Sheng; Sheikh, Farah; Chien, Shu; Chen, Shaochen

2016-02-23

The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.

Hybrid braided 3-D scaffold for bioartificial liver assist devices.

PubMed

Hoque, M E; Mao, H Q; Ramakrishna, S

2007-01-01

Three-dimensional ex vivo hepatocyte culture is a tissue-engineering approach to improve the treatment of liver disease. The extracorporeal bioartificial liver (BAL) assists devices that are used in patients until they either recover or receive a liver transplant. The 3-D scaffold plays a key role in the design of bioreactor that is the most important component of the BAL. Presently available 3-D scaffolds used in BAL have shown good performance. However, existing scaffolds are considered to be less than ideal in terms of high-density cultures of hepatocytes maintaining long-term metabolic functions. This study aims to develop a 3-D hybrid scaffold for a BAL support system that would facilitate high-density hepatocyte anchorage with long-term metabolic functions. The scaffolds were fabricated by interlacing polyethylene terephthalate (PET) fibers onto the polysulfone hollow fibers utilizing a modern microbraiding technique. Scaffolds with various pore sizes and porosities were developed by varying braiding angle which was controlled by the gear ratio of the microbraiding machine. The morphological characteristics (pore size and porosity) of the scaffolds were found to be regulated by the gear ratio. Smaller braiding angle yields larger pore and higher porosity. On the other hand, a larger braiding angle causes smaller pore and lower porosity. In hepatocyte culture it was investigated how the morphological characteristics (pore size and porosity) of scaffolds influenced the cell anchorage and metabolic functions. Scaffolds with larger pores and higher porosity resulted in more cell anchorage and higher cellular functions, like albumin and urea secretion, compared to that of smaller pores and lower porosity.

Combination of vildagliptin and rosiglitazone ameliorates nonalcoholic fatty liver disease in C57BL/6 mice

PubMed Central

Mookkan, Jeyamurugan; De, Soumita; Shetty, Pranesha; Kulkarni, Nagaraj M.; Devisingh, Vijayaraj; Jaji, Mallikarjun S.; Lakshmi, Vinitha P.; Chaudhary, Shilpee; Kulathingal, Jayanarayan; Rajesh, Navin B.; Narayanan, Shridhar

2014-01-01

Objectives: To evaluate the effect of vildagliptin alone and in combination with metformin or rosiglitazone on murine hepatic steatosis in diet-induced nonalcoholic fatty liver disease (NAFLD). Materials and Methods: Male C57BL/6 mice were fed with high fat diet (60 Kcal %) and fructose (40%) in drinking water for 60 days to induce NAFLD. After the induction period, animals were divided into different groups and treated with vildagliptin (10 mg/kg), metformin (350 mg/kg), rosiglitazone (10 mg/kg), vildagliptin (10 mg/kg) + metformin (350 mg/kg), or vildagliptin (10 mg/kg) + rosiglitazone (10 mg/kg) orally for 28 days. Following parameters were measured: body weight, food intake, plasma glucose, triglyceride (TG), total cholesterol, liver function tests, and liver TG. Liver histopathology was also examined. Results: Oral administration of vildagliptin and rosiglitazone in combination showed a significant reduction in fasting plasma glucose, hepatic steatosis, and liver TGs. While other treatments showed less or no improvement in the measured parameters. Conclusions: These preliminary results demonstrate that administration of vildagliptin in combination with rosiglitazone could be a promising therapeutic strategy for the treatment of NAFLD. PMID:24550584

Stereotactic ablative radiotherapy for oligometastatic disease in liver.

PubMed

Kim, Myungsoo; Son, Seok Hyun; Won, Yong Kyun; Kay, Chul Seung

2014-01-01

Liver metastasis in solid tumors, including colorectal cancer, is the most frequent and lethal complication. The development of systemic therapy has led to prolonged survival. However, in selected patients with a finite number of discrete lesions in liver, defined as oligometastatic state, additional local therapies such as surgical resection, radiofrequency ablation, cryotherapy, and radiotherapy can lead to permanent local disease control and improve survival. Among these, an advance in radiation therapy made it possible to deliver high dose radiation to the tumor more accurately, without impairing the liver function. In recent years, the introduction of stereotactic ablative radiotherapy (SABR) has offered even more intensive tumor dose escalation in a few fractions with reduced dose to the adjacent normal liver. Many studies have shown that SABR for oligometastases is effective and safe, with local control rates widely ranging from 50% to 100% at one or two years. And actuarial survival at one and two years has been reported ranging from 72% to 94% and from 30% to 62%, respectively, without severe toxicities. In this paper, we described the definition and technical aspects of SABR, clinical outcomes including efficacy and toxicity, and related parameters after SABR in liver oligometastases from colorectal cancer.

Integration of technologies for hepatic tissue engineering.

PubMed

Nahmias, Yaakov; Berthiaume, Francois; Yarmush, Martin L

2007-01-01

The liver is the largest internal organ in the body, responsible for over 500 metabolic, regulatory, and immune functions. Loss of liver function leads to liver failure which causes over 25,000 deaths/year in the United States. Efforts in the field of hepatic tissue engineering include the design of bioartificial liver systems to prolong patient's lives during liver failure, for drug toxicity screening and for the study of liver regeneration, ischemia/reperfusion injury, fibrosis, viral infection, and inflammation. This chapter will overview the current state-of-the-art in hepatology including isolated perfused liver, culture of liver slices and tissue explants, hepatocyte culture on collagen "sandwich" and spheroids, coculture of hepatocytes with non-parenchymal cells, and the integration of these culture techniques with microfluidics and reactor design. This work will discuss the role of oxygen and medium composition in hepatocyte culture and present promising new technologies for hepatocyte proliferation and function. We will also discuss liver development, architecture, and function as they relate to these culture techniques. Finally, we will review current opportunities and major challenges in integrating cell culture, bioreactor design, and microtechnology to develop new systems for novel applications.

Zebrafish: an important tool for liver disease research.

PubMed

Goessling, Wolfram; Sadler, Kirsten C

2015-11-01

As the incidence of hepatobiliary diseases increases, we must improve our understanding of the molecular, cellular, and physiological factors that contribute to the pathogenesis of liver disease. Animal models help us identify disease mechanisms that might be targeted therapeutically. Zebrafish (Danio rerio) have traditionally been used to study embryonic development but are also important to the study of liver disease. Zebrafish embryos develop rapidly; all of their digestive organs are mature in larvae by 5 days of age. At this stage, they can develop hepatobiliary diseases caused by developmental defects or toxin- or ethanol-induced injury and manifest premalignant changes within weeks. Zebrafish are similar to humans in hepatic cellular composition, function, signaling, and response to injury as well as the cellular processes that mediate liver diseases. Genes are highly conserved between humans and zebrafish, making them a useful system to study the basic mechanisms of liver disease. We can perform genetic screens to identify novel genes involved in specific disease processes and chemical screens to identify pathways and compounds that act on specific processes. We review how studies of zebrafish have advanced our understanding of inherited and acquired liver diseases as well as liver cancer and regeneration. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Lychee (Litchi chinensis Sonn.) Pulp Phenolic Extract Provides Protection against Alcoholic Liver Injury in Mice by Alleviating Intestinal Microbiota Dysbiosis, Intestinal Barrier Dysfunction, and Liver Inflammation.

PubMed

Xiao, Juan; Zhang, Ruifen; Zhou, Qiuyun; Liu, Lei; Huang, Fei; Deng, Yuanyuan; Ma, Yongxuan; Wei, Zhencheng; Tang, Xiaojun; Zhang, Mingwei

2017-11-08

Liver injury is the most common consequence of alcohol abuse, which is promoted by the inflammatory response triggered by gut-derived endotoxins produced as a consequence of intestinal microbiota dysbiosis and barrier dysfunction. The aim of this study was to investigate whether modulation of intestinal microbiota and barrier function, and liver inflammation contributes to the hepatoprotective effect of lychee pulp phenolic extract (LPPE) in alcohol-fed mice. Mice were treated with an ethanol-containing liquid diet alone or in combination with LPPE for 8 weeks. LPPE supplementation alleviated ethanol-induced liver injury and downregulated key markers of inflammation. Moreover, LPPE supplementation reversed the ethanol-induced alteration of intestinal microbiota composition and increased the expression of intestinal tight junction proteins, mucus protecting proteins, and antimicrobial proteins. Furthermore, in addition to decreasing serum endotoxin level, LPPE supplementation suppressed CD14 and toll-like receptor 4 expression, and repressed the activation of nuclear factor-κB p65 in the liver. These data suggest that intestinal microbiota dysbiosis, intestinal barrier dysfunction, and liver inflammation are improved by LPPE, and therefore, the intake of LPPE or Litchi pulp may be an effective strategy to alleviate the susceptibility to alcohol-induced hepatic diseases.

Effects of Fuzheng Huayu 319 recipe on liver fibrosis in chronic hepatitis B

PubMed Central

Liu, Ping; Liu, Cheng; Xu, Lie-Ming; Hu, Yi-Yang; Xue, Hui-Ming; Liu, Cheng-Hai; Zhang, Zhi-Qing

1998-01-01

AIM: To investigate clinic effects of Fuzheng Huayu 319 recipe (319 recipe) on liver fibrosis in chronic hepatitis B. METHODS: Ninety-five patients with chronic hepatitis B were divide into the treated (63 cases) and control (32 cases) group, and orally administrated with 0.5g 319 capsule or 0.5g Dahuang Zhachong pill tid for 3 months, respectively. The liver functions and serological fibrotic markers were observed before and after treatment, 12 cases in the treated group were examined with liver biopsy. RESULTS: Three hundreds nineteen recipe could remarkably decreased serum ALT level and total bilirubin and significantly improve serum albumin and A/G ratio. Its effects were better than Dahuang Zhachong pill. Before treatment, patients¡äserum monamine oxidase activities, tissue inhibitor of metalloproteinase (TIMP)-1, procollagen type III and laminin were all higher than those of health peoples. These levels decreased remarkably after treatment, and urine hydroxyproline level increased significantly (P<0.001-0.05). Compared with the control, the improvement in treated group was better than that in the control except TIMP-1. According to the scoring system for staging of chronic hepatitis, the fibrotic extents of 7 cases among 12 cases examined by liver biopsy decreased remarkably (1 case decreased by 3 scores, 5 by 2 scores, 1 by 1 score). CONCLUSION: Fuzheng Huayu 319 recipe had good therapeutic effects on chronic hepatitis B, it could reverse the development of liver fibross to some extent. In general its effects were better than that of Dahuang Zhachong pill. PMID:11819318

A Randomized Clinical Trial of Preoperative Administration of Branched-Chain Amino Acids to Prevent Postoperative Ascites in Patients with Liver Resection for Hepatocellular Carcinoma.

PubMed

Kikuchi, Yutaro; Hiroshima, Yukihiko; Matsuo, Kenichi; Kawaguchi, Daisuke; Murakami, Takashi; Yabushita, Yasuhiro; Endo, Itaru; Taguri, Masataka; Koda, Keiji; Tanaka, Kuniya

2016-10-01

Massive postoperative ascites remains a major threat that can lead to liver failure and other fatal complications, especially in patients with poor liver function. Branched-chain amino acid (BCAA) administration increases biosynthesis and secretion of albumin by hepatocytes and increases oncotic pressure by elevating blood albumin concentration, thereby decreasing peripheral edema, ascites, and pleural effusion. We randomly allocated consecutive patients undergoing major liver resection for hepatocellular carcinoma to either a group where oral BCAA administration was initiated 3 weeks before liver resection, or a non-BCAA group. The primary study endpoint was development of postoperative ascites. Overall, 39 patients were allocated to the BCAA group, while 38 were assigned to the non-BCAA group. No significant difference in the rate of refractory ascites, considered alone, was evident between the BCAA (5.1 %) and non-BCAA groups (13.2 %; p = 0.263). However, the occurrence of refractory ascites and/or pleural effusion was significantly less frequent in the BCAA group (5.1 %) than in the non-BCAA group (21.1 %; p = 0.047). Furthermore, the postoperative serum concentration of reduced-state albumin was greater immediately after liver resection in the BCAA group than in the non-BCAA group. Preoperative administration of BCAA did not significantly improve prevention of refractory ascites, but significant effectiveness in preventing ascites, pleural effusion, or both, as well as improving metabolism of albumin, was demonstrated [University Hospital Medical Information Network (UMIN) reference number 000004244].

Overactivity of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus: Electrophysiological Findings in db/db Mice

PubMed Central

Gao, Hong; Molinas, Adrien J.R.; Qiao, Xin

2017-01-01

Preautonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus play a large role in the regulation of hepatic functions via the autonomic nervous system. Activation of hepatic sympathetic nerves increases glucose and lipid metabolism and contributes to the elevated hepatic glucose production observed in the type 2 diabetic condition. This augmented sympathetic output could originate from altered activity of liver-related PVN neurons. Remarkably, despite the importance of the brain-liver pathway, the cellular properties of liver-related neurons are not known. In this study, we provide the first evidence of overall activity of liver-related PVN neurons. Liver-related PVN neurons were identified with a retrograde, trans-synaptic, viral tracer in male lean and db/db mice and whole-cell patch-clamp recordings were conducted. In db/db mice, the majority of liver-related PVN neurons fired spontaneously; whereas, in lean mice the majority of liver-related PVN neurons were silent, indicating that liver-related PVN neurons are more active in db/db mice. Persistent, tonic inhibition was identified in liver-related PVN neurons; although, the magnitude of tonic inhibitory control was not different between lean and db/db mice. In addition, our study revealed that the transient receptor potential vanilloid type 1-dependent increase of excitatory neurotransmission was reduced in liver-related PVN neurons of db/db mice. These findings demonstrate plasticity of liver-related PVN neurons and a shift toward excitation in a diabetic mouse model. Our study suggests altered autonomic circuits at the level of the PVN, which can contribute to autonomic dysfunction and dysregulation of neural control of hepatic functions including glucose metabolism. SIGNIFICANCE STATEMENT A growing body of evidence suggests the importance of the autonomic control in the regulation of hepatic metabolism, which plays a major role in the development and progression of type 2 diabetes mellitus. Despite the importance of the brain-liver pathway, the overall activity of liver-related neurons in control and diabetic conditions is not known. This is a significant gap in knowledge, which prevents developing strategies to improve glucose homeostasis via altering the brain-liver pathway. One of the key findings of our study is the overall shift toward excitation in liver-related hypothalamic neurons in the diabetic condition. This overactivity may be one of the underlying mechanisms of elevated sympathetic activity known in metabolically compromised patients and animal models. PMID:29038244

Overactivity of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus: Electrophysiological Findings in db/db Mice.

PubMed

Gao, Hong; Molinas, Adrien J R; Miyata, Kayoko; Qiao, Xin; Zsombok, Andrea

2017-11-15

Preautonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus play a large role in the regulation of hepatic functions via the autonomic nervous system. Activation of hepatic sympathetic nerves increases glucose and lipid metabolism and contributes to the elevated hepatic glucose production observed in the type 2 diabetic condition. This augmented sympathetic output could originate from altered activity of liver-related PVN neurons. Remarkably, despite the importance of the brain-liver pathway, the cellular properties of liver-related neurons are not known. In this study, we provide the first evidence of overall activity of liver-related PVN neurons. Liver-related PVN neurons were identified with a retrograde, trans-synaptic, viral tracer in male lean and db/db mice and whole-cell patch-clamp recordings were conducted. In db/db mice, the majority of liver-related PVN neurons fired spontaneously; whereas, in lean mice the majority of liver-related PVN neurons were silent, indicating that liver-related PVN neurons are more active in db/db mice. Persistent, tonic inhibition was identified in liver-related PVN neurons; although, the magnitude of tonic inhibitory control was not different between lean and db/db mice. In addition, our study revealed that the transient receptor potential vanilloid type 1-dependent increase of excitatory neurotransmission was reduced in liver-related PVN neurons of db/db mice. These findings demonstrate plasticity of liver-related PVN neurons and a shift toward excitation in a diabetic mouse model. Our study suggests altered autonomic circuits at the level of the PVN, which can contribute to autonomic dysfunction and dysregulation of neural control of hepatic functions including glucose metabolism. SIGNIFICANCE STATEMENT A growing body of evidence suggests the importance of the autonomic control in the regulation of hepatic metabolism, which plays a major role in the development and progression of type 2 diabetes mellitus. Despite the importance of the brain-liver pathway, the overall activity of liver-related neurons in control and diabetic conditions is not known. This is a significant gap in knowledge, which prevents developing strategies to improve glucose homeostasis via altering the brain-liver pathway. One of the key findings of our study is the overall shift toward excitation in liver-related hypothalamic neurons in the diabetic condition. This overactivity may be one of the underlying mechanisms of elevated sympathetic activity known in metabolically compromised patients and animal models. Copyright © 2017 the authors 0270-6474/17/3711140-11$15.00/0.

Causes of altered liver function tests - the role of alpha-1 antitrypsin.

PubMed

Stollenwerk, J; Schepke, M; Biecker, E

2016-09-01

Altered liver function tests are a common finding in clinical practice. Our retrospective study aimed to identify the diagnoses in a non-selected cohort of patients with altered liver tests and to investigate whether alpha-1 antitrypsin genotyping should be part of the diagnostic workup. 501 patients who were admitted to our outpatient clinic for further evaluation of altered liver function tests were included in the study. The patients underwent a standardized diagnostic program with history taking, physical examination, laboratory tests and ultrasonography. Liver biopsy was performed if appropriate. More than 50 % of the patients had nonalcoholic fatty liver disease. Alcoholic and drug-induced liver injury were found in 8.6 % and 7 % of patients, respectively. Chronic hepatitis B and C, autoimmune liver disease and inherited causes of liver disease made up for approximately 16 % of the diagnoses. The remaining patients were diagnosed with kryptogenic liver disease or had miscellaneous diagnoses. In 3.7 % of the genotyped patients, the alpha-1 antitrypsin genotype PiMZ was found. Nonalcoholic fatty liver disease is nowadays the most frequent cause of altered liver tests. Alcoholic liver disease might be underrepresented in our study since these patients less often seek medical attention or the diagnosis is already made by the primary care physician. Drug-induced liver injury was found in more patients than expected and might therefore be underdiagnosed in practice. The alpha-1 antitrypsin genotype PiMZ was found in absence of other possible causes of liver disease, indicating that the PiMZ genotype is itself a risk factor for liver disease. Genotyping for alpha-1 antitrypsin should therefore be done when other causes for altered liver function tests have been ruled out. © Georg Thieme Verlag KG Stuttgart · New York.

Enhanced mitochondrial complex gene function and reduced liver size may mediate improved feed efficiency of beef cattle during compensatory growth

USDA-ARS?s Scientific Manuscript database

Growing ruminants maintained under dietary restriction for extended periods will exhibit compensatory growth when reverted to ad libitum feeding. This period of compensatory growth is associated with increased feed efficiency, lower basal energy requirements, and changes in circulating concentration...

Severe leptospirosis with multiple organ failure successfully treated by plasma exchange and high-volume hemofiltration.

PubMed

Bourquin, Vincent; Ponte, Belén; Hirschel, Bernard; Pugin, Jérôme; Martin, Pierre-Yves; Saudan, Patrick

2011-01-01

Background. Leptospirosis is a spirochetal zoonosis with complex clinical features including renal and liver failure. Case report. We report the case of a Swiss fisherman presenting with leptospirosis. After initial improvement, refractory septic shock and severe liver and kidney failure developed. The expected mortality was estimated at 90% with clinical scores. The patient underwent plasma exchanges and high-volume hemofiltration (HVHF) with complete recovery of hepatic and kidney functions. Discussion. Plasma exchanges and HVHF may confer survival benefit on patients with severe leptospirosis, refractory septic shock, and multiple-organ failure.

Automated diagnosis of focal liver lesions using bidirectional empirical mode decomposition features.

PubMed

Acharya, U Rajendra; Koh, Joel En Wei; Hagiwara, Yuki; Tan, Jen Hong; Gertych, Arkadiusz; Vijayananthan, Anushya; Yaakup, Nur Adura; Abdullah, Basri Johan Jeet; Bin Mohd Fabell, Mohd Kamil; Yeong, Chai Hong

2018-03-01

Liver is the heaviest internal organ of the human body and performs many vital functions. Prolonged cirrhosis and fatty liver disease may lead to the formation of benign or malignant lesions in this organ, and an early and reliable evaluation of these conditions can improve treatment outcomes. Ultrasound imaging is a safe, non-invasive, and cost-effective way of diagnosing liver lesions. However, this technique has limited performance in determining the nature of the lesions. This study initiates a computer-aided diagnosis (CAD) system to aid radiologists in an objective and more reliable interpretation of ultrasound images of liver lesions. In this work, we have employed radon transform and bi-directional empirical mode decomposition (BEMD) to extract features from the focal liver lesions. After which, the extracted features were subjected to particle swarm optimization (PSO) technique for the selection of a set of optimized features for classification. Our automated CAD system can differentiate normal, malignant, and benign liver lesions using machine learning algorithms. It was trained using 78 normal, 26 benign and 36 malignant focal lesions of the liver. The accuracy, sensitivity, and specificity of lesion classification were 92.95%, 90.80%, and 97.44%, respectively. The proposed CAD system is fully automatic as no segmentation of region-of-interest (ROI) is required. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effect of perches on liver health of hens.

PubMed

Jiang, S; Hester, P Y; Hu, J Y; Yan, F F; Dennis, R L; Cheng, H W

2014-07-01

Fatty liver is a common energy metabolic disorder in caged laying hens. Considering that the egg industry is shifting from conventional cages to alternative housing systems such as enriched cages, the objective of this study was to determine the effects of perches on fat deposition and liver health in laying hens. Three hundred twenty-four 17-wk-old White Leghorn hens were housed in 1 of 4 treatments with 9 hens per cage. Treatment 1 hens never had access to perches during their life cycle. Treatment 2 hens had access to perches during the pullet phase only. Treatment 3 hens had access to perches during the laying phase only. Treatment 4 hens always had access to perches. Liver weight, abdominal fat pad weight, BW, liver fat, and circulating alanine transaminase, aspartate transaminase, and adiponectin were determined. Provision of perches during either the rearing or laying phase did not affect liver health in 71-wk-old hens. However, perch access compared with no perch access during the egg laying phase reduced relative fat pad weight. These results suggest that providing perches as a means of stimulating activity reduced abdominal fat deposition in caged hens during the laying period. However, perch access in caged hens was ineffective in reducing fat deposition in the liver and altering enzyme activities related to improved liver function. © 2014 Poultry Science Association Inc.

Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus.

PubMed

Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

2016-09-14

The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.

Evaluation of liver function using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging based on a three-dimensional volumetric analysis system.

PubMed

Kudo, Masashi; Gotohda, Naoto; Sugimoto, Motokazu; Kobayashi, Tatsushi; Kojima, Motohiro; Takahashi, Shinichiro; Konishi, Masaru; Hayashi, Ryuichi

2018-06-02

Magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) is a diagnostic modality for liver tumors. Three-dimensional (3D) volumetric analysis systems using EOB-MRI data are used to simulate liver anatomy for surgery. This study was conducted to investigate clinical utility of a 3D volumetric analysis system on EOB-MRI to evaluate liver function. Between August 2014 and December 2015, 181 patients underwent laboratory and radiological exams as standardized preoperative evaluation for liver surgery. The liver-spleen contrast-enhanced ratio (LSR) was measured by a semi-automated 3D volumetric analysis system on EOB-MRI. First, the inter-evaluator variability of the calculated LSR was evaluated. Additionally, a subset of liver surgical specimens was evaluated histologically by using immunohistochemical staining. Finally, the correlations between the LSR and grading systems of liver function, laboratory data, or histological findings were analyzed. The inter-evaluator correlation coefficient of the measured LSR was 0.986. The mean LSR was significantly correlated with the Child-Pugh score (p = 0.014) and the ALBI score (p < 0.001). Significant correlations were also observed between the LSR and indocyanine green retention rate at 15 min (r = - 0.601, p < 0.001), between the LSR and liver fibrosis stage (r = - 0.556, p < 0.001), and between the LSR and liver steatosis grade (r = - 0.396, p < 0.001). The LSR calculated by a 3D volumetric analysis system on EOB-MRI was highly reproducible and was shown to be correlated with liver function parameters and liver histology. These data suggest that this imaging modality can be a reliable tool to evaluate liver function.

Functional properties of hepatocytes in vitro are correlated with cell polarity maintenance.

PubMed

Zeigerer, Anja; Wuttke, Anne; Marsico, Giovanni; Seifert, Sarah; Kalaidzidis, Yannis; Zerial, Marino

2017-01-01

Exploring the cell biology of hepatocytes in vitro could be a powerful strategy to dissect the molecular mechanisms underlying the structure and function of the liver in vivo. However, this approach relies on appropriate in vitro cell culture systems that can recapitulate the cell biological and metabolic features of the hepatocytes in the liver whilst being accessible to experimental manipulations. Here, we adapted protocols for high-resolution fluorescence microscopy and quantitative image analysis to compare two primary hepatocyte culture systems, monolayer and collagen sandwich, with respect to the distribution of two distinct populations of early endosomes (APPL1 and EEA1-positive), endocytic capacity, metabolic and signaling activities. In addition to the re-acquisition of hepatocellular polarity, primary hepatocytes grown in collagen sandwich but not in monolayer culture recapitulated the apico-basal distribution of EEA1 endosomes observed in liver tissue. We found that such distribution correlated with the organization of the actin cytoskeleton in vitro and, surprisingly, was dependent on the nutritional state in vivo. Hepatocytes in collagen sandwich also exhibited faster kinetics of low-density lipoprotein (LDL) and epidermal growth factor (EGF) internalization, showed improved insulin sensitivity and preserved their ability for glucose production, compared to hepatocytes in monolayer cultures. Although no in vitro culture system can reproduce the exquisite structural features of liver tissue, our data nevertheless highlight the ability of the collagen sandwich system to recapitulate key structural and functional properties of the hepatocytes in the liver and, therefore, support the usage of this system to study aspects of hepatocellular biology in vitro. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

TU-F-12A-04: Differential Radiation Avoidance of Functional Liver Regions Defined by 99mTc-Sulfur Colloid SPECT/CT with Proton Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bowen, S; Miyaoka, R; Kinahan, P

2014-06-15

Purpose: Radiotherapy for hepatocellular carcinoma patients is conventionally planned without consideration of spatial heterogeneity in hepatic function, which may increase risk of radiation-induced liver disease. Pencil beam scanning (PBS) proton radiotherapy (pRT) plans were generated to differentially decrease dose to functional liver volumes (FLV) defined on [{sup 99m}Tc]sulfur colloid (SC) SPECT/CT images (functional avoidance plans) and compared against conventional pRT plans. Methods: Three HCC patients underwent SC SPECT/CT scans for pRT planning acquired 15 min post injection over 24 min. Images were reconstructed with OSEM following scatter, collimator, and exhale CT attenuation correction. Functional liver volumes (FLV) were defined bymore » liver:spleen uptake ratio thresholds (43% to 90% maximum). Planning objectives to FLV were based on mean SC SPECT uptake ratio relative to GTV-subtracted liver and inversely scaled to mean liver dose of 20 Gy. PTV target coverage (V{sub 95}) was matched between conventional and functional avoidance plans. PBS pRT plans were optimized in RayStation for single field uniform dose (SFUD) and systematically perturbed to verify robustness to uncertainty in range, setup, and motion. Relative differences in FLV DVH and target dose heterogeneity (D{sub 2}-D{sub 98})/D50 were assessed. Results: For similar liver dose between functional avoidance and conventional PBS pRT plans (D{sub mean}≤5% difference, V{sub 18Gy}≤1% difference), dose to functional liver volumes were lower in avoidance plans but varied in magnitude across patients (FLV{sub 70%max} D{sub mean}≤26% difference, V{sub 18Gy}≤8% difference). Higher PTV dose heterogeneity in avoidance plans was associated with lower functional liver dose, particularly for the largest lesion [(D{sub 2}-D{sub 98})/D{sub 50}=13%, FLV{sub 90%max}=50% difference]. Conclusion: Differential avoidance of functional liver regions defined on sulfur colloid SPECT/CT is feasible with proton therapy. The magnitude of benefit appears to be patient specific and dependent on tumor location, size, and proximity to functional volumes. Further investigation in a larger cohort of patients may validate the clinical utility of functional avoidance planning of HCC radiotherapy.« less

Impact of budesonide on liver function tests and gut inflammation in patients with primary sclerosing cholangitis and ileal pouch anal anastomosis.

PubMed

Navaneethan, Udayakumar; Venkatesh, Preethi G K; Bennett, Ana E; Patel, Viral; Hammel, Jeffrey; Kiran, Ravi P; McCullough, Arthur J; Shen, Bo

2012-06-01

Budesonide has been studied in patients with primary sclerosing cholangitis (PSC). This study was designed to evaluate the efficacy of oral budesonide on liver function tests in patients with PSC and pouchitis associated with ileal pouch-anal anastomosis (IPAA). The study group consisted of 18 pouch patients with underlying ulcerative colitis (UC) and PSC who were treated with 9 mg daily of budesonide for their underlying pre-pouch ileitis and pouchitis for 1-3 months followed by 3-6 mg maintenance for another 9 months. Demographic and clinical variables were analyzed. The mean age was 39.4±12.4 years (range, 21-59 years). There was no significant change in aspartate aminotransferase (AST) [median (interquartile range) (IQR) 32 (25, 43.8) vs. 35.5 (25.5, 53), p=0.35], alanine aminotransferase (ALT) [37.5 (25.5, 49.5) vs. 40 (30, 84.3), p=0.29], alkaline phosphatase [142.5 (98.5, 264.5) vs. 126 (94.3, 189.5), p=0.35], serum bilirubin [0.7 (0.4, 1.3) vs., 0.6 (0.4, 1.6), p=0.13] or albumin levels [4.3 (3.9, 4.4) vs. 4.2 (3.8, 4.4), p=0.22] at the end of the treatment period (1 year). The revised Mayo Risk Score did not change significantly and three patients required evaluation for liver transplantation during treatment. There was a significant improvement in the endoscopy subscores in the afferent limb and pouch after a year of budesonide treatment (p=0.001). Oral budesonide appears to have no impact on liver function tests in pouch patients with PSC. However it significantly improved afferent limb and pouch inflammation in IPAA patients. Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Molecular regulation of urea cycle function by the liver glucocorticoid receptor.

PubMed

Okun, Jürgen G; Conway, Sean; Schmidt, Kathrin V; Schumacher, Jonas; Wang, Xiaoyue; de Guia, Roldan; Zota, Annika; Klement, Johanna; Seibert, Oksana; Peters, Achim; Maida, Adriano; Herzig, Stephan; Rose, Adam J

2015-10-01

One of the major side effects of glucocorticoid (GC) treatment is lean tissue wasting, indicating a prominent role in systemic amino acid metabolism. In order to uncover a novel aspect of GCs and their intracellular-receptor, the glucocorticoid receptor (GR), on metabolic control, we conducted amino acid and acylcarnitine profiling in human and mouse models of GC/GR gain- and loss-of-function. Blood serum and tissue metabolite levels were determined in Human Addison's disease (AD) patients as well as in mouse models of systemic and liver-specific GR loss-of-function (AAV-miR-GR) with or without dexamethasone (DEX) treatments. Body composition and neuromuscular and metabolic function tests were conducted in vivo and ex vivo, the latter using precision cut liver slices. A serum metabolite signature of impaired urea cycle function (i.e. higher [ARG]:[ORN + CIT]) was observed in human (CTRL: 0.45 ± 0.03, AD: 1.29 ± 0.04; p < 0.001) and mouse (AAV-miR-NC: 0.97 ± 0.13, AAV-miR-GR: 2.20 ± 0.19; p < 0.001) GC/GR loss-of-function, with similar patterns also observed in liver. Serum urea levels were consistently affected by GC/GR gain- (∼+32%) and loss (∼-30%) -of-function. Combined liver-specific GR loss-of-function with DEX treatment revealed a tissue-autonomous role for the GR to coordinate an upregulation of liver urea production rate in vivo and ex vivo, and prevent hyperammonaemia and associated neuromuscular dysfunction in vivo. Liver mRNA expression profiling and GR-cistrome mining identified Arginase I (ARG1) a urea cycle gene targeted by the liver GR. The liver GR controls systemic and liver urea cycle function by transcriptional regulation of ARG1 expression.

Quality Improvement of Liver Ultrasound Images Using Fuzzy Techniques.

PubMed

Bayani, Azadeh; Langarizadeh, Mostafa; Radmard, Amir Reza; Nejad, Ahmadreza Farzaneh

2016-12-01

Liver ultrasound images are so common and are applied so often to diagnose diffuse liver diseases like fatty liver. However, the low quality of such images makes it difficult to analyze them and diagnose diseases. The purpose of this study, therefore, is to improve the contrast and quality of liver ultrasound images. In this study, a number of image contrast enhancement algorithms which are based on fuzzy logic were applied to liver ultrasound images - in which the view of kidney is observable - using Matlab2013b to improve the image contrast and quality which has a fuzzy definition; just like image contrast improvement algorithms using a fuzzy intensification operator, contrast improvement algorithms applying fuzzy image histogram hyperbolization, and contrast improvement algorithms by fuzzy IF-THEN rules. With the measurement of Mean Squared Error and Peak Signal to Noise Ratio obtained from different images, fuzzy methods provided better results, and their implementation - compared with histogram equalization method - led both to the improvement of contrast and visual quality of images and to the improvement of liver segmentation algorithms results in images. Comparison of the four algorithms revealed the power of fuzzy logic in improving image contrast compared with traditional image processing algorithms. Moreover, contrast improvement algorithm based on a fuzzy intensification operator was selected as the strongest algorithm considering the measured indicators. This method can also be used in future studies on other ultrasound images for quality improvement and other image processing and analysis applications.

Quality Improvement of Liver Ultrasound Images Using Fuzzy Techniques

PubMed Central

Bayani, Azadeh; Langarizadeh, Mostafa; Radmard, Amir Reza; Nejad, Ahmadreza Farzaneh

2016-01-01

Background: Liver ultrasound images are so common and are applied so often to diagnose diffuse liver diseases like fatty liver. However, the low quality of such images makes it difficult to analyze them and diagnose diseases. The purpose of this study, therefore, is to improve the contrast and quality of liver ultrasound images. Methods: In this study, a number of image contrast enhancement algorithms which are based on fuzzy logic were applied to liver ultrasound images - in which the view of kidney is observable - using Matlab2013b to improve the image contrast and quality which has a fuzzy definition; just like image contrast improvement algorithms using a fuzzy intensification operator, contrast improvement algorithms applying fuzzy image histogram hyperbolization, and contrast improvement algorithms by fuzzy IF-THEN rules. Results: With the measurement of Mean Squared Error and Peak Signal to Noise Ratio obtained from different images, fuzzy methods provided better results, and their implementation - compared with histogram equalization method - led both to the improvement of contrast and visual quality of images and to the improvement of liver segmentation algorithms results in images. Conclusion: Comparison of the four algorithms revealed the power of fuzzy logic in improving image contrast compared with traditional image processing algorithms. Moreover, contrast improvement algorithm based on a fuzzy intensification operator was selected as the strongest algorithm considering the measured indicators. This method can also be used in future studies on other ultrasound images for quality improvement and other image processing and analysis applications. PMID:28077898

[Kidney function and liver transplantation].

PubMed

Gámán, György; Gelley, Fanni; Gerlei, Zsuzsa; Dabasi, Eszter; Görög, Dénes; Fehérvári, Imre; Kóbori, László; Lengyel, Gabriella; Zádori, Gergely; Fazakas, János; Doros, Attila; Sárváry, Enikő; Nemes, Balázs

2013-06-30

In liver cirrhosis renal function decreases as well. Hepatorenal syndrome is the most frequent cause of the decrease, but primary kidney failure, diabetes mellitus and some diseases underlying endstage liver failure (such as hepatitis C virus infection) can also play an important role. In liver transplantation several further factors (total cross-clamping of vena cava inferior, polytransfusion, immunosuppression) impair the renal function, too. The aim of this study was to analyse the changes in kidney function during the first postoperative year after liver transplantation. Retrospective data analysis was performed after primary liver transplantations (n = 319). impaired preoperative renal function increased the devepolment of postoperative complications and the first year cumulative patient survival was significantly worse (91,7% vs 69,9%; p<0,001) in this group. If renal function of the patients increased above 60 ml/min/1,73 m2 after the first year, patient survival was better. Independently of the preoperative kidney function, 76% of the patients had impaired kidney function at the first postoperative year. In this group, de novo diabetes mellitus was more frequently diagnosed (22,5% vs 9,5%; p = 0,023). Selection of personalized immunosuppressive medication has a positive effect on renal function.

Liver Transplant

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Function of GATA Factors in the Adult Mouse Liver

PubMed Central

Zheng, Rena; Rebolledo-Jaramillo, Boris; Zong, Yiwei; Wang, Liqing; Russo, Pierre; Hancock, Wayne; Stanger, Ben Z.; Hardison, Ross C.; Blobel, Gerd A.

2013-01-01

GATA transcription factors and their Friend of Gata (FOG) cofactors control the development of diverse tissues. GATA4 and GATA6 are essential for the expansion of the embryonic liver bud, but their expression patterns and functions in the adult liver are unclear. We characterized the expression of GATA and FOG factors in whole mouse liver and purified hepatocytes. GATA4, GATA6, and FOG1 are the most prominently expressed family members in whole liver and hepatocytes. GATA4 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) identified 4409 occupied sites, associated with genes enriched in ontologies related to liver function, including lipid and glucose metabolism. However, hepatocyte-specific excision of Gata4 had little impact on gross liver architecture and function, even under conditions of regenerative stress, and, despite the large number of GATA4 occupied genes, resulted in relatively few changes in gene expression. To address possible redundancy between GATA4 and GATA6, both factors were conditionally excised. Surprisingly, combined Gata4,6 loss did not exacerbate the phenotype resulting from Gata4 loss alone. This points to the presence of an unusually robust transcriptional network in adult hepatocytes that ensures the maintenance of liver function. PMID:24367609

Acute Kidney Injury in Patients with Cirrhosis

PubMed Central

Russ, Kirk B.; Stevens, Todd M; Singal, Ashwani K.

2015-01-01

Acute kidney injury (AKI) occurs commonly in patients with advanced cirrhosis and negatively impacts pre- and post-transplant outcomes. Physiologic changes that occur in patients with decompensated cirrhosis with ascites, place these patients at high risk of AKI. The most common causes of AKI in cirrhosis include prerenal injury, acute tubular necrosis (ATN), and the hepatorenal syndrome (HRS), accounting for more than 80% of AKI in this population. Distinguishing between these causes is particularly important for prognostication and treatment. Treatment of Type 1 HRS with vasoconstrictors and albumin improves short term survival and renal function in some patients while awaiting liver transplantation. Patients with HRS who fail to respond to medical therapy or those with severe renal failure of other etiology may require renal replacement therapy. Simultaneous liver kidney transplant (SLK) is needed in many of these patients to improve their post-transplant outcomes. However, the criteria to select patients who would benefit from SLK transplantation are based on consensus and lack strong evidence to support them. In this regard, novel serum and/or urinary biomarkers such as neutrophil gelatinase-associated lipocalin, interleukins-6 and 18, kidney injury molecule-1, fatty acid binding protein, and endothelin-1 are emerging with a potential for accurately differentiating common causes of AKI. Prospective studies are needed on the use of these biomarkers to predict accurately renal function recovery after liver transplantation alone in order to optimize personalized use of SLK. PMID:26623266

Protein Expression Profile of Twenty-Week-Old Diabetic db/db and Non-Diabetic Mice Livers: A Proteomic and Bioinformatic Analysis.

PubMed

Guzmán-Flores, Juan Manuel; Flores-Pérez, Elsa Cristina; Hernández-Ortiz, Magdalena; Vargas-Ortiz, Katya; Ramírez-Emiliano, Joel; Encarnación-Guevara, Sergio; Pérez-Vázquez, Victoriano

2018-06-01

Type 2 diabetes mellitus is characterized by insulin resistance in the liver. Insulin is not only involved in carbohydrate metabolism, it also regulates protein synthesis. This work describes the expression of proteins in the liver of a diabetic mouse and identifies the metabolic pathways involved. Twenty-week-old diabetic db/db mice were hepatectomized, after which proteins were separated by 2D-Polyacrylamide Gel Electrophoresis (2D-PAGE). Spots varying in intensity were analyzed using mass spectrometry, and biological function was assigned by the Database for Annotation, Visualization and Integrated Discovery (DAVID) software. A differential expression of 26 proteins was identified; among these were arginase-1, pyruvate carboxylase, peroxiredoxin-1, regucalcin, and sorbitol dehydrogenase. Bioinformatics analysis indicated that many of these proteins are mitochondrial and participate in metabolic pathways, such as the citrate cycle, the fructose and mannose metabolism, and glycolysis or gluconeogenesis. In addition, these proteins are related to oxidation⁻reduction reactions and molecular function of vitamin binding and amino acid metabolism. In conclusion, the proteomic profile of the liver of diabetic mouse db/db exhibited mainly alterations in the metabolism of carbohydrates and nitrogen. These differences illustrate the heterogeneity of diabetes in its different stages and under different conditions and highlights the need to improve treatments for this disease.

Berberine attenuates oxidative stress and hepatocytes apoptosis via protecting mitochondria in blunt snout bream Megalobrama amblycephala fed high-fat diets.

PubMed

Lu, Kang-Le; Wang, Li-Na; Zhang, Ding-Dong; Liu, Wen-Bin; Xu, Wei-Na

2017-02-01

High-fat diets may have favorable effects on growth and cost, but high-fat diets often induce excessive fat deposition, resulting in liver damage. This study aimed to identify the hepatoprotective of a Chinese herb (berberine) for blunt snout bream (Megalobrama amblycephala). Fish were fed with a normal diet (LFD, 5 % fat), high-fat diet (HFD, 15 % fat) or berberine-supplemented diets (BSD, 15 % fat with berberine 50 or 100 mg/kg level) for 8 weeks. After the feeding, histology, oxidative status and mitochondrial function of liver were assessed. The results showed that HFD caused fat accumulation, oxidative stress and apoptosis in hepatocytes of fish. Hepatocytes in HFD group appeared to be hypertrophied, with larger liver cells diameter than these of LFD group. Berberine-supplemented diets could attenuate oxidative stress and hepatocytes apoptosis. HFD induced the decreasing mitochondrial complexes activities and bulk density and surface area density. Berberine improved function of mitochondrial respiratory chain via increasing the complex activities. Moreover, the histological results showed that berberine has the potential to repair mitochondrial ultrastructural damage and elevate the density in cells. In conclusion, our study demonstrated that berberine has attenuated liver damage induced by the high fat mainly via the protection for mitochondria.

Necroptosis: an emerging type of cell death in liver diseases.

PubMed

Saeed, Waqar Khalid; Jun, Dae Won

2014-09-21

Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ's physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ's physiological function can be prevented.

Hepato- and neuro-protective influences of biopropolis on thioacetamide-induced acute hepatic encephalopathy in rats.

PubMed

Mostafa, Rasha E; Salama, Abeer A A; Abdel-Rahman, Rehab F; Ogaly, Hanan A

2017-05-01

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that ultimately occurs as a complication of acute or chronic liver failure; accompanied by hyperammonemia. This study aimed to evaluate the potential of biopropolis as a hepato- and neuro-protective agent using thioacetamide (TAA)-induced acute HE in rats as a model. Sixty Wistar rats were divided into 5 groups: Group 1 (normal control) received only saline and paraffin oil. Group 2 (hepatotoxic control) received TAA (300 mg/kg, once). Groups 3, 4, and 5 received TAA followed by vitamin E (100 mg/kg) and biopropolis (100 and 200 mg/kg), respectively, daily for 30 days. Evidences of HE were clearly detected in TAA-hepatotoxic group including significant elevation in the serum level of ammonia, liver functions, increased oxidative stress in liver and brain, apoptotic DNA fragmentation and overexpression of iNOS gene in brain tissue. The findings for groups administered biopropolis, highlighted its efficacy as a hepato- and neuro-protectant through improving the liver functions, oxidative status and DNA fragmentation as well as suppressing the brain expression of iNOS gene. In conclusion, biopropolis, at a dose of 200 mg/kg per day protected against TAA-induced HE through its antioxidant and antiapoptotic influence; therefore, it can be used as a protective natural product.

Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety

PubMed Central

Welker, Martin-Walter; Trojan, Joerg

2013-01-01

Hepatocellular carcinoma (HCC) is a severe complication of advanced liver disease with a worldwide incidence of more than 600,000 patients per year. Liver function, clinical performance status, and tumor size are considered in the Barcelona Clinic Liver Cancer (BCLC) system. While curative treatment options are available for early stages, most patients present with intermediate- or advanced-stage HCC, burdened with a poor prognosis, substantially influenced by the degree of liver-function impairment. Hypervascularization is a major characteristic of HCC, and antiangiogenic treatments are the basis of treatment in noncurative stages, including interventional and pharmacological treatments. Currently, the tyrosine-kinase inhibitor sorafenib is still the only approved drug for HCC. Further improvements in survival in patients with intermediate- and advanced-stage HCC may be anticipated by both multimodal approaches, such as combination of interventional and systemic treatments, and new systemic treatment options. Until now, the Phase III development of other tyrosine-kinase inhibitors in patients with advanced HCC has failed due to minor efficacy and/or increased toxicity compared to sorafenib. However, promising Phase II data have been reported with MET inhibitors in this hard-to-treat population. This review gives a critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC, with a special focus on safety. PMID:24204170

Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction.

PubMed

Wang, Wei-Wei; Zhang, Yu; Huang, Xiao-Bing; You, Nan; Zheng, Lu; Li, Jing

2017-10-14

To investigate whether fecal microbiota transplantation (FMT) prevents hepatic encephalopathy (HE) in rats with carbon tetrachloride (CCl 4 )-induced acute hepatic dysfunction. A rat model of HE was established with CCl 4 . Rat behaviors and spatial learning capability were observed, and hepatic necrosis, intestinal mucosal barrier, serum ammonia levels and intestinal permeability were determined in HE rats receiving FMT treatment. Furthermore, the expression of tight junction proteins (Claudin-1, Claudin-6 and Occludin), Toll-like receptor (TLR) 4/TLR9, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α was examined. FMT improved rat behaviors, HE grade and spatial learning capability. Moreover, FMT prevented hepatic necrosis and intestinal mucosal barrier damage, leading to hepatic clearance of serum ammonia levels and reduced intestinal permeability. The expression of TLR4 and TLR9, two potent mediators of inflammatory response, was significantly downregulated in the liver of rats treated with FMT. Consistently, circulating pro-inflammatory factors such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α were remarkably decreased, indicating that FMT is able to limit systemic inflammation by decreasing the expression of TLR4 and TLR9. Importantly, HE-induced loss of tight junction proteins (Claudin-1, Claudin-6 and Occludin) was restored in intestinal tissues of rats receiving FMT treatment. FMT enables protective effects in HE rats, and it improves the cognitive function and reduces the liver function indexes. FMT may cure HE by altering the intestinal permeability and improving the TLR response of the liver.

Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition.

PubMed

Huang, Jiansheng; Schriefer, Andrew E; Yang, Wei; Cliften, Paul F; Rudnick, David A

2014-11-01

Liver regeneration has been well studied with hope of discovering strategies to improve liver disease outcomes. Nevertheless, the signals that initiate such regeneration remain incompletely defined, and translation of mechanism-based pro-regenerative interventions into new treatments for hepatic diseases has not yet been achieved. We previously reported the isoform-specific regulation and essential function of zinc-dependent histone deacetylases (Zn-HDACs) during mouse liver regeneration. Those data suggest that epigenetically regulated anti-proliferative genes are deacetylated and transcriptionally suppressed by Zn-HDAC activity or that pro-regenerative factors are acetylated and induced by such activity in response to partial hepatectomy (PH). To investigate these possibilities, we conducted genome-wide interrogation of the liver histone acetylome during early PH-induced liver regeneration in mice using acetyL-histone chromatin immunoprecipitation and next generation DNA sequencing. We also compared the findings of that study to those seen during the impaired regenerative response that occurs with Zn-HDAC inhibition. The results reveal an epigenetic signature of early liver regeneration that includes both hyperacetylation of pro-regenerative factors and deacetylation of anti-proliferative and pro-apoptotic genes. Our data also show that administration of an anti-regenerative regimen of the Zn-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) not only disrupts gene-specific pro-regenerative changes in liver histone deacetylation but also reverses PH-induced effects on histone hyperacetylation. Taken together, these studies offer new insight into and suggest novel hypotheses about the epigenetic mechanisms that regulate liver regeneration.

Five-Year Follow-Up on Transplanted Organs From Donors After Brain Death After Acute Stroke.

PubMed

Spatenkova, Vera; Pokorna, Eva; Suchomel, Petr

2017-08-01

Efficient intensive care donor management can help alleviate the shortage of organs for transplant. The aim of this study was to investigate the efficiency of management of donors after brain death from our neurointensive care unit. We conducted a prospective observational 5-year follow-up on 29 transplanted organs from 14 brain-dead donors after acute stroke (7 subarachnoid and 4 intracerebral hemorrhages, 3 ischemic strokes). Mean age of donors was 56.2 ± 8.70 years, and mean number of days of artificial ventilation was 5.0 ± 3.84. We transplanted 27 kidneys and 2 livers to 29 patients with mean age of 55.3 ± 9.76 years. No hearts or lungs were transplanted from these donors. Of the 27 patients who underwent kidney transplant, 21 patients (78%) lived 5 years; of those, 17 patients (63%) had functional grafts. One patient (4%) had a primary afunctional graft, and 3 patients (11%) had graft rejection (at 3, 15, and 41 mo). Six patients (22%) died after kidney transplant, with 1 patient in this group having a functional graft, 1 patient having a primary afunctional graft, and 4 patients (15%) having graft rejection (at 1, 12, 44, and 56 mo). The 2 patients with liver transplants lived 5 years with functional grafts. The 5-year follow-up showed that organs from 14 brain-dead donors improved and saved 19 lives, with 17 patients receiving kidney transplants and 2 patients receiving liver transplants. Another 7 patients had only partially improved quality of life.

One year of baclofen in 100 patients with or without cirrhosis: a French real-life experience.

PubMed

Barrault, Camille; Lison, Hortensia; Roudot-Thoraval, Françoise; Garioud, Armand; Costentin, Charlotte; Béhar, Véronique; Medmoun, Mourad; Pulwermacher, Georges; Hagège, Hervé; Cadranel, Jean-François

2017-10-01

Several studies have suggested the efficacy of baclofen in reducing alcohol consumption, leading to a temporary recommendation for use in France. Our aim was to report our experience in using baclofen in alcohol-dependant patients with or without liver cirrhosis. Consecutive patients from two liver and alcohol units were recruited over a 3-year period and received increasing doses of baclofen associated with social, psychological, and medical care. One hundred patients were treated, of whom 65 were cirrhotic. After 1 year, 86 patients were still being followed up. At a mean dosage of 40 mg/day (extremes: 30-210), the median daily alcohol consumption reduced from 80 to 0 g/day (P<0.001). Twenty patients drank a small amount of alcohol of up to 30 g/day and 44 patients were completely abstinent. These declarative results were associated with a significant improvement in alcohol-related biological markers in this 'low-consumption' group of 64 patients: the median γ-glutamyl transferase decreased from 3.9 to 2.0 UNL (P<0.001), the mean aspartate transaminase decreased from 2.6 to 1.2 UNL (P<0.001), and the mean corpuscular volume decreased from 101 to 93 µm (P<0.001). In cirrhotic patients, bilirubinemia decreased significantly from 22 to 11 µmol/l (P=0.026), prothrombin time increased from 68 to 77% (P<0.001), and albuminemia increased from 34.1 to 37.4 g/l (P<0.001). Twenty patients reported grades 1-2 adverse events. No liver or renal function deterioration occurred in cirrhotic patients. In our cohort, baclofen associated with a global care was very well tolerated even in cirrhotic patients. The marked reduction in alcohol consumption in 64 patients translated into a significant improvement in biological markers and in liver function tests. Baclofen could be very useful, especially in cases of severe alcoholic liver disease.

Functional hepatocyte clusters on bioactive blend silk matrices towards generating bioartificial liver constructs.

PubMed

Janani, G; Nandi, Samit K; Mandal, Biman B

2018-02-01

The creation of in vitro functional hepatic tissue simulating micro-environmental niche of native liver is a keen area of research due to its demand in bioartificial liver (BAL) and cell-based tissue engineering. Here, we investigated the potential of novel blend (BA) silk scaffold fabricated by blending mulberry (Bombyx mori, BM) silk fibroin with cell adhesion motif (RGD) rich non-mulberry (Antheraea assamensis, AA) silk fibroin, in generating a functional liver construct. Three-dimensional (3D) porous silk scaffolds (BM, AA and BA) were physico-chemically characterized and functionally evaluated using human hepatocarcinoma cells (HepG2) and primary neonatal rat hepatocytes. The growth and distribution of hepatocytes within the scaffolds were tracked by FESEM, alamar blue proliferation assay and live/dead staining. Hemocompatible BA scaffolds supported the formation of high density hepatocyte clusters, facilitating cell-matrix and cell-cell interactions. Blend scaffolds evinced enhanced liver-specific functions of cultured hepatocytes in terms of albumin synthesis, urea synthesis and cytochrome P450 enzyme activity over 21 days. Subcutaneous implantation of scaffolds demonstrated minimal macrophage infiltration in blend scaffolds. These findings substantiate that the integral property of blend (BA) scaffold offers a befitting environment by influencing spheroidal growth of hepatocytes with enhanced biological activity. Collectively, the present study provides a new 3D bio-matrix niche for growing functional liver cells that would have future prospects in BAL as well as regenerative medicine. An end stage liver disease called cirrhosis perturbs the self-healing ability and physiological functions of liver. Due to the scarcity of healthy donors, a functional in vitro hepatic construct retaining the liver-specific functions is in great demand for its prospects in bioartificial liver (BAL) and cell-based tissue engineering. Physicochemical attributes of a matrix influence the behavior of cultured hepatocytes in terms of attachment, morphology and functionality. Mulberry and non-mulberry silk fibroin presents unique amino acid sequence with difference in hydrophobicity and crystallinity. Considering this, the present study focuses on the development of a suitable three-dimensional (3D) bioactive matrix incorporating both mulberry silk fibroin and cell adhesion motif (RGD) rich non-mulberry silk fibroin. Porous silk blend scaffolds facilitated the formation of hepatocyte clusters with enhanced liver-specific functions emphasizing both cell-cell and cell-matrix interactions. Hemocompatibility and integral property of blend scaffolds offers a biological niche for seeding functional liver cells that would have future prospects in biohybrid devices. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis.

PubMed

Forsyth, Christopher B; Farhadi, Ashkan; Jakate, Shriram M; Tang, Yueming; Shaikh, Maliha; Keshavarzian, Ali

2009-03-01

Because only 30% of alcoholics develop alcoholic liver disease (ALD), a factor other than heavy alcohol consumption must be involved in the development of alcohol-induced liver injury. Animal and human studies suggest that bacterial products, such as endotoxins, are the second key co-factors, and oxidant-mediated gut leakiness is one of the sources of endotoxemia. Probiotics have been used to prevent and treat diseases associated with gut-derived bacterial products and disorders associated with gut leakiness. Indeed, "probiotic"Lactobacillus rhamnosus has been successfully used to treat alcohol-induced liver injury in rats. However, the mechanism of action involved in the potential beneficial effects of L. rhamnosus in alcohol liver injury is not known. We hypothesized that probiotics could preserve normal barrier function in an animal model of ALD by preventing alcohol-induced oxidative stress and thus prevent the development of hyperpermeability and subsequent alcoholic steatohepatitis (ASH). Male Sprague-Dawley rats were gavaged with alcohol twice daily (8 gm/kg) for 10 weeks. In addition, alcoholic rats were also treated with once daily gavage of either 2.5 x 10(7) live L. rhamnosus Gorbach-Goldin (LGG) or vehicle (V). Intestinal permeability (baseline and at 10 weeks) was determined using a sugar bolus and GC analysis of urinary sugars. Intestinal and liver tissues were analyzed for markers of oxidative stress and inflammation. In addition, livers were assessed histologically for severity of ASH and total fat (steatosis). Alcohol+LGG (ALC+LGG)-fed rats had significantly (P< or =.05) less severe ASH than ALC+V-fed rats. L. rhamnosus Gorbach-Goldin also reduced alcohol-induced gut leakiness and significantly blunted alcohol-induced oxidative stress and inflammation in both intestine and the liver. L. rhamnosus Gorbach-Goldin probiotic gavage significantly ameliorated ASH in rats. This improvement was associated with reduced markers of intestinal and liver oxidative stress and inflammation and preserved gut barrier function. Our study provides a scientific rationale to test probiotics for treatment and/or prevention of alcoholic liver disease in man.

Benign Liver Tumors

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Dan-gua fang improves glycolipid metabolic disorders by promoting hepatic adenosine 5'-monophosphate activated protein kinase expression in diabetic Goto-Kakizaki rats.

PubMed

Lan, Yuan-long; Huang, Su-ping; Heng, Xian-pei; Chen, Ling; Li, Peng-hui; Wu, Jing; Yang, Liu-qing; Pan, Xu-dong; Lin, Tong; Cheng, Xin-ling; Lin, Qing; Chen, Si-xin

2015-03-01

To investigate the effect of Dan-gua Fang on adenosine 5'-monophosphate (AMP) activated protein kinase (AMPK) α expression in liver and subsequent improvement of glucose and lipid metabolism. Forty 13-week-old diabetic Goto-Kakizaki (GK) rats were randomly divided into model, Dan-gua Fang, metformin and simvastatin groups (n=10 for each), and fed high-fat diet ad libitum. Ten Wistar rats were used as normal group and fed normal diet. After 24 weeks, liver expression of AMPKα mRNA was assessed by real-time PCR. AMPKα and phospho-AMPKα protein expression in liver was evaluated by Western blot. Liver histomorphology was carried out after hematoxylin-eosin staining, and blood glucose (BG), glycosylated hemoglobin A1c (HbA1c), food intake and body weight recorded. Similar AMPKα mRNA levels were found in the Dan-gua Fang group and normal group, slightly higher than the values obtained for the remaining groups (P<0.05). AMPKα protein expression in the Dan-gua Fang group animals was similar to other diabetic rats, whereas phospho-AMPKα (Thr-172) protein levels were markedly higher than in the metformin group and simvastatin group (P<0.05), respectively. However, phosphor-AMPKα/AMPKα ratios were similar in all groups. Dan-gua Fang reduced fasting blood glucose with similar strength to metformin, and was superior in reducing cholesterol, triglycerides, high-density lipoprotein cholesterol as well as improving low-density lipoprotein cholesterol in comparison with simvastatin and metformin. Dan-gua Fang decreases plasma alanine aminotransferase (ALT) significantly. Dan-gua Fang, while treating phlegm-stasis, could decrease BG and lipid in type 2 diabetic GK rats fed with high-fat diet, and effectively protect liver histomorphology and function. This may be partly explained by increased AMPK expression in liver. Therefore, Dan-gua Fang might be an ideal drug for comprehensive intervention for glucose and lipid metabolism disorders in type 2 diabetes mellitus.

Echocardiography and NAFLD (non-alcoholic fatty liver disease).

PubMed

Trovato, Francesca M; Martines, Giuseppe F; Catalano, Daniela; Musumeci, Giuseppe; Pirri, Clara; Trovato, Guglielmo M

2016-10-15

Non-alcoholic-fatty-liver-disease (NAFLD) is associated with atherosclerosis, increased cardiovascular risks and mortality. We investigated if, independently of insulin resistance, diet, physical activity and obesity, fatty liver involvement has any relationship with echocardiographic measurements in NAFLD. 660 NAFLD and 791 non-NAFLD subjects, referred to the same out-patients medical unit for lifestyle-nutritional prescription, were studied. Congestive heart failure, myocardial infarction, malignancies, diabetes mellitus, extreme obesity, underweight-bad-nourished subjects and renal insufficiency were exclusion criteria. Liver steatosis was assessed by Ultrasound-Bright-Liver-Score (BLS), left ventricular ejection fraction (LVEF), trans-mitral E/A doppler ratio (diastolic relaxation) and left ventricular myocardial mass (LVMM/m(2)) by echocardiography. Doppler Renal artery Resistive Index (RRI), insulin resistance (HOMA) and lifestyle profile were also included in the clinical assessment. LVMM/m(2) is significantly greater in NAFLD, 101.62±34.48 vs. 88.22±25.61, p<0.0001 both in men and in women. Ejection fraction is slightly smaller only in men with NAFLD; no significant difference was observed for the E/A ratio. BMI (30.42±5.49 vs. 24.87±3.81; p<0.0001) and HOMA (2.90±1.70 vs. 1.85±1.25; p: 0.0001) were significantly greater in NAFLD patients. By Multiple-Linear-Regression, NAFLD and unhealthy dietary profile are associated also in lean non-diabetic subjects with lower systolic function, independently of BMI, dietary profile, physical activity, RRI and insulin resistance. NAFLD may be a meaningful early clue suggestive of diminishing heart function, with similar determining factors. NAFLD is amenable to management and improvement by lifestyle change counseling, addressing a dual target: reducing fatty liver, which is easily monitored by ultrasound, and, independently, maintaining a normal heart function. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Urinary Copper Elevation in a Mouse Model of Wilson's Disease Is a Regulated Process to Specifically Decrease the Hepatic Copper Load

PubMed Central

Gray, Lawrence W.; Peng, Fangyu; Molloy, Shannon A.; Pendyala, Venkata S.; Muchenditsi, Abigael; Muzik, Otto; Lee, Jaekwon; Kaplan, Jack H.; Lutsenko, Svetlana

2012-01-01

Body copper homeostasis is regulated by the liver, which removes excess copper via bile. In Wilson's disease (WD), this function is disrupted due to inactivation of the copper transporter ATP7B resulting in hepatic copper overload. High urinary copper is a diagnostic feature of WD linked to liver malfunction; the mechanism behind urinary copper elevation is not fully understood. Using Positron Emission Tomography-Computed Tomography (PET-CT) imaging of live Atp7b−/− mice at different stages of disease, a longitudinal metal analysis, and characterization of copper-binding molecules, we show that urinary copper elevation is a specific regulatory process mediated by distinct molecules. PET-CT and atomic absorption spectroscopy directly demonstrate an age-dependent decrease in the capacity of Atp7b−/− livers to accumulate copper, concomitant with an increase in urinary copper. This reciprocal relationship is specific for copper, indicating that cell necrosis is not the primary cause for the initial phase of metal elevation in the urine. Instead, the urinary copper increase is associated with the down-regulation of the copper-transporter Ctr1 in the liver and appearance of a 2 kDa Small Copper Carrier, SCC, in the urine. SCC is also elevated in the urine of the liver-specific Ctr1 −/− knockouts, which have normal ATP7B function, suggesting that SCC is a normal metabolite carrying copper in the serum. In agreement with this hypothesis, partially purified SCC-Cu competes with free copper for uptake by Ctr1. Thus, hepatic down-regulation of Ctr1 allows switching to an SCC-mediated removal of copper via kidney when liver function is impaired. These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion may contribute to an improved diagnosis and monitoring of WD. PMID:22802922

KEAP1-NRF2 COMPLEX IN ISCHEMIA-INDUCED HEPATOCELLULAR DAMAGE OF MOUSE LIVER TRANSPLANTS

PubMed Central

Ke, Bibo; Shen, Xiu-Da; Zhang, Yu; Ji, Haofeng; Gao, Feng; Yue, Shi; Kamo, Naoko; Zhai, Yuan; Yamamoto, Masayuki; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.

2015-01-01

Background The Keap1-Nrf2 signaling pathway regulates host cell defense responses against oxidative stress and maintains the cellular redox balance. Aims&Methods: We investigated the function/molecular mechanisms by which Keap1-Nrf2 complex may influence liver ischemia/reperfusion injury (IRI) in a mouse model of hepatic cold storage (20h at 4 C) followed by orthotopic liver transplantation (OLT). Results The Keap1 hepatocyte-specific knock-out (HKO) in the donor liver ameliorated post-transplant IRI, evidenced by improved hepatocellular function and OLT outcomes (Keap1HKO Keap1HKO; 100% survival), as compared with controls (WT WT; 50% survival; p<0.01). In contrast, donor liver Nrf2 deficiency exacerbated IRI in transplant recipients (Nrf2KO Nrf2KO; 40% survival). Ablation of Keap1 signaling reduced macrophage/neutrophil trafficking, pro-inflammatory cytokine programs, and hepatocellular necrosis/apoptosis, while simultaneously promoting anti-apoptotic functions in OLTs. At the molecular level, Keap1HKO increased Nrf2 levels, stimulated Akt phosphorylation, and enhanced expression of anti-oxidant Trx1, HIF-1 , and HO-1. Pretreatment of liver donors with PI3K inhibitor (LY294002) disrupted Akt/HIF-1 signaling and recreated hepatocellular damage in otherwise IR-resistant Keap1HKO transplants. In parallel in vitro studies, hydrogen peroxide-stressed Keap1-deficient hepatocytes were characterized by enhanced expression of Nrf2, Trx1, and Akt phosphorylation, in association with decreased release of lactate dehydrogenase (LDH) in cell culture supernatants. Conclusions Keap1-Nrf2 complex prevents oxidative injury in IR-stressed OLTs through Keap1 signaling, which negatively regulates Nrf2 pathway. Activation of Nrf2 induces Trx1 and promotes PI3K/Akt, crucial for HIF-1 activity. HIF-1 -mediated overexpression of HO-1/CyclinD1 facilitates cytoprotection by limiting hepatic inflammatory responses, and hepatocellular necrosis/apoptosis in PI3K-dependent manner. PMID:23867319

Ad Integrum Functional and Volumetric Recovery in Right Lobe Living Donors: Is It Really Complete 1 Year After Donor Hepatectomy?

PubMed

Duclos, J; Bhangui, P; Salloum, C; Andreani, P; Saliba, F; Ichai, P; Elmaleh, A; Castaing, D; Azoulay, D

2016-01-01

The partial liver's ability to regenerate both as a graft and remnant justifies right lobe (RL) living donor liver transplantation. We studied (using biochemical and radiological parameters) the rate, extent of, and predictors of functional and volumetric recovery of the remnant left liver (RLL) during the first year in 91 consecutive RL donors. Recovery of normal liver function (prothrombin time [PT] ≥70% of normal and total bilirubin [TB] ≤20 µmol/L), liver volumetric recovery, and percentage RLL growth were analyzed. Normal liver function was regained by postoperative day's 7, 30, and 365 in 52%, 86%, and 96% donors, respectively. Similarly, mean liver volumetric recovery was 64%, 71%, and 85%; whereas the percentage liver growth was 85%, 105%, and 146%, respectively. Preoperative PT value (p = 0.01), RLL/total liver volume (TLV) ratio (p = 0.03), middle hepatic vein harvesting (p = 0.02), and postoperative peak TB (p < 0.01) were predictors of early functional recovery, whereas donor age (p = 0.03), RLL/TLV ratio (p = 0.004), and TLV/ body weight ratio (p = 0.02) predicted early volumetric recuperation. One-year post-RL donor hepatectomy, though functional recovery occurs in almost all (96%), donors had incomplete restoration (85%) of preoperative total liver volume. Modifiable predictors of regeneration could help in better and safer donor selection, while continuing to ensure successful recipient outcomes. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Platelet aggregation but not activation and degranulation during the acute post-ischemic reperfusion phase in livers with no underlying disease

PubMed Central

van Golen, Rowan F.; Stevens, Katarzyna M.; Colarusso, Pina; Jaeschke, Hartmut; Heger, Michal

2016-01-01

Background Platelets and P-selectin (CD62P) play an unequivocal role in the pathology of hepatic ischemia/reperfusion (I/R) injury. Inhibition or knock-out of P-selectin or immunodepletion of platelets results in amelioration of post-ischemic inflammation, reduced hepatocellular damage, and improved survival. However, P-selectin expression on platelets and endothelial cells, which concurs with platelet activation, has never been clearly demonstrated in I/R-subjected livers. Aims To determine whether platelets become activated and degranulate in the acute phase of liver I/R and whether the platelets interact with neutrophils. Methods Hepatic I/R was induced in male C57BL/6J mice (N = 12) using 37.5-min ischemia time. Platelets, endothelial cells, and neutrophils were fluorescently labeled by systemic administration of non-blocking antibodies. Cell kinetics were monitored by intravital spinning disk confocal microscopy during 90 min of reperfusion. Image analysis and quantification was performed with dedicated software. Results Platelets adhered to sinusoids more extensively in post-ischemic livers compared to livers not subjected to I/R and formed aggregates, which occurred directly after ischemia. Platelets and endothelial cells did not express P-selectin in post-ischemic livers. There was no interaction between platelets and neutrophils. Conclusions Platelets aggregate but do not become activated and do not degranulate in post-ischemic livers. There is no platelet-neutrophil interplay during the early reperfusion phase in a moderate model of hepatic I/R injury. The mechanisms underlying the biological effects of platelets and P-selectin in this setting warrant further investigation. Relevance for patients I/R in surgical liver patients may compromise outcome due to post-ischemic oxidative stress and sterile inflammation. Both processes are mediated in part by platelets. Understanding platelet function during I/R is key to developing effective interventions for I/R injury and improving clinical outcomes. PMID:26925465

Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier.

PubMed

Zhou, Da; Pan, Qin; Xin, Feng-Zhi; Zhang, Rui-Nan; He, Chong-Xin; Chen, Guang-Yu; Liu, Chang; Chen, Yuan-Wen; Fan, Jian-Gao

2017-01-07

To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the internal mechanisms. Male C57BL/6J mice were divided into three groups, normal control were fed standard chow and model group were fed a high-fat diet (HFD) for 16 wk, the intervention group were fed HFD for 16 wk and treated with NaB for 8 wk. Gut microbiota from each group were detected at baseline and at 16 wk, liver histology were evaluated and gastrointestinal barrier indicator such as zonula occluden-1 (ZO-1) were detected by immunohistochemistry and realtime-PCR, further serum or liver endotoxin were determined by ELISA and inflammation- or metabolism-associated genes were quantified by real-time PCR. NaB corrected the HFD-induced gut microbiota imbalance in mice, while it considerably elevated the abundances of the beneficial bacteria Christensenellaceae , Blautia and Lactobacillus . These bacteria can produce butyric acid in what seems like a virtuous circle. And butyrate restored HFD induced intestinal mucosa damage, increased the expression of ZO-1 in small intestine, further decreased the levels of gut endotoxin in serum and liver compared with HF group. Endotoxin-associated genes such as TLR4 and Myd88, pro-inflammation genes such as MCP-1, TNF-α, IL-1, IL-2, IL-6 and IFN-γ in liver or epididymal fat were obviously downregulated after NaB intervention. Liver inflammation and fat accumulation were ameliorated, the levels of TG and cholesterol in liver were decreased after NaB intervention, NAS score was significantly decreased, metabolic indices such as FBG and HOMA-IR and liver function indicators ALT and AST were improved compared with HF group. NaB may restore the dysbiosis of gut microbiota to attenuate steatohepatitis, which is suggested to be a potential gut microbiota modulator and therapeutic substance for NAFLD.

Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C.

PubMed

Mauro, Ezequiel; Crespo, Gonzalo; Montironi, Carla; Londoño, Maria-Carlota; Hernández-Gea, Virginia; Ruiz, Pablo; Sastre, Lydia; Lombardo, Julissa; Mariño, Zoe; Díaz, Alba; Colmenero, Jordi; Rimola, Antoni; Garcia-Pagán, Juan Carlos; Brunet, Mercé; Forns, Xavier; Navasa, Miquel

2018-05-01

Sustained virological response (SVR) improves survival in post-liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post-SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after-SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus-infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post-SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty-seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%-85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post-SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post-SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). In conclusion, SVR post-LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683-1694). © 2017 by the American Association for the Study of Liver Diseases.

Primary biliary cirrhosis

MedlinePlus

... stools Itching Poor appetite and weight loss As liver function worsens, symptoms may include: Fluid buildup in the ... your liver is working properly: Albumin blood test Liver function tests (serum alkaline phosphatase is most important) Prothrombin ...

Bioengineered transplantable porcine livers with re-endothelialized vasculature.

PubMed

Ko, In Kap; Peng, Li; Peloso, Andrea; Smith, Charesa J; Dhal, Abritee; Deegan, Daniel B; Zimmerman, Cindy; Clouse, Cara; Zhao, Weixin; Shupe, Thomas D; Soker, Shay; Yoo, James J; Atala, Anthony

2015-02-01

Donor shortage remains a continued challenge in liver transplantation. Recent advances in tissue engineering have provided the possibility of creating functional liver tissues as an alternative to donor organ transplantation. Small bioengineered liver constructs have been developed, however a major challenge in achieving functional bioengineered liver in vivo is the establishment of a functional vasculature within the scaffolds. Our overall goal is to bioengineer intact livers, suitable for transplantation, using acellular porcine liver scaffolds. We developed an effective method for reestablishing the vascular network within decellularized liver scaffolds by conjugating anti-endothelial cell antibodies to maximize coverage of the vessel walls with endothelial cells. This procedure resulted in uniform endothelial attachment throughout the liver vasculature extending to the capillary bed of the liver scaffold and greatly reduced platelet adhesion upon blood perfusion in vitro. The re-endothelialized livers, when transplanted to recipient pigs, were able to withstand physiological blood flow and maintained for up to 24 h. This study demonstrates, for the first time, that vascularized bioengineered livers, of clinically relevant size, can be transplanted and maintained in vivo, and represents the first step towards generating engineered livers for transplantation to patients with end-stage liver failure. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nivolumab as salvage treatment in a patient with HIV-related relapsed/refractory Hodgkin lymphoma and liver failure with encephalopathy.

PubMed

Sandoval-Sus, Jose D; Mogollon-Duffo, Francis; Patel, Ankita; Visweshwar, Nathan; Laber, Damian A; Kim, Richard; Jagal, Michael V

2017-01-01

We report the first case to our knowledge of a patient with relapsed/refractory classical hodgkin lymphoma and liver failure with encephalopathy along with human immunodeficiency virus/acquired immunodeficiency syndrome infection, successfully treated with nivolumab without major side effects and encouraging prolonged disease control. In December 2015, at the time of the patient's progression from his Hodgkin lymphoma after fourth line treatment, he developed persistent fevers, abdominal distension, jaundice and worsening of his liver function tests. Magnetic resonance imaging of abdomen/pelvis demonstrated hepatomegaly with innumerable new liver lesions, splenomegaly with multiple splenic nodules and several new mediastinal, intraperitoneal and retroperitoneal lymphadenopathy. In accordance with the patient's wishes before admission, and after agreement with the family, nivolumab (3 mg/kg every 2 weeks) was given. Of note, antiretroviral therapy was on hold due to liver function tests, his viral load was undectable and cluster of differentiation 4 counts were 103/uL at the time of nivolumab administration. One week after the first dose of nivolumab both his hepatic encephalopathy and constitutional symptoms started to improve, and after 2 doses, (January 2016) his LFTs were almost back to normal. After 5 months of nivolumab treatment (10 doses), restaging (computerized tomography scans of neck, chest, abdomen, pelvis) done on May 2016 showed resolution of hepatosplenomegaly with two residual small hepatic lesions, heterogeneous spleen with no splenic lesions, and stable non-enlarged retroperitoneal lymph nodes without intraabdominal lymphadenopathy; consistent with partial response. We report a case of a patient with human immunodeficiency virus/acquired immunodeficiency syndrome -related relapsed/refractory classical Hodgkin lymphoma and acute liver failure with encephalopathy successfully treated with nivolumab after failing all standard therapeutic options. Unlike classic cytotoxic chemotherapy, which relies on preserved organ function to ameliorate potential severe side effects (i.e. myelosuppression), elimination of monoclonal antibodies is fairly independent of baseline renal and hepatic function since they are usually metabolized by circulating phagocytes and/or by their target antigen-expressing cell.

Postoperative Decrease in Platelet Counts Is Associated with Delayed Liver Function Recovery and Complications after Partial Hepatectomy.

PubMed

Takahashi, Kazuhiro; Kurokawa, Tomohiro; Oshiro, Yukio; Fukunaga, Kiyoshi; Sakashita, Shingo; Ohkohchi, Nobuhiro

2016-05-01

Peripheral platelet counts decrease after partial hepatectomy; however, the implications of this phenomenon are unclear. We assessed if the observed decrease in platelet counts was associated with postoperative liver function and morbidity (complications grade ≤ II according to the Clavien-Dindo classification). We enrolled 216 consecutive patients who underwent partial hepatectomy for primary liver cancers, metastatic liver cancers, benign tumors, and donor hepatectomy. We classified patients as either low or high platelet percentage (postoperative platelet count/preoperative platelet count) using the optimal cutoff value calculated by a receiver operating characteristic (ROC) curve analysis, and analyzed risk factors for delayed liver functional recovery and morbidity after hepatectomy. Delayed liver function recovery and morbidity were significantly correlated with the lowest value of platelet percentage based on ROC analysis. Using a cutoff value of 60% acquired by ROC analysis, univariate and multivariate analysis determined that postoperative lowest platelet percentage ≤ 60% was identified as an independent risk factor of delayed liver function recovery (odds ratio (OR) 6.85; P < 0.01) and morbidity (OR, 4.90; P < 0.01). Furthermore, patients with the lowest platelet percentage ≤ 60% had decreased postoperative prothrombin time ratio and serum albumin level and increased serum bilirubin level when compared with patients with platelet percentage ≥ 61%. A greater than 40% decrease in platelet count after partial hepatectomy was an independent risk factor for delayed liver function recovery and postoperative morbidity. In conclusion, the decrease in platelet counts is an early marker to predict the liver function recovery and complications after hepatectomy.

Physiological Ranges of Matrix Rigidity Modulate Primary Mouse Hepatocyte Function In Part Through Hepatocyte Nuclear Factor 4 Alpha

PubMed Central

Desai, Seema S.; Tung, Jason C.; Zhou, Vivian X.; Grenert, James P.; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M.; Chang, Tammy T.

2016-01-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of hepatic-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150Pa and increased to 1–6kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α) whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase (FAK). In addition, blockade of the Rho/Rho-associated protein kinase (ROCK) pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Conclusion Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/ROCK pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. PMID:26755329

Progression of Liver Disease

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Design of liver functional reserve monitor based on three-wavelength from IR to NIR.

PubMed

Ye, Fuli; Zhan, Huimiao; Shi, Guilian

2018-05-04

The preoperative evaluation of liver functional reserve is very important to determine the excision of liver lobe for the patients with liver cancer. There already exist many effective evaluation methods, but these ones have many disadvantages such as large trauma, complicated process and so on. Therefore, it is essential to develop a fast, accurate and simple detection method of liver functional reserve for the practical application in the clinical engineering field. According to the principle of spectrophotometry, this paper proposes a detection method of liver functional reserve based on three-wavelength from infrared light (IR) to near-infrared light (NIR), in which the artery pulse, the vein pulse and the move of tissue are taken into account. By using near-infrared photoelectric sensor technology and excreting experiment of indocyanine green, a minimally invasive, fast and simple testing equipment is designed in this paper. The testing result shows this equipment can greatly reduce the interference from human body and ambient, realize continuous and real-time detection of arterial degree of blood oxygen saturation and liver functional reserve.

Functions of autophagy in normal and diseased liver

PubMed Central

Czaja, Mark J.; Ding, Wen-Xing; Donohue, Terrence M.; Friedman, Scott L.; Kim, Jae-Sung; Komatsu, Masaaki; Lemasters, John J.; Lemoine, Antoinette; Lin, Jiandie D.; Ou, Jing-hsiung James; Perlmutter, David H.; Randall, Glenn; Ray, Ratna B.; Tsung, Allan; Yin, Xiao-Ming

2013-01-01

Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases. PMID:23774882

Weight loss and severe jaundice in a patient with hyperthyroidism.

PubMed

Breidert, M; Offensperger, S; Blum, H E; Fischer, R

2011-09-01

Thyrotoxicosis may significantly alter hepatic function and is associated with autoimmune disorders of the liver. We report the case of a thyrotoxic patient with Graves' disease and histologically established cholestatic hepatitis. Medical treatment of hyperthyroidism normalized liver function tests. In patients with elevated liver function parameters and jaundice of unknown origin, thyroid function should generally be tested. Moreover, medical treatment of hyperthyroidism with thyrostatics may cause severe hepatitis whereas untreated hyperthyroid patients are at risk of developing chronic liver failure. © Georg Thieme Verlag KG Stuttgart · New York.

HEPATIC FUNCTION AFTER GENETICALLY-ENGINEERED PIG LIVER TRANSPLANTATION IN BABOONS

PubMed Central

Ekser, Burcin; Echeverri, Gabriel J.; Hassett, Andrea Cortese; Yazer, Mark H.; Long, Cassandra; Meyer, Michael; Ezzelarab, Mohamed; Lin, Chih Che; Hara, Hidetaka; van der Windt, Dirk J.; Dons, Eefje M.; Phelps, Carol; Ayares, David; Cooper, David K.C.; Gridelli, Bruno

2010-01-01

Background If ‘bridging’ to allotransplantation is to be achieved by a pig liver xenograft, adequate hepatic function needs to be assured. Methods We have studied hepatic function in baboons after transplantation of livers from α1,3-galactosyltransferase gene-knockout (GTKO,n=1) or GTKO pigs transgenic for CD46 (GTKO/CD46,n=5). Monitoring was by liver function tests and coagulation parameters. Pig-specific proteins in the baboon serum/plasma were identified by Western blot. In 4 baboons, coagulation factors were measured. The results were compared with values from healthy humans, baboons, and pigs. Results Recipient baboons died or were euthanized after 4-7 days following internal bleeding associated with profound thrombocytopenia. However, parameters of liver function, including coagulation, remained in the near-normal range, except for some cholestasis. Western blot demonstrated that pig proteins (albumin, fibrinogen, haptoglobin, plasminogen) were produced by the liver from day 1. Production of several pig coagulation factors was confirmed. Conclusions After the transplantation of genetically-engineered pig livers into baboons (1) many parameters of hepatic function, including coagulation, were normal or near-normal; (2) there was evidence for production of pig proteins, including coagulation factors, and (3) these appeared to function adequately in baboons, though inter-species compatibility of such proteins remains to be confirmed. PMID:20606605

Enhanced hepatic insulin signaling in the livers of high altitude native rats under basal conditions and in the livers of low altitude native rats under insulin stimulation: a mechanistic study.

PubMed

Al Dera, Hussain; Eleawa, Samy M; Al-Hashem, Fahaid H; Mahzari, Moeber M; Hoja, Ibrahim; Al Khateeb, Mahmoud

2017-07-01

This study was designed to investigate the role of the liver in lowering fasting blood glucose levels (FBG) in rats native to high (HA) and low altitude (LA) areas. As compared with LA natives, besides the improved insulin and glucose tolerance, HA native rats had lower FBG, at least mediated by inhibition of hepatic gluconeogenesis and activation of glycogen synthesis. An effect that is mediated by the enhancement of hepatic insulin signaling mediated by the decreased phosphorylation of TSC induced inhibition of mTOR function. Such effect was independent of activation of AMPK nor stabilization of HIF1α, but most probably due to oxidative stress induced REDD1 expression. However, under insulin stimulation, and in spite of the less activated mTOR function in HA native rats, LA native rats had higher glycogen content and reduced levels of gluconeogenic enzymes with a more enhanced insulin signaling, mainly due to higher levels of p-IRS1 (tyr612).

The hepatoprotective role of Silymarin in isoniazid induced liver damage of rabbits.

PubMed

Jahan, Sarwat; Khan, Moosa; Imran, Sana; Sair, Mohammad

2015-06-01

To evaluate the hepatoprotective role of Silymarin against isonicotinylhydrazine-induced hepatotoxicity in rabbit model. The experimental animal study was held at Jinnah Postgraduate Medical Centre, Karachi, from April to September 2013 and comprised rabbits weighing 1-1.5kgof either gender. The animals were divided randomly into equal groups: group I underwent liver function test without any drug; in group II effects of Silymarin (50mg/kg/day orally) was observed; in group III isoniazid (50mg/kg/dayorally) was administered; and in group IV combined effects of isoniazid and silymarin were observed. Liver function tests were performed at day0 and after the treatment at day19. SPSS 16 was used for statistical analysis. The 28 rabbits in the study were divided in four groups of 7(25%) each. No mortality was recorded in any group. In group III, bilirubin level was increased and alanine transaminase was decreased significantly (p<0.05 each). In group IV, there was significant improvement in serum billirubin and serum alanine transaminase (p<0.05 each). Isonicotinylhydrazine-induced hepatotoxicity was well treated by concurrent administration of Silymarin.

Systemic effects of inflammation on health during chronic HIV infection.

PubMed

Deeks, Steven G; Tracy, Russell; Douek, Daniel C

2013-10-17

Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging. Copyright © 2013 Elsevier Inc. All rights reserved.

A simple and economical route to generate functional hepatocyte-like cells from hESCs and their application in evaluating alcohol induced liver damage.

PubMed

Pal, Rajarshi; Mamidi, Murali Krishna; Das, Anjan Kumar; Gupta, Pawan Kumar; Bhonde, Ramesh

2012-01-01

The in vitro derived hepatocytes from human embryonic stem cells (hESC) is a promising tool to acquire improved knowledge of the cellular and molecular events underlying early human liver development under physiological and pathological conditions. Here we report a simple two-step protocol employing conditioned medium (CM) from human hepatocellular carcinoma cell line, HepG2 to generate functional hepatocyte-like cells from hESC. Immunocytochemistry, flow cytometry, quantitative RT-PCR, and biochemical analyses revealed that the endodermal progenitors appeared as pockets in culture, and the cascade of genes associated with the formation of definitive endoderm (HNF-3β, SOX-17, DLX-5, CXCR4) was consistent and in concurrence with the up-regulation of the markers for hepatic progenitors [alpha-feto protein (AFP), HNF-4α, CK-19, albumin, alpha-1-antitrypsin (AAT)], followed by maturation into functional hepatocytes [tyrosine transferase (TAT), tryptophan-2, 3-dioxygenase (TDO), glucose 6-phosphate (G6P), CYP3A4, CYP7A1]. We witnessed that the gene expression profile during this differentiation process recapitulated in vivo liver development demonstrating a gradual down-regulation of extra embryonic endodermal markers (SOX-7, HNF-1β, SNAIL-1, LAMININ-1, CDX2), and the generated hepatic cells performed multiple liver functions. Since prenatal alcohol exposure is known to provoke irreversible abnormalities in the fetal cells and developing tissues, we exposed in vitro generated hepatocytes to ethanol (EtOH) and found that EtOH treatment not only impairs the survival and proliferation, but also induces apoptosis and perturbs differentiation of progenitor cells into hepatocytes. This disruption was accompanied by alterations in the expression of genes and proteins involved in hepatogenesis. Our results provide new insights into the wider range of destruction caused by alcohol on the dynamic process of liver organogenesis. Copyright © 2011 Wiley Periodicals, Inc.

Liver transplantations in Bulgaria--initial experience.

PubMed

Vladov, N; Mihaylov, V; Takorov, I; Vasilevski, I; Lukanova, T; Odisseeva, E; Katzarov, K; Simonova, M; Tomova, D; Konakchieva, M; Petrov, N; Mladenov, N; Sergeev, S; Mutafchiiski, V

2014-01-01

The filed of liver transplantation (LT) continues to evolve and is highly effective therapy for many patients with acute and chronic liver failure resulting from a variety of causes. Improvement of perioperative care, surgical technique and immunosuppression in recent years has led to its transformation into a safe and routine procedure with steadily improving results. The aim of this paper is to present the initial experience of the transplant team at Military Medical Academy - Sofia, Bulgaria. For the period of April 2007 - August 2014 the team performed 38 liver transplants in 37 patients (one retransplantation). Patients were followed up prospectively and retrospectively. In 36 (95%) patients a graft from a cadaveric donor was used and in two cases--a right liver grafts from live donor. The mean MELD score of the transplanted patients was 17 (9-40). The preferred surgical technique was "piggyback" with preservation of inferior vena cava in 33 (86%) of the cases and classical technique in 3 (8%) patients. The overall complication rate was 48%. Early mortality rate was 13% (5 patients). The overall 1- and 5-year survival is 81% and 77% respectivelly. The setting of a new LT program is a complex process which requires the effort and effective colaboration of a wide range of speciacialists (hepatologists, surgeons, anesthesiologists, psychologists, therapists, coordinators, etc.) and institutions. The good results are function of a proper selection of the donors and the recipients. Living donation is an alternative in the shortage of cadaveric donors.

Role of nitric oxide and KATP channel in the protective effect mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats.

PubMed

Mohamed, Yasmin S; Ahmed, Lamiaa A; Salem, Hesham A; Agha, Azza M

2018-05-01

Liver fibrosis is one of the most serious conditions affecting patients worldwide. In the present study, the role of nitric oxide and KATP channel was investigated for the first time in the possible protection mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats. Nicorandil (3 mg/kg/day) was given orally 24 h after bile duct ligation for 14 days till the end of the experiment. Nicorandil group showed marked improvement in liver function tests, hepatic oxidative stress and inflammatory markers as well as inducible and endothelial nitric oxide synthase protein expressions. Furthermore, nicorandil administration led to significant decrement of phosphorylated protein kinase C, fibrosis and hepatic stellate cells activation as indicated by decreased alpha smooth muscle actin expression. Oral co-administration of glibenclamide (5 mg/kg/day) (a KATP channel blocker) with nicorandil mostly showed similar improvement though not reaching to that of nicorandil group. However, co-adminstration of L-NAME (15 mg/kg/day) (an inhibitor of nitric oxide synthase) completely abolished the protective effects of nicorandil and produced more or less similar results to that of untreated bile duct ligated group. In conclusion, nicorandil is an effective therapy against the development of bile duct ligation-induced liver fibrosis in rats where nitric oxide plays a more prominent role in the protective effect of nicorandil than KATP channel opening. Copyright © 2018 Elsevier Inc. All rights reserved.

[Use of fish oil lipid emulsions in hospitalized patients under 18 years old with abnormal results in liver tests associated with total parental nutrition].

PubMed

Giraldo Villa, Adriana; Henao Roldan, Catherine; García Loboguerrero, Fanny; Martínez Volkmar, María Isabel; Contreras Ramírez, Mónica María; Ruiz Navas, Patricia

2014-04-01

Prolonged Total Parental Nutrition (TPN) is associated with life-threatening complications in the pediatric population, being cholestasis one of the most important ones. The source of fatty acids, the amount of phytosterols and the dose of lipids in the nutritional support, have been linked to the development of this complication. To describe the behavior of liver function tests in pediatric patients with TPN where lipid based omega 3 fatty acids (OmegavenR) were used. A retrospective research was made in a population of children under 18 years old where omega 3 fatty acids were used for a minimum of 8 days. Patients were initially classified into two groups: cholestasis and abnormal liver tests. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), direct bilirubin (DB) gamma glutamyl transferase (GGT) and alkaline phosphatase (AP) before and after treatment with OmegavenR was evaluated. 33 patients met the inclusion criteria. At the end of treatment with OmegavenR, 82.4% of patients who initially presented cholestasis showed resolution or improvement. The group of patients with abnormal liver tests 18.8% progressed to cholestasis. Our study suggests that the use of OmegavenR in pediatric patients with TPN and DB ≥ 2 mg/dL, seem to reverse or improve cholestasis while in patients with abnormal liver tests we still don't have clear effect. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Trends in net survival from liver cancer in six European Latin countries: results from the SUDCAN population-based study.

PubMed

Ferretti, Stefano; Bossard, Nadine; Binder-Fouchard, Florence; Faivre, Jean; Bordoni, Andrea; Biavati, Patrizia; Frassoldati, Antonio

2017-01-01

Liver cancer represents a major clinical challenge. The aim of the SUDCAN collaborative study was to compare the net survival from liver cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland) and provide trends in net survival and dynamics of excess mortality rates (EMRs) up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000-2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. These trend analyses were carried out using a flexible excess-rate modeling strategy. There were little differences between the six countries in the 5-year age-standardized net survival (2000-2004): it ranged from 13% (France and Portugal) to 16% (Belgium). An increase in the net age-standardized survival was observed in all countries between 1992 and 2004, both at 1 year and at 5 years (the highest in Spain, the lowest in France). Generally, patients aged 60 years showed the highest increase. There was a progressive decrease in EMR over the 5-year- period following diagnosis. The study confirmed the poor prognosis of liver cancer. Innovative treatments might improve the prognosis as well as preventive screening of cirrhotic patients with good liver function. Efforts are also needed to improve registration practices.

Obesity-Linked Phosphorylation of SIRT1 by Casein Kinase 2 Inhibits Its Nuclear Localization and Promotes Fatty Liver.

PubMed

Choi, Sung E; Kwon, Sanghoon; Seok, Sunmi; Xiao, Zhen; Lee, Kwan-Woo; Kang, Yup; Li, Xiaoling; Shinoda, Kosaku; Kajimura, Shingo; Kemper, Byron; Kemper, Jongsook Kim

2017-08-01

Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD) and diabetes, and has received great attention as a drug target. SIRT1 function is aberrantly low in obesity, so understanding the underlying mechanisms is important for drug development. Here, we show that obesity-linked phosphorylation of SIRT1 inhibits its function and promotes pathological symptoms of NAFLD. In proteomic analysis, Ser-164 was identified as a major serine phosphorylation site in SIRT1 in obese, but not lean, mice, and this phosphorylation was catalyzed by casein kinase 2 (CK2), the levels of which were dramatically elevated in obesity. Mechanistically, phosphorylation of SIRT1 at Ser-164 substantially inhibited its nuclear localization and modestly affected its deacetylase activity. Adenovirus-mediated liver-specific expression of SIRT1 or a phosphor-defective S164A-SIRT1 mutant promoted fatty acid oxidation and ameliorated liver steatosis and glucose intolerance in diet-induced obese mice, but these beneficial effects were not observed in mice expressing a phosphor-mimic S164D-SIRT1 mutant. Remarkably, phosphorylated S164-SIRT1 and CK2 levels were also highly elevated in liver samples of NAFLD patients and correlated with disease severity. Thus, inhibition of phosphorylation of SIRT1 by CK2 may serve as a new therapeutic approach for treatment of NAFLD and other obesity-related diseases. Copyright © 2017 American Society for Microbiology.

Obesity-Linked Phosphorylation of SIRT1 by Casein Kinase 2 Inhibits Its Nuclear Localization and Promotes Fatty Liver

PubMed Central

Choi, Sung E.; Kwon, Sanghoon; Seok, Sunmi; Xiao, Zhen; Lee, Kwan-Woo; Kang, Yup; Li, Xiaoling; Shinoda, Kosaku; Kajimura, Shingo; Kemper, Byron

2017-01-01

ABSTRACT Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD) and diabetes, and has received great attention as a drug target. SIRT1 function is aberrantly low in obesity, so understanding the underlying mechanisms is important for drug development. Here, we show that obesity-linked phosphorylation of SIRT1 inhibits its function and promotes pathological symptoms of NAFLD. In proteomic analysis, Ser-164 was identified as a major serine phosphorylation site in SIRT1 in obese, but not lean, mice, and this phosphorylation was catalyzed by casein kinase 2 (CK2), the levels of which were dramatically elevated in obesity. Mechanistically, phosphorylation of SIRT1 at Ser-164 substantially inhibited its nuclear localization and modestly affected its deacetylase activity. Adenovirus-mediated liver-specific expression of SIRT1 or a phosphor-defective S164A-SIRT1 mutant promoted fatty acid oxidation and ameliorated liver steatosis and glucose intolerance in diet-induced obese mice, but these beneficial effects were not observed in mice expressing a phosphor-mimic S164D-SIRT1 mutant. Remarkably, phosphorylated S164-SIRT1 and CK2 levels were also highly elevated in liver samples of NAFLD patients and correlated with disease severity. Thus, inhibition of phosphorylation of SIRT1 by CK2 may serve as a new therapeutic approach for treatment of NAFLD and other obesity-related diseases. PMID:28533219

Liver cell therapy and tissue engineering for transplantation.

PubMed

Vacanti, Joseph P; Kulig, Katherine M

2014-06-01

Liver transplantation remains the only definitive treatment for liver failure and is available to only a tiny fraction of patients with end-stage liver diseases. Major limitations for the procedure include donor organ shortage, high cost, high level of required expertise, and long-term consequences of immune suppression. Alternative cell-based liver therapies could potentially greatly expand the number of patients provided with effective treatment. Investigative research into augmenting or replacing liver function extends into three general strategies. Bioartificial livers (BALs) are extracorporeal devices that utilize cartridges of primary hepatocytes or cell lines to process patient plasma. Injection of liver cell suspensions aims to foster organ regeneration or provide a missing metabolic function arising from a genetic defect. Tissue engineering recreates the organ in vitro for subsequent implantation to augment or replace patient liver function. Translational models and clinical trials have highlighted both the immense challenges involved and some striking examples of success. Copyright © 2014. Published by Elsevier Inc.

The phytochemical, EGCG, extends lifespan by reducing liver and kidney function damage and improving age-associated inflammation and oxidative stress in healthy rats.

PubMed

Niu, Yucun; Na, Lixin; Feng, Rennan; Gong, Liya; Zhao, Yue; Li, Qiang; Li, Ying; Sun, Changhao

2013-12-01

It is known that phytochemicals have many potential health benefits in humans. The aim of this study was to investigate the effects of long-term consumption of the phytochemical, epigallocatechin gallate (EGCG), on body growth, disease protection, and lifespan in healthy rats. 68 male weaning Wistar rats were randomly divided into the control and EGCG groups. Variables influencing lifespan such as blood pressure, serum glucose and lipids, inflammation, and oxidative stress were dynamically determined from weaning to death. The median lifespan of controls was 92.5 weeks. EGCG increased median lifespan to 105.0 weeks and delayed death by approximately 8-12 weeks. Blood pressure and serum glucose and lipids significantly increased with age in both groups compared with the levels at 0 week. However, there were no differences in these variables between the two groups during the whole lifespan. Inflammation and oxidative stress significantly increased with age in both groups compared with 0 week and were significantly lower in serum and liver and kidney tissues in the EGCG group. Damage to liver and kidney function was significantly alleviated in the EGCG group. In addition, EGCG decreased the mRNA and protein expressions of transcription factor NF-κB and increased the upstream protein expressions of silent mating type information regulation two homolog one (SIRT1) and forkhead box class O 3a (FOXO3a). In conclusion, EGCG extends lifespan in healthy rats by reducing liver and kidney damage and improving age-associated inflammation and oxidative stress through the inhibition of NF-κB signaling by activating the longevity factors FoxO3a and SIRT1. © 2013 the Anatomical Society and John Wiley & Sons Ltd.

Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat*

PubMed Central

Munkacsi, Andrew B.; Hammond, Natalie; Schneider, Remy T.; Senanayake, Dinindu S.; Higaki, Katsumi; Lagutin, Kirill; Bloor, Stephen J.; Ory, Daniel S.; Maue, Robert A.; Chen, Fannie W.; Hernandez-Ono, Antonio; Dahlson, Nicole; Repa, Joyce J.; Ginsberg, Henry N.; Ioannou, Yiannis A.; Sturley, Stephen L.

2017-01-01

Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Npc1nmf164 mice, which express a missense mutation in the Npc1 gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 μm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null (Npc1−/−) and missense (Npc1nmf164) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the Npc1 locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease. PMID:28031458

Alcoholic liver disease.

PubMed

Penny, Steven M

2013-01-01

In the United States, approximately 100,000 deaths are attributed to alcohol abuse each year. In 2009, the World Health Organization listed alcohol use as one of the leading causes of the global burden of disease and injury. Alcoholic liver disease, a direct result of chronic alcohol abuse, insidiously destroys the normal functions of the liver. The end result of the disease, cirrhosis, culminates in a dysfunctional and diffusely scarred liver. This article discusses the clinical manifestations, imaging considerations, and treatment of alcoholic liver disease and cirrhosis. Normal liver function, liver hemodynamics, the disease of alcoholism, and the deleterious effects of alcohol also are reviewed.