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 transplantation for the treatment of hyperammonemia due to urea cycle disorder: report of four cases].

PubMed

Zhu, Zhijun; Sun, Liying; Wei, Lin; Qu, Wei; Zeng, Zhigui; Liu, Ying; Zhang, Liang; He, Enhui; Wang, Dong

2015-02-01

To analyze clinical efficacy and prognosis of liver transplantation in children with hyperammonemia caused by urea cycle disorders. A retrospective analysis was performed on the occurrence of disease, operation and the follow-up post liver transplantation in 4 patients with urea cycle disorders who underwent liver transplantation during June 2001 to May 2014. Four girls were diagnosed with ornithine carbamoyl transferase deficiency by genetic test. They had the clinical onset at the age of 1.5 to 3.0 years. Liver transplantation had been performed at their age of 53.9 months, 40.6 months, 40.3 months and 22.8 months, respectively. The grafts of case 1 and case 2 were from left lateral lobe of liver of cadaveric donor, the graft of case 3 was from left lateral lobe of liver of a living donor, the graft of case 4 was a whole liver of a dead child. The liver function of 4 patients gradually returned to normal, blood ammonia levels were normal and restored the normal diet, 4 children were discharged on postoperative 25-30 days. Regular follow-up was done, the liver function, biochemical features and growth status have been followed up for 162.2 months, 124.2 months, 12.0 months and 4.8 months after liver transplantation, respectively. Now, all the four cases are healthy and growth is normal. Liver transplantation is an important way to the patients with severe hyperammonemia caused by urea cycle disorders. In this study, the patients with ornithine carbamoyl transferase defect got satisfactory long-term outcome after liver transplantation.

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.

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.

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.

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.

Measuring functioning hepatocytes using Tc-99m galactosylneoglycoalbumin (Tc-NGA)

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

Stadalnik, R.C.; Vera, D.R.; Quadro, R.E.

1984-01-01

Tc-NGA is a synthetic ligand which binds only to hepatic binding protein (HBP), a receptor found only in the liver. It exhibits the properties of high tissue specificity, affinity-dependent uptake, and dose-dependent uptake. Tc-NGA provides an opportunity to study the functioning hepatocyte. The authors evaluated the usefulness of this technique in patients with hepatitis and hepatoma. After intravenous administration of 5 mCi Tc-NGA, dynamic images were acquired for 30 minutes followed by static views. Estimates of HBP concentrations were obtained by kinetic analysis of blood and liver time-activity curves. Kinetic estimates (reduced chi-squares < 3.0) of HBP correlated well withmore » the clinical course and histology. For example, a patient with hepatoma whose calculated receptor population (functioning hepatocytes) was 3.0 +- 0.9 x 10/sup -7/ mole, which is the normal range, is doing well undergoing chemotherapy. Liver biopsy demonstrated normal liver tissue except for the hepatoma. Another patient with hepatoma who had a severely depressed receptor population, 1.2 +- 0.2 x 10/sup -8/ mole, expired one week after the study. Liver biopsy demonstrated practically no normal tissue. Thus, by means of a complementary, receptor radiopharmaceutical and mathematical model, one should be able to quantitatively follow hepatocyte function and predict response to a therapeutic regimen.« less

Multiparametric or practical quantitative liver MRI: towards millisecond, fat fraction, kilopascal and function era.

PubMed

Unal, Emre; Idilman, Ilkay Sedakat; Karçaaltıncaba, Muşturay

2017-02-01

New advances in liver magnetic resonance imaging (MRI) may enable diagnosis of unseen pathologies by conventional techniques. Normal T1 (550-620 ms for 1.5 T and 700-850 ms for 3 T), T2, T2* (>20 ms), T1rho (40-50 ms) mapping, proton density fat fraction (PDFF) (≤5%) and stiffness (2-3kPa) values can enable differentiation of a normal liver from chronic liver and diffuse diseases. Gd-EOB-DTPA can enable assessment of liver function by using postcontrast hepatobiliary phase or T1 reduction rate (normally above 60%). T1 mapping can be important for the assessment of fibrosis, amyloidosis and copper overload. T1rho mapping is promising for the assessment of liver collagen deposition. PDFF can allow objective treatment assessment in NAFLD and NASH patients. T2 and T2* are used for iron overload determination. MR fingerprinting may enable single slice acquisition and easy implementation of multiparametric MRI and follow-up of patients. Areas covered: T1, T2, T2*, PDFF and stiffness, diffusion weighted imaging, intravoxel incoherent motion imaging (ADC, D, D* and f values) and function analysis are reviewed. Expert commentary: Multiparametric MRI can enable biopsyless diagnosis and more objective staging of diffuse liver disease, cirrhosis and predisposing diseases. A comprehensive approach is needed to understand and overcome the effects of iron, fat, fibrosis, edema, inflammation and copper on MR relaxometry values in diffuse liver disease.

Liver Transplantation for Budd-Chiari Syndrome

PubMed Central

Putnam, Charles W.; Porter, Kendrick A.; Well, Richard; Reid, H. A. S.; Starzl, Thomas E.

2011-01-01

Orthotopic liver transplantation was accomplished in a 22-year-old woman dying of the Budd-Chiarl syndrome. She Is well and has normal liver function 16 months postoperatively. In view of the good early result, it will be appropriate to consider liver replacement for this disease in further well-selected cases. PMID:781334

Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves.

PubMed

Marinò, M; Morabito, E; Altea, M A; Ambrogini, E; Oliveri, F; Brunetto, M R; Pollina, L E; Campani, D; Vitti, P; Bartalena, L; Pincheral, A; Marcocci, C

2005-03-01

We report a case of acute hepatitis of autoimmune origin which occurred in a 43-yr-old woman during iv glucocorticoid (GC) pulse therapy for Graves' ophthalmopathy (GO). Prior to therapy, liver function tests were normal with no previous history of liver disorders or conditions predisposing to GC-associated liver damage. After the administration of a 4.7-g cumulative dose of methylprednisolone acetate, there was a marked increase of liver enzymes, prompting immediate discontinuation of iv GC. Nevertheless, liver enzymes increased further, reaching a peak 45 days later, with values 30- to 50-fold greater than those prior to therapy, associated with evidence of impaired liver function. Liver biopsy showed a marked lymphocytic infiltration, likely indicating an autoimmune hepatitis. Based on the assumption that following GC-induced immune suppression, autoimmune hepatitis might have been precipitated by sudden re-activation of the immune system during interpulse periods, we treated the patient with im and then oral GC, in order to re-induce immune suppression. Within three days from re-institution of GC therapy, there was a marked reduction of liver enzymes and amelioration of liver function. Complete normalization was achieved two months later, while the patient was still receiving a low maintenance dose of oral prednisone.

Fatty acid methyl esters are detectable in the plasma and their presence correlates with liver dysfunction.

PubMed

Aleryani, Samir Lutf; Cluette-Brown, Joanne E; Khan, Zia A; Hasaba, Hasan; Lopez de Heredia, Luis; Laposata, Michael

2005-09-01

Methanol is a component of certain alcoholic beverages and is also an endogenously formed product. On this basis, we have proposed that methanol may promote synthesis of fatty acid methyl esters (FAMEs) in the same way that ethanol promotes fatty acid ethyl ester (FAEE) synthesis. We tested the hypothesis that FAMEs appear in the blood after ethanol intake. Patient plasma samples obtained from our laboratory (n=78) were grouped according to blood ethanol concentrations (intoxicated, blood ethanol >800 mg/l) and non-intoxicated. These samples were further subdivided into groups based on whether the patient had normal or abnormal liver function tests (abnormal, defined as > or =1 abnormality of plasma alanine and aspartate aminotransferase, albumin, total bilirubin, and alkaline phosphatase). A separate set of plasma samples were also divided into normal and abnormal groups based on pancreatic function tests (amylase and lipase). There were no patients with detectable ethanol in this group. Patients with abnormalities in pancreatic function tests were included upon recognition of endogenously produced FAMEs by patients with liver function test abnormalities. FAMEs were extracted from plasma and individual species of FAMEs quantified by gas chromatography-mass spectrometry (GC/MS). Increased concentrations of FAME were found in patient samples with evidence of liver dysfunction, regardless of whether or not they were intoxicated (n=21, p=0.01). No significant differences in plasma FAME concentrations were found between patients with normal (n=15) versus abnormal pancreatic function tests (n=22, p=0.72). The presence of FAMEs in human plasma may be related to the existence of liver disease, and not to blood ethanol concentrations or pancreatic dysfunction. The metabolic pathways associated with FAME production in patients with impaired liver function remain to be identified.

Successful outcome of transplant of kidneys recovered from a brain-dead liver transplant recipient: case report.

PubMed

Domagała, Piotr; Kwiatkowski, Artur; Drozdowski, Jakub; Ostrowski, Krzysztof; Wszola, Michal; Diuwe, Piotr; Durlik, Magdalena; Paczek, Leszek; Chmura, Andrzej

2012-12-01

Few reports describing the use of organs donated by transplant recipients have been published. In this case report, kidneys procured from a brain-dead liver recipient were transplanted successfully. A 21-year-old man was referred for liver transplant after an overdose of acetaminophen. The patient's kidney function was initially normal, with proper urine production and normal kidney laboratory parameters. On the third day after admission, the patient's kidney laboratory parameters became elevated and hepatic encephalopathy requiring mechanical ventilation developed. An orthotopic liver transplant was performed the next day. The patient did not recover consciousness, and brain death was diagnosed on the third day after the liver transplant surgery. The maximum serum concentration of creatinine was 5.8 mg/dL (513 μmol/L) before kidney recovery, and urine production was normal. The kidneys were recovered with organ-perfusion support and were preserved by using machine perfusion. The kidneys were transplanted into 2 male recipients. Twelve months after transplant, the recipients remained in good health with satisfactory kidney function. This case demonstrates that transplanting kidneys recovered from liver transplant recipients is possible and beneficial, thus expanding the pool of potential donors.

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.

Cadaveric domino liver transplantation: the first case in Japan.

PubMed

Wakayama, Kenji; Jin, Maeng Bong; Furukawa, Hiroyuki; Todo, Satoru; Shimamura, Tsuyoshi; Suzuki, Tomomi; Hattori, Masahiro; Yokoyama, Ryouji; Iwasaki, Sari; Sato, Masanori; Nakagawa, Takahito; Kurauchi, Noriaki; Kamachi, Hirohumi; Kamiyama, Toshiya; Matsushita, Michiaki

2004-01-01

The first case of domino liver transplantation from a brain-dead donor in Japan is described. A 49-year-old man with familial amyloidotic polyneuropathy received a cadaver liver, and his native liver was transplanted into a 53-year-old man with polycystic liver and kidney disease. The cadaveric liver allograft was transplanted by the conventional technique. The graft taken from the first recipient had four outflow orifices (the left, middle, and right hepatic veins, and upper vena cava), for which a single orifice was created at the back table. This graft was transplanted in piggy-back fashion. The first recipient developed acute rejection on day 13 and hepatic artery stenosis on day 36. These were treated by steroid recycle therapy and percutaneous transarterial angioplasty. He was discharged on day 57 with normal liver function. The second recipient underwent re-operation for bleeding from the right adrenal gland and left thoracic cavity. He was diagnosed with acute rejection on day 7, which was treated by steroid pulse therapy. He was discharged uneventfully on day 39 with normal liver function.

Impacts of exposure to 900 MHz mobile phone radiation on liver function in rats.

PubMed

Ma, Hui-rong; Ma, Zhi-hong; Wang, Gui-ying; Song, Cui-miao; Ma, Xue-lian; Cao, Xiao-hui; Zhang, Guo-hong

2015-11-01

To study the impacts of exposure to electromagnetic radiation (EMR) on liver function in rats. Twenty adult male Sprague-Dawley rats were randomly divided into normal group and radiated group. The rats in normal group were not radiated, those in radiated group were exposed to EMR 4 h/ d for 18 consecutive days. Rats were sacrificed immediately after the end of the experiment. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and those of malondialdehyde (MDA) and glutathione (GSH) in liver tissue were evaluated by colorimetric method. The liver histopathological changes were observed by hematoxylin and eosin staining and the protein expression of bax and bcl- 2 in liver tissue were detected by immunohistochemical method. Terminal-deoxynucleotidyl transferase mediated nick and labelling (TUNEL) method was used for analysis of apoptosis in liver. Compared with the normal rats, the serum levels of ALT and AST in the radiated group had no obvious changes (P>0.05), while the contents of MDA increased (P < 0.01) and those of GSH decreased (P < 0.01) in liver tissues. The histopathology examination showed diffuse hepatocyte swelling and vacuolation, small pieces and focal necrosis. The immunohistochemical results displayed that the expression of the bax protein was higher and that of bcl-2 protein was lower in radiated group. The hepatocyte apoptosis rates in radiated group was higher than that in normal group (all P < 0.01). The exposure to 900 MHz mobile phone 4 h/d for 18 days could induce the liver histological changes, which may be partly due to the apoptosis and oxidative stress induced in liver tissue by electromagnetic radiation.

Examination of the liver in personnel working with liquid rocket propellant

PubMed Central

Petersen, Palle; Bredahl, Erik; Lauritsen, Ove; Laursen, Thomas

1970-01-01

Petersen, P., Bredahl, E., Lauritsen, O., and Laursen, T. (1970).Brit. J. industr. Med.,27, 141-146. Examination of the liver in personnel working with liquid rocket propellants. Personnel working with liquid rocket propellants were subjected to routine health examinations, including liver function tests, as the propellant, unsymmetrical dimethylhydrazine (UDMH) is potentially toxic to the liver. In 46 persons the concentrations of serum alanine aminotransferase (SGPT) were raised. Liver biopsy was performed in 26 of these men; 6 specimens were pathological (fatty degeneration), 5 were uncertain, and 15 were normal. All 6 pathological biopsies were from patients with a raised SGPT at the time of biopsy. Of the 15 persons with a normal liver biopsy, 14 had a normal SGPT, while one (who was an alcoholic) had a raised SGPT. The connection between SGPT and histology of the liver, as well as the possible causal relation between the pathological findings and exposure to UDMH, is discussed. Images PMID:5428632

Application of Cox model in coagulation function in patients with primary liver cancer.

PubMed

Guo, Xuan; Chen, Mingwei; Ding, Li; Zhao, Shan; Wang, Yuefei; Kang, Qinjiong; Liu, Yi

2011-01-01

To analyze the distribution of coagulation parameters in patients with primary liver cancer; explore the relationship between clinical staging, survival, and coagulation parameters by using Coxproportional hazard model; and provide a parameter for clinical management and prognosis. Coagulation parameters were evaluated in 228 patients with primary liver cancer, 52 patients with common liver disease, and 52 normal healthy controls. The relationship between primary livercancer staging and coagulation parameters wasanalyzed. Follow-up examinations were performed. The Cox proportional hazard model was used to analyze the relationship between coagulationparameters and survival. The changes in the coagulation parameters in patients with primary liver cancer were significantly different from those in normal controls. The effect of the disease on coagulation function became more obvious as the severity of liver cancer increased (p<0.05). The levels of D-dimer, fibrinogen degradation products (FDP), fibrinogen (FIB), and platelets (PLT) were negatively correlated with the long-term survival of patients with advanced liver cancer. The stages of primary liver cancer are associated with coagulation parameters. Coagulation parameters are related to survival and risk factors. Monitoring of coagulation parameters may help ensure better surveillance and treatment for liver cancer patients.

Elevated trimethylamine-N-oxide (TMAO) is associated with poor prognosis in primary sclerosing cholangitis patients with normal liver function.

PubMed

Kummen, Martin; Vesterhus, Mette; Trøseid, Marius; Moum, Bjørn; Svardal, Asbjørn; Boberg, Kirsten Muri; Aukrust, Pål; Karlsen, Tom Hemming; Berge, Rolf Kristian; Hov, Johannes Roksund

2017-06-01

Trimethylamine- N -oxide (TMAO) is produced in the liver from trimethylamine, which is exclusively generated by gut bacteria. The objective of this article is to investigate the relationship between TMAO and primary sclerosing cholangitis (PSC) and its clinical characteristics. Serum TMAO was measured in 305 PSC patients, 90 ulcerative colitis patients and 99 healthy controls. In PSC patients with normal liver function ( n  = 197), TMAO was higher in patients reaching liver transplantation or death during follow-up than those who did not, with an optimal TMAO cut-off of 4.1 µM (AUC = 0.64, p  < 0.001). PSC patients with high TMAO (>4.1 µM, n  = 77) exhibited shorter transplantation-free survival than patients with low TMAO ( n  = 120, log-rank test: p  < 0.0001). High TMAO (>4.1 µM) was associated with reduced transplantation-free survival (HR 1.87, p  = 0.011), independently of the Mayo risk score (HR 1.74, p  < 0.001). Overall, PSC patients demonstrated reduced TMAO values compared with ulcerative colitis and healthy controls, mainly caused by PSC patients with reduced liver function (INR > 1.2), suggesting impaired oxidation of trimethylamine to TMAO. PSC patients with and without inflammatory bowel disease had similar TMAO levels. In PSC patients with normal liver function, elevated TMAO was associated with shorter transplantation-free survival, potentially reflecting clinically relevant metabolic changes resulting from dietary interactions with the gut microbiota.

[A case report of simultaneous liver, pancreas-duodenum, and kidney transplantation in a patient with post-hepatitic cirrhosis combined with uremia and insulin-dependent diabetes related to chronic pancreatitis].

PubMed

Wang, He; Dou, Ke-feng; Yang, Xiao-jian; Qin, Wei-jun; Zhang, Geng; Yu, Lei; Kang, Fu-xia; Chen, Shao-yang; Xiong, Li-ze; Song, Zhen-shun; Liu, Zheng-cai

2006-09-12

To study the effect of triple organ transplantation (liver, kidney, and pancreas) in patient of end-stage liver disease with renal failure and diabetes, and to explore the optimal surgical procedure. Simultaneous piggyback orthotopic heterotopic liver, pancreas-duodenum, and kidney transplantation was performed on a 43-year-old male patient with exocrine pancreatic insufficiency and insulin-dependent diabetes related to chronic pancreatitis (CP) who developed hepatic and renal failure. The pancreatic exocrine secretions were drained enterically to the jejunum. Prednisone, tacrolimus, mycophenolate mofetil, and ATG were used as immunosuppression therapy. Good liver and pancreas allograft function recovery was achieved within 7 days after the operation. And the recovery of renal allograft function was delayed. The renal allograft was removed because of break-down of renal blood flow 16 days after the transplantation. A new renal transplantation was performed at the same position. The second kidney graft recovered its normal function 3 days later. Up to the writing of this paper no acute rejection of organs and such complications as pancreatitis, thrombosis, and localized infection occurred. The patient became insulin independent with normal liver and renal function. Simultaneous piggyback orthotopic heterotopic liver, pancreas-duodenum, and kidney transplantation can be a good method for the patients with exocrine pancreatic insufficiency and insulin-dependent diabetes combined with hepatic and renal failure.

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

Effect of Boron Neutron Capture Therapy (BNCT) on Normal Liver Regeneration: Towards a Novel Therapy for Liver Metastases

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

Jorge E. Cardoso; Elisa M. Heber; David W. Nigg

2007-10-01

The “TAORMINA project” developed a new method for Boron Neutron Capture Therapy (BNCT) of human multifocal unresectable liver metastases based on whole liver ex-situ BNCT mediated by boronophenylalanine (BPA), followed by whole liver autograft. This technique involved a high risk, prolonged anhepatic phase. The Roffo Institute liver surgeons (JEC) herein propose a novel technique to pursue ex-situ liver BNCT studies with a drastically lower surgical risk for the patient. The technique would involve, sequentially, ex-situ BNCT of left liver segments II and III, partial liver autograft, and induction of partial atrophy of the untreated right liver. The working hypothesis ismore » that the atrophy of the right, untreated, diseased liver would stimulate regeneration of the left, treated, “cured” liver to yield a healthy liver mass, allowing for the resection of the remaining portion of diseased liver. This technique does not involve an anhepatic phase and would thus pose a drastically lower surgical risk to the patient but requires sine qua non that BNCT should not impair the regenerative capacity of normal hepatocytes. The aim of the present study was to assess the effect of therapeutic doses of BNCT mediated by BPA, GB-10 (Na2 10B10H10) or (GB- 10 + BPA) on normal liver regeneration in the Wistar rat employing partial hepatectomy as a regenerative stimulus. BNCT did not cause alterations in the outcome of normal liver regeneration, regenerated liver function or histology. We provide proof of principle to support the development of a novel, promising BNCT technique for the treatment of liver metastases.« less

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.

Can Patients Who Develop Cerebral Death in Fulminant Liver Failure Despite Liver Transplantation Be Previously Forseen?

PubMed

Sarici, K B; Karakas, S; Otan, E; Ince, V; Koc, C; Koc, S; Bayraktar, H; Aydin, C; Kayaalp, C; Gungor, S; Kablan, Y; Yilmaz, S

2017-04-01

The outcome of medical treatment is worse in fulminant liver failure (FLF) developing on acute or chronic ground. Recently, liver transplantations with the use of living and cadaveric donors have been performed in these diseases and good results obtained. In this study, we aimed to present the factors affecting the recovery of cerebral functions after liver transplantation in hepatic encephalopathy (HE) developing in FLF, to identify irreversible patient groups and to prevent unnecessary liver transplantation. In Inonu University's Liver Transplant Institute, 69 patients who made an emergency notice to the National Coordination Center for liver transplantation owing to FLF from January 2012 to December 2015 were included in the study. Patients were divided into 2 groups. Group 1 consisted of 52 patients who underwent liver transplantation and recovered normal brain function, and group 2 had 17 patients who underwent liver transplantation and did not recover normal brain function and had cerebral death. All patients were evaluated before surgery for clinical encephalopathy stage, light reflex, and convulsions. Groups were compared and assessed according to age (>40, 10-40 and <10 years), body mass index, etiologic factor, preoperative laboratory values, transplantation type, mortality, and encephalopathy level. Multivariate analysis was done for specific parameters. Prothrombin time (PT), international normalized ratio (INR), and total bilirubin values were significantly different between the groups. There was no significant difference between the groups regarding ammonia and lactate levels. There was a statistically significant difference between the groups regarding sodium and potassium levels from serum electrolytes. However, the averages of both groups were within normal limits. pH and total bilirubin levels were meaningful for multivariate analysis. HE reversibility, mortality, and morbidity are important in patients with HE who undergo liver transplantation. Therefore, West Haven clinical staging and serum INR, PT, and total bilirubin level may be helpful in predicting the reversibility of FLF patients with HE before liver transplantation. It was determined that West Haven encephalopathy grading is important in determining the reversibility of HE after transplantation in FLF; especially the probability of reversibility of stage 4 HE decreases significantly. High PT and INR levels, hyperbilirubinemia, and serum sodium and potassium concentrations were risk factors for the reversibility of HE in this study. Copyright © 2017 Elsevier Inc. All rights reserved.

Neurologic Manifestations of Chronic Liver Disease and Liver Cirrhosis.

PubMed

Sureka, Binit; Bansal, Kalpana; Patidar, Yashwant; Rajesh, S; Mukund, Amar; Arora, Ankur

2015-01-01

The normal functioning of brain is intimately as well as intricately interrelated with normal functioning of the liver. Liver plays a critical role of not only providing vital nutrients to the brain but also of detoxifying the splanchnic blood. Compromised liver function leads to insufficient detoxification thus allowing neurotoxins (such as ammonia, manganese, and other chemicals) to enter the cerebral circulation. In addition, portosystemic shunts, which are common accompaniments of advanced liver disease, facilitate free passage of neurotoxins into the cerebral circulation. The problem is compounded further by additional variables such as gastrointestinal tract bleeding, malnutrition, and concurrent renal failure, which are often associated with liver cirrhosis. Neurologic damage in chronic liver disease and liver cirrhosis seems to be multifactorial primarily attributable to the following: brain accumulation of ammonia, manganese, and lactate; altered permeability of the blood-brain barrier; recruitment of monocytes after microglial activation; and neuroinflammation, that is, direct effects of circulating systemic proinflammatory cytokines such as tumor necrosis factor, IL-1β, and IL-6. Radiologist should be aware of the conundrum of neurologic complications that can be encountered in liver disease, which include hepatic encephalopathy, hepatocerebral degeneration, hepatic myelopathy, cirrhosis-related parkinsonism, cerebral infections, hemorrhage, and osmotic demyelination. In addition, neurologic complications can be exclusive to certain disorders, for example, Wilson disease, alcoholism (Wernicke encephalopathy, alcoholic cerebellar degeneration, Marchiafava-Bignami disease, etc). Radiologist should be aware of their varied clinical presentation and radiological appearances as the diagnosis is not always straightforward. Copyright © 2015 Mosby, Inc. All rights reserved.

VIRTUAL LIVER: AN IN SILICO FRAMEWORK FOR ANALYZING CHEMICAL-INDUCED HEPATOTOXICITY

EPA Science Inventory

The US EPA Virtual Liver (v-LiverTM) is an in silico framework for the dose-dependent perturbation of normal hepatic functions by chemicals using in vitro data. The framework consists of a computable knowledge-base (KB) to infer putative pathways in hepatotoxicity and a cellular...

Hepatic encephalopathy secondary to a splenorenal shunt that manifested a long time after a liver transplantation.

PubMed

Tomás Pujante, Paula; Jiménez Sánchez, Andrés Francisco; Iglesias Jorquera, Elena; Pons Miñano, José Antonio

2018-04-24

Splenorenal shunts are a rare cause of hyperammonemia and hepatic encephalopathy in the absence of cirrhosis. We report the case of a woman, who presented hepatic encephalopathy, with a normal functioning graft, after 14 years of liver transplantation, confirmed by liver biopsy.

Liver receptor homolog-1 is a critical determinant of methyl-pool metabolism

USDA-ARS?s Scientific Manuscript database

Balance of labile methyl groups (choline, methionine, betaine, and folate) is important for normal liver function. Quantitatively, a significant use of labile methyl groups is in the production of phosphatidylcholines (PCs), which are ligands for the nuclear liver receptor homolog-1 (LRH-1). We stud...

Regional radiation dose-response modeling of functional liver in hepatocellular carcinoma patients with longitudinal sulfur colloid SPECT/CT: a proof of concept.

PubMed

Price, Ryan G; Apisarnthanarax, Smith; Schaub, Stephanie K; Nyflot, Matthew J; Chapman, Tobias R; Matesan, Manuela; Vesselle, Hubert J; Bowen, Stephen R

2018-06-19

We report on patient-specific quantitative changes in longitudinal sulfur colloid SPECT/CT as a function of regional radiation dose distributions to normal liver in a cohort of hepatocellular carcinoma patients. Dose-response thresholds and slopes varied with baseline liver function metrics, and extreme values were found in patients with fatal hepatotoxicity. Dose-response modeling of normal liver in individual HCC patients has potential to characterize in vivo radiosensitivity, identify high risk subgroups, and personalize treatment planning dose constraints. Hepatotoxicity risk in hepatocellular carcinoma (HCC) patients is modulated by radiation dose delivered to normal liver tissue, but reported dose-response data are limited. Our prior work established baseline [ 99m Tc]sulfur colloid (SC) SPECT/CT liver function imaging biomarkers that predict clinical outcomes. We conducted a proof-of-concept investigation with longitudinal SC SPECT/CT to characterize patient-specific radiation dose-response relationships as surrogates for liver radiosensitivity. SC SPECT/CT images of 15 HCC patients with variable Child-Pugh status (8 CP-A, 7 CP-B/C) were acquired in treatment position prior to and 1 month (nominal) after SBRT (n=6) or proton therapy (n=9). Localized rigid registrations between pre/post-treatment CT to planning CT scans were performed, and transformations were applied to pre/post-treatment SC SPECT images. Radiotherapy doses were converted to EQD2 α/β=3 and Gy (RBE), and binned in 5 GyEQD2 increments within tumor-subtracted livers. Mean dose and percent change (%ΔSC) between pre- and post-treatment SPECT uptake, normalized to regions receiving < 5 GyEQD2, were calculated in each binned dose region. Dose-response data were parameterized by sigmoid functions (double exponential) consisting of maximum reduction (%ΔSC max ), dose midpoint (D mid ), and dose-response slope (α mid ) parameters. Individual patient sigmoid dose-response curves had high goodness-of-fit (median R 2 = 0.96, range 0.76-0.99). Large inter-patient variability was observed, with median (range) in %ΔSC max of 44% (20-75%), D mid of 13 Gy (4-27 GyEQD2), and α mid of 0.11 GyEQD2 -1 (0.04-0.29 GyEQD2 -1 ), respectively. Eight of 15 patients had %ΔSC max = 20-45%, while 7/15 had %ΔSC max = 60-75%, with subgroups made up of variable baseline liver function status and radiation treatment modality. Fatal hepatotoxicity occurred in patients (2/15) with low TLF (< 0.12) and low D mid (< 7 GyEQD2). Longitudinal SC SPECT/CT imaging revealed patient-specific variations in dose-response, and may identify patients with poor baseline liver function and increased sensitivity to radiation therapy. Validation of this regional liver dose-response modeling concept as a surrogate for patient-specific radiosensitivity has potential to guide HCC therapy regimen selection and planning constraints. Copyright © 2018 Elsevier Inc. All rights reserved.

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.

Thallium-201 per rectum for the diagnosis of cirrhosis in patients with asymptomatic chronic hepatitis

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

D'Arienzo, A.; Celentano, L.; Scuotto, A.

1988-07-01

In normal subjects, thallium-201, administered per rectum, is taken up mainly by the liver (heart/liver ratio in normal subjects: 0.04 to 0.12). It has been claimed that an increased heart/liver ratio is suggestive of portal-caval shunting and portal hypertension. To evaluate the possibility of using thallium-201 as a test to diagnose cirrhosis, we administered this substance per rectum to 33 patients with biochemical evidence, but no clinical symptoms, of liver disease. Laparoscopy and liver biopsy revealed chronic active hepatitis without cirrhosis in 18 patients, and chronic active hepatitis with cirrhosis in the others. The results of conventional liver function testsmore » were similar in both groups. A significant difference, however, was found between the means of fasting serum bile acid concentrations (9.8 +/- 3.2 and 18.3 +/- 4.2 microM per liter) in chronic active hepatitis without cirrhosis and cirrhotic patients, and between the means of the heart/liver ratios 20 min after thallium-201 administration (heart/liver: 0.09 +/- 0.03 and 0.54 +/- 0.13, respectively). Unlike the serum bile acid concentration which gave some overlapping values, the thallium-201 test clearly distinguished the chronic active hepatitis without cirrhosis group from the cirrhotics. In the cirrhotic group, there was a significant correlation between the heart/liver ratio and signs of portal hypertension such as esophageal varices, increased diameter of the vena porta and hypersplenism. The thallium-201 test is therefore useful in discriminating between chronic active hepatitis with and without cirrhosis in clinically asymptomatic subjects with biochemical evidence of moderate liver function impairment. A heart/liver uptake ratio much higher than normal (above 0.30) strongly suggests the development of hepatic cirrhosis.« less

Mesenchymal stem cells: In vivo therapeutic application ameliorates carbon tetrachloride induced liver fibrosis in rats.

PubMed

Raafat, Nermin; Abdel Aal, Sara M; Abdo, Fadia K; El Ghonaimy, Nabila M

2015-11-01

Egypt has the highest prevalence of hepatitis C virus in the world with infection rate up to 60%, for which liver fibrosis or hepatic carcinoma is the final outcome. Stem cell therapy provides a new hope for hepatic repair instead of traditional treatment, liver transplantation, as it is safer, gives long term engraftment and avoid expensive immunosuppressive drugs and unexpected hazardous effects. This work aimed at determining the therapeutic potential of mesenchymal stem cells (MSC) in hepatic repair as a new line of therapy for liver fibrosis. 33 female albino rats were divided into three groups: Group I: 10 rats injected subcutaneously with olive oil, Group II: 13 rats injected with carbon tetrachloride (CCl4) and Group III: 10 rats injected with CCl4 then bone marrow derived MSC from male rats. Blood and liver tissue samples were taken from all rats for biochemical and histological study. Liver functions for group II rats showed significant deterioration in response to CCl4 in addition to significant histological changes in liver lobules and portal areas. Those parameters tend to be normal in MSC-treated group. Group III rats revealed normalized liver function and histological picture. Meanwhile, most of the pathological lesions were still detected in rats of second group. Undifferentiated MSCs have the ability to ameliorate CCl4 induced liver injury in albino rats in terms of liver functions and histological features. So, stem cell therapy can be considered clinically to offer a hope for patients suffering from liver fibrosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biochemical studies on hepatic involvement in infectious mononucleosis

PubMed Central

Baron, D. N.; Bell, Joyce L.; Dunnet, W. N.

1965-01-01

Eighty cases of infectious mononucleosis have been investigated by serum enzyme studies and other liver function tests. Maximum abnormalities occurred between the second and fourth weeks of illness and all tests were usually normal by the sixth week. Serum isocitric dehydrogenase activity was increased in 93% of cases and serum glutamic-oxaloacetic transaminase in 74%. Conventional liver function tests were less sensitive. Serum bilirubin was above normal in 40% of cases; in 17% of cases the increase was sufficient to show as clinical jaundice. No patient has developed chronic hepatitis. PMID:14276157

Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

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

Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki

Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effectmore » of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.« less

Clinical and surgical anatomy of the liver: a review for clinicians.

PubMed

Juza, Ryan M; Pauli, Eric M

2014-07-01

The liver is the largest gland in the body occupying 2.5% of total body weight and providing a host of functions necessary for maintaining normal physiological homeostasis. Despite the complexity of its functions, the liver has a homogenous appearance, making hepatic anatomy a challenging topic of discussion. To address this issue, scholars have devoted time to establishing a framework for describing hepatic anatomy to aid clinicians. Work by the anatomist Sir James Cantlie provided the first accurate division between the right and left liver in 1897. The French surgeon and anatomist Claude Couinaud provided additional insight by introducing the Couinaud segments on the basis of hepatic vasculature. These fundamental studies provided a framework for medical and surgical discussions of hepatic anatomy and were essential for the advancement of modern medicine. In this article, the authors review the normal anatomy and physiology of the liver with a view to enhancing the clinician's knowledge base. They also provide a convenient model to assist with understanding and discussion of liver anatomy. Copyright © 2014 Wiley Periodicals, Inc.

Endovascular diagnosis and intervention in patients with isolated hyperammonemia, with or without ascites, after liver transplantation.

PubMed

Belenky, Alexander; Igov, Igor; Konstantino, Youval; Bachar, Gil N; Mor, Eitan; Graif, Franklyn; Ben-Ari, Ziv; Tur-Kaspa, Ran; Atar, Eli

2009-02-01

Hyperammonemia with or without ascites with normal synthetic liver functions after liver transplantation might indicate the presence of anastomotic stenosis of the portal or hepatic vein or the existence of a patent portosystemic shunt. The authors describe six patients, three children after split-liver transplantation and three adults after cadaver liver transplantation, who presented with hyperammonemia. Three patients had ascites. All lesions were successfully treated percutaneously; stents were placed in patients with anastomotic stenoses and coil embolization was performed in patients with patent portosystemic shunts--with either transhepatic or transjugular approaches according to the site of the abnormality. Ammonia levels returned to normal, and ascites had regressed completely for at least 3 months.

FXR and liver carcinogenesis

PubMed Central

Huang, Xiong-fei; Zhao, Wei-yu; Huang, Wen-dong

2015-01-01

Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer. PMID:25500874

Atherosclerosis and Liver Function Tests in Coronary Angiography Patients.

PubMed

Doganer, Y C; Rohrer, J E; Aydogan, U; Agerter, D C; Cayci, T; Barcin, C

2015-09-01

Elevated aminotransferase levels indicating liver function, even in the normal range, have attracted great concern as potential novel markers of cardiovascular risk assessment. We hypothesized the possibility that liver function test variations in the normal range might be meaningfully associated to coronary artery disease (CAD). Eighty-eight patients were randomly selected from those who underwent coronary angiography from June 2010 to June 2011 after applying to the outpatient cardiology clinic in Gulhane Military Medical Academy. According to the results of angiographies, patients were classified into three groups as normal, non-critical (< 50% involvement in coronaries), and critical (≥ 50% involvement in coronaries). In addition to angiographic intervention, measurements of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, albumin and the other serum parameters were performed in all patients. The patient groups of CAD were balanced (28 critical cases, 30 non-critical cases and 30 normal cases). Mean age was 51.93 ± 9.3 (range 32-65) years and 19.3 per cent (n = 17) were females. Multiple linear regression analysis of all three liver function tests explained a significant portion of the variance, but adjusted r-squares were small (AST = 0.174, ALT = 0.242, albumin = 0.124). Albumin was significantly higher for patients with critical CAD than for patients with no CAD (beta = 3.205, p = 0.002). Non-critical CAD was not significantly different from no CAD for any of the dependent variables. Mean AST was significantly higher for patients taking aspirin (beta = 0.218, p = 0.049), as was mean ALT (beta = 0.264, p = 0.015). Alanine aminotransferase and AST may not be associated with angiographically determined coronary atherosclerosis. Albumin may be more sensitive to demonstrate the burden of atherosclerosis. These results indicate that the association between the liver function tests and coronary atherosclerosis may be more complex than generally appreciated.

[Perioperative changes of coagulation functions in the local advanced liver cancer patients receiving liver transplantation].

PubMed

Wang, Hao-Yuan; Zhao, Qing-Yu; Yuan, Yun-Fei

2008-07-01

Liver transplantation is widely accepted as an effective therapy of hepatoma. Perioperative dynamic observation of coagulation function is important for graft-receivers. This study was to explore perioperative changes of coagulation functions in the local advanced liver cancer patients who received liver transplantation. Clinical data of 31 local advanced liver cancer patients, underwent liver transplantation from Sep. 2003 to Jan. 2007, were analyzed. Platelet (PLT) counting, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fib) and international normalized ratio (INR) before operation, at anhepatic phase and the first week after operation were analyzed to evaluate congulation function. The coagulation functions of most patients were normal before operation. The six parameters varied significantly at anhepatic phase and on most days of the first week after operation when compared with the preoperative levels (P<0.05). The elevation of PT, APTT, TT and INR and the decrease of Fib and PLT were more apparent at anhepatic phase when compared with the preoperative levels [PT: (19.51+/-3.78) s vs. (14.16+/-1.46) sû APTT: (77.01+/-30.51) s vs. (40.19+/-4.11) sû TT: (27.50+/-15.10) s vs. (19.46+/-3.05) sû INR: 1.61+/-0.37 vs. 1.11+/-0.16û Fib: (1.73+/-0.70) g/L vs. (3.38+/-1.00) g/Lû PLT: (108+/-60)x10(9)/L vs. (184+/-108)x10(9)/L, all P<0.01]. In the first week after operation, the elevated PT, APTT, TT and INR levels decreased gradually, APTT was even lower than the preoperative level [(32.05+/-6.50) s vs. (40.19+/-4.11) s, P<0.01]. These changes appeared usually on 1-2 days after operation. Decreased PLT and Fib regained slowly at the first week after operation when compared with the preoperative levels [Fib: (2.13+/-0.53) g/L vs. (3.38+/-1.00) g/L, P<0.01û PLT: (145+/-90)x10(9)/L vs. 184+/-108]x10(9)/L, P<0.05], but the values were normal. According to stratification analysis, the hypocoagulability was more obvious in the patients with moderate or severe cirrhosis and those with Child-Pugh B level than in their counterparts. The coagulation functions of local advanced liver cancer patients shift from hypocoagulatory to hypercoagulatory or normal in perioperative period, therefore, prevention of bleeding should be focused on at anhepatic phase and on 1-2 days after operation while prevention of thrombosis should be focused on after the first week after operation. The degree of liver cirrhosis and Child-Pugh level could help to evaluate postoperative coagulation disorder.

Radiation Exposure Alters Expression of Metabolic Enzyme Genes in Mice

NASA Technical Reports Server (NTRS)

Wotring, V. E.; Mangala, L. S.; Zhang, Y.; Wu, H.

2011-01-01

Most administered pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand the effects of spaceflight on the enzymes of the liver and exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. Additionally, it has been previous noted that pre-exposure to small radiation doses seems to confer protection against later and larger radiation doses. This protective power of pre-exposure has been called a priming effect or radioadaptation. This study is an effort to examine the drug metabolizing effects of radioadaptation mechanisms that may be triggered by early exposure to low radiation doses.

Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy.

PubMed

Ezquer, Fernando; Bahamonde, Javiera; Huang, Ya-Lin; Ezquer, Marcelo

2017-01-28

The liver has the remarkable capacity to regenerate in order to compensate for lost or damaged hepatic tissue. However, pre-existing pathological abnormalities, such as hepatic steatosis (HS), inhibits the endogenous regenerative process, becoming an obstacle for liver surgery and living donor transplantation. Recent evidence indicates that multipotent mesenchymal stromal cells (MSCs) administration can improve hepatic function and increase the potential for liver regeneration in patients with liver damage. Since HS is the most common form of chronic hepatic illness, in this study we evaluated the role of MSCs in liver regeneration in an animal model of severe HS with impaired liver regeneration. C57BL/6 mice were fed with a regular diet (normal mice) or with a high-fat diet (obese mice) to induce HS. After 30 weeks of diet exposure, 70% hepatectomy (Hpx) was performed and normal and obese mice were divided into two groups that received 5 × 10 5 MSCs or vehicle via the tail vein immediately after Hpx. We confirmed a significant inhibition of hepatic regeneration when liver steatosis was present, while the hepatic regenerative response was promoted by infusion of MSCs. Specifically, MSC administration improved the hepatocyte proliferative response, PCNA-labeling index, DNA synthesis, liver function, and also reduced the number of apoptotic hepatocytes. These effects may be associated to the paracrine secretion of trophic factors by MSCs and the hepatic upregulation of key cytokines and growth factors relevant for cell proliferation, which ultimately improves the survival rate of the mice. MSCs represent a promising therapeutic strategy to improve liver regeneration in patients with HS as well as for increasing the number of donor organs available for transplantation.

Case Report: First Reported Combined Heart-Liver Transplant in a Patient With a Congenital Solitary Kidney.

PubMed

Hanna, R M; Kamgar, M; Hasnain, H; Khorsan, R; Nsair, A; Kaldas, F; Baas, A; Bunnapradist, S; Wilson, J M

2018-04-01

We report a case of successful combined heart liver transplant in a patient with a congenital solitary kidney. The patient had normal renal function before combined heart-liver transplantation and developed acute kidney injury requiring slow continuous dialysis and subsequent intermittent dialysis for almost 8 weeks post transplantation. Her renal function recovered and she remains off dialysis now 7 months post transplantation. She only currently has mild chronic renal insufficiency. We believe this is the first reported case of successful heart liver transplant in a patient with a congenital solitary kidney. Published by Elsevier Inc.

Study of MicroRNAs Related to the Liver Regeneration of the Whitespotted Bamboo Shark, Chiloscyllium plagiosum

PubMed Central

Lu, Conger; Nie, Zuoming; Chen, Jian; Zhang, Wenping; Ren, Xiaoyuan; Yu, Wei; Liu, Lili; Jiang, Caiying; Zhang, Yaozhou; Guo, Jiangfeng; Wu, Wutong; Shu, Jianhong; Lv, Zhengbing

2013-01-01

To understand the mechanisms of liver regeneration better to promote research examining liver diseases and marine biology, normal and regenerative liver tissues of Chiloscyllium plagiosum were harvested 0 h and 24 h after partial hepatectomy (PH) and used to isolate small RNAs for miRNA sequencing. In total, 91 known miRNAs and 166 putative candidate (PC) miRNAs were identified for the first time in Chiloscyllium plagiosum. Through target prediction and GO analysis, 46 of 91 known miRNAs were screened specially for cellular proliferation and growth. Differential expression levels of three miRNAs (xtr-miR-125b, fru-miR-204, and hsa-miR-142-3p_R-1) related to cellular proliferation and apoptosis were measured in normal and regenerating liver tissues at 0 h, 6 h, 12 h, and 24 h using real-time PCR. The expression of these miRNAs showed a rising trend in regenerative liver tissues at 6 h and 12 h but exhibited a downward trend compared to normal levels at 24 h. Differentially expressed genes were screened in normal and regenerating liver tissues at 24 h by DDRT-PCR, and ten sequences were identified. This study provided information regarding the function of genes related to liver regeneration, deepened the understanding of mechanisms of liver regeneration, and resulted in the addition of a significant number of novel miRNAs sequences to GenBank. PMID:24151623

Flow dynamics analyses of pathophysiological liver lobules using porous media theory

NASA Astrophysics Data System (ADS)

Hu, Jinrong; Lü, Shouqin; Feng, Shiliang; Long, Mian

2017-08-01

Blood flow inside the liver plays a key role in hepatic functions, and abnormal hemodynamics are highly correlated with liver diseases. To date, the flow field in an elementary building block of the organ, the liver lobule, is difficult to determine experimentally in humans due to its complicated structure, with radially branched microvasculature and the technical difficulties that derive from its geometric constraints. Here we established a set of 3D computational models for a liver lobule using porous media theory and analyzed its flow dynamics in normal, fibrotic, and cirrhotic lobules. Our simulations indicated that those approximations of ordinary flow in portal tracts (PTs) and the central vein, and of porous media flow in the sinusoidal network, were reasonable only for normal or fibrotic lobules. Models modified with high resistance in PTs and collateral vessels inside sinusoids were able to describe the flow features in cirrhotic lobules. Pressures, average velocities, and volume flow rates were profiled and the predictions compared well with experimental data. This study furthered our understanding of the flow dynamics features of liver lobules and the differences among normal, fibrotic, and cirrhotic lobules.

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.

Cimetidine and hepatic blood flow in polytrauma patients.

PubMed

Ivatury, R R; Khan, M B; Nallathambi, M; Davis, K; Stahl, W M

1985-05-01

Recent reports suggest that cimetidine acutely reduces liver blood flow in normal healthy subjects. To determine whether this finding is applicable to critically ill patients, we studied nine polytrauma patients admitted to a surgical ICU. All patients were being monitored with pulmonary artery catheters; all were stable with normal liver function. Liver blood flow was estimated by indocyanine green clearance, before and after administration of a single dose of 600 mg cimetidine. Hemodynamic variables were measured at the same times. Cimetidine did not significantly alter either hepatic blood flow or cardiovascular status in these critically ill patients.

Protein tyrosine phosphatase of liver regeneration-1 is required for normal timing of cell cycle progression during liver regeneration

PubMed Central

Jiao, Yang; Ye, Diana Z.; Li, Zhaoyu; Teta-Bissett, Monica; Peng, Yong; Taub, Rebecca; Greenbaum, Linda E.

2014-01-01

Protein tyrosine phosphatase of liver regeneration-1 (Prl-1) is an immediate-early gene that is significantly induced during liver regeneration. Several in vitro studies have suggested that Prl-1 is important for the regulation of cell cycle progression. To evaluate its function in liver regeneration, we ablated the Prl-1 gene specifically in mouse hepatocytes using the Cre-loxP system. Prl-1 mutant mice (Prl-1loxP/loxP;AlfpCre) appeared normal and fertile. Liver size and metabolic function in Prl-1 mutants were comparable to controls, indicating that Prl-1 is dispensable for liver development, postnatal growth, and hepatocyte differentiation. Mutant mice demonstrated a delay in DNA synthesis after 70% partial hepatectomy, although ultimate liver mass restoration was not affected. At 40 h posthepatectomy, reduced protein levels of the cell cycle regulators cyclin E, cyclin A2, cyclin B1, and cyclin-dependent kinase 1 were observed in Prl-1 mutant liver. Investigation of the major signaling pathways involved in liver regeneration demonstrated that phosphorylation of protein kinase B (AKT) and signal transducer and activator of transcription (STAT) 3 were significantly reduced at 40 h posthepatectomy in Prl-1 mutants. Taken together, this study provides evidence that Prl-1 is required for proper timing of liver regeneration after partial hepatectomy. Prl-1 promotes G1/S progression via modulating expression of several cell cycle regulators through activation of the AKT and STAT3 signaling pathway. PMID:25377314

Liver regeneration in donors and adult recipients after living donor liver transplantation.

PubMed

Haga, Junko; Shimazu, Motohide; Wakabayashi, Go; Tanabe, Minoru; Kawachi, Shigeyuki; Fuchimoto, Yasushi; Hoshino, Ken; Morikawa, Yasuhide; Kitajima, Masaki; Kitagawa, Yuko

2008-12-01

In living donor liver transplantation, the safety of the donor operation is the highest priority. The introduction of the right lobe graft was late because of concerns about donor safety. We investigated donor liver regeneration by the types of resected segments as well as recipients to assess that appropriate regeneration was occurring. Eighty-seven donors were classified into 3 groups: left lateral section donors, left lobe donors, and right lobe donors. Forty-seven adult recipients were classified as either left or right lobe grafted recipients. Volumetry was retrospectively performed at 1 week, 1, 2, 3, and 6 months, and 1 year after the operation. In the right lobe donor group, the remnant liver volume was 45.4%, and it rapidly increased to 68.9% at 1 month and 89.8% at 6 months. At 6 months, the regeneration ratios were almost the same in all donor groups. The recipient liver volume increased rapidly until 2 months, exceeding the standard liver volume, and then gradually decreased to 90% of the standard liver volume. Livers of the right lobe donor group regenerated fastest in the donor groups, and the recipient liver regenerated faster than the donor liver. Analyzing liver regeneration many times with a large number of donors enabled us to understand the normal liver regeneration pattern. Although the donor livers did not reach their initial volume, the donors showed normal liver function at 1 year. The donors have returned to their normal daily activities. Donor hepatectomy, even right hepatectomy, can be safely performed with accurate preoperative volumetry and careful decision-making concerning graft-type selection.

Exaggerated Liver Injury Induced by Renal Ischemia Reperfusion in Diabetes: Effect of Exenatide

PubMed Central

Vaghasiya, Jitendra D.; Sheth, Navin R.; Bhalodia, Yagnik S.; Jivani, Nurudin P.

2010-01-01

Background/Aim: This study was designed to investigate the possible effect of exenatide (Glucagon like Peptide-1 receptor agonist) on liver injury (distant organ) induced by renal ischemia reperfusion (IR) in diabetic rats. Materials and Methods: In vivo renal IR was performed in both type 2 diabetic and normal rats. Each protocol comprised ischemia for 30 minutes followed by reperfusion for 24 hours and a treatment period of 14 days before induction of ischemia. Results: Lipid peroxidation, xanthine oxidase activity, myeloperoxidase activity and nitric oxide level in liver tissue were significantly increased (P < 0.01, P < 0.001, P < 0.001, P < 0.05, respectively), after IR in diabetic rats compared to normal rats. Antioxidant enzymes like glutathione, superoxide dismutase, catalase and glutathione peroxidase were significantly reduced (P < 0.05, P < 0.05, P < 0.01, P < 0.05, respectively), after IR in diabetic rats compared to normal rats. Exenatide treatment significantly normalized (P < 0.01), these biochemical parameters in treated rats compared to diabetic IR rats. Serum creatinine phosphokinase activity and liver function enzymes were also significantly normalized (P < 0.001, P < 0.001, respectively), after administration of exenatide. Conclusion: Exenatide exerted protective effect on exaggerated remote organ (liver) injury induced by renal IR in diabetes. PMID:20616412

Evaluation of hepatic function with (99m)Tc-galactosylated serum albumin scintigraphy in patients with malaria: comparison with (99m)Tc-colloid scintigraphy and liver ultrasonography.

PubMed

Lee, Sang-Woo; Lee, Jaetae; Lee, Deog-Young; Chun, Kyung-Ah; Ahn, Byeong-Cheol; Kang, Young-Mo; Lee, Kyubo

2007-02-01

Malarial parasites injected by the mosquito rapidly target hepatocytes, and hepatomegaly is commonly observed during the progress of the disease in malaria patients. To evaluate the degree of hepatic damage and functional status of hepatocytes in malaria patients, we performed liver scintigraphy using (99m)Tc-galactosylated serum albumin (GSA) prospectively and the findings were compared with those of (99m)Tc-colloid scintigraphy, ultrasonography and clinical results in the same subject. Eight malaria patients (all male, mean age 22 years) confirmed to be infected with Plasmodium vivax underwent (99m)Tc-GSA liver scintigraphy, followed by liver ultrasonography and (99m)Tc-colloid scintigraphy using phytate within 3 days. For hepatocyte scintigraphy, anterior images of cardiac blood-pool and liver were continuously acquired for 30 min after injection of 185 MBq (99m)Tc-GSA (3 mg). In addition to visual interpretation of the images, quantitative measurement of hepatic function was performed with several functional parameters, such as hepatic uptake index (LHL15), blood clearance index (HH15) and modified receptor index (LHL/HH) calculated from the radioactivity of the liver and heart. (99m)Tc-colloid images were assessed and graded visually. Severity of hepatic dysfunction or reticuloendothelial system activation was classified as normal, mild, moderate and severe on GSA or colloid images. Hepatomegaly was observed in five and splenomegaly in seven of the eight patients. Serum levels of transaminase and alkaline phosphatase were mildly elevated in two. Visual assessment of GSA scintigraphy revealed normal findings in all subjects, except for mild increases in size. The mean values of LHL15, HH15 and LHL/HH were 0.928+/-0.014, 0.537+/-0.031 and 1.732+/-0.106, respectively. They were graded as normal in five, and near-normal to mild dysfunction in three subjects. In contrast, (99m)Tc-colloid scintigraphy revealed abnormal findings in all of the subjects, and graded as moderate in three or severe reticuloendothelial system activation in five subjects. Liver ultrasonographic findings were normal for all subjects except mild hepatomegaly. Malaria-induced injury of the hepatocyte is likely to be minimal whereas hepatomegaly is commonly seen during disease process. This suggests that hepatic damage in malarial infection is mainly due to involvement of the reticuloendothelial system. (99m)Tc-GSA scintigraphy can be used in differentiating hepatocellular damage from reticuloendothelial system involvement in patients with infectious disease showing hepatomegaly.

Extended normothermic extracorporeal perfusion of isolated human liver after warm ischaemia: a preliminary report.

PubMed

Bellomo, Rinaldo; Marino, Bruno; Starkey, Graeme; Fink, Michael; Wang, Bao Zhong; Eastwood, Glenn M; Peck, Leah; Young, Helen; Houston, Shane; Skene, Alison; Opdam, Helen; Jones, Robert

2014-09-01

Donation after circulatory death (DCD) livers are at markedly increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to transplant DCD livers and may allow their use for artificial extracorporeal liver support of patients with fulminant liver failure. We conducted two proof-of-concept experiments using human livers after DCD to assess the feasibility and functional efficacy of NELP over an extended period. We applied extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion and physiological perfusion pressures to two livers obtained after DCD. We achieved NELP and evidence of liver function (bile production, paracetamol removal and maintenance of normal lactate levels) in both livers; one for 24 hours and the other for 43 hours. Histological examination showed areas of patchy ischaemia but preserved biliary ducts and canaliculi. Our experiments justify further investigations of the feasibility and efficacy of extended DCD liver preservation by ex-vivo perfusion.

Change in hepatic function, hemodynamics, and morphology after liver transplant. Physiological effect of therapy.

PubMed

Millikan, W J; Henderson, J M; Stewart, M T; Warren, W D; Marsh, J W; Galloway, J R; Jennings, H; Kawasaki, S; Dodson, T F; Perlino, C A

1989-05-01

Orthotopic liver transplantation (OLT) has become standard therapy for patients with acute hepatic necrosis and end-stage liver disease. This study measured change in hepatic function (galactose elimination capacity [GEC]), liver blood flow (low dose galactose clearance: flow), hepatic volume (CT scan; volume) and morphology after OLT. The aim was to measure the physiologic response after OLT and compare this response with that after selective shunt (SS) and sclerotherapy (ES) to determine which patients should receive specific therapy. Between January 1987 and November 1988, 37 patients underwent OLT. Operative mortality was 18%, which was similar to that of SS in Child's C cirrhotics. GEC and volume were less in transplant patients than in cirrhotics treated with SS or ES. GEC, flow, and volume normalized after OLT; GEC was preserved after ES and SS, but volume decreased. Three preoperative patterns were observed that can aid in selection of OLT candidates. Patients with chronic cirrhosis (chronic active hepatitis; cryptogenic) need OLT when GEC is less than or equal to 225 mg/min and volume is less than or equal to 50% normal. Patients with Budd-Chiari Syndrome require OLT if cirrhosis has evolved. Patients with sclerosing cholangitis and primary biliary cirrhosis qualify for transplants when complications of the portal hypertensive syndrome develop. The studies can also direct therapy for ES failures. Selective shunt is indicated in those patients with stable disease whose GEC is greater than or equal to 300 mg/min and liver volume is greater than 75% normal; OLT is indicated for cirrhotics with GEC that is less than 225 mg/min and liver volume that is less than 50% predicted normal.

Normothermic extracorporeal perfusion of isolated porcine liver after warm ischaemia: a preliminary report.

PubMed

Bellomo, Rinaldo; Suzuki, Satoshi; Marino, Bruno; Starkey, Graeme K; Chambers, Brenton; Fink, Michael A; Wang, Bao Zhong; Houston, Shane; Eastwood, Glenn; Calzavacca, Paolo; Glassford, Neil; Skene, Alison; Jones, Daryl A; Jones, Robert

2012-09-01

Liver transplantation is a major life-saving procedure, and donation after cardiac death (DCD) has increased the pool of potential liver donors. However, DCD livers are at increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to protect, evaluate and, in future, transplant DCD livers. We conducted proof-of-concept experiments using a DCD model in the pig to assess the short-term (4 hours) feasibility and functional efficacy of NELP. Using extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion, and physiological perfusion pressures, we achieved NELP and evidence of function (bile production, paracetamol removal, maintenance of normal ammonia and lactate levels) for 4 hours in pig livers subjected to 15 and 30 minutes of cardiac arrest before explantation. Our experiments justify further investigations of the feasibility and efficacy of human DCD liver preservation by ex-vivo perfusion.

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.

Radiographic liver size in Pekingese dogs versus other dog breeds.

PubMed

Choi, Jihye; Keh, Seoyeon; Kim, Hyunwook; Kim, Junyoung; Yoon, Junghee

2013-01-01

Differential diagnoses for canine liver disease are commonly based on radiographic estimates of liver size, however little has been published on breed variations. Aims of this study were to describe normal radiographic liver size in Pekingese dogs and to compare normal measurements for this breed with other dog breeds and Pekingese dogs with liver disease. Liver measurements were compared for clinically normal Pekingese (n = 61), normal non-Pekingese brachycephalic (n = 45), normal nonbrachycephalic (n = 71), and Pekingese breed dogs with liver disease (n = 22). For each dog, body weight, liver length, T11 vertebral length, thoracic depth, and thoracic width were measured on right lateral and ventrodorsal abdominal radiographs. Liver volume was calculated using a formula and ratios of liver length/T11 vertebral length and liver volume/body weight ratio were determined. Normal Pekingese dogs had a significantly smaller liver volume/body weight ratio (16.73 ± 5.67, P < 0.05) than normal non-Pekingese brachycephalic breed dogs (19.54 ± 5.03) and normal nonbrachycephalic breed dogs (18.72 ± 6.52). The liver length/T11 vertebral length ratio in normal Pekingese (4.64 ± 0.65) was significantly smaller than normal non-Pekingese brachycephalic breed dogs (5.16 ± 0.74) and normal nonbrachycephalic breed dogs (5.40 ± 0.74). Ratios of liver volume/body weight and liver length/T11 vertebral length in normal Pekingese were significantly different from Pekingese with liver diseases (P < 0.05). Findings supported our hypothesis that Pekingese dogs have a smaller normal radiographic liver size than other breeds. We recommend using 4.64× the length of the T11 vertebra as a radiographic criterion for normal liver length in Pekingese dogs. © 2012 Veterinary Radiology & Ultrasound.

Festival food coma in cystic fibrosis.

PubMed

Pandit, Chetan; Graham, Christie; Selvadurai, Hiran; Gaskin, Kevin; Cooper, Peter; van Asperen, Peter

2013-07-01

Children with cystic fibrosis liver disease and portal hypertension are at risk of developing acute hepatic encephalopathy. Even in the presence of normal synthetic liver function these children may have porto-systemic shunting. We report a case of an adolosecent who had cystic fibrosis liver disease and presented with life threatening hepatinc encephalopathy. This case illustrates that it is necessary to consider an appropriate dietary regimen in adolosecents with liver disease to prevent hepatic decompensation. Copyright © 2012 Wiley Periodicals, Inc.

Assessing the uncertainty in a normal tissue complication probability difference (∆NTCP): radiation-induced liver disease (RILD) in liver tumour patients treated with proton vs X-ray therapy.

PubMed

Kobashi, Keiji; Prayongrat, Anussara; Kimoto, Takuya; Toramatsu, Chie; Dekura, Yasuhiro; Katoh, Norio; Shimizu, Shinichi; Ito, Yoichi M; Shirato, Hiroki

2018-03-01

Modern radiotherapy technologies such as proton beam therapy (PBT) permit dose escalation to the tumour and minimize unnecessary doses to normal tissues. To achieve appropriate patient selection for PBT, a normal tissue complication probability (NTCP) model can be applied to estimate the risk of treatment-related toxicity relative to X-ray therapy (XRT). A methodology for estimating the difference in NTCP (∆NTCP), including its uncertainty as a function of dose to normal tissue, is described in this study using the Delta method, a statistical method for evaluating the variance of functions, considering the variance-covariance matrix. We used a virtual individual patient dataset of radiation-induced liver disease (RILD) in liver tumour patients who were treated with XRT as a study model. As an alternative option for individual patient data, dose-bin data, which consists of the number of patients who developed toxicity in each dose level/bin and the total number of patients in that dose level/bin, are useful for multi-institutional data sharing. It provides comparable accuracy with individual patient data when using the Delta method. With reliable NTCP models, the ∆NTCP with uncertainty might potentially guide the use of PBT; however, clinical validation and a cost-effectiveness study are needed to determine the appropriate ∆NTCP threshold.

Assessing the uncertainty in a normal tissue complication probability difference (∆NTCP): radiation-induced liver disease (RILD) in liver tumour patients treated with proton vs X-ray therapy

PubMed Central

Kobashi, Keiji; Kimoto, Takuya; Toramatsu, Chie; Dekura, Yasuhiro; Katoh, Norio; Shimizu, Shinichi; Ito, Yoichi M; Shirato, Hiroki

2018-01-01

Abstract Modern radiotherapy technologies such as proton beam therapy (PBT) permit dose escalation to the tumour and minimize unnecessary doses to normal tissues. To achieve appropriate patient selection for PBT, a normal tissue complication probability (NTCP) model can be applied to estimate the risk of treatment-related toxicity relative to X-ray therapy (XRT). A methodology for estimating the difference in NTCP (∆NTCP), including its uncertainty as a function of dose to normal tissue, is described in this study using the Delta method, a statistical method for evaluating the variance of functions, considering the variance–covariance matrix. We used a virtual individual patient dataset of radiation-induced liver disease (RILD) in liver tumour patients who were treated with XRT as a study model. As an alternative option for individual patient data, dose-bin data, which consists of the number of patients who developed toxicity in each dose level/bin and the total number of patients in that dose level/bin, are useful for multi-institutional data sharing. It provides comparable accuracy with individual patient data when using the Delta method. With reliable NTCP models, the ∆NTCP with uncertainty might potentially guide the use of PBT; however, clinical validation and a cost-effectiveness study are needed to determine the appropriate ∆NTCP threshold. PMID:29538699

CD24-Positive Cells from Normal Adult Mouse Liver Are Hepatocyte Progenitor Cells

PubMed Central

Qiu, Qiong; Hernandez, Julio Cesar; Dean, Adam M.; Rao, Pulivarthi H.

2011-01-01

The identification of specific cell surface markers that can be used to isolate liver progenitor cells will greatly facilitate experimentation to determine the role of these cells in liver regeneration and their potential for therapeutic transplantation. Previously, the cell surface marker, CD24, was observed to be expressed on undifferentiated bipotential mouse embryonic liver stem cells and 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced oval cells. Here, we describe the isolation and characterization of a rare, primary, nonhematopoietic, CD24+ progenitor cell population from normal, untreated mouse liver. By immunohistochemistry, CD24-expressing cells in normal adult mouse liver were colocalized with CK19-positive cholangiocytes. This nonhematopoietic (CD45−, Ter119−) CD24+ cell population isolated by flow cytometry represented 0.04% of liver cells and expressed several markers of liver progenitor/oval cells. The immunophenotype of nonhematopoietic CD24+ cells was CD133, Dlk, and Sca-1 high, but c-Kit, Thy-1, and CD34 low. The CD24+ cells had increased expression of CK19, epithelial cell adhesion molecule, Sox 9, and FN14 compared with the unsorted cells. Upon transplantation of nonhematopoietic CD24+ cells under the sub-capsule of the livers of Fah knockout mice, cells differentiated into mature functional hepatocytes. Analysis of X and Y chromosome complements were used to determine whether or not fusion of the engrafted cells with the recipient hepatocytes occurred. No cells were found that contained XXXY or any other combination of donor and host sex chromosomes as would be expected if cell fusion had occurred. These results suggested that CD24 can be used as a cell surface marker for isolation of hepatocyte progenitor cells from normal adult liver that are able to differentiate into hepatocytes. PMID:21361791

CD24-positive cells from normal adult mouse liver are hepatocyte progenitor cells.

PubMed

Qiu, Qiong; Hernandez, Julio Cesar; Dean, Adam M; Rao, Pulivarthi H; Darlington, Gretchen J

2011-12-01

The identification of specific cell surface markers that can be used to isolate liver progenitor cells will greatly facilitate experimentation to determine the role of these cells in liver regeneration and their potential for therapeutic transplantation. Previously, the cell surface marker, CD24, was observed to be expressed on undifferentiated bipotential mouse embryonic liver stem cells and 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced oval cells. Here, we describe the isolation and characterization of a rare, primary, nonhematopoietic, CD24+ progenitor cell population from normal, untreated mouse liver. By immunohistochemistry, CD24-expressing cells in normal adult mouse liver were colocalized with CK19-positive cholangiocytes. This nonhematopoietic (CD45-, Ter119-) CD24+ cell population isolated by flow cytometry represented 0.04% of liver cells and expressed several markers of liver progenitor/oval cells. The immunophenotype of nonhematopoietic CD24+ cells was CD133, Dlk, and Sca-1 high, but c-Kit, Thy-1, and CD34 low. The CD24+ cells had increased expression of CK19, epithelial cell adhesion molecule, Sox 9, and FN14 compared with the unsorted cells. Upon transplantation of nonhematopoietic CD24+ cells under the sub-capsule of the livers of Fah knockout mice, cells differentiated into mature functional hepatocytes. Analysis of X and Y chromosome complements were used to determine whether or not fusion of the engrafted cells with the recipient hepatocytes occurred. No cells were found that contained XXXY or any other combination of donor and host sex chromosomes as would be expected if cell fusion had occurred. These results suggested that CD24 can be used as a cell surface marker for isolation of hepatocyte progenitor cells from normal adult liver that are able to differentiate into hepatocytes.

Liver Immunology

PubMed Central

Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric

2014-01-01

The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323

Abnormal Liver Function Tests in an Anorexia Nervosa Patient and an Atypical Manifestation of Refeeding Syndrome.

PubMed

Vootla, Vamshidhar R; Daniel, Myrta

2015-01-01

Refeeding syndrome is defined as electrolyte and fluid abnormalities that occur in significantly malnourished patients when they are refed orally, enterally, or parenterally. The principal manifestations include hypophosphatemia, hypokalemia, vitamin deficiencies, volume overload and edema. This can affect multiple organ systems, such as the cardiovascular, pulmonary, or neurological systems, secondary to the above-mentioned abnormalities. Rarely, patients may develop gastrointestinal symptoms and show abnormal liver function test results. We report the case of a 52-year-old woman with anorexia nervosa who developed refeeding syndrome and simultaneous elevations of liver function test results, which normalized upon the resolution of the refeeding syndrome.

[Pilot study of levosimendan : Effect on liver blood flow and liver function in acute decompensated heart failure].

PubMed

Lenz, K; Gegenhuber, A; Firlinger, F; Lohr, G; Piringer, P

2014-05-01

In a pilot study, 9 patients (39-48 years) with acute decompensated heart failure and a cardiac index (CI) of 1.9 ± 0.3 l/min/m(2) were included after exclusion of an underlying hepatic disease. The effect of levosimendan on liver blood flow and liver function was measured with the LiMON(®) system using the indocyane green plasma disappearance rate (ICG PDR). Levosimendan (Simdax(®)) infusion resulted in a significant increase of the CI, thus, achieving normal ranges of 2.9 ± 0.9 l/min/m(2) after 4 h and 3.3 ± 1 l/min/m(2) (p = 0.003) after 24 h. ICG PDR increased from 8.2 ± 0.8 % to 10.2 + 1.8 % after 4 h and to 11.9 ± 2.9 % after 24 h (p = 0.04). The reason for the early increase in systemic blood flow with no concomitant change in ICG PDR is not clear. A primary increase in liver blood flow with sustained low liver function might be one explanation; a low flow-mediated increased release of cytokines from liver cells with consequent deterioration of liver function is another possible explanation.

Liver Function Tests Following Irreversible Electroporation of Liver Tumors: Experience in 174 Procedures.

PubMed

Froud, Tatiana; Venkat, Shree R; Barbery, Katuzka J; Gunjan, Arora; Narayanan, Govindarajan

2015-09-01

Irreversible electroporation (IRE) is a relatively new ablation modality that uses electric currents to cause cell death. It is commonly used to treat primary and secondary liver tumors in patients with normal liver function and preexisting cirrhosis. Retrospective analysis of 205 procedures sought to evaluate changes in liver function after IRE. Liver function tests (LFTs) results before and after IRE were evaluated from 174 procedures in 124 patients. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase (ALKP), and total bilirubin levels were analyzed. The study was Health Insurance Portability and Accountability Act compliant and institutional review board approved. Informed consent was waived. Changes in LFT results after IRE were compared with baseline and were followed up over time to see if they resolved. Changes were compared with volume of ablation. The greatest perturbations were in transaminase levels. The levels increased sharply within 24 hours after IRE in 129 (74.1%) procedures to extreme levels (more than 20 times the upper limit of normal in one-third of cases). Resolution occurred in 95% and was demonstrated to have occurred by a mean of approximately 10 weeks, many documented as early as 7 days after procedure. ALKP levels elevated in 10% procedures, was slower to increase, and was less likely to resolve. Total bilirubin level demonstrated 2 different patterns of elevation--early and late--and similar to ALKP, it was more likely to remain elevated. There was no increased risk in patients with cirrhosis or cholangiocarcinoma. There was no correlation of levels with volume of ablation. IRE results in significant abnormalities in LFT results, but in most of the cases, these are self-limiting, do not preclude treatment, and are similar to the changes seen after radiofrequency and cryoablation in the liver. Copyright © 2015. Published by Elsevier Inc.

Evaluation of Liver Biomarkers as Prognostic Factors for Outcomes to Yttrium-90 Radioembolization of Primary and Secondary Liver Malignancies.

PubMed

Henrie, Adam M; Wittstrom, Kristina; Delu, Adam; Deming, Paulina

2015-09-01

The objective of this study was to examine indicators of liver function and inflammation for prognostic value in predicting outcomes to yttrium-90 radioembolization (RE). In a retrospective analysis, markers of liver function and inflammation, biomarkers required to stage liver function and inflammation, and data regarding survival, tumor response, and progression after RE were recorded. Univariate regression models were used to investigate the prognostic value of liver biomarkers in predicting outcome to RE as measured by survival, tumor progression, and radiographic and biochemical tumor response. Markers from all malignancy types were analyzed together. A subgroup analysis was performed on markers from patients with metastatic colorectal cancer. A total of 31 patients received RE from 2004 to 2014. Median survival after RE for all malignancies combined was 13.6 months (95% CI: 6.7-17.6 months). Results from an exploratory analysis of patient data suggest that liver biomarkers, including albumin concentrations, international normalized ratio, bilirubin concentrations, and the model for end-stage liver disease score, possess prognostic value in predicting outcomes to RE.

Matrix metalloproteinases in liver injury, repair and fibrosis

PubMed Central

Duarte, Sergio; Baber, John; Fujii, Takehiro; Coito, Ana J.

2015-01-01

The liver is a large highly vascularized organ with a central function in metabolic homeostasis, detoxification, and immunity. Due to its roles, the liver is frequently exposed to various insults which can cause cell death and hepatic dysfunction. Alternatively, the liver has a remarkable ability to self-repair and regenerate after injury. Liver injury and regeneration have both been linked to complex extracellular matrix (ECM) related pathways. While normal degradation of ECM components is an important feature of tissue repair and remodeling, irregular ECM turnover contributes to a variety of liver diseases. Matrix metalloproteinases (MMPs) are the main enzymes implicated in ECM degradation. MMPs not only remodel the ECM, but also regulate immune responses. In this review, we highlight some of the MMP-attributed roles in acute and chronic liver injury and emphasize the need for further experimentation to better understand their functions during hepatic physiological conditions and disease progression. PMID:25599939

Frostbite of the liver: an unrecognized cause of primary non-function?

PubMed

Potanos, Kristina; Kim, Heung Bae

2014-02-01

Appropriate hypothermic packaging techniques are an essential part of organ procurement. We present a case in which deviation from standard packaging practice may have caused sub-zero storage temperatures during transport, resulting in a clinical picture resembling PNF. An 18-month-old male with alpha-1-antitrypsin deficiency underwent liver transplant from a size-matched pediatric donor. Upon arrival at the recipient hospital, ice crystals were noted in the UW solution. The transplant proceeded uneventfully with short ischemia times. Surprisingly, transaminases, INR, and total bilirubin were markedly elevated in the postoperative period but returned to near normal by discharge. Follow-up of over five yr has demonstrated normal liver function. Upon review, it was discovered that organ packaging during recovery included storage in the first bag with only 400 mL of UW solution, and pure ice in the second bag instead of slush. This suggests that the postoperative delayed graft function was related to sub-zero storage of the graft during transport. This is the first report of sub-zero cold injury, or frostbite, following inappropriate packaging of an otherwise healthy donor liver. The clinical picture closely resembled PNF, perhaps implicating this mechanism in other unexpected cases of graft non-function. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

Hepatic encephalopathy in a liver transplant recipient with stable liver function.

PubMed

Arab, Juan Pablo; Meneses, Luis; Pérez, Rosa M; Arrese, Marco; Benítez, Carlos

2013-04-01

Postshunt hepatic encephalopathy after liver transplantation (LT) is an infrequent condition and is commonly associated with portal occlusion or stenosis and the presence of a patent portosystemic shunt. Portal vein stenosis (PVS) or thrombosis (PVT) are uncommon complications after LT. The overall frequency of both complications is reported to be less than 3%. When PVS or PVT develop early after LT, the occlusion of the portal vein can have catastrophic consequences to the graft including acute liver failure and graft loss. Late PVT/PVS are asymptomatic in approximately 50% of the cases and mainly diagnosed by a routine ultrasound. Symptomatic postshunt hepatic encephalopathy (HE) is a very infrequent condition after LT that has been scarcely reported in the literature. We present here the case of a liver recipient with normal graft function who presented with hepatic encephalopathy 3 months after LT with stable liver function but a severe portal stenosis and the presence of a spontaneous portosystemic shunt whose successful endovascular treatment was followed by the complete resolution of the HE.

Hepatic artery pseudoaneurysm with hemobilia following angioplasty after liver transplantation.

PubMed

Narumi, S; Osorio, R W; Freise, C E; Stock, P G; Roberts, J P; Ascher, N L

1998-12-01

A 58-yr-old female with primary biliary cirrhosis underwent an uncomplicated orthotopic liver transplantation. Elevated liver function tests 2 months post-transplantation were evaluated with Doppler ultrasound and a hepatic artery stricture was documented. The hepatic artery stenosis was treated with angioplasty. She developed hemobilia 1 d after the procedure, which was confirmed by angiography. Emergent exploratory laparotomy revealed a pseudoaneurysm at the hepatic artery anastomosis. The pseudoaneurysm was resected and the proper hepatic artery of the graft was anastomosed to the splenic artery of the host using preserved homograft. Her post-operative course was uneventful and liver function tests returned to normal quickly after the surgery. This report will discuss the unusual nature of this complication, and review the problem of hemobilia and pseudoaneurysms in liver transplant recipients.

Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer.

PubMed

Wagner, Philipp; Koch, Moritz; Nummer, Daniel; Palm, Sylvia; Galindo, Luis; Autenrieth, Daniel; Rahbari, Nuh; Schmitz-Winnenthal, Friedrich H; Schirrmacher, Volker; Büchler, Markus W; Beckhove, Philipp; Weitz, Jürgen

2008-08-01

Tumor-infiltrating T lymphocytes (TIL) play an important role in primary colorectal cancer, but their activity in liver metastases has not yet been investigated. The aim of this study was to examine whether tumor-selective infiltration, activation, and cytotoxic activity of TIL can be demonstrated in situ in colorectal liver metastases. TIL were obtained from liver metastases and corresponding normal liver tissue of 16 patients with colorectal liver metastases. Characterization of TIL in situ was performed by multicolor flowcytometric analysis. Presence of tumor antigen-reactive T cells was evaluated by interferon gamma Elispot analysis. TIL in colorectal liver metastases responding against tumor antigens were present in most patients. Although the proportions of CD3(+) T cells were comparable in liver metastasis and normal liver tissue, metastases contained significantly enhanced proportions of CD4(+) cells (49% vs. 22%, P < .001). Among all CD4(+) T helper cells, the proportion of activated (CD4(+)CD25(+)) effector cells was significantly increased in liver metastases (15.0% vs. 7.8%, P = .003). Metastases showed significantly higher proportions of activated (CD69(+) [70.1% vs. 49.8%, P = .02] and CD25(+) [4.1% vs. .6%, P = .06]) and cytotoxically active (CD107a(+)) CD8(+) TIL (3.2% vs. 1.3%, P = .03). Importantly, the presence of activated T helper cells correlated with the frequencies of cytotoxic T lymphocytes that exerted cytotoxic activity in situ (P = .02). CD4(+) and CD8(+) TIL are selectively activated in liver metastases, and cytotoxic T lymphocytes exert tumor-selective cytotoxic activity in situ in the presence of activated T helper cells, suggesting the requirement of in-situ-activated T helper cells for efficient cytotoxic T lymphocytes effector function.

Abnormal Liver Function Tests in an Anorexia Nervosa Patient and an Atypical Manifestation of Refeeding Syndrome

PubMed Central

Vootla, Vamshidhar R.; Daniel, Myrta

2015-01-01

Refeeding syndrome is defined as electrolyte and fluid abnormalities that occur in significantly malnourished patients when they are refed orally, enterally, or parenterally. The principal manifestations include hypophosphatemia, hypokalemia, vitamin deficiencies, volume overload and edema. This can affect multiple organ systems, such as the cardiovascular, pulmonary, or neurological systems, secondary to the above-mentioned abnormalities. Rarely, patients may develop gastrointestinal symptoms and show abnormal liver function test results. We report the case of a 52-year-old woman with anorexia nervosa who developed refeeding syndrome and simultaneous elevations of liver function test results, which normalized upon the resolution of the refeeding syndrome. PMID:26351414

Betaine chemistry, roles, and potential use in liver disease.

PubMed

Day, Christopher R; Kempson, Stephen A

2016-06-01

Betaine is the trimethyl derivative of glycine and is normally present in human plasma due to dietary intake and endogenous synthesis in liver and kidney. Betaine is utilized in the kidney primarily as an osmoprotectant, whereas in the liver its primary role is in metabolism as a methyl group donor. In both organs, a specific betaine transporter mediates cellular uptake of betaine from plasma. The abundance of both betaine and the betaine transporter in liver greatly exceeds that of other organs. The remarkable contributions of betaine to normal human and animal health are summarized together with a discussion of the mechanisms and potential beneficial effects of dietary betaine supplements on liver disease. A significant amount of data from animal models of liver disease indicates that administration of betaine can halt and even reverse progression of the disruption of liver function. Betaine is well-tolerated, inexpensive, effective over a wide range of doses, and is already used in livestock feeding practices. The accumulated data indicate that carefully controlled additional investigations in humans are merited. The focus should be on the long-term use of betaine in large patient populations with liver diseases characterized by development of fatty liver, especially non-alcoholic fatty liver disease and alcoholic liver disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimizing global liver function in radiation therapy treatment planning

NASA Astrophysics Data System (ADS)

Wu, Victor W.; Epelman, Marina A.; Wang, Hesheng; Romeijn, H. Edwin; Feng, Mary; Cao, Yue; Ten Haken, Randall K.; Matuszak, Martha M.

2016-09-01

Liver stereotactic body radiation therapy (SBRT) patients differ in both pre-treatment liver function (e.g. due to degree of cirrhosis and/or prior treatment) and radiosensitivity, leading to high variability in potential liver toxicity with similar doses. This work investigates three treatment planning optimization models that minimize risk of toxicity: two consider both voxel-based pre-treatment liver function and local-function-based radiosensitivity with dose; one considers only dose. Each model optimizes different objective functions (varying in complexity of capturing the influence of dose on liver function) subject to the same dose constraints and are tested on 2D synthesized and 3D clinical cases. The normal-liver-based objective functions are the linearized equivalent uniform dose (\\ell \\text{EUD} ) (conventional ‘\\ell \\text{EUD} model’), the so-called perfusion-weighted \\ell \\text{EUD} (\\text{fEUD} ) (proposed ‘fEUD model’), and post-treatment global liver function (GLF) (proposed ‘GLF model’), predicted by a new liver-perfusion-based dose-response model. The resulting \\ell \\text{EUD} , fEUD, and GLF plans delivering the same target \\ell \\text{EUD} are compared with respect to their post-treatment function and various dose-based metrics. Voxel-based portal venous liver perfusion, used as a measure of local function, is computed using DCE-MRI. In cases used in our experiments, the GLF plan preserves up to 4.6 % ≤ft(7.5 % \\right) more liver function than the fEUD (\\ell \\text{EUD} ) plan does in 2D cases, and up to 4.5 % ≤ft(5.6 % \\right) in 3D cases. The GLF and fEUD plans worsen in \\ell \\text{EUD} of functional liver on average by 1.0 Gy and 0.5 Gy in 2D and 3D cases, respectively. Liver perfusion information can be used during treatment planning to minimize the risk of toxicity by improving expected GLF; the degree of benefit varies with perfusion pattern. Although fEUD model optimization is computationally inexpensive and often achieves better GLF than \\ell \\text{EUD} model optimization does, the GLF model directly optimizes a more clinically relevant metric and can further improve fEUD plan quality.

Hepatoprotective effect of manual acupuncture at acupoint GB34 against CCl4-induced chronic liver damage in rats

PubMed Central

Yim, Yun-Kyoung; Lee, Hyun; Hong, Kwon-Eui; Kim, Young-Il; Lee, Byung-Ryul; Kim, Tae-Han; Yi, Ji-Young

2006-01-01

AIM: To investigate the hepatoprotective effect of manual acupuncture at Yanglingquan (GB34) on CCl4-induced chronic liver damage in rats. METHODS: Rats were injected intraperitoneally with CCl4 (1 mL/kg) and treated with manual acupuncture using reinforcing manipulation techniques at left GB34 (Yanglingquan) 3 times a week for 10 wk. A non-acupoint in left gluteal area was selected as a sham point. To estimate the hepatoprotective effect of manual acupuncture at GB34, measurement of liver index, biochemical assays including serum ALT, AST, ALP and total cholesterol, histological analysis and blood cell counts were conducted. RESULTS: Manual acupuncture at GB34 reduced the liver index, serum ALT, AST, ALP and total cholesterol levels as compared with the control group and the sham acupuncture group. It also increased and normalized the populations of WBC and lymphocytes. CONCLUSION: Manual acupuncture with reinforcing manipulation techniques at left GB34 reduces liver toxicity, protects liver function and liver tissue, and normalizes immune activity in CCl4-intoxicated rats. PMID:16610030

Imaging of irradiated liver with Tc-99m-sulfur colloid and Tc-99m-IDA

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

Gelfand, M.J.; Saha, S.; Aron, B.S.

1981-09-01

In three cases, irradiated regions of liver failed to concentrate Tc-99m-sulfur colloid. In two of these three, imaging with Tc-99m-acetanilide iminodiacetic acid (IDA) agents within five days showed near normal hepatic uptake of this hepatobiliary imaging agent. The hepatic parenchymal cells may be imaged with Tc-99m-IDA in some irradiated regions of liver, despite loss of reticuloendothelial cell function.

Bacterial microflora of normal and telangiectatic livers in cattle.

PubMed

Stotland, E I; Edwards, J F; Roussel, A J; Simpson, R B

2001-07-01

To identify potential bacterial pathogens in normal and telangiectatic livers of mature cattle at slaughter and to identify consumer risk associated with hepatic telangiectasia. 50 normal livers and 50 severely telangiectatic livers. Normal and telangiectatic livers were collected at slaughter for aerobic and anaerobic bacterial culture. Isolates were identified, and patterns of isolation were analyzed. Histologic examination of all livers was performed. Human pathogens isolated from normal and telangiectatic livers included Escherichia coli O157:H7 and group-D streptococci. Most livers in both groups contained bacteria in low numbers; however, more normal livers yielded negative culture results. More group-D streptococci were isolated from the right lobes of telangiectatic livers than from the left lobes, and more gram-negative anaerobic bacteria were isolated from left lobes of telangiectatic livers than from right lobes. All telangiectatic lesions were free of fibrosis, active necrotizing processes, and inflammation. The USDA regulation condemning telangiectatic livers is justified insofar as these livers contain more bacteria than normal livers do; however, normal livers contain similar species of microflora. Development of telangiectasia could not be linked to an infectious process. The finding of E coli O157:H7 in bovine livers suggests that information regarding bacterial content of other offal and muscle may identify sources of this and other potential foodborne pathogens and assist in establishing critical control points for the meat industry.

Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism.

PubMed

Goday Arno, Albert; Farré, Magí; Rodríguez-Morató, Jose; Ramon, Jose M; Pérez-Mañá, Clara; Papaseit, Esther; Civit, Ester; Langohr, Klaus; Lí Carbó, Marcel; Boix, David Benaiges; Nino, Olga Castañer; Le Roux, Juana Antonia Flores; Pera, Manuel; Grande, Luis; de la Torre, Rafael

2017-12-01

The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy (n = 10) or Roux-en-Y gastric bypass (n = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity).

A case of moderate liver enzyme elevation after acute acetaminophen overdose despite undetectable acetaminophen level and normal initial liver enzymes.

PubMed

Bebarta, Vikhyat S; Shiner, Drew C; Varney, Shawn M

2014-01-01

Liver function test (LFT) increase is an early sign of acetaminophen (APAP) toxicity. Typically, when an acute overdose patient is evaluated and has an initial undetectable APAP level and normal liver enzymes, the patient is not treated with N-acetylcysteine, and liver enzymes are not expected to increase later. We report a case of moderate LFT increase despite normal LFTs and an undetectable APAP level after delayed presentation of an APAP ingestion. A 22-year-old male with no medical history ingested 15-25 hydrocodone/APAP tablets (5 mg/500 mg). His suicide note and his bunkmate corroborated the overdose time. He arrived at the emergency department 16 hours after ingestion. At that time, his APAP level was <10 μg/mL, and his liver enzymes were normal [aspartate transaminase (AST) 31 U/L and alanine transaminase (ALT) 34 U/L]. Twenty-nine hours after ingestion, the psychiatry team obtained LFTs (AST 45, ALT 61). He had persistent nausea and diffuse abdominal pain. On repeat analysis, the APAP level at 36 hours was found to be <10 μg/mL, AST 150, and ALT 204. After 2 more days of increasing LFTs and persistent abdominal pain and nausea, the toxicology department was consulted, the patient was transferred to the medicine department, and intravenous N-acetylcysteine was started 66 hours after ingestion. He was treated for 16 hours and had a significant decline in LFTs and symptom resolution. His prothrombin time, bilirubin, lactate, creatinine, and mental status were normal throughout the admission. Other cases of LFT increase were excluded. Our case report illustrates that a moderate increase in liver transaminase may occur despite an initial undetectable APAP level and normal transaminases after a delayed presentation. In our case, no serious clinical effects were reported.

Well Preserved Renal Function in Children With Untreated Chronic Liver Disease.

PubMed

Berg, Ulla B; Németh, Antal

2018-04-01

On the basis of studies with hepatorenal syndrome, it is widely regarded that renal function is impacted in chronic liver disease (CLD). Therefore, we investigated renal function in children with CLD. In a retrospective study of 277 children with CLD, renal function was investigated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), measured as clearance of inulin and para-amino hippuric acid or clearance of iohexol. The data were analyzed with regard to different subgroups of liver disease and to the grade of damage. Hyperfiltration (>+2 SD of controls) was found in the subgroups of progressive familial intrahepatic cholestasis (44%), glycogenosis (75%), and acute fulminant liver failure (60%). Patients with biliary atresia, most other patients with metabolic disease and intrahepatic cholestasis, and those with vascular anomalies and cryptogenic cirrhosis had normal renal function. Decreased renal function was found in patients with Alagille's syndrome (64% < -2 SD). Increased GFR and ERPF was found in patients with elevated transaminases, low prothrombin level, high bile acid concentration, and high aspartate-aminotransferase-to-platelet ratio. Most children with CLD had surprisingly well preserved renal function and certain groups had even hyperfiltration. The finding that children with decompensated liver disease and ongoing liver failure had stable kidney function suggests that no prognostic markers of threatening hepatorenal syndrome were at hand. Moreover, estimation of GFR based on serum creatinine fails to reveal hyperfiltration.

Corticosteroid therapy in a case of severe cholestasic hepatitis associated with amoxicillin-clavulanate.

PubMed

Herrero-Herrero, José-Ignacio; García-Aparicio, Judit

2010-12-01

Amoxicillin-clavulanate is the most common drug involved in drug-induced liver injury and the single most frequently prescribed product leading to hospitalization for drug-induced liver disease in Spain. The liver damage most frequently associated with amoxicillin-clavulanate is cholestasic type. The latency period between first intake and onset of symptoms is 3-4 weeks on average. A 76-year-old man developed fever, pruritus, and jaundice 3 weeks after having completed treatment with amoxicillin-clavulanate. Liver function tests showed cholestasic hepatitis (up to 50.75 mg/dL of total serum bilirubin level). The ultrasound-guided liver biopsy revealed severe canalicular cholestasis and portal and lobular eosinophilic infiltrates. Prednisone and ursodeoxycholic acid therapy were then prescribed. The patient became symptom-free with normal liver function tests. Amoxicillin-clavulanate can cause hepatocellular, cholestasic, or mixed liver injury. The presence of eosinophilic infiltrates in the liver biopsy and the clinical signs of hypersensitivity in some of the cholestasic cases suggest a pathophysiological immunoallergic mechanism. For this reason, corticosteroid treatment should be considered for patients with severe cholestasic liver injury.

[Effects of acute exposure to high altitude on hepatic function and CYP1A2 and CYP3A4 activities in rats].

PubMed

Li, Wenbin; Jia, Zhengping; Xie, Hua; Zhang, Juanhong; Wang, Yanling; Hao, Ying; Wang, Rong

2014-07-01

To investigate the changes in hepatic functions and activities of CYP1A2 and CYP3A4 in rats after acute exposure to high altitude. Twelve healthy male Wistar rats were randomly divided into control group and exposure group for acute exposure to normal and high altitude (4010 m) environment. Blood samples were collected from the vena orbitalis posterior for detection of the hepatic function. Hepatic pathologies of the rats were examined microscopically with HE staining. Liver microsomes were extracted by differential centrifugation to assess the activities of CYP1A2 and 3A4 using P450-GloTM kit. In rats with acute exposure to high altitude, AST, ALT, and ALP all increased significantly by 48.50%, 47.90%, and 103.02%, respectively, and TP decreased significantly by 17.80% as compared with those in rats maintained in normal altitude environment (P<0.05). Pathological examination of the liver revealed edema of the central vein of the liver and hepatocyte karyopyknosis in rats after acute exposure to high altitude, which also resulted in significantly lowered activities of CYP1A2 and 3A4 in the liver (by 96.56% and 43.53%, respectively). Acute exposure to high altitude can cause obvious liver injuries and lowered activities of CYP1A2 and 3A4 in rats to severely affect drug metabolism in the liver and result in increased concentration, prolonged half-life and reduced clearance of drugs.

Liver Transplantation for Classical Maple Syrup Urine Disease: Long-Term Follow-Up in 37 Patients and Comparative United Network for Organ Sharing Experience

PubMed Central

Mazariegos, George V.; Morton, D. Holmes; Sindhi, Rakesh; Soltys, Kyle; Nayyar, Navdeep; Bond, Geoffrey; Shellmer, Diana; Shneider, Benjamin; Vockley, Jerry; Strauss, Kevin A.

2012-01-01

Objective To assess clinical and neurocognitive function in children who have undergone liver transplantation for classical maple syrup urine disease (MSUD). Study design A total of 35 patients with classical MSUD (age 9.9 ± 7.9 years) underwent liver transplantation between 2004 and 2009. Six patients donated their liver to recipients without MSUD (“domino” transplant). We analyzed clinical outcomes for our cohort and 17 additional cases from the national United Network for Organ Sharing registry; 33 patients completed IQ and adaptive testing before transplantation, and 14 completed testing 1 year later. Results Patient and graft survival were 100% at 4.5 ± 2.2 years of follow-up. Liver function was normal in all patients. Branched-chain amino acid levels were corrected within hours after surgery and remained stable, with leucine tolerance increasing more than 10-fold. All domino transplant recipients were alive and well with normal branched-chain amino acid homeostasis at the time of this report. Patient and graft survival for all 54 patients with MSUD undergoing liver transplantation in the United States during this period were 98%and 96%, respectively. One-third of our patients were mentally impaired (IQ ≤ 70) before transplantation, with no statistically significant change 1 year later. Conclusion Liver transplantation is an effective long-term treatment for classical MSUD and may arrest brain damage, but will not reverse it. PMID:21839471

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.

In vivo antioxidant effect of aqueous root bark, stem bark and leaves extracts of Vitex doniana in CCl4 induced liver damage rats.

PubMed

Adetoro, Kadejo Olubukola; Bolanle, James Dorcas; Abdullahi, Sallau Balarebe; Ahmed, Ozigi Abdulrahaman

2013-05-01

The antioxidant effects of aqueous root bark, stem bark and leaves of Vitex doniana (V. doniana) were evaluated in carbon tetrachloride (CCl4) induced liver damage and non induced liver damage albino rats. A total of 60 albino rats (36 induced liver damage and 24 non induced liver damage) were assigned into liver damage and non liver damage groups of 6 rats in a group. The animals in the CCl4 induced liver damage groups, were induced by intraperitoneal injection with a single dose of CCl4 (148 mg·ml(-1)·kg(-1) body weight) as a 1:1 (v/v) solution in olive oil and were fasted for 36 h before the subsequent treatment with aqueous root bark, stem bark and leaves extracts of V. doniana and vitamin E as standard drug (100 mg/kg body weighy per day) for 21 d, while the animals in the non induced groups were only treated with the daily oral administration of these extracts at the same dose. The administration of CCl4 was done once a week for a period of three weeks. The liver of CCl4 induced not treated group showed that the induction with CCl4, significantly (P<0.05) increased thiobarbituric acid reactive substance (TBARS) and significantly (P<0.05) decreased superoxide dismutase (SOD) and catalase (CAT). However there was no significant (P>0.05) difference between TBARS, SOD and CAT in the liver of the induced treated groups and normal control group. In the kidney, TBARS showed no significant (P>0.05) difference between the normal and the induced groups, SOD was significantly (P<0.05) reduced in the CCl4 group compared to standard drug and normal control groups, CAT was significantly (P<0.05) increased in root and vitamin E groups when compared to induced not treated group. The studies also showed that when the extracts were administered to normal animals, there was no significant (P>0.05) change in the liver and kidney level of TBARS, SOD and CAT compared with the normal control except in the kidney of animals treated with stem extract where TBARS was significantly (P<0.05) lowered compared to control group. The result of the present study suggests that application of V. doniana plant would play an important role in increasing the antioxidant effect and reducing the oxidative damage that formed both in liver and in kidney tissues. However stem bark has potential to improve renal function in normal rats.

Simultaneous liver, pancreas-duodenum and kidney transplantation in a patient with hepatitis B cirrhosis, uremia and insulin dependent diabetes mellitus.

PubMed

Li, Jiang; Guo, Qing-Jun; Cai, Jin-Zhen; Pan, Cheng; Shen, Zhong-Yang; Jiang, Wen-Tao

2017-12-07

Simultaneous liver, pancreas-duodenum, and kidney transplantation has been rarely reported in the literature. Here we present a new and more efficient en bloc technique that combines classic orthotopic liver and pancreas-duodenum transplantation and heterotopic kidney transplantation for a male patient aged 44 years who had hepatitis B related cirrhosis, renal failure, and insulin dependent diabetes mellitus (IDDM). A quadruple immunosuppressive regimen including induction with basiliximab and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids was used in the early stage post-transplant. Postoperative recovery was uneventful and the patient was discharged on the 15 th postoperative day with normal liver and kidney function. The insulin treatment was completely withdrawn 3 wk after operation, and the blood glucose level remained normal. The case findings support that abdominal organ cluster and kidney transplantation is an effective method for the treatment of end-stage liver disease combined with uremia and IDDM.

Steatotic livers are susceptible to normothermic ischemia-reperfusion injury from mitochondrial Complex-I dysfunction

PubMed Central

Chu, Michael JJ; Premkumar, Rakesh; Hickey, Anthony JR; Jiang, Yannan; Delahunt, Brett; Phillips, Anthony RJ; Bartlett, Adam SJR

2016-01-01

AIM: To assess the effects of ischemic preconditioning (IPC, 10-min ischemia/10-min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury (IRI). METHODS: Sixty male Sprague-Dawley rats were fed 8-wk with either control chow or high-fat/high-sucrose diet inducing > 60% mixed steatosis. Three groups (n = 10/group) for each dietary state were tested: (1) the IRI group underwent 60 min partial hepatic ischemia and 4 h reperfusion; (2) the IPC group underwent IPC prior to same standard IRI; and (3) sham underwent the same surgery without IRI or IPC. Hepatic mitochondrial function was analyzed by oxygraphs. Mitochondrial Complex-I, Complex-II enzyme activity, serum alanine aminotransferase (ALT), and histological injury were measured. RESULTS: Steatotic-IRI livers had a greater increase in ALT (2476 ± 166 vs 1457 ± 103 IU/L, P < 0.01) and histological injury following IRI compared to the lean liver group. Steatotic-IRI demonstrated lower Complex-I activity at baseline [78.4 ± 2.5 vs 116.4 ± 6.0 nmol/(min.mg protein), P < 0.001] and following IRI [28.0 ± 6.2 vs 104.3 ± 12.6 nmol/(min.mg protein), P < 0.001]. Steatotic-IRI also demonstrated impaired Complex-I function post-IRI compared to the lean liver IRI group. Complex-II activity was unaffected by hepatic steatosis or IRI. Lean liver mitochondrial function was unchanged following IRI. IPC normalized ALT and histological injury in steatotic livers but had no effect on overall steatotic liver mitochondrial function or individual mitochondrial complex enzyme activities. CONCLUSION: Warm IRI impairs steatotic liver Complex-I activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria. PMID:27217699

Successful treatment of donor-derived hepatitis C viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens.

PubMed

Shah, Ashesh P; Cameron, Andrew; Singh, Pooja; Frank, Adam M; Fenkel, Jonathan M

2017-04-01

We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)-negative donor to three HCV-negative recipients-two renal transplants and one liver. Both renal recipients underwent standard deceased-donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39-year-old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV-infected male partner. Recipient 1 was a 45-year-old man with a history of end-stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62-year-old woman with a history of end-stage renal disease caused by hypertension and insulin-dependent diabetes. Recipient 3 was a 42-year-old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post-transplant follow-up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipient's liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor-derived HCV in transplant recipients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Encephalopathy in acute liver failure resulting from acetaminophen intoxication: new observations with potential therapy.

PubMed

Brusilow, Saul W; Cooper, Arthur J L

2011-11-01

Hyperammonemia is a major contributing factor to the encephalopathy associated with liver disease. It is now generally accepted that hyperammonemia leads to toxic levels of glutamine in astrocytes. However, the mechanism by which excessive glutamine is toxic to astrocytes is controversial. Nevertheless, there is strong evidence that glutamine-induced osmotic swelling, especially in acute liver failure, is a contributing factor: the osmotic gliopathy theory. The object of the current communication is to present evidence for the osmotic gliopathy theory in a hyperammonemic patient who overdosed on acetaminophen. Case report. Johns Hopkins Hospital. A 22-yr-old woman who, 36 hrs before admission, ingested 15 g acetaminophen was admitted to the Johns Hopkins Hospital. She was treated with N-acetylcysteine. Physical examination was unremarkable; her mental status was within normal limits and remained so until approximately 72 hrs after ingestion when she became confused, irritable, and agitated. She was intubated, ventilated, and placed on lactulose. Shortly thereafter, she was noncommunicative, unresponsive to painful stimuli, and exhibited decerebrate posturing. A clinical diagnosis of cerebral edema and increased intracranial pressure was made. She improved very slowly until 180 hrs after ingestion when she moved all extremities. She woke up shortly thereafter. Despite the fact that hyperammonemia is a major contributing factor to the encephalopathy observed in acute liver failure, the patient's plasma ammonia peaked when she exhibited no obvious neurologic deficit. Thereafter, her plasma ammonia decreased precipitously in parallel with a worsening neurologic status. She was deeply encephalopathic during a period when her liver function and plasma ammonia had normalized. Plasma glutamine levels in this patient were high but began to normalize several hours after plasma ammonia had returned to normal. The patient only started to recover as her plasma glutamine began to return to normal. We suggest that the biochemical data are consistent with the osmotic gliopathy theory--high plasma ammonia leads to high plasma glutamine--an indicator of excess glutamine in astrocytes (the site of brain glutamine synthesis). This excess glutamine leads to osmotic stress in these cells. The lag in recovery of brain function presumably reflects time taken for the astrocyte glutamine concentration to return to normal. We hypothesize that an inhibitor of brain glutamine synthesis may be an effective treatment modality for acute liver failure.

Eosin fluorescence: A diagnostic tool for quantification of liver injury.

PubMed

Ali, Hamid; Ali, Safdar; Mazhar, Maryam; Ali, Amjad; Jahan, Azra; Ali, Abid

2017-09-01

Hepatitis is one of the most common life threatening diseases. The diagnosis is mainly based on biochemical analysis such as liver function test. However, histopathological evaluation of liver serves far better for more accurate final diagnosis. The goal of our study was to evaluate the eosin fluorescence pattern in CCl 4 -induced liver injury model compared with normal and different treatment groups. For this purpose, liver tissues were stained with H/E and examined under bright field microscope but the fluorescence microscopy of H/E stained slides provided an interesting fluorescence pattern and was quite helpful in identifying different structures. Interesting fluorescence patterns were obtained with FITC, Texas Red and Dual channel filter cubes that were quite helpful in identifying different morphological features of the liver. During the course of hepatic injury, liver cells undergo necrosis, apoptosis and overall cellular microenvironment is altered due to the modification of proteins and other intracellular molecules. Intensified eosin fluorescence was observed around the central vein of injured liver compared to normal indicating enhanced binding of eosin to the more exposed amino acid residues. To conclude, eosin fluorescence pattern varies with the health status of a tissue and can be used further for the diagnosis and quantification of severity of various liver diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location

PubMed Central

Yovchev, Mladen; Jaber, Fadi L.; Lu, Zhonglei; Patel, Shachi; Locker, Joseph; Rogler, Leslie E.; Murray, John W.; Sudol, Marius; Dabeva, Mariana D.; Zhu, Liang; Shafritz, David A.

2016-01-01

Liver repopulation by transplanted hepatocytes has not been achieved previously in a normal liver microenvironment. Here we report that adult rat hepatocytes transduced ex vivo with a lentivirus expressing a human YapERT2 fusion protein (hYapERT2) under control of the hepatocyte-specific transthyretin (TTR) promoter repopulate normal rat liver in a tamoxifen-dependent manner. Transplanted hepatocytes expand very slowly but progressively to produce 10% repopulation at 6 months, showing clusters of mature hepatocytes that are fully integrated into hepatic parenchyma, with no evidence for dedifferentiation, dysplasia or malignant transformation. Thus, we have developed the first vector designed to regulate the growth control properties of Yap that renders it capable of producing effective cell therapy. The level of liver repopulation achieved has significant translational implications, as it is 2-3x the level required to cure many monogenic disorders of liver function that have no underlying hepatic pathology and is potentially applicable to diseases of other tissues and organs. PMID:26763940

[Change in Perioperative Hemostatic Function in Patients Undergoing Hepatic Resection for Primary and Metastatic Liver Cancer].

PubMed

Komasawa, Nobuyasu; Ueki, Ryusuke; Atagi, Kazuaki; Nishi, Shinichi

2015-08-01

Patients undergoing primary hepatic resection often develop hemostatic dysfunction associated with cirrhosis. We retrospectively surveyed pre- and postoperative prothrombin time (PT) and the PT expressed as international normalized ratio (PT-INR) in 39 patients undergoing primary liver resection. We also compared PT changes between primary and metastatic cancer cases (8 cases). Postoperative PT-INR was 1.40 ± 0.38, which was significantly prolonged compared to preoperative PT-INR of 1.08 ± 0.07. Preoperative PT was over 70% in all 39 patients undergoing primary liver resection, whereas postoperative PT was less than 60% in 13 of 39 patients. No significant difference was found in preoperative PT-INR between primary and metastatic cancer cases, but postoperative PT-INR was significantly prolonged in primary cancer cases. Patients undergoing primary liver resection are susceptible to hemostatic dysfunction, even with preoperative PT levels within normal limits.

Protective effects of ACLF sera on metabolic functions and proliferation of hepatocytes co-cultured with bone marrow MSCs in vitro

PubMed Central

Shi, Xiao-Lei; Gu, Jin-Yang; Zhang, Yue; Han, Bing; Xiao, Jiang-Qiang; Yuan, Xian-Wen; Zhang, Ning; Ding, Yi-Tao

2011-01-01

AIM: To investigate whether the function of hepatocytes co-cultured with bone marrow mesenchymal stem cells (MSCs) could be maintained in serum from acute-on-chronic liver failure (ACLF) patients. METHODS: Hepatocyte supportive functions and cytotoxicity of sera from 18 patients with viral hepatitis B-induced ACLF and 18 healthy volunteers were evaluated for porcine hepatocytes co-cultured with MSCs and hepatocyte mono-layered culture, respectively. Chemokine profile was also examined for the normal serum and liver failure serum. RESULTS: Hepatocyte growth factor (HGF) and Tumor necrosis factor; tumor necrosis factor (TNF)-α were remarkably elevated in response to ACLF while epidermal growth factor (EGF) and VEGF levels were significantly decreased. Liver failure serum samples induced a higher detachment rate, lower viability and decreased liver support functions in the homo-hepatocyte culture. Hepatocytes co-cultured with MSCs could tolerate the cytotoxicity of the serum from ACLF patients and had similar liver support functions compared with the hepatocytes cultured with healthy human serum in vitro. In addition, co-cultured hepatocytes maintained a proliferative capability despite of the insult from liver failure serum. CONCLUSION: ACLF serum does not impair the cell morphology, viability, proliferation and overall metabolic capacities of hepatocyte co-cultured with MSCs in vitro. PMID:21633639

Metastases to the Liver from Neuroendocrine Tumors: Effect of Duration of Scan Acquisition on CT Perfusion Values

PubMed Central

Hobbs, Brian P.; Chandler, Adam G.; Anderson, Ella F.; Herron, Delise H.; Charnsangavej, Chusilp; Yao, James

2013-01-01

Purpose To assess the effects of acquisition duration on computed tomographic (CT) perfusion parameter values in neuroendocrine liver metastases and normal liver tissue. Materials and Methods This retrospective study was institutional review board approved, with waiver of informed consent. CT perfusion studies in 16 patients (median age, 57.5 years; range, 42.0–69.7 years), including six men (median, 54.1 years; range, 42.0–69.7), and 10 women (median, 59.3 years; range 43.6–66.3), with neuroendocrine liver metastases were analyzed by means of distributed parametric modeling to determine tissue blood flow, blood volume, mean transit time, permeability, and hepatic arterial fraction for tumors and normal liver tissue. Analyses were undertaken with acquisition time of 12–590 seconds. Nonparameteric regression analyses were used to evaluate the functional relationships between CT perfusion parameters and acquisition duration. Evidence for time invariance was evaluated for each parameter at multiple time points by inferring the fitted derivative to assess its proximity to zero as a function of acquisition time by using equivalence tests with three levels of confidence (20%, 70%, and 90%). Results CT perfusion parameter values varied, approaching stable values with increasing acquisition duration. Acquisition duration greater than 160 seconds was required to obtain at least low confidence stability in any of the CT perfusion parameters. At 160 seconds of acquisition, all five CT perfusion parameters stabilized with low confidence in tumor and normal tissues, with the exception of hepatic arterial fraction in tumors. After 220 seconds of acquisition, there was stabilization with moderate confidence for blood flow, blood volume, and hepatic arterial fraction in tumors and normal tissue, and for mean transit time in tumors; however, permeability values did not satisfy the moderate stabilization criteria in both tumors and normal tissue until 360 seconds of acquisition. Blood flow, mean transit time, permeability, and hepatic arterial fraction were significantly different between tumor and normal tissue at 360 seconds (P < .001). Conclusion CT perfusion parameter values are affected by acquisition duration and approach progressively stable values with increasing acquisition times. © RSNA, 2013 Online supplemental material is available for this article. PMID:23824990

Protein C activity and postoperative metabolic liver function after liver transplantation.

PubMed

Wagener, G; Diaz, G; Guarrera, J V; Minhaz, M; Renz, J F; Sladen, R N

2012-06-01

Protein C is a natural thrombin antagonist produced by hepatocytes. Its levels are low in liver failure and predispose patients to increased risk for thrombosis. Little is known about the relationship between protein C activity and hepatic function after orthotopic liver transplantation (OLT). We measured protein C activity of 41 patients undergoing liver transplantation by the Staclot method (normal range, 70%-130%) preoperatively and then daily on postoperative days (POD) 0-5. The mean protein C activity was low before OLT (34.3 ± 4.3%) and inversely correlated with the preoperative Model for End-Stage Liver Disease score (Spearman's r = -0.643; P < .0001). Mean activity increased significantly on POD 1 (58.9 ± 4.5%), and remained above preoperative levels through POD 5. Ten patients developed metabolic liver dysfunction defined by a serum total bilirubin >5 mg/dL on POD 7. These patients had significantly lower protein C activity from POD 3 (47.2 ± 9.6% vs 75.9 ± 5.8%; P = .01) to POD 5. Preoperative protein C activity correlated inversely with the severity of liver failure as indicated by preoperative MELD score. Protein C activity recovered rapidly in patients with good allograft function but remained significantly lower in patients who had limited metabolic function as evidenced by increased total bilirubin levels. Copyright © 2012 Elsevier Inc. All rights reserved.

Effect of evacuation on liver function after the Fukushima Daiichi Nuclear Power Plant accident: The Fukushima Health Management Survey.

PubMed

Takahashi, Atsushi; Ohira, Tetsuya; Hosoya, Mitsuaki; Yasumura, Seiji; Nagai, Masato; Ohira, Hiromasa; Hashimoto, Shigeatsu; Satoh, Hiroaki; Sakai, Akira; Ohtsuru, Akira; Kawasaki, Yukihiko; Suzuki, Hitoshi; Kobashi, Gen; Ozasa, Kotaro; Yamashita, Shunichi; Kamiya, Kenji; Abe, Masafumi

2017-04-01

The Great East Japan Earthquake and subsequent Fukushima Daiichi Nuclear Power Plant accident caused residents to switch from their normal lives to lives focused on evacuation. We evaluated liver function before and after this disaster to elucidate the effects of evacuation on liver function. This study was a longitudinal survey of 26,006 Japanese men and women living near the Fukushima Daiichi Nuclear Power Plant. This study was undertaken using data from annual health checkups conducted for persons aged 40-90 years between 2008 and 2010. Follow-up examinations were conducted from June 2011 to the end of March 2013, with a mean follow up of 1.6 years. Changes in liver function before and after the disaster were compared among evacuees and non-evacuees. We also assessed groups according to alcohol drinking status. The prevalence of liver dysfunction significantly increased in all participants from 16.4% before to 19.2% after the disaster. The incidence of liver dysfunction was significantly higher in evacuees than in non-evacuees. Multivariate logistic regression analysis showed that evacuation was significantly associated with liver dysfunction among residents. This is the first study to show that evacuation due to the Fukushima Daiichi nuclear power plant disaster was associated with an increase in liver dysfunction. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Doxorubicin coupled to lactosaminated albumin: Effects on rats with liver fibrosis and cirrhosis.

PubMed

Di Stefano, G; Fiume, L; Domenicali, M; Busi, C; Chieco, P; Kratz, F; Lanza, M; Mattioli, A; Pariali, M; Bernardi, M

2006-06-01

The conjugate of doxorubicin with lactosaminated human albumin has the potential of increasing the doxorubicin efficacy in the treatment of hepatocellular carcinomas expressing the asialoglycoprotein receptor. However, coupled doxorubicin also accumulates in the liver, which might damage hepatocytes. To verify whether coupled doxorubicin impairs liver function in rats with liver fibrosis and cirrhosis. Coupled doxorubicin was administered using the same schedule which exerted an antineoplastic effect on rat hepatocellular carcinomas (4-weekly injections of doxorubicin at 1 microg/g). Liver fibrosis/cirrhosis was produced by carbon tetrachloride (CCl4) poisoning. Liver samples were studied histologically. Serum parameters of liver function and viability were determined. In normal rats, administration of coupled doxorubicin neither caused microscopic changes of hepatocytes nor modified serum liver parameters. In rats with fibrosis/cirrhosis, although a selective doxorubicin accumulation within the liver followed coupled doxorubicin administration, the drug did not have a detrimental effect on the histology of the liver and, among serum liver tests, only alanine aminotransferase and aspartate aminotransferase levels were moderately modified. Coupled doxorubicin can be administered to rats with liver fibrosis/cirrhosis without inducing a severe liver damage. If further studies will confirm the efficacy and safety of this compound, coupled doxorubicin therapy may open a new perspective in the treatment of hepatocellular carcinoma.

Adrenal and liver in normal and cld/cld mice synthesize and secrete hepatic lipase, but the lipase is inactive in cld/cld mice.

PubMed

Schultz, C J; Blanchette-Mackie, E J; Scow, R O

2000-02-01

Combined lipase deficiency (cld) is a recessive mutation in mice that causes a severe lack of lipoprotein lipase (LPL) and hepatic lipase (HL) activities, hyperlipemia, and death within 3 days after birth. Earlier studies showed that inactive LPL and HL were synthesized by cld/cld tissues and that LPL synthesized by cld/cld brown adipocytes was retained in their ER. We report here a study of HL in liver, adrenal, and plasma of normal newborn and cld/cld mice. Immunofluorescence studies showed HL was present in extracellular space, but not in cells, in liver and adrenal of both normal and cld/cld mice. When protein secretion was blocked with monensin, HL was retained intracellularly in liver cell cultures and in incubated adrenal tissues of both groups of mice. These findings demonstrated that HL was synthesized and secreted by liver and adrenal cells in normal newborn and cld/cld mice. HL activities in liver, adrenal, and plasma in cld/cld mice were very low, <8% of that in normal newborn mice, indicating that HL synthesized and secreted by cld/cld cells was inactive. Livers of both normal newborn and cld/cld mice synthesized LPL, but the level of LPL activity in cld/cld liver was very low, <9% of that in normal liver. Immunofluorescence studies showed that LPL was present intracellularly in liver of cld/cld mice, indicating that LPL was synthesized but not secreted by cld/cld liver cells. Immunofluorescent LPL was not found in normal newborn liver cells unless the cells were treated with monensin, thus demonstrating that normal liver cells synthesized and secreted LPL. Livers of both groups of mice contained an unidentified alkaline lipase activity which accounted for 34-54% of alkaline lipase activity in normal and 65% of that in cld/cld livers. Our findings indicate that liver and adrenal cells synthesized and secreted HL in both normal newborn and cld/cld mice, but the lipase was inactive in cld/cld mice. That cld/cld liver cells secreted inactive HL while retaining inactive LPL indicates that these closely related lipases were processed differently.

Transplantation of Declined Liver Allografts Following Normothermic Ex-Situ Evaluation.

PubMed

Mergental, H; Perera, M T P R; Laing, R W; Muiesan, P; Isaac, J R; Smith, A; Stephenson, B T F; Cilliers, H; Neil, D A H; Hübscher, S G; Afford, S C; Mirza, D F

2016-11-01

The demand for liver transplantation (LT) exceeds supply, with rising waiting list mortality. Utilization of high-risk organs is low and a substantial number of procured livers are discarded. We report the first series of five transplants with rejected livers following viability assessment by normothermic machine perfusion of the liver (NMP-L). The evaluation protocol consisted of perfusate lactate, bile production, vascular flows, and liver appearance. All livers were exposed to a variable period of static cold storage prior to commencing NMP-L. Four organs were recovered from donors after circulatory death and rejected due to prolonged donor warm ischemic times; one liver from a brain-death donor was declined for high liver function tests (LFTs). The median (range) total graft preservation time was 798 (range 724-951) min. The transplant procedure was uneventful in every recipient, with immediate function in all grafts. The median in-hospital stay was 10 (range 6-14) days. At present, all recipients are well, with normalized LFTs at median follow-up of 7 (range 6-19) months. Viability assessment of high-risk grafts using NMP-L provides specific information on liver function and can permit their transplantation while minimizing the recipient risk of primary graft nonfunction. This novel approach may increase organ availability for LT. © Copyright 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

Liver function in cats with hyperthyroidism before and after 131I therapy.

PubMed

Berent, Allyson C; Drobatz, Kenneth J; Ziemer, Lisa; Johnson, Victoria S; Ward, Cynthia R

2007-01-01

The clinical significance of high serum concentration or activity of markers of liver damage in cats with hyperthyroidism is unknown. To evaluate serum markers of liver function and damage, and ultrasonographic changes in cats with hyperthyroidism and with high liver enzymes, and to determine if abnormalities resolve after treatment with 131I. Nineteen cats with hyperthyroidism (15 with high serum activities of liver enzymes) and 4 age-matched healthy control cats. Serum bile acids, albumin, ammonia, cholesterol, and blood urea nitrogen concentrations, and activities of liver-derived enzymes, and blood glucose concentrations were measured before and after 131I therapy. These values were compared with those of cats that were euthyroid. In addition, gross liver parenchymal changes detected by abdominal ultrasonographic examination, before and after 131I therapy were evaluated. High serum liver enzyme activities were not associated with abnormalities in hepatic parenchyma and liver functional variables, regardless of the degree of increase. Serum liver enzyme activities return to normal after control of hyperthyroidism with 131I therapy. Cats with hyperthyroidism have a significantly higher serum fasting ammonia concentration than cats who were euthyroid (P = .019). Cats with hyperthyroidism also have significantly lower serum cholesterol (P = .005) and glucose (P = .002) concentrations before compared with after 131I therapy. Nine of 19 cats with hyperthyroidism had trace ketonuria. These results demonstrate that extensive examination for hepatobiliary disease in most cats with hyperthyroidism is unnecessary.

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

Choi, Y.; Hawkins, R.A.; Huang, S.C.

The liver plays an important role in glucose homeostasis. PET studies with 2-[F-18]fluro-2-deoxy-D-glucose (FDG) of the liver (e.g., in neoplasms) require an understanding of the effects of dietary conditions on hepatic FDG uptake. Twenty studies were performed on 10 normal volunteers (ages 24 {+-} 4) after fasting 4 to 19 hr and again after oral consumption of 100 g of dextrose to investigate tracer kinetic model configurations of FDG in the normal liver and to evaluate the impact of oral glucose on liver in normal subjects. Dynamic PET images were acquired for about 1 hr using a Siemens/CTI 931 tomograph.more » A three-compartment model with an input function delay time parameter was the statistically preferred model configuration. The model estimated transport rate constant from plasma to liver, K{sub 1}, increased significantly (p < 0.05) from 0.864 {+-} 0.136 ml/min/g in fasting studies to 1.058 {+-} 0.269 ml/min/g in postglucose studies. Glucose loading also significantly increased (p < 0.01) the rate constant for FDG phosphorylation, k{sub 3}, from 0.005 {+-} 0.003 min{sup -1} in fasting studies to 0.013 {+-} 0.007 min{sup -1} in postglucose administration and, consequently, significantly increased both the phosphorylation fraction (k{sub 3}/(k{sub 2} + k{sub 3})) and the influx constant (K{sub 1}k{sub 3}/(k{sub 2} + k{sub 3})). No significant differences in the liver-to-plasma transport rate constant, k{sub 2}, dephosphorylation constant, k{sub 4}, or distribution volume of FDG (K{sub 1}/(k{sub 2} + k{sub 3})) were observed. Dynamic FDG-PET studies can be used to evaluate kinetics of liver glucose metabolism. The results indicate that dietary conditions have a significant effect on hepatic FDG kinetics. Because of the higher net FDG uptake by normal liver after glucose loading, fasting conditions are preferred for FDG liver tumor studies to increase the tumor-to-background contrast. 22 refs., 2 figs., 3 tabs.« 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.

Living Donor Liver Transplantation for Unresectable Liver Adenomatosis Associated with Congenital Absence of Portal Vein: A Case Report and Literature Review.

PubMed

Brasoveanu, Vladislav; Ionescu, Mihnea Ioan; Grigorie, Razvan; Mihaila, Mariana; Bacalbasa, Nicolae; Dumitru, Radu; Herlea, Vlad; Iorgescu, Andreea; Tomescu, Dana; Popescu, Irinel

2015-09-19

Abernethy malformation (AM), or congenital absence of portal vein (CAPV), is a very rare disease which tends to be associated with the development of benign or malignant tumors, usually in children or young adults. We report the case of a 21-year-old woman diagnosed with type Ib AM (portal vein draining directly into the inferior vena cava) and unresectable liver adenomatosis. The patient presented mild liver dysfunction and was largely asymptomatic. Living donor liver transplantation was performed using a left hemiliver graft from her mother. Postoperatively, the patient attained optimal liver function and at 9-month follow-up has returned to normal life. We consider that living donor liver transplantation is the best therapeutic solution for AM associated with unresectable liver adenomatosis, especially because compared to receiving a whole liver graft, the waiting time on the liver transplantation list is much shorter.

Is liver SUV stable over time in ¹⁸F-FDG PET imaging?

PubMed

Laffon, Eric; Adhoute, Xavier; de Clermont, Henri; Marthan, Roger

2011-12-01

This work investigated whether (18)F-FDG PET standardized uptake value (SUV) is stable over time in the normal human liver. The SUV-versus-time curve, SUV(t), of (18)F-FDG in the normal human liver was derived from a kinetic model analysis. This derivation involved mean values of (18)F-FDG liver metabolism that were obtained from a patient series (n = 11), and a noninvasive population-based input function was used in each individual. Mean values (±95% reliability limits) of the (18)F-FDG uptake and release rate constant and of the fraction of free tracer in blood and interstitial volume were as follows: K = 0.0119 mL·min(-1)·mL(-1) (±0.0012), k(R) = 0.0065·min(-1) (±0.0009), and F = 0.21 mL·mL(-1) (±0.11), respectively. SUV(t) (corrected for (18)F physical decay) was derived from these mean values, showing that it smoothly peaks at 75-80 min on average after injection and that it is within 5% of the peak value between 50 and 110 min after injection. In the normal human liver, decay-corrected SUV(t) remains nearly constant (with a reasonable ±2.5% relative measurement uncertainty) if the time delay between tracer injection and PET acquisition is in the range of 50-110 min. In current clinical practice, the findings suggest that SUV of the normal liver can be used for comparison with SUV of suspected malignant lesions, if comparison is made within this time range.

Functional pitch of a liver: fatty liver disease diagnosis with photoacoustic spectrum analysis

NASA Astrophysics Data System (ADS)

Xu, Guan; Meng, Zhuoxian; Lin, Jiandie; Carson, Paul; Wang, Xueding

2014-03-01

To provide more information for classification and assessment of biological tissues, photoacoustic spectrum analysis (PASA) moves beyond the quantification of the intensities of the photoacoustic (PA) signals by the use of the frequency-domain power distribution, namely power spectrum, of broadband PA signals. The method of PASA quantifies the linear-fit to the power spectrum of the PA signals from a biological tissue with 3 parameters, including intercept, midband-fit and slope. Intercept and midband-fit reflect the total optical absorption of the tissues whereas slope reflects the heterogeneity of the tissue structure. Taking advantage of the optical absorption contrasts contributed by lipid and blood at 1200 and 532 nm, respectively and the heterogeneous tissue microstructure in fatty liver due to the lipid infiltration, we investigate the capability of PASA in identifying histological changes of fatty livers in mouse model. 6 and 9 pairs of normal and fatty liver tissues from rat models were examined by ex vivo experiment with a conventional rotational PA measurement system. One pair of rat models with normal and fatty livers was examined non-invasively and in situ with our recently developed ultrasound and PA parallel imaging system. The results support our hypotheses that the spectrum analysis of PA signals can provide quantitative measures of the differences between the normal and fatty liver tissues and that part of the PA power spectrum can suffice for characterization of microstructures in biological tissues. Experimental results also indicate that the vibrational absorption peak of lipid at 1200nm could facilitate fatty liver diagnosis.

Cu isotopic signature in blood serum of liver transplant patients: a follow-up study

NASA Astrophysics Data System (ADS)

Lauwens, Sara; Costas-Rodríguez, Marta; van Vlierberghe, Hans; Vanhaecke, Frank

2016-07-01

End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient’s condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post-LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about -0.50‰). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the δ65Cu value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of liver failure.

Cu isotopic signature in blood serum of liver transplant patients: a follow-up study

PubMed Central

Lauwens, Sara; Costas-Rodríguez, Marta; Van Vlierberghe, Hans; Vanhaecke, Frank

2016-01-01

End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient’s condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post-LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about −0.50‰). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the δ65Cu value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of liver failure. PMID:27468898

Cu isotopic signature in blood serum of liver transplant patients: a follow-up study.

PubMed

Lauwens, Sara; Costas-Rodríguez, Marta; Van Vlierberghe, Hans; Vanhaecke, Frank

2016-07-29

End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient's condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post-LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about -0.50‰). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the δ(65)Cu value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of 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.

[A young boy with elevated aminotransferases in physical examination--Two novel missense mutations associated with Wilson's disease were found].

PubMed

Zhu, Yu; Deng, Si-Yan; Wan, Chao-Min

2015-07-01

A 3-year-old boy had abnormal liver function, which was found in physical examination, for 5 months before admission. He had no symptoms such as anorexia, poor appetite, and jaundice, had normal growth and development, and showed no hepatosplenomegaly. Laboratory examination revealed significantly reduced ceruloplasmin (35 mg/L), as well as negative hepatotropic virus, cytomegalovirus, and Epstein-Barr virus. There were normal muscle enzymes, blood glucose, and blood ammonia and negative liver-specific autoantibodies. The boy had negative K-F ring and normal 24-hour urine copper (0.56 μmol/L). The ATP7B gene testing for the boy, his sister, and their parents detected two novel missense mutations in the boy and his sister, i.e., compound heterozygous mutations in exon 7 (c.2075T>C, p.L692P) and exon 13 (c.3044T>C, p.L1015P), which were inherited from their father and mother, respectively. Wilson's disease was confirmed by genetic diagnosis in the boy and his sister. The boy and his sister were given a low-copper diet. The boy was administered with penicillamine for decoppering and zinc supplement against copper uptake. His sister received zinc supplement alone because no clinical symptoms were observed. The boy showed normal liver function in the reexamination after 3 months of treatment.

Macrophage function in murine allogeneic bone marrow radiation chimeras in the early phase after transplantation

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

Roesler, J.; Baccarini, M.; Vogt, B.

1989-08-01

We tested several of the functions of macrophages (M phi) in the early phase after allogeneic bone marrow transfer to get information about this important aspect of the nonspecific immune system in the T-cell-deficient recipient. On days 3-5 after transfer, the number of M phi was reduced in the spleen, liver, lungs, and peritoneal cavity (Pe). The phagocytosis of sheep red blood cells (SRBC) by these M phi was normal or even enhanced, as in the case of Pe-M phi. Already on days 8-12 after transfer, the number of M phi in spleen and liver exceeded that of controls, whereasmore » the number was still reduced in lungs and Pe. We examined their ability to kill P815 tumor cells, to produce tumor necrosis factor-alpha (TNF alpha), to phagocytose SRBC, to produce reactive oxygen intermediates (ROI) in vitro and to kill Listeria monocytogenes in vivo. Most functions were normal and often even enhanced, depending on the organ origin, but the ability of Pe-M phi to produce ROI was reduced. Proliferative response to macrophage colony-stimulating factor (M-CSF) and killing of YAC-1 tumor cells revealed a high frequency of macrophage precursor cells in the spleen and liver and a high natural killer (NK) activity in the liver. Altogether, enhanced nonspecific immune function, especially preactivated M phi, may enable chimeras to survive attacks by opportunistic pathogens.« less

Targeting Dysbiosis for the Treatment of Liver Disease.

PubMed

Anand, Gobind; Zarrinpar, Amir; Loomba, Rohit

2016-02-01

The gut microbiome is composed of a vast number of microbes in the gastrointestinal tract, which benefit host metabolism, aid in digestion, and contribute to normal immune function. Alterations in microbial composition can result in intestinal dysbiosis, which has been implicated in several diseases including obesity, inflammatory bowel disease, and liver diseases. Over the past several years, significant interactions between the intestinal microbiota and liver have been discovered, with possible mechanisms for the development as well as progression of liver disease and promising therapeutic targets to either prevent or halt the progression of liver disease. In this review the authors examine mechanisms of dysbiosis-induced liver disease; highlight current knowledge regarding the role of dysbiosis in nonalcoholic liver disease, alcoholic liver disease, and cirrhosis; and discuss potential therapeutic targets. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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.

Molecular and functional characterization of CD133+ stem/progenitor cells infused in patients with end-stage liver disease reveals their interplay with stromal liver cells.

PubMed

Catani, Lucia; Sollazzo, Daria; Bianchi, Elisa; Ciciarello, Marilena; Antoniani, Chiara; Foscoli, Licia; Caraceni, Paolo; Giannone, Ferdinando Antonino; Baldassarre, Maurizio; Giordano, Rosaria; Montemurro, Tiziana; Montelatici, Elisa; D'Errico, Antonia; Andreone, Pietro; Giudice, Valeria; Curti, Antonio; Manfredini, Rossella; Lemoli, Roberto Massimo

2017-12-01

Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133 + stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133 + cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133 + and LX-2 hepatic stellate cells. We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133 + SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133 + SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. We demonstrated that the interaction between CD133 + SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Liver injury in hypervitaminosis A: Evidence for activation of Kupffer cell function

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

Sim, W.L.W.

1988-01-01

The most important and novel finding of this work was enhanced liver Kupffer cell phagocytic and metabolic function by hypervitaminosis A. An animal model of hypervitaminosis A was developed in male Sprague-Dawley rats gavaged with 250,000 I.U. retinol/kg body weight/day for 3 weeks. Presence of hypervitaminosis A was indicated by characteristic changes in the fur coat, presence of brittle bones and spontaneous fractures and a significant increase in plasma and liver concentrations of retinyl palmitate while retinol levels remained the same as in controls. Hypervitaminosis A did not cause severe liver abnormalities as reflected by normal plasma glutamate pyruvate transaminasemore » activity and bilirubin. The main change was a marked increase in size of the fat or Vitamin A storing cells. Measurement of clearance from blood of indocyanine green and {sup 99m}Tc-disofenin indicated this hepatocyte function was normal. Kupffer cell phagocytic function was enhanced in hypervitaminosis A as determined by clearance from blood of {sup 99m}Tc-sulfur colloid. In vitro, there was also evidence that treatment with high doses of Vitamin A activated or enhanced Kupffer cell function. Kupffer cells from control and Vitamin A treated rats were isolated by enzymatic dispersion, purified by centrifugal elutriation, and placed in culture. Activation was indicated by (1) increased phagocytosis of {sup 51}Cr-labeled opsonized sheep red blood cells (2) enhanced release of superoxide anion and (3) enhanced production of tumor cytolytic factor by Kupffer cells from Vitamin A treated rats.« less

Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants.

PubMed

Feng, Sandy; Ekong, Udeme D; Lobritto, Steven J; Demetris, Anthony J; Roberts, John P; Rosenthal, Philip; Alonso, Estella M; Philogene, Mary C; Ikle, David; Poole, Katharine M; Bridges, Nancy D; Turka, Laurence A; Tchao, Nadia K

2012-01-18

Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03). In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology.

A novel mutation in the FGB: c.1105C>T turns the codon for amino acid Bβ Q339 into a stop codon causing hypofibrinogenemia.

PubMed

Marchi, Rita; Brennan, Stephen; Meyer, Michael; Rojas, Héctor; Kanzler, Daniela; De Agrela, Marisela; Ruiz-Saez, Arlette

2013-03-01

Routine coagulation tests on a 14year-old male with frequent epistaxis showed a prolonged thrombin time together with diminished functional (162mg/dl) and gravimetric (122mg/dl) fibrinogen concentrations. His father showed similar aberrant results and sequencing of the three fibrinogen genes revealed a novel heterozygous nonsense mutation in the FGB gene c.1105C>T, which converts the codon for residue Bβ 339Q to stop, causing deletion of Bβ chain residues 339-461. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and RP-HPLC (reverse-phase high-pressure liquid chromatography) of purified fibrinogen showed only normal Aα, Bβ, and γ chains, indicating that molecules with the truncated 37,990Da β chain were not secreted into plasma. Functional analysis showed impaired fibrin polymerization, fibrin porosity, and elasticity compared to controls. By laser scanning confocal microscopy the patient's fibers were slightly thinner than normal. Electrospray ionization mass spectrometry (ESI MS) presented normal sialylation of the oligosaccharide chains, and liver function tests showed no evidence of liver dysfunction that might explain the functional abnormalities. Copyright © 2012 Elsevier Inc. All rights reserved.

[The specificity between "fei and dachang" in the lung injury of rats with ulcerative colitis].

PubMed

Zhu, Li; Wang, Xin-yue; Yang, Xue; Jing, Shan; Zhou, Bo; Huang, Xiu-xia; Jia, Xu

2013-03-01

To observe the features of bronchopulmonary lesions in ulcerative colitis (UC) rats and the specificity with Fei and Dachang, thus providing reliance for the theory of "intestinal diseases involved Fei". The UC rat model was duplicated by using rabbit intestine mucosa tissue allergenic model and TNBS-ethanol model. A normal rat group was set up as the control. The pulmonary functions [including inspiratory resistance (Ri), expiratory resistance (Re), forced vital capacity (FVC); FEV. 2/FVC, maximal voluntary ventilation (MVV), forced expiratory flow rate (FEF25% - 75%)], and indicators of liver and kidney functions [serum alanine aminotransferase (ALT), aspartate amino transferase (AST), blood urea nitrogen (BUN), and creatinine (Cr)] were detected in the two groups. The pathological changes of colon, lung, liver, and kidney were observed in the two groups. Rats in the model group in both acute and chronic stages had weight loss, mucus and loose stool. Partial rats had such symptoms as dyspnea, shortness of breath, and wheezing. Compared with the normal group, the MW, FVC, FEV0.2 and FEF25% -75% in the acute stage; Ri, Re, MVV, FVC, and FEF25% - 75% in the chronic stage all significantly decreased (P <0.05, P <0.01), and FEV0.2/FVC significantly increased in the model group (P <0.05). The pathological results showed interstitial pneumonia and pulmonary interstitial fibrosis in the model group. But the indicators of liver and kidney functions were all in the normal range. No obvious pathological change was seen in the renal and liver tissues in the two groups. UC could specifically induce bronchopulmonary lesions. Lung injury was one of UC's intestinal manifestations. The theory of "Fei and Dachang being interior-exteriorly correlated" was demonstrated from the theory of "intestinal diseases involved Fei".

Vitamin A Status is Associated With T-Cell Responses In Bangladeshi Men

USDA-ARS?s Scientific Manuscript database

Recommendations for vitamin A intake are based on maintaining liver stores of equal to or greater than 0.070 umol/g, which is sufficient to maintain normal vision. We propose that higher levels may be required to maintain normal immune function. To test this hypothesis, we conducted an 8 wk resident...

Pediatric living donor liver transplantation for congenital hepatic fibrosis using a mother's graft with von Meyenburg complex: A case report.

PubMed

Yamada, Naoya; Sanada, Yukihiro; Katano, Takumi; Tashiro, Masahisa; Hirata, Yuta; Okada, Noriki; Ihara, Yoshiyuki; Miki, Atsushi; Sasanuma, Hideki; Urahashi, Taizen; Sakuma, Yasunaru; Mizuta, Koichi

2016-11-28

This is the first report of living donor liver transplantation (LDLT) for congenital hepatic fibrosis (CHF) using a mother's graft with von Meyenburg complex. A 6-year-old girl with CHF, who suffered from recurrent gastrointestinal bleeding, was referred to our hospital for liver transplantation. Her 38-year-old mother was investigated as a living donor and multiple biliary hamartoma were seen on her computed tomography and magnetic resonance imaging scan. The mother's liver function tests were normal and she did not have any organ abnormality, including polycystic kidney disease. LDLT using the left lateral segment (LLS) graft from the donor was performed. The donor LLS graft weighed 250 g; the graft recipient weight ratio was 1.19%. The operation and post-operative course of the donor were uneventful and she was discharged on post-operative day (POD) 8. The graft liver function was good, and the recipient was discharged on POD 31. LDLT using a graft with von Meyenburg complex is safe and useful. Long-term follow-up is needed with respect to graft liver function and screening malignant tumors.

Transient oxidative stress and inflammation after intraperitoneal administration of multiwalled carbon nanotubes functionalized with single strand DNA in rats

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

Clichici, Simona, E-mail: simonaclichici@yahoo.com; Biris, Alexandru Radu; Tabaran, Flaviu

2012-03-15

Multi-walled carbon nanotubes (MWCNTs) are widely used for nanotechnology. Their impact on living organisms is, however, not entirely clarified. Oxidative stress and inflammation seem to be the key mechanisms involved in MWCNTs' cytotoxicity. Until present, pulmonary and skin models were the main tested experimental designs to assess carbon nanotubes' toxicity. The systemic administration of MWCNTs is essential, with respect for future medical applications. Our research is performed on Wistar rats and is focused on the dynamics of oxidative stress parameters in blood and liver and pro-inflammatory cytokines in liver, after single dose (270 mg l{sup −1}) ip administration of MWCNTsmore » (exterior diameter 15–25 nm, interior diameter 10–15 nm, surface 88 m{sup 2} g{sup −1}) functionalized with single strand DNA (ss-DNA). The presence of MWCNTs in blood was assessed by Raman spectroscopy, while in liver histological examination and confocal microscopy were used. It was found that ss-DNA-MWCNTs induce oxidative stress in plasma and liver, with the return of the tested parameters to normal values, 6 h after ip injection of nanotubes, with the exception of reduced glutathione in plasma. The inflammatory cytokines (TNF-α, IL-1β) had a similar pattern of evolution. We also assessed the level of ERK1/2 and the phosphorylation of p65 subunit of NF-kB in liver that had a transient increase and returned to normal at the end of the tested period. Our results demonstrate that ss-DNA-MWCNTs produce oxidative stress and inflammation, but with a transient pattern. Given the fact that antioxidants modify the profile not only for oxidative stress, but also of inflammation, the dynamics of these alterations may be of practical importance for future protective strategies. -- Highlights: ► ss-DNA-MWCNTs ip administration induce oxidative stress in plasma and liver. ► ss-DNA-MWCNTs ip administration determine liver inflammation. ► ERK1/2 and p65 phosphorylated NF-KB increase in liver after MWCNTs ip injection. ► All the alterations, except plasma GSH, return to normal within 6 days.« less

Evidence for organ-specific stem cell microenvironments.

PubMed

Ghinassi, Barbara; Martelli, Fabrizio; Verrucci, Maria; D'Amore, Emanuela; Migliaccio, Giovanni; Vannucchi, Alessandro Maria; Hoffman, Ronald; Migliaccio, Anna Rita

2010-05-01

The X-linked Gata1(low) mutation in mice induces strain-restricted myeloproliferative disorders characterized by extramedullary hematopoiesis in spleen (CD1 and DBA/2) and liver (CD1 only). To assess the role of the microenvironment in establishing this myeloproliferative trait, progenitor cell compartments of spleen and marrow from wild-type and Gata1(low) mice were compared. Phenotype and clonal assay of non-fractionated cells indicated that Gata1(low) mice contain progenitor cell numbers 4-fold lower and 10-fold higher than normal in marrow and spleen, respectively. However, progenitor cells prospectively isolated from spleen, but not from marrow, of Gata1(low) mice expressed colony-forming function in vitro. Therefore, calculation of cloning activity of purified cells demonstrated that the total number of Gata1(low) progenitor cells was 10- to 100-fold lower than normal in marrow and >1,000 times higher than normal in spleen. This observation indicates that Gata1(low) hematopoiesis is favored by the spleen and is in agreement with our previous report that removal of this organ induces wild-type hematopoiesis in heterozygous Gata1(low/+) females (Migliaccio et al., 2009, Blood 114:2107). To clarify if rescue of wild-type hematopoiesis by splenectomy prevented extramedullary hematopoiesis in liver, marrow cytokine expression profile and liver histopathology of splenectomized Gata1(low/+) females were investigated. After splenectomy, the marrow expression levels of TGF-beta, VEGF, osteocalcin, PDGF-alpha, and SDF-1 remained abnormally high while Gata1(low) hematopoiesis was detectable in liver of both CD1 and DBA/2 mutants. Therefore, in the absence of the spleen, Gata1(low) hematopoiesis is supported by the liver suggesting that treatment of myelofibrosis in these animals requires the rescue of both stem cell and microenvironmental functions.

Standard value of ultrasound elastography using acoustic radiation force impulse imaging (ARFI) in healthy liver tissue of children and adolescents.

PubMed

Eiler, J; Kleinholdermann, U; Albers, D; Dahms, J; Hermann, F; Behrens, C; Luedemann, M; Klingmueller, V; Alzen, G F P

2012-10-01

Ultrasound elastography by acoustic radiation force impulse imaging (ARFI) is used in adults for non invasive measurement of liver stiffness, indicating liver diseases like fibrosis. To establish ARFI in children and adolescents we determined standard values of healthy liver tissue and analysed potentially influencing factors. 132 patients between 0 and 17 years old were measured using ARFI. None of them had any liver disease or any other disease that could affect the liver secondarily. All patients had a normal ultrasound scan, a normal BMI and normal liver function tests. The mean value of all ARFI measurements was calculated and potentially influencing factors were analysed. The mean value of all ARFI elastography measurements was 1.16 m/sec (SD ± 0.14 m/sec). Neither age (p = 0.533) nor depth of measurement (p = 0.066) had no significant influence on ARFI values, whereas a significant effect of gender was found with lower ARFI values in females (p = 0.025), however, there was no significant interaction between age groups (before or after puberty) and gender (p = 0.276). There was an interlobar difference with lower values in the right liver lobe compared to the left (p = 0.036) and with a significantly lower variance (p < 0.001). Consistend values were measured by different examiners (p = 0.108), however, the inter examiner variance deviated significantly (p < 0.001). ARFI elastography is a reliable method to measure liver stiffness in children and adolescents. In relation to studies which analyse liver diseases, the standard value of 1.16 m/sec (± 0.14 m/sec) allows a differentiation of healthy versus pathological liver tissue. © Georg Thieme Verlag KG Stuttgart · New York.

Failure to obtain an autoimmune response following cryosurgery to the normal rat liver.

PubMed Central

Townell, N H; Tsantoulas, D; Holborow, E J; Hobbs, K E

1980-01-01

Smooth muscle antibody (SMA) and anti-liver-specific lipoprotein (anti-LSP) responses were investigated following five different freeze thaw regimes to the normal rat liver. The livers were examined histologically for evidence of autoimmune liver disease. No SMA or anti-LSP was found in any animal and on histological examination the unfrozen part of all livers was normal. It is concluded that cryosurgical damage to the liver is unlikely to provoke an autoimmune response. PMID:7460392

Shared liver-like transcriptional characteristics in liver metastases and corresponding primary colorectal tumors.

PubMed

Cheng, Jun; Song, Xuekun; Ao, Lu; Chen, Rou; Chi, Meirong; Guo, You; Zhang, Jiahui; Li, Hongdong; Zhao, Wenyuan; Guo, Zheng; Wang, Xianlong

2018-01-01

Background & Aims : Primary tumors of colorectal carcinoma (CRC) with liver metastasis might gain some liver-specific characteristics to adapt the liver micro-environment. This study aims to reveal potential liver-like transcriptional characteristics associated with the liver metastasis in primary colorectal carcinoma. Methods: Among the genes up-regulated in normal liver tissues versus normal colorectal tissues, we identified "liver-specific" genes whose expression levels ranked among the bottom 10% ("unexpressed") of all measured genes in both normal colorectal tissues and primary colorectal tumors without metastasis. These liver-specific genes were investigated for their expressions in both the primary tumors and the corresponding liver metastases of seven primary CRC patients with liver metastasis using microdissected samples. Results: Among the 3958 genes detected to be up-regulated in normal liver tissues versus normal colorectal tissues, we identified 12 liver-specific genes and found two of them, ANGPTL3 and CFHR5 , were unexpressed in microdissected primary colorectal tumors without metastasis but expressed in both microdissected liver metastases and corresponding primary colorectal tumors (Fisher's exact test, P < 0.05). Genes co-expressed with ANGPTL3 and CFHR5 were significantly enriched in metabolism pathways characterizing liver tissues, including "starch and sucrose metabolism" and "drug metabolism-cytochrome P450". Conclusions: For primary CRC with liver metastasis, both the liver metastases and corresponding primary colorectal tumors may express some liver-specific genes which may help the tumor cells adapt the liver micro-environment.

[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.

Estimation of Characteristics of Echo Envelope Using RF Echo Signal from the Liver

NASA Astrophysics Data System (ADS)

Yamaguchi, Tadashi; Hachiya, Hiroyuki; Kamiyama, Naohisa; Ikeda, Kazuki; Moriyasu, Norifumi

2001-05-01

To realize quantitative diagnosis of liver cirrhosis, we have been analyzing the probability density function (PDF) of echo amplitude using B-mode images. However, the B-mode image is affected by the various signal and image processing techniques used in the diagnosis equipment, so a detailed and quantitative analysis is very difficult. In this paper, we analyze the PDF of echo amplitude using RF echo signal and B-mode images of normal and cirrhotic livers, and compare both results to examine the validity of the RF echo signal.

[Preoperative imaging/operation planning for liver surgery].

PubMed

Schoening, W N; Denecke, T; Neumann, U P

2015-12-01

The currently established standard for planning liver surgery is multistage contrast media-enhanced multidetector computed tomography (CM-CT), which as a rule enables an appropriate resection planning, e.g. a precise identification and localization of primary and secondary liver tumors as well as the anatomical relation to extrahepatic and/or intrahepatic vascular and biliary structures. Furthermore, CM-CT enables the measurement of tumor volume, total liver volume and residual liver volume after resection. Under the condition of normal liver function a residual liver volume of 25 % is nowadays considered sufficient and safe. Recent studies in patients with liver metastases of colorectal cancer showed a clear staging advantage of contrast media-enhanced magnetic resonance imaging (CM-MRI) versus CM-CT. In addition, most recent data showed that the use of liver-specific MRI contrast media further increases the sensitivity and specificity of detection of liver metastases. This imaging technology seems to lead closer to the ideal "one stop shopping" diagnostic tool in preoperative planning of liver resection.

Hepatic progenitor cells of biliary origin with liver repopulation capacity

PubMed Central

Boulter, Luke; Tsuchiya, Atsunori; Cole, Alicia M; Hay, Trevor; Guest, Rachel V; Wojtacha, Davina; Man, Tak Yung; Mackinnon, Alison; Ridgway, Rachel A; Kendall, Timothy; Williams, Michael J; Jamieson, Thomas; Raven, Alex; Hay, David C; Iredale, John P; Clarke, Alan R; Sansom, Owen J; Forbes, Stuart J

2015-01-01

Summary Hepatocytes and cholangiocytes self renew following liver injury. Following severe injury hepatocytes are increasingly senescent, whether Hepatic Progenitor Cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where Mdm2 is inducibly deleted in over 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease. PMID:26192438

Spirulina maxima Protects Liver From Isoniazid and Rifampicin Drug Toxicity.

PubMed

Jatav, Santosh Kumar; Kulshrestha, Archana; Zacharia, Anish; Singh, Nita; Tejovathi, G; Bisen, P S; Prasad, G B K S

2014-07-01

Hepatotoxicity associated with isoniazid and rifampicin is one of the major impediments in antituberculosis therapy. The present study explored the prophylactic and therapeutic efficacies of Spirulina maxima in isoniazid and rifampicin induced hepatic damage in a rat model. Hepatic damage induced in Wistar rats by isoniazid and rifampicin resulted in significant alterations in biomarkers of liver function, namely, bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, and oxidative stress markers such as superoxide dismutase, catalase, glutathione, and thiobarbituric acid reactive substances. Co-administration of Spirulina maxima along with antituberculosis drugs protected liver from hepatotoxicity due to isoniazid and rifampicin. Administration of Spirulina maxima consecutively for 2 weeks to hepatodamaged animals resulted in restoration of hepatic function as evident from normalization of serum markers of liver function. Thus, the present study revealed remarkable prophylactic and therapeutic potential of Spirulina maxima. Co-administration of Spirulina maxima and antituberculosis drugs is advantageous as it provides extra nutritional benefit. © The Author(s) 2014.

Long-term reversal of diabetes in non-obese diabetic mice by liver-directed gene therapy.

PubMed

Ren, Binhai; O'Brien, Bronwyn A; Byrne, Michelle R; Ch'ng, Edwin; Gatt, Prudence N; Swan, M Anne; Nassif, Najah T; Wei, Ming Q; Gijsbers, Rik; Debyser, Zeger; Simpson, Ann M

2013-01-01

Type 1 diabetes (T1D) results from an autoimmune attack against the insulin-producing β-cells of the pancreas. The present study aimed to reverse T1D by gene therapy. We used a novel surgical technique, which involves isolating the liver from the circulation before the delivery of a lentiviral vector carrying furin-cleavable human insulin (INS-FUR) or empty vector to the livers of diabetic non-obese diabetic mice (NOD). This was compared with the direct injection of the vector into the portal circulation. Mice were monitored for body weight and blood glucose. Intravenous glucose tolerance tests were performed. Expression of insulin and pancreatic transcription factors was determined by the reverse transcriptase-polymerase chain reaction and immunohistochemistry and immunoelectron microscopy was used to localise insulin. Using the novel surgical technique, we achieved long-term transduction (42% efficiency) of hepatocytes, restored normoglycaemia for 150 days (experimental endpoint) and re-established normal glucose tolerance. We showed the expression of β-cell transcription factors, murine insulin, glucagon and somatostatin, and hepatic storage of insulin in granules. The expression of hepatic markers, C/EBP-β, G6PC, AAT and GLUI was down-regulated in INS-FUR-treated livers. Liver function tests remained normal, with no evidence of intrahepatic inflammation or autoimmune destruction of the insulin-secreting liver tissue. By comparison, direct injection of INS-FUR reduced blood glucose levels, and no pancreatic transdifferentiation or normal glucose tolerance was observed. This gene therapy protocol has, for the first time, permanently reversed T1D with normal glucose tolerance in NOD mice and, as such, represents a novel therapeutic strategy for the treatment of T1D. Copyright © 2013 John Wiley & Sons, Ltd.

Prediction of Liver Function by Using Magnetic Resonance-based Portal Venous Perfusion Imaging

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

Cao Yue, E-mail: yuecao@umich.edu; Department of Radiology, University of Michigan, Ann Arbor, Michigan; Wang Hesheng

2013-01-01

Purpose: To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning. Methods and Materials: Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation betweenmore » mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model. Results: There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT. Conclusions: This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.« less

Kit formulated asialoglycoprotein receptor targeting tracer based on copolymer for liver SPECT imaging.

PubMed

Liu, Chang; Guo, Zhide; Zhang, Pu; Song, Manli; Zhao, Zuoquan; Wu, Xiaowei; Zhang, Xianzhong

2014-08-01

Specific targeting of galactose-carrying molecule to ASGP-R in normal hepatocytes has been demonstrated before. In this study, galactosyl polystyrene was synthesized from controllable ratio of functional monomers and radio-labelled with (99m)Tc by formulated kit for SPECT imaging of hepatic function. p(VLA-co-VNI)(46:54) was synthesized by free-radical copolymerization initiated by AIBN, purified by dialysis, lyophilized to kit with Tricine and TPPTS as co-ligands for (99m)Tc labeling. Radiotracer (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was prepared and evaluated by in vitro stability, in vivo metabolism, ex vivo biodistribution and microSPECT/CT imaging in normal KM mice. MicroSPECT/CT and microMRI imaging were also performed in C57BL/b6 mice with xenograft hepatic carcinoma for hepatic function evaluation. (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was obtained in high radio chemical purity (RCP) (>99%) by using instant kit without further purification and excellent in vitro and in vivo stability. The result of biodistribution showed that liver had high uptake (90.49±10.68 ID%/g) at 30 min after injection and was blocked significantly by cold copolymer. MicroSPECT imaging in normal KM mice at 1h and 4h after injection showed good liver retention and targeting properties. Significant defect of activity was observed in the tumor site which was confirmed by MRI imaging. (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) with lower ratio of targeting moiety has no observable effect on the specific binding affinity and liver uptake. This makes it possible to introduce more imaging units for multi-modality imaging. Furthermore, the instant kit preparation of (99m)Tc-labeling provides great potential for the evaluation of hepatocyte function in clinical application. Copyright © 2014 Elsevier Inc. All rights reserved.

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

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.

Hepatic Dendritic Cells, the Tolerogenic Liver Environment, and Liver Disease.

PubMed

Dou, Lei; Ono, Yoshihiro; Chen, Yi-Fa; Thomson, Angus W; Chen, Xiao-Ping

2018-05-01

The unique liver immune microenvironment favors resistance to inflammation that promotes normal physiological function. At the same time, it endows the liver with tolerogenic properties that may promote pathological processes. Hepatic dendritic cells (HDCs) initiate and orchestrate immune responses depending on signals they receive from the local environment and are thought to contribute to liver tolerance. Thus, HDCs facilitate impaired T cell responses that are observed in persistent hepatitis C virus (HCV) infection, hepatocellular carcinoma progression, and liver allograft transplantation. HDCs also participate in anti-inflammatory responses in liver ischemia-reperfusion injury (IRI). Moreover, they promote the regression of fibrosis from various fibrogenic liver injuries. These findings suggest that HDCs regulate intrahepatic immune responses, allowing the liver to maintain homeostasis and integrity even under pathological conditions. This review focuses on the tolerogenic properties of HDCs based on recent research and in relation to liver disease pathogenesis and its therapy. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure

PubMed Central

2004-01-01

The liver plays an important role in insulin-regulated glucose homoeostasis. To study the function of the PDK1 (3-phosphoinositide-dependent protein kinase-1) signalling pathway in mediating insulin's actions in the liver, we employed CRE recombinase/loxP technology to generate L(liver)-PDK1−/− mice, which lack expression of PDK1 in hepatocytes and in which insulin failed to induce activation of PKB in liver. The L-PDK1−/− mice were not insulin-intolerant, possessed normal levels of blood glucose and insulin under normal feeding conditions, but were markedly glucose-intolerant when injected with glucose. The L-PDK1−/− mice also possessed 10-fold lower levels of hepatic glycogen compared with control littermates, and were unable to normalize their blood glucose levels within 2 h after injection of insulin. The glucose intolerance of the L-PDK1−/− mice may be due to an inability of glucose to suppress hepatic glucose output through the gluconeogenic pathway, since the mRNA encoding hepatic PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase) and SREBP1 (sterol-regulatory-element-binding protein 1), which regulate gluconeogenesis, are no longer controlled by feeding. Furthermore, three other insulin-controlled genes, namely IGFBP1 (insulin-like-growth-factor-binding protein-1), IRS2 (insulin receptor substrate 2) and glucokinase, were regulated abnormally by feeding in the liver of PDK1-deficient mice. Finally, the L-PDK1−/− mice died between 4–16 weeks of age due to liver failure. These results establish that the PDK1 signalling pathway plays an important role in regulating glucose homoeostasis and controlling expression of insulin-regulated genes. They suggest that a deficiency of the PDK1 pathway in the liver could contribute to development of diabetes, as well as to liver failure. PMID:15554902

Muscular exercise can cause highly pathological liver function tests in healthy men

PubMed Central

Pettersson, Jonas; Hindorf, Ulf; Persson, Paula; Bengtsson, Thomas; Malmqvist, Ulf; Werkström, Viktoria; Ekelund, Mats

2008-01-01

Aim To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Methods Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10–12 days postexercise. Results Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, γGT and ALP remained within the normal range. Conclusion The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice. What is already known about this subject The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals.Physical exercise can result in transient elevations of liver function tests.There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. What this study adds Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting.Liver function tests are significantly increased for at least 7 days after weightlifting.It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. PMID:17764474

Muscular exercise can cause highly pathological liver function tests in healthy men.

PubMed

Pettersson, Jonas; Hindorf, Ulf; Persson, Paula; Bengtsson, Thomas; Malmqvist, Ulf; Werkström, Viktoria; Ekelund, Mats

2008-02-01

The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals. Physical exercise can result in transient elevations of liver function tests. There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting. Liver function tests are significantly increased for at least 7 days after weightlifting. It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (gamma GT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10-12 days postexercise. Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, gamma GT and ALP remained within the normal range. The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice.

Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

PubMed

Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

2016-07-05

The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

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.

HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology.

PubMed

Berndt, Nikolaus; Bulik, Sascha; Wallach, Iwona; Wünsch, Tilo; König, Matthias; Stockmann, Martin; Meierhofer, David; Holzhütter, Hermann-Georg

2018-06-19

The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).

[The influence of hepatoprotector 2-ethylthiobenzimidazole hydrobromide (bemithyl) on the content of glycogen in cirrhotic rat liver hepatocytes located in various microenvironments].

PubMed

Kudriavtseva, M V; Bezborodkina, N N; Okovityĭ, S V; Kudriavtsev, B N

2004-01-01

Using absorption and fluorescent cytophotometry methods, glycogen contents were studied in hepatocytes located in liver lobules and in hepatocytes, which make the general population of these cells in normal and cirrhotic rat liver. In cirrhosis, the content of glycogen in hepatocytes located in lobules obviously rises in comparison with the norm, but to a lesser degree, than in hepatocytes making the general population of these cells in cirrhotic liver. The content of glycogen in hepatocytes, located in lobules of pathologically changed liver in bemithyl treated rats, did not differ from the norm. At the same time, the glycogen content in hepatocytes, representing the general population of these cells in cirrhotically altered bemithyl injected rat liver, remained higher than in the norm. The data obtained indicate that distinctions in particular cell microinvironment, obviously present in cirrhotic liver, render essential influence on hepatocyte functional activity.

Anabolic steroid-induced cardiomyopathy underlying acute liver failure in a young bodybuilder.

PubMed

Bispo, Miguel; Valente, Ana; Maldonado, Rosário; Palma, Rui; Glória, Helena; Nóbrega, João; Alexandrino, Paula

2009-06-21

Heart failure may lead to subclinical circulatory disturbances and remain an unrecognized cause of ischemic liver injury. We present the case of a previously healthy 40-year-old bodybuilder, referred to our Intensive-Care Unit of Hepatology for treatment of severe acute liver failure, with the suspicion of toxic hepatitis associated with anabolic steroid abuse. Despite the absence of symptoms and signs of congestive heart failure at admission, an anabolic steroid-induced dilated cardiomyopathy with a large thrombus in both ventricles was found to be the underlying cause of the liver injury. Treatment for the initially unrecognized heart failure rapidly restored liver function to normal. To our knowledge, this is the first reported case of severe acute liver failure due to an unrecognized anabolic steroid-induced cardiomyopathy. Awareness of this unique presentation will allow for prompt treatment of this potentially fatal cause of liver failure.

The absence of obstructive sleep apnea may protect against non-alcoholic fatty liver in patients undergoing bariatric surgery.

PubMed

Corey, Kathleen E; Misdraji, Joseph; Zheng, Hui; Malecki, Kyle M; Kneeman, Jacob; Gelrud, Louis; Chung, Raymond T

2013-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and its progressive form, steatohepatitis, will be the leading indication for liver transplant by 2020. While risk factors for steatohepatitis have been identified, little work has been performed to identify factors protective against NAFLD development. This study sought to identify factors predictive of normal liver histology in a bariatric cohort. Patients undergoing weight loss surgery with liver biopsies at the time of surgery were included. Patients with other causes of chronic liver disease were excluded. One hundred fifty-nine patients were included. Forty-nine patients had normal liver histology and 110 patients had NAFLD. Several previously identified factors associated with normal liver histology were found. Black race was the strongest predictor of the absence of NAFLD with an odds ratio (OR) of 6.8, 95% confidence interval (CI) 2.4-18.9. Low HOMA-IR was also associated with normal histology (OR 1.4, 95% CI 1.03-1.9). In contrast, low HDL was associated with a decreased chance of normal histology (OR 0.38, 95% CI 0.05-0.83). Interestingly, a novel protective factor, the absence of obstructive sleep apnea (OSA) was strongly associated with normal histology (OR 5.6, 95% CI 2.0-16.1). In multivariate regression controlling for BMI, black race, absence of OSA, low HOMA-IR and low ALT independently predicted normal liver histology with an area under the ROC curve of 0.85. Our study confirmed several factors associated with normal liver histology, including black race and identified a novel factor, absence of OSA. Further evaluation of these factors will allow for improved understanding of the pathogenesis of NAFLD.

Analysis of normal and diseased liver tissue using auto-fluorescence and Raman spectroscopy

NASA Astrophysics Data System (ADS)

Li, Xiaozhou; Jia, Chunde; Lin, Junxiu; Kang, Youping

2003-12-01

In this paper, laser induced human serum Raman spectra of liver cancer are measured. The spectra differences in serum from normal people and liver cancer patients are analyzed. For the typical spectrum of normal serum, there are three sharp Raman peaks and relative intensity of Raman peaks excited by 514.5 nm is higher than that excited by 488.0 nm. However, for the Raman spectrum of liver cancer serum there are no peaks or very weak Raman peaks at the same positions. Results from more than two hundred case measurements show that clinical diagnostic accuracy is 92.86%. And then, the liver fibrosis and liver cirrhosis are studied applying the technology of LIF. To liver cirrhosis, the shape of Raman peak is similar to normal and fluorescence spectrum is similar to that of liver cancer from statistic data. The experiment indicates that there is notable fluorescence difference between the abnormal and normal liver tissue and have blue shift in fluorescence peak. These results have important reference values to explore the method of laser spectrum diagnosis.

Evaluation of Lung Function in Liver Transplant Candidates.

PubMed

Roque, L; Sankarankutty, A K; Silva, O C; Mente, E D

2018-04-01

A wide variety of pulmonary conditions are found in cirrhotic patients and may compromise the pleura, diaphragm, parenchyma, and pulmonary vasculature, influencing the results of liver transplantation. To evaluate the pulmonary function (lung capacities, volumes, and gasometric study) of patients with liver cirrhosis awaiting liver transplantation. Cirrhotic patients, subdivided into 3 groups stratified by liver disease severity using the Child-Pugh-Turcotte score, were compared with a control group of healthy volunteers. In spirometry, the parameters evaluated were total lung capacity, forced volume in the first second, and the relationship between forced volume in the first minute and forced vital capacity. Blood gas analysis was performed. In the control group, arterial oxygenation was evaluated by peripheral oxygen saturation by pulse oximetry. Of the 55 patients (75% men, 51 ± 12.77 years), 11 were Child A (73% men, 52 ± 14.01 years), 23 were Child B (75% men, 51 ± 12.77 years), and 21 were Child C (95% men, 50 ± 12.09 years). The control group had 20 individuals (50% men, 47 ± 8.15 years). Pulmonary capacities and volumes by the parameters evaluated were within the normal range. Arterial blood gas analysis detected no hypoxemia, but a tendency to low partial gas pressure was noted. In this population of cirrhotic patients the parameters of spirometry were normal in relation to the lung capacities and volumes in the different groups. No hypoxemia was detected, but a tendency to hypocapnia in the blood gas was noted. Copyright © 2018. Published by Elsevier Inc.

Xenotransplantation of neonatal porcine liver cells.

PubMed

Garkavenko, O; Emerich, D F; Muzina, M; Muzina, Z; Vasconcellos, A V; Ferguson, A B; Cooper, I J; Elliott, R B

2005-01-01

Xenotransplantation of porcine liver cell types may provide a means of overcoming the shortage of suitable donor tissues to treat hepatic diseases characterized by inherited inborn errors of metabolism or protein production. Here we report the successful isolation, culture, and xenotransplantation of liver cells harvested from 7- to 10-day-old piglets. Liver cells were isolated and cultured immediately after harvesting. Cell viability was excellent (>90%) over the duration of the in vitro studies (3 weeks) and the cultured cells continued to significantly proliferate. These cells also retained their normal secretory and metabolic capabilities as determined by continued release of albumin, factor 8, and indocyanin green (ICG) uptake. After 3 weeks in culture, porcine liver cells were loaded into immunoisolatory macro devices (Theracyte devices) and placed into the intraperitoneal cavity of immunocompetant CD1 mice. Eight weeks later, the devices were retrieved and the cells analyzed for posttransplant determinations of survival and function. Post mortem analysis confirmed that the cell-loaded devices were biocompatible, and were well-tolerated without inducing any notable inflammatory reaction in the tissues immediately surrounding the encapsulated cells. Finally, the encapsulated liver cells remained viable and functional as determined by histologic analyses and ICG uptake/release. The successful harvesting, culturing, and xenotransplantation of functional neonatal pig liver cells support the continued development of this approach for treating a range of currently undertreated or intractable hepatic diseases.

Quantification of tissue texture with photoacoustic spectrum analysis

NASA Astrophysics Data System (ADS)

Wang, Xueding; Xu, Guan; Meng, Zhuo-Xian; Lin, Jiandie; Carson, Paul

2014-05-01

Photoacoustic (PA) imaging is an emerging technology that could map the functional contrasts in deep biological tissues in high resolution by "listening" to the laser induced thermoelastic waves. Almost all of the current studies in PA imaging are focused on the intensity of the PA signals as an indication of the optical absorbance of the biological tissues. Our group has for the first time demonstrated that the frequency domain power distribution of the broadband PA signals encode the texture information within the regions-of-interest (ROI). Following the similar method of ultrasound spectral analysis (USSA), photoacoustic spectrum analysis (PASA) could evaluate the relative concentrations and, more importantly, the dimensions of microstructures of the optically absorbing materials in biological tissues, including lipid, collagen, water and hemoglobin. By providing valuable insights into tissue pathology, PASA should benefit basic research and clinical management of many diseases, and may help achieve eventual "noninvasive biopsy". In this work, taking advantage of the optical absorption contrasts contributed by lipid and hemoglobin at 1200-nm and 532-nm wavelengths respectively, we investigated the capability of PASA in identifying histological changes corresponding to fat accumulation livers through the study on ex vivo and in situ mouse models. The PA signals from the mouse livers were acquired using our PA and US dual-modality imaging system, and analyzed in the frequency domain. After quantifying the power spectrum by fitting it to a first order model, three spectral parameters, including the intercept, the midband fit and the slope, were extracted and used to differentiate fatty livers from normal livers. The comparison between the PASA parameters from the normal and the fatty livers supports our hypotheses that PASA can quantitatively identify the microstructure changes in liver tissues for differentiating normal and fatty livers.

Untangling the Etiology of Ascites

PubMed Central

Lopez-Molina, Michael; Shiani, Ashok V.; Oller, Kellee L.

2015-01-01

Patient: Male, 72 Final Diagnosis: Systemic amyloidosis Symptoms: — Medication: — Clinical Procedure: Liver biopsy Specialty: Gastroenterology and Hepatology Objective: Unusual clinical course Background: Amyloidosis is a systemic disease known to affect a vast range of organs, including the liver, heart, and kidney. When infiltrating the liver, amyloidosis typically does not present with cirrhosis. Typical presentation includes hepatomegaly with some mild laboratory abnormalities. Case Report: A 72-year-old man presented with a 2-week history of worsening abdominal, scrotal, and extremity swelling. He endorsed melanotic stools and intermittent dizziness with a 10-pound weight gain. Vitals revealed a blood pressure of 82/57 mmHg and a pulse of 83 beats/min with positive orthostatic changes. Mild bibasilar crackles were noted. His abdomen was moderately distended with a fluid wave present, but no hepatosplenomegaly was noted. He displayed anasarca with significant extremity and scrotal edema, but no jaundice, telangiectasias, or other stigmata of chronic liver disease were present. Liver function tests demonstrated a total bilirubin of 1.5 mg/dL (normal value: 0.2–1.2 mg/dL), AST 111 IU/L (normal value 5–34 IU/L), ALT 51 IU/L (normal value 5–55 IU/L), and GGT 583 U/L (12–64 U/L). Alkaline phosphatase was 645 U/L (40–150 U/L). Analysis of peritoneal fluid was consistent with portal hypertension due to liver disease. Given an atypical presentation of cirrhosis with unclear etiology, a biopsy was performed and revealed amyloid deposition. Conclusions: Liver disease can be due to various etiologies, many of which can present ambiguously. Although the most typical etiologies have been well defined, we present a case of an atypical presentation of hepatic amyloidosis discovered in a patient with ascites and without typical hepatomegaly. PMID:25844525

Pearson disease in an infant presenting with severe hypoplastic anemia, normal pancreatic function, and progressive liver failure.

PubMed

Shapira, Adi; Konopnicki, Muriel; Hammad-Saied, Mohammed; Shabad, Evelyn

2014-07-01

Pearson disease is a rare, usually fatal, mitochondrial disorder affecting primarily the bone marrow and the exocrine pancreas. We report a previously healthy 10-week-old girl who presented with profound macrocytic anemia followed by pancytopenia, synthetic liver dysfunction with liver steatosis, and metabolic acidosis with high lactate levels. She had no pancreatic involvement. Multiple cytoplasmic vacuoles in myelocytes and monocytes were seen upon microscopic evaluation of the bone marrow. Genetic analysis of the mitochondrial genome revealed a 5 kbp deletion, thus establishing the diagnosis of Pearson disease.

Polycystic Liver Disease

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

Linda, Nguyen, E-mail: nguyenli@einstein.edu

A 77-year-old African American male presented with intermittent abdominal pain for one week. He denied nausea, vomiting, diarrhea, constipation, fevers, anorexia, or weight loss. He denied a family history of liver disease, recent travel, or history of intravenous drug abuse. His vital signs were normal. Labs revealed total bilirubin of 1.5 mg/dl, hypoalbuminaemia 3.0 gm/dl and prolonged prothrombin time of 14.8 sec. Computed Tomography of the abdomen and pelvis with contrast showed multiple hepatic cysts with the largest cyst occupying the right abdomen, measuring 20.6 cm (Panel A and). This cyst had predominantly fluid attenuation, but also contained several septations.more » The patient underwent laparoscopic fenestration of the large hepatic cyst with hepatic cyst wall biopsy. Pathology revealed blood without malignant cells. The patient tolerated the procedure well with improvement of his abdominal pain and normalization of his liver function tests and coagulation profile.« less

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.

Pushing the boundaries in liver graft utilisation in transplantation: Case report of a donor with previous bile duct injury repair.

PubMed

Sultana, Asma; Powell, James J; Oniscu, Gabriel C

2017-01-01

Liver transplantation is a recognised treatment for extensive bile duct injuries with secondary biliary cirrhosis or recurring sepsis. However, there have been no reports of successful liver transplantation from a donor who sustained a previous bile duct injury. Here we discuss the case of a liver transplant from a 51-year-old brain dead donor who had suffered a Strasberg E1 bile duct injury and had undergone a Roux-en-Y hepaticojejunostomy 24 years prior to donation. The liver was successfully recovered and transplanted into a 56-year-old male recipient with end stage liver disease consequent to alpha 1 antitrypsin deficiency. The graft continues to function well 36 months post-transplant, with normal liver function tests and imaging revealing a patent hepaticojejunostomy. The potential associated vascular injuries should be identified during bench preparation whilst the management of biliary reconstruction at the time of transplant should follow the principles of biliary reconstruction in cases with biliary injuries, extending the hilar opening into the left duct. This case highlights the successful utilisation of a post bile duct injury repair liver, employing an experienced procurement team and careful bench assessment and reconstruction. Copyright © 2017. Published by Elsevier Ltd.

The classification of secondary colorectal liver cancer in human biopsy samples using angular dispersive x-ray diffraction and multivariate analysis

NASA Astrophysics Data System (ADS)

Theodorakou, Chrysoula; Farquharson, Michael J.

2009-08-01

The motivation behind this study is to assess whether angular dispersive x-ray diffraction (ADXRD) data, processed using multivariate analysis techniques, can be used for classifying secondary colorectal liver cancer tissue and normal surrounding liver tissue in human liver biopsy samples. The ADXRD profiles from a total of 60 samples of normal liver tissue and colorectal liver metastases were measured using a synchrotron radiation source. The data were analysed for 56 samples using nonlinear peak-fitting software. Four peaks were fitted to all of the ADXRD profiles, and the amplitude, area, amplitude and area ratios for three of the four peaks were calculated and used for the statistical and multivariate analysis. The statistical analysis showed that there are significant differences between all the peak-fitting parameters and ratios between the normal and the diseased tissue groups. The technique of soft independent modelling of class analogy (SIMCA) was used to classify normal liver tissue and colorectal liver metastases resulting in 67% of the normal tissue samples and 60% of the secondary colorectal liver tissue samples being classified correctly. This study has shown that the ADXRD data of normal and secondary colorectal liver cancer are statistically different and x-ray diffraction data analysed using multivariate analysis have the potential to be used as a method of tissue classification.

Untangling the etiology of ascites.

PubMed

Lopez-Molina, Michael; Shiani, Ashok V; Oller, Kellee L

2015-04-06

Amyloidosis is a systemic disease known to affect a vast range of organs, including the liver, heart, and kidney. When infiltrating the liver, amyloidosis typically does not present with cirrhosis. Typical presentation includes hepatomegaly with some mild laboratory abnormalities. A 72-year-old man presented with a 2-week history of worsening abdominal, scrotal, and extremity swelling. He endorsed melanotic stools and intermittent dizziness with a 10-pound weight gain. Vitals revealed a blood pressure of 82/57 mmHg and a pulse of 83 beats/min with positive orthostatic changes. Mild bibasilar crackles were noted. His abdomen was moderately distended with a fluid wave present, but no hepatosplenomegaly was noted. He displayed anasarca with significant extremity and scrotal edema, but no jaundice, telangiectasias, or other stigmata of chronic liver disease were present. Liver function tests demonstrated a total bilirubin of 1.5 mg/dL (normal value: 0.2-1.2 mg/dL), AST 111 IU/L (normal value 5-34 IU/L), ALT 51 IU/L (normal value 5-55 IU/L), and GGT 583 U/L (12-64 U/L). Alkaline phosphatase was 645 U/L (40-150 U/L). Analysis of peritoneal fluid was consistent with portal hypertension due to liver disease. Given an atypical presentation of cirrhosis with unclear etiology, a biopsy was performed and revealed amyloid deposition. Liver disease can be due to various etiologies, many of which can present ambiguously. Although the most typical etiologies have been well defined, we present a case of an atypical presentation of hepatic amyloidosis discovered in a patient with ascites and without typical hepatomegaly.

Lesions of the segmental and lobar hepatic ducts.

PubMed Central

Longmire, W P; Tompkins, R K

1975-01-01

Despite reports to the contrary, unobstructed drainage of 50% of an otherwise normal liver through either the right or left uninfected hepatic duct is adequate to restore normal liver function, even if the obstructed lobe remains in place. An undrained liver lobe, if present, may require no further treatment. As long as it is completely obstructed and uninfected, it will undergo a progressive asymptomatic atrophy. Cholangitis invariably develops behind a partial lobar ductal obstruction, producing jaundice, pruritis, and fever. Unless unobstructed, uninfected biliary flow can be achieved through a segmental or lobar duct, it is better that the duct be completely obstructed and the affected liver parenchyma allowed to atrophy, provided there is normal biliary flow from the residual 50% of liver. This concept is important in the management of injured anomalous segmental or lobar hepatic duct and in the palliative treatment of bile duct carcinoma. Localized intrahepatic infections communicating with abnormal biliary ducts will require hepatic resection of the infected parenchyma and ducts for cure. The abnormality may be saccular dilatation of the intrahepatic ductal system with abscess formation or intrahepatic abscess associated with stenosis of the ductal system from trauma to the duct, to the duct and liver, or to retained intrahepatic stones. Diffusely situated intrahepatic abscesses secondary to ductal abnormalities can be treated with systemic antibiotics, local drainage of a dmoninant abscess, and efforts to improve biliary drainage. Images Fig. 4. Fig. 5. Fig. 6. Fig. 8. Fig. 9. Fig. 10. Figs. 11A and B Figs. 12A and B. Fig. 13. Fig. 14. Fig. 15. Fig. 16. Fig. 17. PMID:1180585

Evaluation of fatty liver by using in-phase and opposed-phase MR images and in-vivo proton MR spectroscopy

NASA Astrophysics Data System (ADS)

Lee, Jae-Seung; Im, In-Chul; Goo, Eun-Hoe; Park, Hyong-Hu; Kwak, Byung-Joon

2012-12-01

The purpose of this study was to evaluate the necessity of in-phase and opposed-phase MR images and their correlations with weight, the aspartate aminotransferase/alanine aminotransferase (AST/ALT) value, and age. Magnetic resonance spectroscopy (MRS) was used as a reference in this study. We selected 68 people as subjects, among which 14 were volunteers with normal AST/ALT values ( <40/35 U/L) on a liver function study and 54 were non-alcoholic fatty liver patients for whom ultrasonic images had been obtained within 3 months of the study. In this study, the liver was more enhanced than the spleen or kidney. When the Eq. (3) formula was applied to normal volunteers, the difference between the in-phase and the opposed-phase images was -3.54 ± 12.56. The MRS study result showed a high sensitivity of 96.6% and a specificity of 100% ( p = 0.000) when the cutoff value was 20%. Furthermore, this result showed a high sensitivity of 94% and a specificity of 80% with a similar cutoff when the Eq. (2) formula was applied to non-alcoholic fatty liver patients ( p = 0.000). The MRS study revealed a strong correlation between normal volunteers and non-alcoholic fatty liver patients (r = 0.59, p = 0.04). The correlations between AST/ALT and Eq. (3) (r = 0.45, p = 0.004), age and Eq. (3) (r = 0.73, p = 0.03), and weight and Eq. (3) (r = 0.77, p = 0.000) values were all statistically significant. In the case of non-alcoholic liver disease, MRS was found to be significantly correlated with Eq. (1) (r = 0.39, p = 0.002), Eq. (2) (r = 0.68, p = 0.04), Eq. (3) (r = 0.67, p = 0.04), and AST/ALT (r = 0.77, p = 0.000). In conclusion, in-phase and opposed-phase images can help to distinguish a normal liver from a fatty liver in order to identify non-alcoholic fatty liver patients. The intensity difference between the in-phase and opposed-phase MR signals showed valuable correlations with respect to weight, AST/ALT value, and age, with all values being above the mild lipid value (r = 0.3).

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

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

[Changes in serotonin and noradrenaline in hepatic encephalopathy as a result of liver failure in rat].

PubMed

Song, Min-ning; Song, Yu-na; Chen, Fu; Luo, Mei-lan

2007-01-01

To investigate the changes in serotonin (5-HT) and noradrenaline (NA) in hepatic encephalopathy as a result of acute and chronic liver failure in rat. One hundred and ten Sprague-Dawley (SD) rats were randomly divided into groups of normal control (n=20), experimental group of acute liver failure (ALF) encephalopathy (n=45), and experimental group of chronic liver failure (CLF) encephalopathy (n=45). Two dosages of thioacetamide (TAA) of 500 mg/kg were gavaged with an interval of 24 hours to reproduce ALF model. To reproduce CLF model rats were fed with 0.03% TAA in drinking water for 10 weeks, and 50% of TAA dosage was added or withheld according to the change in weekly body weight measurement. Animals were sacrificed and venous blood specimens were obtained after successful replication of model, and 5-HT, NA, ammonia, parameters of liver function were determined, and liver and brain were studied pathologically. The experiment showed that the liver functions of rats in groups ALF encephalopathy and CLF encephalopathy deteriorated seriously, changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumen (ALB), ALB/globulin (A/G), and blood ammonia were observed(P<0.05 or P<0.01). The clinical manifestations, liver and brain pathologies were identical to those of ALF and CLF encephalopathy. The values of 5-HT were increased in groups ALF encephalopathy and CLF encephalopathy [(16.06+/-1.08) micromol/L and (15.32+/-1.48) micromol/L] compared with the normal group [(2.75+/-0.26) micromol/L, both P<0.01], while the value of NA decreased in the group of CLF encephalopathy [(94.0+/-2.13) pmol/L vs.(121.2+/-14.8) pmol/L,P<0.05]. The levels of 5-HT are elevated in the groups of ALF encephalopathy and CLF encephalopathy. The content of NA decreases remarkably in CLF encephalopathy.

Hepatoprotective Effect and Synergism of Bisdemethoycurcumin against MCD Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

PubMed Central

Lee, Young-Seob; Han, Sin-Hee; Ahn, Young-Sup; Cha, Seon-Woo; Seo, Yun-Soo; Kong, Ryong; Kwon, Dong-Yeul

2016-01-01

Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has become one of the most common causes of chronic liver disease over the last decade in developed countries. NAFLD includes a spectrum of pathological hepatic changes, such as steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Bisdemethoxycurcumin (BDMC) is polyphenolic compounds with a diarylheptanoid skeleton, curcumin close analogues, which is derived from the Curcumae Longae Rhizoma. While the rich bioavailability research of curcumin, BDMC is the poor studies. We investigated whether BDMC has the hepatoprotective effect and combinatory preventive effect with silymarin on methionine choline deficient (MCD)-diet-induced NAFLD in C57BL/6J mice. C57BL/6J mice were divided into five groups of normal (normal diet without any treatment), MCD diet (MCD diet only), MCD + silymarin (SIL) 100 mg/kg group, MCD + BDMC 100 mg/kg group, MCD + SIL 50 mg/kg + BDMC 50 mg/kg group. Body weight, liver weight, liver function tests, histological changes were assessed and quantitative real-time polymerase chain reaction and Western blot analyses were conducted after 4 weeks. Mice lost body weight on the MCD-diet, but BDMC did not lose less than the MCD-diet group. Liver weights decreased from BDMC, but they increased significantly in the MCD-diet groups. All liver function test values decreased from the MCD-diet, whereas those from the BDMC increased significantly. The MCD- diet induced severe hepatic fatty accumulation, but the fatty change was reduced in the BDMC. The BDMC showed an inhibitory effect on liver lipogenesis by reducing associated gene expression caused by the MCD-diet. In all experiments, the combinations of BDMC with SIL had a synergistic effect against MCD-diet models. In conclusion, our findings indicate that BDMC has a potential suppressive effect on NAFLD. Therefore, our data suggest that BDMC may act as a novel and potent therapeutic agent against NAFLD. PMID:26881746

Human serum cholinesterase from liver pathological samples exhibit highly elevated aryl acylamidase activity.

PubMed

Boopathy, Rathanam; Rajesh, Ramanna Valmiki; Darvesh, Sultan; Layer, Paul G

2007-05-01

Although aspartate aminotransferase (AST) and gamma-glutamyltransferase (gamma GT) enzymes are widely used as markers for liver disorders, the ubiquitous enzyme butyrylcholinesterase (BChE), synthesized in liver is also used as marker in the assessment of liver pathophysiology. This BChE enzyme in addition to its esterase activity has yet another enzymatic function designated as aryl acylamidase (AAA) activity. It is determined in in vitro based on the hydrolysis of the synthetic substrate o-nitroacetanilide. In the present study, human serum cholinesterase (BChE) activity was studied with respect to its AAA activity on the BChE protein (AAA(BChE)) in patients with liver disorders. AST and gamma GT values were taken into account in this study as known markers for liver disorders. Blood samples were grouped into 3 based on esterase activity associated with BChE protein. They are normal, low, and very low BChE activity but with markedly increased AST and gamma GT levels. These samples were tested for their respective AAA function. Association of AAA with BChE from samples was proved using BChE monoclonal antibody precipitation experiment. The absolute levels of AAA were increased as BChE activity decreased while deviating from normal samples and such deviation was directly proportional to the severity of the liver disorder. Differences between these groups became prominent after determining the ratios of AAA(BChE) to BChE activities. Samples showing very high AAA(BChE) to BChE ratio were also showing high to very high gamma GT values. These findings establish AAA(BChE) as an independently regulated enzymatic activity on BChE especially in liver disorders. Moreover, since neither the low esterase activity of BChE by itself nor increased levels of AST/gamma GT are sufficient pathological indicators, this pilot study merits replication with large sample numbers.

Hepatoprotective Effect and Synergism of Bisdemethoycurcumin against MCD Diet-Induced Nonalcoholic Fatty Liver Disease in Mice.

PubMed

Kim, Sung-Bae; Kang, Ok-Hwa; Lee, Young-Seob; Han, Sin-Hee; Ahn, Young-Sup; Cha, Seon-Woo; Seo, Yun-Soo; Kong, Ryong; Kwon, Dong-Yeul

2016-01-01

Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has become one of the most common causes of chronic liver disease over the last decade in developed countries. NAFLD includes a spectrum of pathological hepatic changes, such as steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Bisdemethoxycurcumin (BDMC) is polyphenolic compounds with a diarylheptanoid skeleton, curcumin close analogues, which is derived from the Curcumae Longae Rhizoma. While the rich bioavailability research of curcumin, BDMC is the poor studies. We investigated whether BDMC has the hepatoprotective effect and combinatory preventive effect with silymarin on methionine choline deficient (MCD)-diet-induced NAFLD in C57BL/6J mice. C57BL/6J mice were divided into five groups of normal (normal diet without any treatment), MCD diet (MCD diet only), MCD + silymarin (SIL) 100 mg/kg group, MCD + BDMC 100 mg/kg group, MCD + SIL 50 mg/kg + BDMC 50 mg/kg group. Body weight, liver weight, liver function tests, histological changes were assessed and quantitative real-time polymerase chain reaction and Western blot analyses were conducted after 4 weeks. Mice lost body weight on the MCD-diet, but BDMC did not lose less than the MCD-diet group. Liver weights decreased from BDMC, but they increased significantly in the MCD-diet groups. All liver function test values decreased from the MCD-diet, whereas those from the BDMC increased significantly. The MCD- diet induced severe hepatic fatty accumulation, but the fatty change was reduced in the BDMC. The BDMC showed an inhibitory effect on liver lipogenesis by reducing associated gene expression caused by the MCD-diet. In all experiments, the combinations of BDMC with SIL had a synergistic effect against MCD-diet models. In conclusion, our findings indicate that BDMC has a potential suppressive effect on NAFLD. Therefore, our data suggest that BDMC may act as a novel and potent therapeutic agent against NAFLD.

Health outcomes following liver function testing in primary care: a retrospective cohort study.

PubMed

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

2009-08-01

patients who present with abnormal liver function tests (LFTs) in primary care and no obvious symptoms can be difficult to manage. The objective is to follow-up a cohort of liver function tested patients to determine their outcome. This population-based retrospective cohort study was conducted in Tayside, Scotland, from 1989 to 2003. Subjects were patients with no clinically obvious liver disease at initial liver function testing in primary care. Main outcomes were diagnosed liver disease and mortality. Record linkage of databases ascertained risk factors and outcomes. Measures of performance were calculated and Weibull regression analysis from initial LFT date was performed on all outcomes by level of abnormality. In total, 95 977 patients had 364 194 incident initial LFTs, with median follow-up 3.7 years. A total of 21.7% had at least one abnormal LFT and 1108 (1.15%) developed liver disease. Elevated transaminase was strongly associated with diagnosed liver disease, hazard ratio (HR) = 4.23 (95% confidence interval 3.55, 5.04) for mild levels and HR = 12.67 (95% CI 9.74, 16.47) for severe levels versus normal. For gamma-glutamyl transferase, these hazards were 2.54 (95% CI 2.17, 2.96) and 13.44 (95% CI 10.71, 16.87), respectively. Low albumin was strongly associated with all-cause mortality, HR = 2.65 (95% CI 2.47, 2.85) for mild levels and HR = 4.99 (95% CI 4.26, 5.84) for severe levels. Sensitivity for predicting events over 5 years was low and specificity high. All LFTs were predictive markers for liver disease as well as general ill health, although sensitivity was poor. Most patients with abnormal LFTs had no later formal diagnosis of liver disease within the study period. The time taken to develop liver disease in these patients provides opportunity to intervene.

Ischemia-reperfusion injury in rat fatty liver: role of nutritional status.

PubMed

Caraceni, P; Nardo, B; Domenicali, M; Turi, P; Vici, M; Simoncini, M; De Maria, N; Trevisani, F; Van Thiel, D H; Derenzini, M; Cavallari, A; Bernardi, M

1999-04-01

Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P <.01). Accordingly, fasting and fatty degeneration had a synergistic effect in exacerbating liver injury. Mitochondrial damage was a predominant feature of ultrastructural hepatocyte injury in fasted fatty livers. Glucose supplementation partially prevented the fasting-induced depletion of glycogen and improved the 7-day rat survival to 45%. These data indicate that rat fatty livers exposed to normothermic ischemia-reperfusion injury are much more sensitive to fasting than histologically normal livers. Because glucose supplementation improves both the hepatic glycogen stores and the rat survival, a nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

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.

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.

Relationship Between Speed of Sound in and Density of Normal and Diseased Rat Livers

NASA Astrophysics Data System (ADS)

Hachiya, Hiroyuki; Ohtsuki, Shigeo; Tanaka, Motonao

1994-05-01

Speed of sound is an important acoustic parameter for quantitative characterization of living tissues. In this paper, the relationship between speed of sound in and density of rat liver tissues are investigated. The speed of sound was measured by the nondeformable technique based on frequency-time analysis of a 3.5 MHz pulse response. The speed of sound in normal livers varied minimally between individuals and was not related to body weight or age. In liver tissues which were administered CCl4, the speed of sound was lower than the speed of sound in normal tissues. The relationship between speed of sound and density in normal, fatty and cirrhotic livers can be fitted well on the line which is estimated using the immiscible liquid model assuming a mixture of normal liver and fat tissues. For 3.5 MHz ultrasound, it is considered that the speed of sound in fresh liver with fatty degeneration is responsible for the fat content and is not strongly dependent on the degree of fibrosis.

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.

[Relationship between phenotype and genotype of ABCB11 deficiency in siblings and literature review].

PubMed

Peng, X R; Lu, Y; Zhang, M H; Li, L T; Xie, X B; Gong, J Y; Wang, J S

2018-06-02

Objective: To explore the relationship between genotype and phenotype of ABCB11 deficiency. Methods: Clinical data of two siblings with ABCB11 deficiency were retrospectively analyzed. Related literature from PubMed, CNKI and Wangfang databases was reviewed to date (up to August 2017) with 'ABCB11 gene' or 'bile salt export pump', 'cholestasis' and 'child' as key words. Results: The patients were siblings. Both of them presented as jaundice, pruritus and hepatosplenomegaly since 3 days after birth. Significant laboratory findings on admission of the older sister included high total bilirubin, 170 µmol/L;conjugated bilirubin, 115.8 µmol/L;alanine aminotransferase, 168 U/L;total bile acid 186.3 µmol/L and normal gamma-glutamyl transpeptidase. While routine laboratory data of the younger brother were as follows: total bilirubin, 148.8 µmol/L;conjugated bilirubin, 96.3 µmol/L;alanine aminotransferase, 232.8 U/L;total bile acid 226 µmol/L, and normal gamma-glutamyl transpeptidase.Both received ursodeoxycholic acid and fat-soluble vitamins. Liver pathology of the younger brother showed giant hepatocytes with ballooning degeneration, focal necrosis and intrahepatic cholestasis. Both the patients harbor the same compound heterozygous mutations in ABCB11 gene, c.145C>T (p.Q49X) and c.1510G>A (p.E504K). The sister is 9 years old now, with normal liver function. Jaundice faded around 3 months after birth, pruritus relieved at age 5, and medications was stopped since then. The brother progressed to liver failure after an operation on perianal abscess when he was 8-month-old, and received living-related liver transplantation when he was 9 month and 20 days old (from his mother). Now he is 1 year and 5 months old, with normal liver function. Both are under our follow-up. Literature review revealed 18 ABCB11 deficiency patients from 7 families who had apparent different prognoses, within each family the siblings had the same ABCB11 gene mutation. Seven cases relieved after ursodeoxycholic acid therapy and/or partial external biliary diversion, 5 received orthotopic liver transplantation, 2 developed hepatocellular carcinoma and 4 cases died in childhood. Conclusions: The clinical manifestations of ABCB11 deficiency may vary greatly in patients carrying the same genotype, even in siblings. Patients should be managed in individualized maner.

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.

Sugammadex antagonism of rocuronium-induced neuromuscular blockade in patients with liver cirrhosis undergoing liver resection: a randomized controlled study.

PubMed

Abdulatif, Mohamed; Lotfy, Maha; Mousa, Mahmoud; Afifi, Mohamed H; Yassen, Khaled

2018-02-05

This randomized controlled study compared the recovery times of sugammadex and neostigmine as antagonists of moderate rocuroniuminduced neuromuscular block in patients with liver cirrhosis and controls undergoing liver resection. The study enrolled 27 adult patients with Child class "A" liver cirrhosis and 28 patients with normal liver functions. Normal patients and patients with liver cirrhosis were randomized according to the type of antagonist (sugammadex 2mg/kg or neostigmine 50μg/kg). The primary outcome was the time from antagonist administration to a trainoffour (TOF) ratio of 0.9 using mechanosensor neuromuscular transmission module. The durations of the intubating and topup doses of rocuronium, the length of stay in the postanesthesia care unit (PACU), and the incidence of postoperative re curarization were recorded. The durations of the intubating and topup doses of rocuronium were prolonged in patients with liver cirrhosis than controls. The times to a TOF ratio of 0.9 were 3.1 (1.0) and 2.6 (1.0) min after sugammadex administration in patients with liver cirrhosis and controls, respectively, p=1.00. The corresponding times after neostigmine administration were longer than sugammadex 14.5 (3.6) and 15.7 (3.6) min, respectively, p<0.001. The duration of PACU stay was shorter with the use of sugammadex compared to neostigmine. We did not encounter postoperative recurarization after sugammadex or neostigmine. Sugammadex rapidly antagonize moderate residual rocuronium induced neuromuscular block in patients with Child class "A" liver cirrhosis undergoing liver resection. Sugammadex antagonism is associated with 80% reduction in the time to adequate neuromuscular recovery compared to neostigmine.

Liver cirrhosis in Fontan patients does not affect 1-year post-heart transplant mortality or markers of liver function.

PubMed

Simpson, Kathleen E; Esmaeeli, Amir; Khanna, Geetika; White, Francis; Turnmelle, Yumirle; Eghtesady, Pirooz; Boston, Umar; Canter, Charles E

2014-02-01

Liver cirrhosis is recognized with long-term follow-up of patients after the Fontan procedure. The effect of liver cirrhosis on the use of heart transplant (HT) and on post-HT outcomes is unknown. We reviewed Fontan patients evaluated for HT from 2004 to 2012 with hepatic computed tomography (CT) imaging, classified as normal, non-cirrhotic changes, or cirrhosis. The primary outcome was 1-year all-cause mortality, and the secondary outcome was differences in serial post-HT liver evaluation. CT imaging in 32 Fontan patients evaluated for HT revealed 20 (63%) with evidence of liver disease, including 13 (41%) with cirrhosis. Twenty underwent HT, including 5 non-cirrhotic and 7 cirrhosis patients. Characteristics at listing between normal or non-cirrhotic (n = 13) and cirrhosis (n = 7) groups were similar, except cirrhosis patients were older (median 17.6 vs 9.6 years, p = 0.002) and further from Fontan (median 180 vs 50 months, p < 0.05). Serial liver evaluation was similar, including aspartate aminotransferase, alanine aminotransferase, bilirubin, albumin, and tacrolimus dose at 1, 3, 6, 9, and 12 months. Overall patient survival was 80% at 1 year, with no difference between cirrhosis and non-cirrhosis patients (86% vs 77%, p = 0.681). Liver biopsies were performed in 7 patients before HT, and all specimens showed architectural changes with bridging fibrosis. Most patients evaluated for HT had abnormal liver findings by CT, with cirrhosis in 41%. One-year mortality and serial liver evaluation were similar between groups after HT. Liver cirrhosis identified by CT imaging may not be an absolute contraindication to HT alone in this population. © 2014 International Society for Heart and Lung Transplantation Published by International Society for the Heart and Lung Transplantation All rights reserved.

Hepatic metabolic response to injury and sepsis.

PubMed

Dahn, M S; Mitchell, R A; Lange, M P; Smith, S; Jacobs, L A

1995-05-01

Experimental reports have indicated that hepatic oxidative and synthetic metabolism may become depressed in sepsis. Because the mechanism of infection-related liver dysfunction has not been established, further study of these functional alterations could contribute to the therapeutic management of septic organ failure syndromes. However, recently controversy has arisen over the existence of these derangements that must be reconciled before further progress in this field can be made. Splanchnic balance studies for the measurement of glucose output and oxygen consumption were used to assess hepatic function in fasted normal volunteers (n = 18), injured patients (n = 10), and patients with sepsis (n = 18). The liver's contribution to splanchnic metabolism was estimated from a comparison of splanchnic oxygen utilization in response to increases in the liver-specific process of glucogenesis. In addition, in vivo liver albumin production was determined by using the [14C] carbonate technique. Glucose output after injury and sepsis was increased by 12.8% and 76.6%, respectively, compared with controls. On the basis of substrate balance studies, gluconeogenesis was estimated to account for 46%, 87%, and 93%, respectively, of splanchnic glucose output in each of the three groups. In patients with sepsis glucose output was also noted to be linearly related to regional oxygen consumption, indicating that these processes were coupled and increases in the respiratory activity of the splanchnic cellular mass could be accounted for by increases in new glucose output and gluconeogenic substrate clearance. The mean albumin synthetic rate increased during injury and sepsis by 22% and 29%, respectively, compared with normal volunteers. These studies cast doubt on the commonly held notion that tissue respiratory dysfunction may occur during sepsis. On the contrary, hepatic function is accelerated during hyperdynamic sepsis, and evidence indicating oxidative or synthetic functional depression is lacking.

[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.

Liver-fat and liver-function indices derived from Gd-EOB-DTPA-enhanced liver MRI for prediction of future liver remnant growth after portal vein occlusion.

PubMed

Barth, Borna K; Fischer, Michael A; Kambakamba, Patryk; Lesurtel, Mickael; Reiner, Caecilia S

2016-04-01

To evaluate the use of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI)-derived fat- and liver function-measurements for prediction of future liver remnant (FLR) growth after portal vein occlusion (PVO) in patients scheduled for major liver resection. Forty-five patients (age, 59 ± 13.9 y) who underwent Gd-EOB-DTPA-enhanced liver MRI within 24 ± 18 days prior to PVO were included in this study. Fat-Signal-Fraction (FSF), relative liver enhancement (RLE) and corrected liver-to-spleen ratio (corrLSR) of the FLR were calculated from in- and out-of-phase (n=42) as well as from unenhanced T1-weighted, and hepatocyte-phase images (n=35), respectively. Kinetic growth rate (KGR, volume increase/week) of the FLR after PVO was the primary endpoint. Receiver operating characteristics analysis was used to determine cutoff values for prediction of impaired FLR-growth. FSF (%) showed significant inverse correlation with KGR (r=-0.41, p=0.008), whereas no significant correlation was found with RLE and corrLSR. FSF was significantly higher in patients with impaired FLR-growth than in those with normal growth (%FSF, 8.1 ± 9.3 vs. 3.0 ± 5.9, p=0.02). ROC-analysis revealed a cutoff-FSF of 4.9% for identification of patients with impaired FLR-growth with a specificity of 82% and sensitivity of 47% (AUC 0.71 [95%CI:0.54-0.87]). Patients with impaired FLR-growth according to the FSF-cutoff showed a tendency towards higher postoperative complication rates (posthepatectomy liver failure in 50% vs. 19%). Liver fat-content, but not liver function derived from Gd-EOB-DTPA-enhanced MRI is a predictor of FLR-growth after PVO. Thus, liver MRI could help in identifying patients at risk for insufficient FLR-growth, who may need re-evaluation of the therapeutic strategy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation.

PubMed

Todo, Satoru; Yamashita, Kenichiro; Goto, Ryoichi; Zaitsu, Masaaki; Nagatsu, Akihisa; Oura, Tetsu; Watanabe, Masaaki; Aoyagi, Takeshi; Suzuki, Tomomi; Shimamura, Tsuyoshi; Kamiyama, Toshiya; Sato, Norihiro; Sugita, Junichi; Hatanaka, Kanako; Bashuda, Hisashi; Habu, Sonoko; Demetris, Anthony J; Okumura, Ko

2016-08-01

Potent immunosuppressive drugs have significantly improved early patient survival after liver transplantation (LT). However, long-term results remain unsatisfactory because of adverse events that are largely associated with lifelong immunosuppression. To solve this problem, different strategies have been undertaken to induce operational tolerance, for example, maintenance of normal graft function and histology without immunosuppressive therapy, but have achieved limited success. In this pilot study, we aimed to induce tolerance using a novel regulatory T-cell-based cell therapy in living donor LT. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early post-LT. Cells were generated using a 2-week coculture of recipient lymphocytes with irradiated donor cells in the presence of anti-CD80/86 monoclonal antibodies. Immunosuppressive agents were tapered from 6 months, reduced every 3 months, and completely discontinued by 18 months. After the culture, the generated cells displayed cell-number-dependent donor-specific inhibition in the mixed lymphocyte reaction. Infusion of these cells caused no significant adverse events. Currently, all patients are well with normal graft function and histology. Seven patients have completed successful weaning and cessation of immunosuppressive agents. At present, they have been drug free for 16-33 months; 4 patients have been drug free for more than 24 months. The other 3 recipients with autoimmune liver diseases developed mild rejection during weaning and then resumed conventional low-dose immunotherapy. A cell therapy using an ex vivo-generated regulatory T-cell-enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases. (Hepatology 2016;64:632-643). © 2016 by the American Association for the Study of Liver Diseases.

Liver transplantation in children with Alagille syndrome--a study of twelve cases.

PubMed

Cardona, J; Houssin, D; Gauthier, F; Devictor, D; Losay, J; Hadchouel, M; Bernard, O

1995-08-27

Cholestasis associated with Alagille syndrome may, in a few cases, be extremely severe and result in major impairment in the quality of life during early childhood and end up in cirrhosis eventually. We report the results of liver transplantation in 12 children with a severe hepatic form of Alagille syndrome. All children presented with cholestatic jaundice from birth, peculiar facies, stenosis of the peripheral pulmonary artery, and posterior embryotoxon; butterfly-like vertebrae were present in 9 children. At the time of transplantation (mean age 7 years 10 months) refractory pruritus was present in 9 children, xanthoma in 11, and height and weight retardation in 11. Total serum bilirubin ranged from 116 to 322 mumol/L and total serum cholesterol from 3.5 to 29 mmol/L. Systolic right ventricular pressure was moderately raised (36 to 48 mmHg) in 5 children; mean creatinine clearance was 99 ml/min/1.73 m2. Histologic examination of the removed livers showed cirrhosis, severe annular fibrosis, and moderate portal fibrosis in 4 children each. Follow-up in the 11 survivors has ranged from 14 months to 5 1/2 years. All lead normal lives. Pruritus and xanthomas disappeared. Increase in height was observed in 8 of the 10 survivors who had growth retardation prior to transplantation. School level is normal in 4 (median age at LT: 5 yr 9 mo) and below normal in 6 (median age at OLT: 9 yr 9 mo). Liver function tests are normal in 10 children. Mean creatinine clearance is 101 ml/min/1.73 m2. These results indicate that the quality of life can be considerably improved after liver transplantation in children with a severe hepatic form of Alagille syndrome and suggest that it could be carried out before these children attend elementary school.

Transient elastographic evaluation in adult subjects without overt liver disease: influence of alanine aminotransferase levels.

PubMed

Kumar, Manoj; Sharma, Praveen; Garg, Hitendra; Kumar, Ramesh; Bhatia, Vikram; Sarin, Shiv K

2011-08-01

  Studies on normal values of liver stiffness (LS) in subjects at "low risk" for liver disease are scant. The aim of the present study was to assess liver stiffness values in the subjects without overt liver disease with normal alanine aminotransferases (ALT) and to determine potential factors, which may influence these values with special reference to newly suggested updated upper limits of normal for ALT.   Liver stiffness measurements were performed in 445 subjects without overt liver disease (mean age, 41.1±13.6; male, 73.5%) and normal liver enzymes.   Mean LS value was 5.10±1.19kPa. LS values were higher in men than in women (5.18±1.67 vs 4.86±1.24kPa, respectively, P=0.008); in subjects with higher body mass index (BMI) category (Normal, overweight and obese subjects; 4.10±0.75, 5.08±0.66, and 6.05±1.28kPa, respectively; P<0.001); in subjects with metabolic syndrome than in those without (5.63±1.37 vs 5.01±1.14kPa, P=0.001); and in subjects with ALT levels more than updated limits of normal compared to subjects with ALT levels less than updated limits of normal (5.68±1.21 vs 4.77±1.05kPa, P<0.001). On multiple linear regression, BMI and ALT was found to be significant predictor of LS.   Liver stiffness values in subjects without overt liver disease with normal ALT are influenced by BMI and ALT levels. Subjects with ALT levels less than updated limits of normal have lower LS values as compared to those with higher levels. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Insights on augmenter of liver regeneration cloning and function

PubMed Central

Gatzidou, Elisavet; Kouraklis, Gregory; Theocharis, Stamatios

2006-01-01

Hepatic stimulator substance (HSS) has been referred to as a liver-specific but species non-specific growth factor. Gradient purification and sequence analysis of HSS protein indicated that it contained the augmenter of liver regeneration (ALR), also known as hepatopoietin (HPO). ALR, acting as a hepatotrophic growth factor, specifically stimulated proliferation of cultured hepatocytes as well as hepatoma cells in vitro, promoted liver regeneration and recovery of damaged hepatocytes and rescued acute hepatic failure in vivo. ALR belongs to the new Erv1/Alr protein family, members of which are found in lower and higher eukaryotes from yeast to man and even in some double-stranded DNA viruses. The present review article focuses on the molecular biology of ALR, examining the ALR gene and its expression from yeast to man and the biological function of ALR protein. ALR protein seems to be non-liver-specific as was previously believed, increasing the necessity to extend research on mammalian ALR protein in different tissues, organs and developmental stages in conditions of normal and abnormal cellular growth. PMID:16937489

TNF-{alpha} similarly induces IL-6 and MCP-1 in fibroblasts from colorectal liver metastases and normal liver fibroblasts

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

Mueller, Lars, E-mail: lars.mueller@uksh-kiel.de; Seggern, Lena von; Schumacher, Jennifer

2010-07-02

Cancer-associated fibroblasts (CAFs) represent the predominant cell type of the neoplastic stroma of solid tumors, yet their biology and functional specificity for cancer pathogenesis remain unclear. We show here that primary CAFs from colorectal liver metastases express several inflammatory, tumor-enhancing factors, including interleukin (IL)-6 and monocyte-chemoattractant protein (MCP)-1. Both molecules were intensely induced by TNF-{alpha} on the transcript and protein level, whereas PDGF-BB, TGF-{beta}1 and EGF showed no significant effects. To verify their potential specialization for metastasis progression, CAFs were compared to fibroblasts from non-tumor liver tissue. Interestingly, these liver fibroblasts (LFs) displayed similar functions. Further analyses revealed a comparablemore » up-regulation of intercellular adhesion molecule-1 (ICAM-1) by TNF-{alpha}, and of alpha-smooth muscle actin, by TGF-{beta}1. Moreover, the proliferation of both cell types was induced by PDGF-BB, and CAFs and LFs displayed an equivalent migration towards HT29 colon cancer cells in Boyden chamber assays. In conclusion, colorectal liver metastasis may be supported by CAFs and resident fibroblastic cells competent to generate a prometastatic microenvironment through inflammatory activation of IL-6 and MCP-1.« less

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction.

PubMed

van Zutphen, Tim; Ciapaite, Jolita; Bloks, Vincent W; Ackereley, Cameron; Gerding, Albert; Jurdzinski, Angelika; de Moraes, Roberta Allgayer; Zhang, Ling; Wolters, Justina C; Bischoff, Rainer; Wanders, Ronald J; Houten, Sander M; Bronte-Tinkew, Dana; Shatseva, Tatiana; Lewis, Gary F; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M; Jonker, Johan W; Kim, Peter K; Bandsma, Robert H J

2016-12-01

Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. Peroxisomes and mitochondria play key roles in various hepatic metabolic functions including lipid metabolism and energy production. To investigate the involvement of these organelles in the mechanisms underlying malnutrition-induced hepatic dysfunction we developed a rat model of malnutrition. Weanling rats were placed on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Peroxisomal and mitochondrial structural features were characterized using immunofluorescence and electron microscopy. Mitochondrial function was assessed using high-resolution respirometry. A novel targeted quantitative proteomics method was applied to analyze 47 mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle and fatty acid β-oxidation pathways. Low protein diet-fed rats developed hypoalbuminemia and hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated peroxisomal dysfunction. This was followed by changes in mitochondrial ultrastructure and increased mitochondrial content. Mitochondrial function was impaired due to multiple defects affecting respiratory chain complex I and IV, pyruvate uptake and several β-oxidation enzymes, leading to strongly reduced hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial β-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. Malnutrition leads to severe impairments in hepatic peroxisomal and mitochondrial function, and hepatic metabolic dysfunction. We discuss the potential future implications of our findings for the clinical management of malnourished children. Severe malnutrition in children is associated with metabolic disturbances that are poorly understood. In order to study this further, we developed a malnutrition animal model and found that severe malnutrition leads to an impaired function of liver mitochondria which are essential for energy production and a loss of peroxisomes, which are important for normal liver metabolic function. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Transcriptome analysis of duck liver and identification of differentially expressed transcripts in response to duck hepatitis A virus genotype C infection.

PubMed

Tang, Cheng; Lan, Daoliang; Zhang, Huanrong; Ma, Jing; Yue, Hua

2013-01-01

Duck is an economically important poultry and animal model for human viral hepatitis B. However, the molecular mechanisms underlying host-virus interaction remain unclear because of limited information on the duck genome. This study aims to characterize the duck normal liver transcriptome and to identify the differentially expressed transcripts at 24 h after duck hepatitis A virus genotype C (DHAV-C) infection using Illumina-Solexa sequencing. After removal of low-quality sequences and assembly, a total of 52,757 unigenes was obtained from the normal liver group. Further blast analysis showed that 18,918 unigenes successfully matched the known genes in the database. GO analysis revealed that 25,116 unigenes took part in 61 categories of biological processes, cellular components, and molecular functions. Among the 25 clusters of orthologous group categories (COG), the cluster for "General function prediction only" represented the largest group, followed by "Transcription" and "Replication, recombination, and repair." KEGG analysis showed that 17,628 unigenes were involved in 301 pathways. Through comparison of normal and infected transcriptome data, we identified 20 significantly differentially expressed unigenes, which were further confirmed by real-time polymerase chain reaction. Of the 20 unigenes, nine matched the known genes in the database, including three up-regulated genes (virus replicase polyprotein, LRRC3B, and PCK1) and six down-regulated genes (CRP, AICL-like 2, L1CAM, CYB26A1, CHAC1, and ADAM32). The remaining 11 novel unigenes that did not match any known genes in the database may provide a basis for the discovery of new transcripts associated with infection. This study provided a gene expression pattern for normal duck liver and for the previously unrecognized changes in gene transcription that are altered during DHAV-C infection. Our data revealed useful information for future studies on the duck genome and provided new insights into the molecular mechanism of host-DHAV-C interaction.

Histology Atlas of the Developing Mouse Hepatobiliary System with Emphasis on Embryonic Days 9.5-18.5

PubMed Central

Crawford, Laura Wilding; Foley, Julie F.; Elmore, Susan A.

2012-01-01

Animal model phenotyping, in utero exposure toxiciy studies, and investigation into causes of embryonic, fetal, or perinatal deaths have required pathologists to recognize and diagnose developmental disorders in spontaneous and engineered mouse models of disease. In mammals, the liver is the main site of hematopoiesis during fetal development, has endocrine and exocrine functions important for maintaining homeostasis in fetal and adult life; and performs other functions including waste detoxification, production and removal of glucose, glycogen storage, triglyceride and fatty acid processing, and serum protein production. Due to its role in many critical functions, alterations in the size, morphology, or function(s) of the liver often lead to embryonic lethality. Many publications and websites describe individual aspects of hepatobiliary development at defined stages. However, no single resource provides a detailed histological evaluation of H&E-stained sections of the developing murine liver and biliary systems using high-magnification and high-resolution color images. The work herein provides a histology atlas of hepatobiliary development between embryonic days 9.5-18.5. Although the focus of this work is normal hepatobiliary development, common defects in liver development are also described as a reference for pathologists who may be asked to phenotype mice with congenital, inherited, or treatment-related hepatobiliary defects. PMID:20805319

Hepatoprotective Effect of Essential Oils from Hyptis crenata in Sepsis-Induced Liver Dysfunction.

PubMed

Lima, Glauber Cruz; Vasconcelos, Yuri de Abreu Gomes; de Santana Souza, Marilia Trindade; Oliveira, Alan Santos; Bomfim, Rangel Rodrigues; de Albuquerque Júnior, Ricardo Luiz Cavalcanti; Camargo, Enilton Aparecido; Portella, Viviane Gomes; Coelho-de-Souza, Andrelina Noronha; Diniz, Lúcio Ricardo Leite

2018-02-28

No specific therapeutics are available for the treatment of sepsis-induced liver dysfunction, a clinical complication strongly associated with the high mortality rate of septic patients. This study investigated the effect of the essential oil of Hyptis crenata (EOHc), a lamiaceae plant used to treat liver disturbances in Brazilian folk medicine, on liver function during early sepsis. Sepsis was induced by the cecal ligation and puncture (CLP) model. Rats were divided into four groups: Sham, Sham+EOHc, CLP, and CLP+EOHc. EOHc (300 mg/kg) was orally administered 12 and 24 h after surgery. The animals were sacrificed for blood collection and liver tissue samples 48 h after surgery. Hepatic function was evaluated by measuring serum bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase, and alanine aminotransferase (ALT) levels. The levels of malondialdehyde and the activity of superoxide dismutase, catalase, and GSH peroxidase (GSH-Px) were measured for assessment of oxidative stress. Liver morphology was analyzed by hematoxylin and eosin staining. EOHc normalized serum ALP, ALT, and bilirubin levels and inhibited morphological changes. In addition, we observed that EOHc inhibited elevation in hepatic lipid peroxidation and reduction of the glutathione peroxidase activity induced by sepsis. Our data show that EOHc plays a protective effect against liver injury induced by sepsis.

Orthotopic liver transplantation for portosystemic encephalopathy in an adult with congenital absence of the portal vein.

PubMed

Wojcicki, Maciej; Haagsma, Elizabeth B; Gouw, Annette S H; Slooff, Maarten J H; Porte, Robert J

2004-09-01

Congenital absence of the portal vein (CAPV) is a very rare venous malformation in which mesenteric venous blood drains directly into the systemic circulation. There is no portal perfusion of the liver and no portal hypertension. This abnormality is usually coincidentally discovered in children, the majority of whom have no signs of encephalopathy and only slightly abnormal liver function tests. Additional anomalies common in CAPV are cardiovascular abnormalities and hepatic tumors. To date, only 5 adult patients (>18 years) with CAPV have been described, none of whom underwent liver transplantation. We describe a 45-year-old man with CAPV and end-stage renal insufficiency due to focal segmental glomerulopathy, who developed therapy-resistant encephalopathy with intermittently high ammonia levels. The patient underwent a combined liver and kidney transplantation and is doing well at 2.5 years of follow-up. Histopathological examination of the native liver showed no portal vein branches in the portal tracts. In conclusion, our experience suggests that, although children with CAPV usually have no symptoms of encephalopathy, this may still develop at a later stage in adult life. When encephalopathy becomes refractory to medical therapy, orthotopic liver transplantation (OLT) can be successfully performed with restoration of normal cerebral function.

Living Donor Liver Transplantation for Unresectable Liver Adenomatosis Associated with Congenital Absence of Portal Vein: A Case Report and Literature Review

PubMed Central

Brasoveanu, Vladislav; Ionescu, Mihnea Ioan; Grigorie, Razvan; Mihaila, Mariana; Bacalbasa, Nicolae; Dumitru, Radu; Herlea, Vlad; Iorgescu, Andreea; Tomescu, Dana; Popescu, Irinel

2015-01-01

Patient: Female, 21 Final Diagnosis: Unresectable liver adenomatosis associated with congenital absence of portal vein Symptoms: — Medication: — Clinical Procedure: Living donor liver transplantation Specialty: Transplantology Objective: Rare disease Background: Abernethy malformation (AM), or congenital absence of portal vein (CAPV), is a very rare disease which tends to be associated with the development of benign or malignant tumors, usually in children or young adults. Case Report: We report the case of a 21-year-old woman diagnosed with type Ib AM (portal vein draining directly into the inferior vena cava) and unresectable liver adenomatosis. The patient presented mild liver dysfunction and was largely asymptomatic. Living donor liver transplantation was performed using a left hemiliver graft from her mother. Postoperatively, the patient attained optimal liver function and at 9-month follow-up has returned to normal life. Conclusions: We consider that living donor liver transplantation is the best therapeutic solution for AM associated with unresectable liver adenomatosis, especially because compared to receiving a whole liver graft, the waiting time on the liver transplantation list is much shorter. PMID:26386552

[Protective effect of Tanreqing injection on acute hepatic injury induced by CCl4 in rats].

PubMed

Lei, Yang; Zhou, Ai-Min; Guo, Tao; Tan, Ye; Tao, Yan-Yan; Liu, Cheng-Hai

2013-04-01

To observe the protective effect of Tanreqing injection(TRQ) on carbon tetrachloride-induced acute hepatic injury in rats. Rats were randomly divided into the normal group and the model group, and injected subcutaneously with 100% CCl4 5 mL x kg(-1) to establish the single CCl4 infection model, in order to observe the changes in rat liver injury after 3 h and 6 h. Subsequently, the multiple CCl4 infection liver injury model was reproduced by subcutaneously injecting 100% CCl4 (5 mL x kg(-1)), 50% CCl4 olive oil solution (2 mL x kg(-1)) and then 20% CCl4 olive oil solution (2 mL x kg(-1)). At 6 h after the first CCl4 injection, the rats were divided into six groups: the model group, the control group, the diammonium glycyrrhizinate-treated group, and TRQ high, middle and low dose groups. They were injected through caudal veins, while a normal control group was set up. Their weight and liver-body ratio were observed. Hepatic inflammation was observed with HE staining. Assay kits were adopted to detect ALT, AST, T. Bil, D. Bil, CHE, TBA, gamma-GT and Alb. According to the single injection model, serum AST and T. Bil of model rats were obviously increased at 6 h after single subcutaneous injection of CCl4, with disordered lobular structure in liver tissues, notable swollen liver cells and remarkable liver injury. According to the results of the multiple injection pharmacological experiment, compared with the normal group, the model group had higher serum ALT, AST, and gamma-GT activities (P < 0. 05), TBA and T. Bil contents (P < 0.05) and lower CHE activity (P < 0.05). HE staining showed disorganized lobular structure in liver tissues and notable ballooning degeneration in liver cells. Compared with the model group, TRQ high and middle dose groups and the diammonium glycyrrhizinate-treated group showed significant charges in serum liver function and inflammation in liver cells. Specifically, TRQ high and middle dose groups were superior to the diammonium glycyrrhizinate-treated group. Tanreqing injection has significant protective effect on CCl4-induced acute hepatic injury in rats.

Donor morbidity in right and left hemiliver living donor liver transplantation: the impact of graft selection and surgical innovation on donor safety.

PubMed

Iwasaki, Junji; Iida, Taku; Mizumoto, Masaki; Uemura, Tadahiro; Yagi, Shintaro; Hori, Tomohide; Ogawa, Kohei; Fujimoto, Yasuhiro; Mori, Akira; Kaido, Toshimi; Uemoto, Shinji

2014-11-01

This study investigated adequate liver graft selection for donor safety by comparing postoperative donor liver function and morbidity between the right and left hemilivers (RL and LL, respectively) of living donors. Between April 2006 and March 2012, RL (n = 168) and LL (n = 140) donor operations were performed for liver transplantation at Kyoto University Hospital. Postoperative hyperbilirubinemia and coagulopathy persisted in RL donors, whereas the liver function of LL donors normalized more rapidly. The overall complication rate of the RL donors was significantly higher than that of the LL donors (59.5% vs. 30.7%; P < 0.001). There were no significant differences in severe complications worse than Clavien grade IIIa or in biliary complication rates between the two donor groups. In April 2006, we introduced an innovative surgical procedure: hilar dissection preserving the blood supply to the bile duct during donor hepatectomy. Compared with our previous outcomes (1990-2006), the biliary complication rate of the RL donors decreased from 12.2% to 7.2%, and the severity of these complications was significantly lower. In conclusion, LL donors demonstrated good recovery in postoperative liver function and lower morbidity, and our surgical innovations reduced the severity of biliary complications in living donors. © 2014 Steunstichting ESOT.

Flux balance analysis predicts Warburg-like effects of mouse hepatocyte deficient in miR-122a

PubMed Central

Wu, Hsuan-Hui; Chen, Meng-Chun; Liu, Wen-Huan; Wu, Wu-Hsiung; Chang, Peter Mu-Hsin; Huang, Chi-Ying F.; Tsou, Ann-Ping; Shiao, Ming-Shi

2017-01-01

The liver is a vital organ involving in various major metabolic functions in human body. MicroRNA-122 (miR-122) plays an important role in the regulation of liver metabolism, but its intrinsic physiological functions require further clarification. This study integrated the genome-scale metabolic model of hepatocytes and mouse experimental data with germline deletion of Mir122a (Mir122a–/–) to infer Warburg-like effects. Elevated expression of MiR-122a target genes in Mir122a–/–mice, especially those encoding for metabolic enzymes, was applied to analyze the flux distributions of the genome-scale metabolic model in normal and deficient states. By definition of the similarity ratio, we compared the flux fold change of the genome-scale metabolic model computational results and metabolomic profiling data measured through a liquid-chromatography with mass spectrometer, respectively, for hepatocytes of 2-month-old mice in normal and deficient states. The Ddc gene demonstrated the highest similarity ratio of 95% to the biological hypothesis of the Warburg effect, and similarity of 75% to the experimental observation. We also used 2, 6, and 11 months of mir-122 knockout mice liver cell to examined the expression pattern of DDC in the knockout mice livers to show upregulated profiles of DDC from the data. Furthermore, through a bioinformatics (LINCS program) prediction, BTK inhibitors and withaferin A could downregulate DDC expression, suggesting that such drugs could potentially alter the early events of metabolomics of liver cancer cells. PMID:28686599

Divergent Pseudomonas exotoxin A sensitivity in normal and transformed liver cells is correlated with low-density lipoprotein receptor-related protein expression.

PubMed

Laithwaite, J E; Benn, S J; Marshall, W S; FitzGerald, D J; LaMarre, J

2001-09-01

Pseudomonas exotoxin A (PEA) is an extracellular virulence factor produced by the opportunistic human pathogen Pseudomonas aerguinosa. PEA intoxification begins when PEA binds to the low-density lipoprotein receptor-related protein (LRP). The liver is the primary target of systemic PEA, due largely to the high levels of functional LRP expressed by liver cells. Using a 3H-leucine incorporation assay to measure inhibition of protein synthesis we have demonstrated that normal (BNL CL.2) and transformed (BNL 1ME A7R.1) liver cells exhibit divergent PEA sensitivity; with BNL 1ME A7R.1 cells demonstrating greater PEA sensitivity than their non-transformed counterparts. The receptor-associated protein, a LRP antagonist, decreased PEA toxicity in BNL 1ME A7R.1 cells, confirming the importance of the LRP in PEA intoxification in this cell type. Increased PEA sensitivity in BNL 1ME A7R.1 cells was associated with increased functional cell surface LRP expression, as measured by alpha2-macroglobulin binding and internalization studies, and increased LRP mRNA levels, as determined by Northern blot analysis. Interestingly, BNL CL.2 cells were more sensitive than BNL 1ME A7R.1 cells to conjugate and mutant PEA toxins that do not utilize the LRP for cellular entry. These data demonstrate that increased LRP expression is an important mechanism by which PEA sensitivity is increased in BNL 1ME A7R.1 transformed liver cells.

The Effects of Gymnema sylvestre in High-Fat Diet-Induced Metabolic Disorders.

PubMed

Kim, Hyeon-Jeong; Kim, Sanghwa; Lee, Ah Young; Jang, Yoonjeong; Davaadamdin, Orkhonselenge; Hong, Seong-Ho; Kim, Jun Sung; Cho, Myung-Haing

2017-01-01

This study used an integrated approach to investigate the effects of Gymnema sylvestre (GS) extract as a functional dietary supplement with a high-fat diet. This approach examined insulin resistance, the dysfunction of adipose tissue, and liver steatosis. Male C57BL/6J mice were fed a normal chow or high-fat diet (HFD) for the acute and chronic study, in addition to GS in different doses (100, 250 and 500[Formula: see text]mg/kg body weight). Their body composition changes, serum lipid and glucose parameters, adipose and liver tissue histology, and gene expression were measured. It was found that GS significantly suppressed the increase of body weight, serum levels of lipid, insulin and leptin, and adipose tissue, and liver inflammation. GS also demonstrated hypoglycemic effects due to the amylase inhibition activity. Our results support the existence of a relationship between the HFD induced insulin resistance, adipose dysfunction and liver steatosis. In conclusion, GS works as a functional dietary supplement with preventative effects against metabolic disorder.

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.

Transplantation of a 2-year-old deceased-donor liver to a 61-year-old male recipient.

PubMed

Dai, Wing Chiu; Sharr, William W; Chok, Kenneth S H; Cheung, Tan To; Fung, James Y Y; Chan, Albert C Y; Chan, See Ching; Lo, Chung Mau

2015-04-01

The suitable size of a graft is a key element in the success of liver transplantation. A small-for-size liver graft is very likely to sustain a significant degree of injury as a result of ischemia, preservation, reperfusion, and rejection. Usually, small-for-size grafts are a concern in living-donor liver transplantation rather than in deceased-donor liver transplantation. Here, we describe the successful transplantation of a liver from a 2-year-old deceased donor to a 61-year-old male recipient who suffered from liver failure related to hepatitis B. No report of successful deceased-donor liver transplantation with discrepancies between donor and recipient age and size to such an extent has been found in the literature. Despite unusually large discrepancies, with effort in minimizing the ischemic time, revised surgical techniques, and strong regenerative power of the "young" graft, the old patient's liver function gradually returned to normal. This again proves that the definition of a "suitable graft" evolves with time and experience. Copyright © 2012. Published by Elsevier Taiwan.

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.

Investigation into the distinct subcellular effects of docosahexaenoic acid loaded low-density lipoprotein nanoparticles in normal and malignant murine liver cells

PubMed Central

Moss, Lacy R.; Mulik, Rohit S.; Van Treuren, Tim; Kim, Soo Young; Corbin, Ian R.

2016-01-01

Background Recent studies have shown that low density lipoproteins reconstituted with the natural omega 3 fatty acid docosahexaenoic acid (LDL-DHA) is selectively cytotoxic to liver cancer cells over normal hepatocytes. To date, little is known about the subcellular events which transpire following LDL-DHA treatment. Methods Herein, murine noncancer and cancer liver cells, TIB-73 and TIB-75 respectively, were investigated utilizing confocal microscopy, flow cytometry and viability assays to demonstrate differential actions of LDL-DHA nanoparticles in normal versus malignant cells. Results Our studies first showed that basal levels of oxidative stress are significantly higher in the malignant TIB-75 cells compared to the normal TIB-73 cells. As such, upon entry of LDL-DHA into the malignant TIB-75 cells, DHA is rapidly oxidized precipitating global and lysosomal lipid peroxidation along with increased lysosomal permeability. This leakage of lysosomal contents and lipid peroxidation products trigger subsequent mitochondrial dysfunction and nuclear injury. The cascade of LDL-DHA mediated lipid peroxidation and organelle damage was partially reversed by the administration of the antioxidant, N-acetylcysteine, or the iron-chelator, deferoxamine. LDL-DHA treatment in the normal TIB-73 cells was well tolerated and did not elicit any cell or organelle injury. Conclusion These studies have shown that LDL-DHA is selectively cytotoxic to liver cancer cells and that increased levels of ROS and iron catalyzed reactions promote the peroxidation of DHA which lead to organelle dysfunction and ultimately the demise of the cancer cell. General significance LDL-DHA selectively disrupts lysosomal, mitochondrial and nuclear function in cancer cells as a novel pathway for eliminating cancer cells. PMID:27418237

Caffeine intake decreases oxidative stress and inflammatory biomarkers in experimental liver diseases induced by thioacetamide: Biochemical and histological study.

PubMed

Amer, Mona G; Mazen, Nehad F; Mohamed, Ahmed M

2017-03-01

Liver disease remains a significant global health problem. Increased caffeine consumption has been associated with a lower prevalence of chronic liver disease. This study aimed to investigate the modifying effects of caffeine on liver injury induced by thioacetamide (TAA) administration in male rats and the possible underlying mechanisms. Forty adult male rats were equally classified into four groups: control group, received only tap water; caffeine-treated group, received caffeine (37.5 mg/kg per day); TAA-treated group, received intraperitoneal (i.p.) TAA (200 mg/kg b.w.) twice a week; and caffeine + TAA-treated group, received combined TAA and caffeine in the same previous doses. After eight weeks of treatment, blood samples were collected for biochemical analysis and liver specimens were prepared for histological and immunohistochemical studies and for assessment of oxidative stress. TAA induced liver toxicity with elevated liver enzymes and histological alterations, fatty changes, apoptosis, and fibrosis evidenced by increased immunohistochemical reaction to matrix metalloproteinase-9 (MMP-9) and collagen type IV in hepatocytes. Also, the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in serum were significantly elevated. Co-treatment with caffeine and TAA restored normal liver structure and function. Caffeine provided an anti-fibrogenic, anti-inflammatory, and antioxidant effect that was associated with recovery of hepatic histological and functional alterations from TAA-induced hepatotoxicity.

Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans.

PubMed

Zhang, Shanshan; Wang, Jingxiao; Wang, Haichuan; Fan, Lingling; Fan, Biao; Zeng, Billy; Tao, Junyan; Li, Xiaolei; Che, Li; Cigliano, Antonio; Ribback, Silvia; Dombrowski, Frank; Chen, Bin; Cong, Wenming; Wei, Lixin; Calvisi, Diego F; Chen, Xin

2018-04-01

Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Cajanus cajan Linn. (Leguminosae) prevents alcohol-induced rat liver damage and augments cytoprotective function.

PubMed

Kundu, Rakesh; Dasgupta, Suman; Biswas, Anindita; Bhattacharya, Anirban; Pal, Bikas C; Bandyopadhyay, Debashis; Bhattacharya, Shelley; Bhattacharya, Samir

2008-08-13

Cajanus cajan Linn. (Leguminosae) is a nontoxic edible herb, widely used in Indian folk medicine for the prevention of various liver disorders. In the present study we have demonstrated that methanol-aqueous fraction (MAF2) of Cajanus cajan leaf extract could prevent the chronically treated alcohol induced rat liver damage. Chronic doses of alcohol (3.7 g/ kg) orally administered to rats for 28 days and liver function marker enzymes such as GPT, GOT, ALP and anti-oxidant enzyme activities were determined. Effect of MAF2 at a dose of 50mg/kg body weight on alcohol treated rats was noted. Alcohol effected significant increase in liver marker enzyme activities and reduced the activities of anti-oxidant enzymes. Co-administration of MAF2 reversed the liver damage due to alcohol; it decreased the activities of liver marker enzymes and augmented antioxidant enzyme activities. We also demonstrate significant decrease of the phase II detoxifying enzyme, UDP-glucuronosyl transferase (UGT) activity along with a three- and two-fold decrease of UGT2B gene and protein expression respectively. MAF2 co-administration normalized UGT activity and revived the expression of UGT2B with a concomitant expression and nuclear translocation of Nrf2, a transcription factor that regulates the expression of many cytoprotective genes. Cajanus cajan extract therefore shows a promise in therapeutic use in alcohol induced liver dysfunction.

Dielectric properties of human normal, malignant and cirrhotic liver tissue: in vivo and ex vivo measurements from 0.5 to 20 GHz using a precision open-ended coaxial probe.

PubMed

O'Rourke, Ann P; Lazebnik, Mariya; Bertram, John M; Converse, Mark C; Hagness, Susan C; Webster, John G; Mahvi, David M

2007-08-07

Hepatic malignancies have historically been treated with surgical resection. Due to the shortcomings of this technique, there is interest in other, less invasive, treatment modalities, such as microwave hepatic ablation. Crucial to the development of this technique is the accurate knowledge of the dielectric properties of human liver tissue at microwave frequencies. To this end, we characterized the dielectric properties of in vivo and ex vivo normal, malignant and cirrhotic human liver tissues from 0.5 to 20 GHz. Analysis of our data at 915 MHz and 2.45 GHz indicates that the dielectric properties of ex vivo malignant liver tissue are 19 to 30% higher than normal tissue. The differences in the dielectric properties of in vivo malignant and normal liver tissue are not statistically significant (with the exception of effective conductivity at 915 MHz, where malignant tissue properties are 16% higher than normal). Also, the dielectric properties of in vivo normal liver tissue at 915 MHz and 2.45 GHz are 16 to 43% higher than ex vivo. No statistically significant differences were found between the dielectric properties of in vivo and ex vivo malignant tissue (with the exception of effective conductivity at 915 MHz, where malignant tissue properties are 28% higher than normal). We report the one-pole Cole-Cole parameters for ex vivo normal, malignant and cirrhotic liver tissue in this frequency range. We observe that wideband dielectric properties of in vivo liver tissue are different from the wideband dielectric properties of ex vivo liver tissue, and that the in vivo data cannot be represented in terms of a Cole-Cole model. Further work is needed to uncover the mechanisms responsible for the observed wideband trends in the in vivo liver data.

[Liver injury and intervention of compound 912 liquid on it in rats with endotoxemia].

PubMed

Hu, Lan; Zhang, Shu-Wen; Yin, Cheng-Hong

2007-06-01

To investigate the liver injury in model rats with endotoxemia and to observe the protective effect of Compound 912 Liquid on it. Rats were randomly divided into three groups, the endotoxemia model group (EMG, injected by lipoplysaccharides (LPS) peritoneally), the intervention group (IG, treated with Compound 912 Liquid via gastrogavage 1 h before model establishing) and the normal control group (NCG). Blood samples of rats were taken at the time points of the 2nd, 4th, 8th, 12th, 48th, 72nd hour and the 7th day after modeling for measuring liver function, levels of plasmatic endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-10 (IL-10). The pathological change of liver was observed using light microscope and electro-transmission microscope. The peak concentration of endotoxin detected at 2 hour after modeling in the IG was significantly lower than that in the EMG (0.358 +/- 0.056 vs 0.685 +/- 0.030), but insignificant difference (P > 0.05) was shown between them in TNF-alpha level. The level of IL-10 continuously rose in IG after treatment, it was still higher than normal level until day 7 (49.096 +/- 4.076 vs 43.454 +/- 5.928, P < 0.05). LPS can induce the increase of serum inflammatory cytokines and anti-inflammatory cytokines in rats to injure liver. Therefore, the inflammatory reaction indicated by LPS may be one of the mechanisms for liver injury. Preventive medication with Compound 912 Liquid showed a significant liver protective effect.

Liver glycogen in type 2 diabetic mice is randomly branched as enlarged aggregates with blunted glucose release.

PubMed

Besford, Quinn Alexander; Zeng, Xiao-Yi; Ye, Ji-Ming; Gray-Weale, Angus

2016-02-01

Glycogen is a vital highly branched polymer of glucose that is essential for blood glucose homeostasis. In this article, the structure of liver glycogen from mice is investigated with respect to size distributions, degradation kinetics, and branching structure, complemented by a comparison of normal and diabetic liver glycogen. This is done to screen for differences that may result from disease. Glycogen α-particle (diameter ∼ 150 nm) and β-particle (diameter ∼ 25 nm) size distributions are reported, along with in vitro γ-amylase degradation experiments, and a small angle X-ray scattering analysis of mouse β-particles. Type 2 diabetic liver glycogen upon extraction was found to be present as large loosely bound, aggregates, not present in normal livers. Liver glycogen was found to aggregate in vitro over a period of 20 h, and particle size is shown to be related to rate of glucose release, allowing a structure-function relationship to be inferred for the tissue specific distribution of particle types. Application of branching theories to small angle X-ray scattering data for mouse β-particles revealed these particles to be randomly branched polymers, not fractal polymers. Together, this article shows that type 2 diabetic liver glycogen is present as large aggregates in mice, which may contribute to the inflexibility of interconversion between glucose and glycogen in type 2 diabetes, and further that glycogen particles are randomly branched with a size that is related to the rate of glucose release.

Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France.

PubMed

Young, Jacques; Bertherat, Jérôme; Vantyghem, Marie Christine; Chabre, Olivier; Senoussi, Salima; Chadarevian, Rita; Castinetti, Frédéric

2018-05-01

Ketoconazole (KTZ) is one of few available treatments for Cushing's syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ. An observational prospective French cohort study (Compassionate Use Programme (CUP)). Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury. Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes. These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ. © 2018 European Society of Endocrinology.

Expression and function of the atypical cadherin FAT1 in chronic liver disease.

PubMed

Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E; Müller, Martina; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

2012-09-28

Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NFκB activity. This transcription factor is critical for apoptosis resistance of HSCs, and consequently, we detected a higher apoptosis rate in FAT1 suppressed HSCs compared to control cells. Our findings suggest FAT1 as new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease. Copyright © 2012 Elsevier Inc. All rights reserved.

Cirrhosis and autoimmune liver disease: Current understanding

PubMed Central

Liberal, Rodrigo; Grant, Charlotte R

2016-01-01

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids. PMID:27729952

Optical diagnosis of the progression and reversal of CCl4-induced liver injury in rodent model using minimally invasive autofluorescence spectroscopy.

PubMed

Nazeer, Shaiju S; Sandhyamani, S; Jayasree, Ramapurath S

2015-06-07

Worldwide, liver cancer is the fifth most common cancer in men and seventh most common cancer in women. Intoxicant-induced liver injury is one of the major causes for severe structural damage with fibrosis and functional derangement of the liver leading to cancer in its later stages. This report focuses on the minimally invasive autofluorescence spectroscopic (AFS) studies on intoxicant, carbon tetrachloride (CCl4)-induced liver damage in a rodent model. Different stages of liver damage, including the reversed stage, on stoppage of the intoxicant are examined. Emission from prominent fluorophores, such as collagen, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FAD), and variations in redox ratio have been studied. A direct correlation between the severity of the disease and the levels of collagen and redox ratio was observed. On withdrawal of the intoxicant, a gradual reversal of the disease to normal conditions was observed as indicated by the decrease in collagen levels and redox ratio. Multivariate statistical techniques and principal component analysis followed by linear discriminant analysis (PC-LDA) were used to develop diagnostic algorithms for distinguishing different stages of the liver disease based on spectral features. The PC-LDA modeling on a minimally invasive AFS dataset yielded diagnostic sensitivities of 93%, 87% and 87% and specificities of 90%, 98% and 98% for pairwise classification among normal, fibrosis, cirrhosis and reversal conditions. We conclude that AFS along with PC-LDA algorithm has the potential for rapid and accurate minimally invasive diagnosis and detection of structural changes due to liver injury resulting from various intoxicants.

Fibrinogen Brescia

PubMed Central

Brennan, Stephen O.; Wyatt, Jane; Medicina, Daniela; Callea, Francesco; George, Peter M.

2000-01-01

The proposita suffered from liver cirrhosis and biopsy showed type 1 membrane-bound fiberglass inclusions. The hepatic inclusion bodies were weakly periodic acid-Schiff diastase-positive, and on immunoperoxidase staining reacted specifically with anti-fibrinogen antisera. Coagulation investigations revealed low functional and antigenic fibrinogen together with a prolonged thrombin time of 37 seconds (normal, 17 to 22 seconds) suggestive of a hypodysfibrinogenemia. DNA sequencing of all three fibrinogen genes showed a single heterozygous mutation of GGG (Gly)→CGG (Arg) at codon 284 of the γ-chain gene. However, examination of purified fibrinogen chains by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, reverse-phase high-performance liquid chromatography, ion-exchange high-performance liquid chromatography, and isoelectric focusing, failed to show any evidence of the mutant γBr chain in plasma fibrinogen. This finding was substantiated by electrospray ionization mass spectrometry, which showed only a normal γ (and Bβ) chain mass, but a large increase in the portion of their disialo isoforms. We speculate that misfolding of the variant protein causes hepatic retention and the subsequent hypofibrinogenemia, and that the functional defect (dysfibrinogenemia) results from hypersialylation of otherwise normal Bβ and γ chains consequent to the liver cirrhosis. These conclusions were supported by studies on six other family members with hypofibrinogenemia, and essentially normal clotting times, who were heterozygous for the γ284 Gly→Arg mutation. PMID:10880389

Vitamin K2-enhanced liver regeneration is associated with oval cell expansion and up-regulation of matrilin-2 expression in 2-AAF/PH rat model.

PubMed

Lin, M; Sun, P; Zhang, G; Xu, X; Liu, G; Miao, H; Yang, Y; Xu, H; Zhang, L; Wu, P; Li, M

2014-03-01

Normal liver has a great potential of regenerative capacity after partial hepatectomy. In clinic, however, most patients receiving partial hepatectomy are usually suffering from chronic liver diseases with severely damaged hepatocyte population. Under these conditions, activation of hepatic progenitor cell (oval cell in rodents) population might be considered as an alternative mean to enhance liver functional recovery. Vitamin K2 has been shown to promote liver functional recovery in patients with liver cirrhosis. In this study, we explored the possibility of vitamin K2 treatment in activating hepatic oval cell for liver regeneration with the classic 2-acetamido-fluorene/partial hepatectomy (2-AAF/PH) model in Sprague-Dawley rats. In 2-AAF/PH animals, vitamin K2 treatment induced a dose-dependent increase of liver regeneration as assessed by the weight ratio of remnant liver versus whole body and by measuring serum albumin level. In parallel, a drastic expansion of oval cell population as assessed by anti-OV6 and anti-CK19 immunostaining was noticed in the periportal zone of the remnant liver. Since matrilin-2 was linked to oval cell proliferation and liver regeneration after partial hepatectomy, we assessed its expression at both the mRNA and protein levels. The results revealed a significant increase after vitamin K2 treatment in parallel with the expansion of oval cell population. Consistently, knocking down matrilin-2 expression in vivo largely reduced vitamin K2-induced liver regeneration and oval cell proliferation in 2-AAF/PH animals. In conclusion, these data suggest that vitamin K2 treatment enhances liver regeneration after partial hepatectomy, which is associated with oval cell expansion and matrilin-2 up-regulation.

Analysis of LIF-Raman spectroscopy for the diagnosis of normal and liver diseases

NASA Astrophysics Data System (ADS)

Li, Xiaozhou; Yang, Tianyue; Yu, Ting; Sun, Ruomin; Li, Siqi

2011-07-01

In this paper, 514.5nm argon ion laser induced human serum Raman and auto-fluorescence spectra of normal, liver cirrhosis and liver cancer were measured and analyzed. The spectral differences between these three types of serums were observed and given brief explanations. Three parameters α, φ and Δλ were introduced to describe characteristics of each type of spectrum. Experimental results showed that these parameters might be applicable for discrimination of normal, liver cirrhosis and liver cancer, which will provide some reference values to explore the method of laser spectral diagnosis of cancer.

[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.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease.

PubMed

Payne, Felicity; Lim, Koini; Girousse, Amandine; Brown, Rebecca J; Kory, Nora; Robbins, Ann; Xue, Yali; Sleigh, Alison; Cochran, Elaine; Adams, Claire; Dev Borman, Arundhati; Russel-Jones, David; Gorden, Phillip; Semple, Robert K; Saudek, Vladimir; O'Rahilly, Stephen; Walther, Tobias C; Barroso, Inês; Savage, David B

2014-06-17

Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

PubMed Central

Payne, Felicity; Lim, Koini; Girousse, Amandine; Brown, Rebecca J.; Kory, Nora; Robbins, Ann; Xue, Yali; Sleigh, Alison; Cochran, Elaine; Adams, Claire; Dev Borman, Arundhati; Russel-Jones, David; Gorden, Phillip; Semple, Robert K.; Saudek, Vladimir; O’Rahilly, Stephen; Walther, Tobias C.; Barroso, Inês; Savage, David B.

2014-01-01

Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action. PMID:24889630

Unique activation of matrix metalloproteinase-9 within human liver metastasis from colorectal cancer.

PubMed Central

Zeng, Z. S.; Guillem, J. G.

1998-01-01

Experimental in vitro and animal data support an important role for matrix metalloproteinases (MMPs) in cancer invasion and metastasis via proteolytic degradation of the extracellular matrix (ECM). Our previous data have shown that MMP-9 mRNA is localized to the interface between liver metastasis and normal liver tissue, indicating that MMP-9 may play an important role in liver metastasis formation. In the present study, we analysed the cellular enzymatic expression of MMP-9 in 18 human colorectal cancer (CRC) liver metastasis specimens by enzyme-linked immunosorbent assay (ELISA) and zymography. ELISA analysis reveals that the latent form of MMP-9 is present in both liver metastasis and paired adjacent normal liver tissue. The mean level of the latent form of MMP-9 is 580+/-270 ng per mg total tissue protein (mean+/-s.e.) in liver metastasis vs 220+/-90 in normal liver tissue. However, this difference is not significantly different (P = 0.26). Using gelatin zymography, the 92-kDa band representative of the latent form is present in both liver metastasis and normal liver tissue. However, the 82 kDa band, representative of the active form of MMP-9, was seen only in liver metastasis. This was confirmed by Western blot analysis. Our observation of the unique presence of the active form of MMP-9 within liver metastasis suggests that proMMP-9 activation may be a pivotal event during CRC liver metastasis formation. Images Figure 3 Figure 4 PMID:9703281

Encephalopathy in acute liver failure resulting from acetaminophen intoxication: New observations with potential therapy

PubMed Central

Brusilow, Saul W; Cooper, Arthur J.L.

2011-01-01

Objective Hyperammonemia is a major contributing factor to the encephalopathy associated with liver disease. It is now generally accepted that hyperammonemia leads to toxic levels of glutamine in astrocytes. However, the mechanism by which excessive glutamine is toxic to astrocytes is controversial. Nevertheless, there is strong evidence that glutamine-induced osmotic swelling, especially in acute liver failure (ALF), is a contributing factor – the osmotic gliopathy theory. The object of the current communication is to present evidence for the osmotic gliopathy theory in a hyperammonemic patient who overdosed on acetaminophen. Design Case report. Setting Johns Hopkins Hospital. Patient A 22-year old white female who, 36 hours prior to admission, ingested 15 grams of acetaminophen was admitted to the Johns Hopkins Hospital. Physical examination was unremarkable; her mental status was within normal limits and remained so until approximately 72 hours after ingestion when she became confused, irritable and agitated. Interventions She was intubated, ventilated and placed on lactulose. Shortly thereafter she was non-communicative, unresponsive to painful stimuli and exhibited decerebrate posturing. A clinical diagnosis of cerebral edema and increased intracranial pressure (ICP) was made. She improved very slowly until 180 hours after ingestion when she moved all extremities. She woke up shortly thereafter. Measurements and main results Despite the fact that hyperammonemia is a major contributing factor to the encephalopathy observed in ALF the patient’s plasma ammonia peaked when she exhibited no obvious neurological deficit. Thereafter, her plasma ammonia decreased precipitously in parallel with a worsening neurological status. She was deeply encephalopathic during a period when her liver function and plasma ammonia had normalized. Plasma glutamine levels in this patient were high, but began to normalize several hours after plasma ammonia had returned to normal. The patient only commenced to recover as her plasma glutamine began to return to normal. Conclusions We suggest that the biochemical data are consistent with the osmotic gliopathy theory – high plasma ammonia leads to high plasma glutamine – an indicator of excess glutamine in astrocytes (the site of brain glutamine synthesis). This excess glutamine leads to osmotic stress in these cells. The lag in recovery of brain function presumably reflects time taken for the astrocyte glutamine concentration to return to normal. We hypothesize that an inhibitor of brain glutamine synthesis may be an effective treatment modality for ALF. PMID:21705899

Vasotropic light-chain amyloidosis and ischaemic cholangiopathy.

PubMed

Johnston, Emma L; Wilkinson, Mark; Knisely, A S

2015-06-25

A 75-year-old woman was incidentally found to have deranged liver function tests (LFTs). She was well, apart from 2 years of dyspnoea. Investigations had revealed atrial fibrillation and a right pleural effusion, without identified aetiology. On examination, the only finding was a palpable liver edge. Initial blood and ultrasound screening suggested no cause. The patient underwent liver biopsy. Microscopy showed κ-immunoglobulin light chains deposited exclusively in portal tracts, within blood vessel and bile duct walls. This pattern, although unusual, raised the possibility of κ-light chain disease. Serum electrophoresis was normal, as were serum immunoglobulin values. Serum concentrations of κ-light chains were elevated and microscopy of aspirated bone marrow found light-chain deposits with 10% plasmacytosis. Serum amyloid P (SAP) scintigraphy demonstrated splenic uptake. Myeloma, κ-light chain, with light-chain amyloidosis was diagnosed. The patient has responded well to cyclophosphamide, bortazomib and dexamethasone chemotherapy, and her LFTs are now nearly normal. 2015 BMJ Publishing Group Ltd.

Immunohistochemical study of retinol-binding protein in livers of polar bears (Thalarctos maritimus).

PubMed

Heier, A; Gröne, A; Völlm, J; Kübber-Heiss, A; Bacciarini, L N

2003-03-01

Liver tumors of unknown cause have frequently been described in polar bears. Concurrent decrease of vitamin A levels and chronic liver disease are associated with hepatic carcinogenesis in humans. More than 90% of the body's vitamin A is stored in the liver, where it is bound to an intracellular retinol-binding protein (RBP). Therefore, in this retrospective study, RBP was assessed by immunohistochemistry in liver sections of 11 polar bears. Two of these polar bears had hepatocellular carcinoma, four showed other chronic liver changes, and five had normal livers. In normal livers, the cytoplasm stained diffusely positive with intensely staining cytoplasmic granules. RBP staining was evaluated and the abundance of diffuse cytoplasmic staining and intracytoplasmic large granules was determined. All cases with pathologic liver changes had markedly decreased staining intensities for RBP compared with normal livers. The findings of this study suggest that in polar bears, as in humans, vitamin A metabolism may play a role in hepatic carcinogenesis.

Direct targeting of risk factors significantly increases the detection of liver cirrhosis in primary care: a cross-sectional diagnostic study utilising transient elastography.

PubMed

Harman, David J; Ryder, Stephen D; James, Martin W; Jelpke, Matthew; Ottey, Dominic S; Wilkes, Emilie A; Card, Timothy R; Aithal, Guruprasad P; Guha, Indra Neil

2015-05-03

To assess the feasibility of a novel diagnostic algorithm targeting patients with risk factors for chronic liver disease in a community setting. Prospective cross-sectional study. Two primary care practices (adult patient population 10,479) in Nottingham, UK. Adult patients (aged 18 years or over) fulfilling one or more selected risk factors for developing chronic liver disease: (1) hazardous alcohol use, (2) type 2 diabetes or (3) persistently elevated alanine aminotransferase (ALT) liver function enzyme with negative serology. A serial biomarker algorithm, using a simple blood-based marker (aspartate aminotransferase:ALT ratio for hazardous alcohol users, BARD score for other risk groups) and subsequently liver stiffness measurement using transient elastography (TE). Diagnosis of clinically significant liver disease (defined as liver stiffness ≥8 kPa); definitive diagnosis of liver cirrhosis. We identified 920 patients with the defined risk factors of whom 504 patients agreed to undergo investigation. A normal blood biomarker was found in 62 patients (12.3%) who required no further investigation. Subsequently, 378 patients agreed to undergo TE, of whom 98 (26.8% of valid scans) had elevated liver stiffness. Importantly, 71/98 (72.4%) patients with elevated liver stiffness had normal liver enzymes and would be missed by traditional investigation algorithms. We identified 11 new patients with definite cirrhosis, representing a 140% increase in the number of diagnosed cases in this population. A non-invasive liver investigation algorithm based in a community setting is feasible to implement. Targeting risk factors using a non-invasive biomarker approach identified a substantial number of patients with previously undetected cirrhosis. The diagnostic algorithm utilised for this study can be found on clinicaltrials.gov (NCT02037867), and is part of a continuing longitudinal cohort study. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Seventh-day syndrome: a catastrophic event after liver transplantation: case report.

PubMed

Pereira, M; Ferreira, I; Gandara, J; Ferreira, S; Lopes, V; Coelho, A; Vizcaino, R; Marinho, A; Daniel, J; Miranda, H P

2015-05-01

Seventh-day syndrome (7DS) is an early serious complication of liver transplantation, characterized by sudden failure of a previously normally functioning liver graft ∼1 week after the surgery. Although it is an uncommon event, it has major associated mortality. As its etiology is yet to be recognized, the only currently available treatment is retransplantation. We present 3 cases of orthotopic liver transplantation recipients who had an initial uneventful recovery after surgery followed by a dramatic rise of serum liver enzyme levels ∼7 days later and hepatic failure with subsequent graft loss and death despite high-dose immunosuppressive therapy. Histologic findings showed massive centrolobular hemorrhage and hepatocellular necrosis with reduced inflammation. It is essential to review and accumulate more clinical and laboratory information to better understand this syndrome and to better prevent and treat it. Copyright © 2015 Elsevier Inc. All rights reserved.

Detection of septicemia in chicken livers by spectroscopy,.

PubMed

Dey, B P; Chen, Y R; Hsieh, C; Chan, D E

2003-02-01

To establish a procedure for differentiating normal chickens from chickens with septicemia/toxemia (septox) by machine inspection under the Hazard Analysis and Critical Control Point-Based Inspection Models Project, spectral measurements of 300 chicken livers, of which half were normal and half were condemned due to septox conditions, were collected and analyzed. Neural network classification of the spectral data after principal component analysis (PCA) indicated that normal and septox livers were correctly differentiated by spectroscopy at a rate of 96%. Analysis of the data established 100% correlation between the spectroscopic identification and the subset of samples, both normal and septox, that were histopathologically diagnosed. In an attempt to establish the microbiological etiology of the diseased livers, isolates from 30 livers indicated that the poultry carcasses were contaminated mostly with coliforms present in the environment, hindering the isolation of pathogenic microorganisms. Therefore, to establish the cause of diseased livers, a strictly aseptic environment and procedure for sample collection is required.

Detection of liver cancer and abnormal liver tissue by Raman spectroscopy and fluorescence

NASA Astrophysics Data System (ADS)

Li, Xiaozhou; Ding, Jianhua; Zhang, Xiujun; Lin, Junxiu; Wang, Deli

2005-01-01

In this paper, laser induced human serum Raman spectra of liver cancer are measured. The spectra differences in serum from normal people and liver disease patients are analyzed. For the typical spectrum of normal serum, there are three sharp Raman peaks and relative intensity of Raman peaks excited by 514.5nm is higher than that excited by 488.0nm. For the Raman spectrum of liver cancer serum there are no peaks or very weak Raman peaks at the same positions. Results from more than two hundred case measurements show that clinical diagnostic accuracy is 92.86%. And then, the liver fibrosis and liver cirrhosis are studied applying the technology of LIF. To liver cirrhosis, the shape of Raman peak is similar to normal and fluorescence spectrum is similar to that of liver cancer from statistic data. The experiment indicates that there is notable fluorescence difference between the abnormal and normal liver tissue and have blue shift in fluorescence peak. Except for human serum, we use rats serum for researching either. Compared with results of path al examination, we analyze the spectra of normal cases, hepatic fibrosis and hepatocirrhosis respectively in an attempt to find some difference between them. Red shift of fluorescence peak is observed with disease evolution using 514.5nm excitation of an Ar-ion laser. However, no distinct changes happen with 488.0nm excitation. These results have important reference values to explore the method of laser spectrum diagnosis.

Computer-aided diagnosis of splenic enlargement using wave pattern of spleen in abdominal CT images

NASA Astrophysics Data System (ADS)

Seong, Won; Cho, June-Sik; Noh, Seung-Moo; Park, Jong Won

2006-03-01

It is known that the spleen accompanied by liver cirrhosis is hypertrophied or enlarged. We have examined a wave pattern at the left boundary of spleen on the abdominal CT images having liver cirrhosis, and found that they are different from those on the images having a normal liver. It is noticed that the abdominal CT images of patient with liver cirrhosis shows strong bending in the wave pattern. In the case of normal liver, the images may also have a wave pattern, but its bends are not strong. Therefore, the total waving area of the spleen with liver cirrhosis is found to be greater than that of the spleen with a normal liver. Moreover, we found that the waves of the spleen from the image with liver cirrhosis have the higher degree of circularity compared to the normal liver case. Based on the two observations above, we propose an automatic method to diagnose splenic enlargement by using the wave pattern of the spleen in abdominal CT images. The proposed automatic method improves the diagnostic performance compared with the conventional process based on the size of spleen.

Maple syrup urine disease (MSUD): a case with long-term follow-up after liver transplantation.

PubMed

McLaughlin, Paula M; Hinshaw, Jessica; Stringer, Anthony Y

2013-01-01

Maple syrup urine disease (MSUD) is a rare hereditary metabolic condition where the body is unable to breakdown amino acids causing toxic buildup. Acute and long-term management of MSUD involves a restricted diet and regular monitoring of amino acid levels; however, more recently liver transplants have been shown to be successful in treating this condition. Even with successful management of MSUD there is evidence from pediatric cases that shows a distinct pattern of neurocognitive deficits associated with this condition, including impaired nonverbal skills and psychomotor functioning with relatively intact verbal abilities. In the present paper, we report an adult case of MSUD with associated neurocognitive deficits and functional limitations following liver transplantation. Neuroimaging revealed no structural abnormalities, while the results from the neuropsychological evaluation showed impairment in visual-spatial processing, attention, executive functioning, and psychomotor abilities, with relative strengths in verbal skills. The patient also showed reduced adaptive functioning and mild anxiety. This case demonstrates neurocognitive deficiencies within the context of normal magnetic resonance imaging. The possible underlying mechanism of this neuropsychological profile is discussed in relation to other neurodevelopmental models.

An adolescent girl with abnormal liver profile.

PubMed

Nair, S; Pitchumoni, C S

1998-04-01

A 17-year-old previously healthy high school student who lived in a dormitory was referred to our office by her private physician for evaluation of abnormal liver function tests. She was sexually active with one partner but denied any current or past substance abuse. The patient was not taking any medications or nutritional supplements. Family history was unremarkable. Physical examination revealed scleral icterus and minimal hepatomegaly. Spleen was not palpable. The liver function tests are shown in table 1. Total leucocyte count was 6.3 x 10(9)/1 with 53% lymphocytes. The platelet count was normal. Anti-Hbc IgM antibody was negative, so were anti-HAV IgM and anti-HCV antibodies. HBsAg was negative and anti-HBs antibody was positive. Erythrocyte sedimentation rate was 16 mm in the first hour. An abdominal sonogram was done to evaluate a persistent elevation in alkaline phosphatase and it showed only hepatomegaly.

Can the biliary enhancement of Gd-EOB-DTPA predict the degree of liver function?

PubMed

Okada, Masahiro; Ishii, Kazunari; Numata, Kazushi; Hyodo, Tomoko; Kumano, Seishi; Kitano, Masayuki; Kudo, Masatoshi; Murakami, Takamichi

2012-06-01

Excretion of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) in the bile may be related to liver function, because of elimination from the liver after preferential uptake by hepatocytes. The purpose of this study was to investigate the relation between liver and biliary enhancement in patients with or without liver dysfunction, and to compare the tumor-to-liver contrast in these patients. Forty patients [group 1: normal liver and Child-Pugh class A in 20 patients, group 2: Child-Pugh class B in 18 patients and Child-Pugh C in 2] were evaluated. All patients underwent MR imaging of the liver using a 1.5-Tesla system. T1-weighted 3D images were obtained at 5, 10, 15 and 20 minutes after Gd-EOB-DTPA injection. The relation between group 3 (total bilirubin <1.8 mg/dL) and group 4 (total bilirubin ≥1.8 mg/dL) was investigated at 20 minutes. Liver and biliary signals were measured, and compared between groups 1 and 2 or groups 3 and 4. Tumor-to-liver ratio was also evaluated between groups 1 and 2. Scheffe's post-hoc test after two-way repeated-measures ANOVA and Pearson's correlation test were used for statistical analysis. Liver enhancement showed significant difference at all time points between groups 1 and 2. Biliary enhancement did not show a significant difference between groups 1 and 2 at 5 minutes, but did at 10, 15 and 20 minutes. At 20 minutes, significant differences between groups 3 and 4 were seen for liver and biliary enhancement. At all time points, liver enhancement correlated with biliary enhancement in both groups. At 5 minutes and 20 minutes, statistical differences between groups 1 and 2 were seen for tumor-to-liver ratio. The degree of biliary enhancement has a close correlation to that of liver enhancement. It is especially important that insufficient liver enhancement causes lower tumor-to-liver contrast in the hepatobiliary phase of Gd-EOB-DTPA.

Relationship between vitamin A deficiency and the thyroid axis in clinically stable patients with liver cirrhosis related to hepatitis C virus.

PubMed

El-Eshmawy, Mervat M; Arafa, Mona M; Elzehery, Rasha R; Elhelaly, Rania M; Elrakhawy, Mohamed M; El-Baiomy, Azza A

2016-09-01

Vitamin A deficiency (VAD) and altered thyroid function are commonly encountered in patients with liver cirrhosis. The link between vitamin A metabolism and thyroid function has been previously identified. The aim of this study was to explore the association between VAD and the thyroid axis in clinically stable patients with cirrhosis related to hepatitis C virus (HCV). One hundred and twelve patients with clinically stable HCV-related cirrhosis and 56 healthy controls matched for age, sex, and socioeconomic status were recruited for this study. Vitamin A status, liver function, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), reverse triiodothyronine (rT3), anti-thyroid peroxidase antibodies (anti-TPO), and thyroid volume were evaluated. The prevalence of VAD among patients with HCV-related cirrhosis was 62.5% compared with 5.4% among controls (P < 0.001). Patients with HCV-related cirrhosis had significantly higher FT4, FT3, TSH, and thyroid volume than did healthy controls. Of the 112 patients initially recruited, 18 were excluded (patients with subclinical hypothyroidism and/or anti-TPO positive), so a total of 94 patients with HCV-related cirrhosis were divided into 2 groups according to vitamin A status: VAD and normal vitamin A. Patients with VAD had significantly lower vitamin A intake and serum albumin and higher serum bilirubin, FT4, FT3, and TSH than patients with normal vitamin A status. Multiple logistic regression analysis revealed that VAD was associated with Child-Pugh score (β = 0.11, P = 0.05) and TSH (β = -1.63, P = 0.02) independently of confounding variables. We conclude that VAD may be linked to central hyperthyroidism in patients with clinically stable HCV-related liver cirrhosis.

Effects of oxymatrine from Ku Shen on cancer cells.

PubMed

Ho, John W; Ngan Hon, Parry Lee; Chim, Wai On

2009-10-01

Oxymatrine is one of active constituents isolated from Ku Shen, which is the dried root of Sophora flavescens Ait. The herb used in different herbal formulations is commonly known with specific pharmacological properties for treatment of liver disorders and other diseases such as arrhythmia, eczema and skin disorders, leukopenia and bronchitis. Sophora flavescens Ait is known to enhance liver functions and reduce hepatotoxicity due to oxidative stress and liver injury. The protection of cells from chemical toxicity is important in reducing liver damage. Reduction of oxidative stress by active components of herbal medicines is shown to be beneficial and important in regulating the normal functions of the liver. In this study, effects of oxymatrine on cancer cells after treatment of the cell line with DMSO were reported. This review described for cells without oxymatrine pre-treatment, cell injury was implicated as indicated by the decrease in cell viability. Ku Shen showed protective effects on cells from the DMSO-induced toxicity. The results show that oxymatrine can inhibit the G(2) and M phase of H4IIE. The findings suggest that anti-inflammatory constituents such as oxymatrine could mediate cell division of cancer cells and reduce cell cytotoxicity due probably to its capacity to inhibit the metabolic activation of hepato-toxin, a critical factor in the pathogenesis of chemical-induced liver injury.

Susceptibility to T cell-mediated liver injury is enhanced in asialoglycoprotein receptor-deficient mice.

PubMed

McVicker, Benita L; Thiele, Geoffrey M; Casey, Carol A; Osna, Natalia A; Tuma, Dean J

2013-05-01

T cell activation and associated pro-inflammatory cytokine production is a pathological feature of inflammatory liver disease. It is also known that liver injury is associated with marked impairments in the function of many hepatic proteins including a hepatocyte-specific binding protein, the asialoglycoprotein receptor (ASGPR). Recently, it has been suggested that hepatic ASGPRs may play an important role in the physiological regulation of T lymphocytes, leading to our hypothesis that ASGPR defects correlate with inflammatory-mediated events in liver diseases. Therefore, in this study we investigated whether changes in hepatocellular ASGPR expression were related to the dysregulation of intrahepatic T lymphocytes and correlate with the development of T-cell mediated hepatitis. Mice lacking functional ASGPRs (receptor-deficient, RD), and wild-type (WT) controls were intravenously injected with T-cell mitogens, Concanavalin A (Con A) or anti-CD3 antibody. As a result of T cell mitogen treatment, RD mice lacking hepatic ASGPRs displayed enhancements in liver pathology, transaminase activities, proinflammatory cytokine expression, and caspase activation compared to that observed in normal WT mice. Furthermore, FACS analysis demonstrated that T-cell mitogen administration resulted in a significant rise in the percentage of CD8+ lymphocytes present in the livers of RD animals versus WT mice. Since these two mouse strains differ only in whether they express the hepatic ASGPR, it can be concluded that proper ASGPR function exerts a protective effect against T cell mediated hepatitis and that impairments to this hepatic receptor could be related to the accumulation of cytotoxic T cells that are observed in inflammatory liver diseases. Published by Elsevier B.V.

[Balneotherapeutics of non-alcoholic fatty liver disease with the use of the Essentuki-type drinking mineral waters].

PubMed

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

2012-01-01

The objective of the present work was to estimate the effectiveness of combined spa-and-resort treatment with the use of the Essentuki-type drinking mineral waters for the patients presenting with non-alcoholic fatty liver disease. A total of 40 patients presening with non-alcoholic fatty liver disease (NOFLD) were available for the examination. The study has demonstrated positive dynamics of clinical symptoms and results of liver functional tests, characteristics of intrahepatic dynamics, lipid metabolism, antioxidant hemostais, and the hormonal status of the patients with non-alcoholic fatty liver disease. The intake of the Essentuki-type drinking mineral waters promoted normalization of adiponectin and leptin levels in conjunction with the reduction in the degree of insulin resistance, i.e., the key pathogenetic factors responsible for hepatic steatosis and non-alcoholic steatohepatitis. It is concluded that the Essentuki-type drinking mineral waters may be recommended for the inclusion in the combined treatment and prevention of the progression of non-alcoholic fatty liver disease.

Association between liver failure and hepatic UDP-glucuronosyltransferase activity in dairy cows with follicular cysts.

PubMed

Tanemura, Kouichi; Ohtaki, Tadatoshi; Kuwahara, Yasushi; Tsumagari, Shigehisa

2017-01-20

Uridine 5'-diphospho-glucuronosyltransferase (UGT) liver activity was measured using estradiol-17β as a substrate in dairy cows with follicular cysts. The activity was significantly lower than that in dairy cows with normal estrous cycles (P<0.01). Liver disorders, such as fatty liver and hepatitis, were observed in half cows with follicular cysts, and liver UGT activity was lower than that in cows with normal estrus cycles. In addition, the liver UGT activity was significantly lower in dairy cows with follicular cysts without liver disorders than in dairy cows with normal estrous cycles. Therefore, the cows were divided into those with low, middle and high liver UGT activities, and liver disorder complication rates were investigated. The complication rate was significantly higher in the low- (78.1%) than in the middle- (22.2%) and high-level (8.3%) groups, suggesting that liver disorders are closely associated with the development of follicular cysts in dairy cows and that steroid hormone metabolism is delayed because of reduced liver UGT activity, resulting in follicular cyst formation. We conclude that reduced estradiol-17β glucuronidation in the liver and liver disorders are associated with follicular cyst occurrence in dairy cows.

Association between liver failure and hepatic UDP-glucuronosyltransferase activity in dairy cows with follicular cysts

PubMed Central

TANEMURA, Kouichi; OHTAKI, Tadatoshi; KUWAHARA, Yasushi; TSUMAGARI, Shigehisa

2016-01-01

Uridine 5’-diphospho-glucuronosyltransferase (UGT) liver activity was measured using estradiol-17β as a substrate in dairy cows with follicular cysts. The activity was significantly lower than that in dairy cows with normal estrous cycles (P<0.01). Liver disorders, such as fatty liver and hepatitis, were observed in half cows with follicular cysts, and liver UGT activity was lower than that in cows with normal estrus cycles. In addition, the liver UGT activity was significantly lower in dairy cows with follicular cysts without liver disorders than in dairy cows with normal estrous cycles. Therefore, the cows were divided into those with low, middle and high liver UGT activities, and liver disorder complication rates were investigated. The complication rate was significantly higher in the low- (78.1%) than in the middle- (22.2%) and high-level (8.3%) groups, suggesting that liver disorders are closely associated with the development of follicular cysts in dairy cows and that steroid hormone metabolism is delayed because of reduced liver UGT activity, resulting in follicular cyst formation. We conclude that reduced estradiol-17β glucuronidation in the liver and liver disorders are associated with follicular cyst occurrence in dairy cows. PMID:27666462

Combined use of ursodeoxycholic acid and bosentan prevents liver toxicity caused by endothelin receptor antagonist bosentan monotherapy: two case reports.

PubMed

Ito, Tomoki; Ozaki, Yoshio; Son, Yonsu; Nishizawa, Tohru; Amuro, Hideki; Tanaka, Akihiro; Tamaki, Takeshi; Nomura, Shosaku

2014-07-11

Pulmonary arterial hypertension is a fatal disease characterized by progressive remodeling of the pulmonary arteries and an increase in pulmonary vascular resistance. Up to 50% of patients with systemic sclerosis have pulmonary arterial hypertension, which significantly affects the prognosis. The endothelin receptor antagonist bosentan is used for the treatment of pulmonary arterial hypertension and shows a great beneficial effect. However, the most frequent side effect of bosentan is liver toxicity, which often requires dose reduction and discontinuation. We report two cases (a 64-year-old Japanese woman and a 69-year old Japanese woman) of systemic sclerosis, both with severe Raynaud's phenomenon and pulmonary arterial hypertension. Both patients had initially received bosentan monotherapy, which caused liver toxicity as indicated by increased levels of alanine aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase. After dose reduction or discontinuation of bosentan, these liver function abnormalities were normalized and the patients subsequently received retreatment with a combination of bosentan and ursodeoxycholic acid. The results of liver function tests did not show any abnormalities after this combination therapy. These reports suggest the usefulness of ursodeoxycholic acid for preventing liver toxicity caused by bosentan. Thus, the addition of ursodeoxycholic acid to the treatment protocol is expected to be useful when liver toxicity emerges as a side effect of bosentan.

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.

Biliary excretion of pravastatin and taurocholate in rats with bile salt export pump (Bsep) impairment.

PubMed

Cheng, Yaofeng; Freeden, Chris; Zhang, Yueping; Abraham, Pamela; Shen, Hong; Wescott, Debra; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

2016-07-01

The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC-MS/MS. While the levels of Ntcp and Mrp2 were not significantly altered, Mrp3 expression increased and Oatp1a1 decreased in KO animals. Compared with the WT rats, the KO rats had similar serum chemistry and showed normal liver transaminases. Although the total plasma bile salts and bile flow were not significantly changed in Bsep KO rats, individual bile acids in plasma and liver demonstrated variable changes, indicating the impact of Bsep KO. Following an intravenous dose of deuterium labeled taurocholic acid (D4-TCA, 2 mg/kg), the D4-TCA plasma exposure was higher and bile excretion was delayed by approximately 0.5 h in the KO rats. No differences were observed for the pravastatin plasma concentration-time profile or the biliary excretion after intravenous administration (1 mg/kg). Collectively, the results revealed that these rats have significantly lower Bsep expression, therefore affecting the biliary excretion of endogenous bile acids and Bsep substrates. However, these rats are able to maintain a relatively normal liver function through the remaining Bsep protein and via the regulation of other transporters. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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.

Native fluorescence characterization of human liver abnormalities

NASA Astrophysics Data System (ADS)

Ganesan, Singaravelu; Madhuri, S.; Aruna, Prakasa R.; Suchitra, S.; Srinivasan, T. G.

1999-05-01

Fluorescence spectroscopy of intrinsic biomolecules has been extensively used in biology and medicine for the past several decades. In the present study, we report the native fluorescence characteristics of blood plasma from normal human subjects and patients with different liver abnormalities such as hepatitis, leptospirosis, jaundice, cirrhosis and liver cell failure. Native fluorescence spectra of blood plasma -- acetone extract were measured at 405 nm excitation. The average spectrum of normal blood plasma has a prominent emission peak around 464 nm whereas in the case of liver diseased subjects, the primary peak is red shifted with respect to normal. In addition, liver diseased cases show distinct secondary emission peak around 615 nm, which may be attributed to the presence of endogenous porphyrins. The red shift of the prominent emission peak with respect to normal is found to be maximum for hepatitis and minimum for cirrhosis whereas the secondary emission peak around 615 nm was found to be more prominent in the case of cirrhosis than the rest. The ratio parameter I465/I615 is found to be statistically significant (p less than 0.001) in discriminating liver abnormalities from normal.

Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease in patients with severe obesity.

PubMed

Bedossa, Pierre; Tordjman, Joan; Aron-Wisnewsky, Judith; Poitou, Christine; Oppert, Jean-Michel; Torcivia, Adriana; Bouillot, Jean-Luc; Paradis, Valerie; Ratziu, Vlad; Clément, Karine

2017-09-01

Non-alcoholic fatty liver disease (NAFLD) is a frequent complication of morbid obesity, but its severity varies greatly and thus there is a strong need to better define its natural history in these patients. Liver biopsies were systematically performed in 798 consecutive patients with severe obesity undergoing bariatric surgery. Histology was compared with clinical, biological, anthropometrical and body composition characteristics. Patients with presumably normal liver (n=179, 22%) were significantly younger at bariatric surgery than patients with NAFLD (37.0 vs 44.4 years, p<0.0001). However, both groups showed quite similar obesity duration, since patients with presumably normal liver reported the onset of obesity at a significantly younger age than those with NAFLD (14.8 vs 20.0 year, p<0.0001). The trunk/limb fat mass ratio increased according to liver disease severity (presumably normal liver: 1.00, steatosis: 1.21, non-alcoholic steatohepatitis (NASH): 1.34, p<0.0001), although the total body fat mass decreased (presumably normal liver: 50%, steatosis: 49.1%, NASH: 47.4%, p<0.0001). The volume of subcutaneous adipocytes increased according to severity of liver disease but only in female patients (presumably normal liver: 8543 picolitres, steatosis: 9156 picolitres, NASH: 9996 picolitres). These results suggest that young adults are more prone to store fat in subcutaneous tissue and reach the threshold of bariatric surgery indication before their liver is damaged. A shift of fat storage from subcutaneous to visceral adipose tissue compartment is associated with liver damages. Liver might also be targeted by subcutaneous hypertrophic adipocytes in females since hypertrophic adipocytes are more exposed to lipolysis and to the production of inflammatory mediators. 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/.

Living Donor Liver Transplantation for Wilson’s Disease Associated with Fulminant Hepatic Failure: A Case Report

PubMed Central

Huang, Yu; Takatsuki, Mitsuhisa; Soyama, Akihiko; Hidaka, Masaaki; Ono, Shinichiro; Adachi, Tomohiko; Hara, Takanobu; Okada, Satomi; Hamada, Takashi; Eguchi, Susumu

2018-01-01

Patient: Female, 17 Final Diagnosis: Fulminant Wilson’s disease Symptoms: General jaundice • malaise • abdominal pain Medication: — Clinical Procedure: ICU Specialty: Transplantology Objective: Rare disease Background: Liver transplantation is indicated for patients with Wilson’s disease (WD) who present either with acute liver failure or with end-stage liver disease and severe hepatic insufficiency as the first sign of disease. However, almost all reported cases have been treated with death donor liver transplantation. Here we report the case of a patient with WD associated with fulminant hepatic failure (WD-FHF) who underwent living donor liver transplantation (LDLT). Case Report: A 17-year-old female was diagnosed with WD-FHF based on high uric copper (10 603 μg/day, normal <100 μg/day), low serum ceruloplasmin (15 mg/dL, normal >20 mg/dL) and Kayser-Fleischer (K-F) corneal ring, and acute liver failure (ALF), acute renal failure (ARF) and grade 2 hepatic encephalopathy (HE). The model for end-stage liver disease (MELD) score was 35. Due to her critical condition, the patient underwent LDLT utilizing a right liver graft from her 44-year-old mother. The right hepatic vein (RHV) and inferior right hepatic vein (iRHV) were reconstructed. She developed severe liver dysfunction due to a crooked hepatic vein caused by compression from the large graft. To straighten the bend, a reoperation was performed. During the operation, we tried to relieve the compressed hepatic vein by adjusting the graft location, but the benefits were limited. We therefore performed stenting in both the RHV and iRHV on postoperative day 9. The patient gradually improved, exhibiting good liver and renal functions, and was finally discharged on postoperative day 114. Conclusions: When WD-FHF deteriorates too rapidly for conservative management, LDLT is an effective therapeutic strategy. PMID:29549236

In Vivo Stable Transduction of Humanized Liver Tissue in Chimeric Mice via High-Capacity Adenovirus–Lentivirus Hybrid Vector

PubMed Central

Kataoka, Miho; Tateno, Chise; Yoshizato, Katsutoshi; Kawasaki, Yoshiko; Kimura, Takahiro; Faure-Kumar, Emmanuelle; Palmer, Donna J.; Ng, Philip; Okamura, Haruki; Kasahara, Noriyuki

2010-01-01

Abstract We developed hybrid vectors employing high-capacity adenovirus as a first-stage carrier encoding all the components required for in situ production of a second-stage lentivirus, thereby achieving stable transgene expression in secondary target cells. Such vectors have never previously been tested in normal tissues, because of the scarcity of suitable in vivo systems permissive for second-stage lentivirus assembly. Here we employed a novel murine model in which endogenous liver tissue is extensively reconstituted with engrafted human hepatocytes, and successfully achieved stable transduction by the second-stage lentivirus produced in situ from first-stage adenovirus. This represents the first demonstration of the functionality of adenoviral-lentiviral hybrid vectors in a normal parenchymal organ in vivo. PMID:19725756

Effects of Radiation and Dietary Iron on Expression of Genes and Proteins Involved in Drug Metabolism

NASA Technical Reports Server (NTRS)

Faust, K. M.; Wotring, V. E.

2014-01-01

Liver function, especially the rate of metabolic enzyme activities, determines the concentration of circulating drugs and the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Dietary factors and exposure to radiation are aspects of spaceflight that are potential oxidative stressors and both can be modeled in ground experiments. In this experiment, we examined the effects of high dietary iron and low dose gamma radiation (individually and combined) on the gene expression of enzymes involved in drug metabolism, redox homeostasis, and DNA repair. METHODS All procedures were approved by the JSC Animal Care and Use Committee. Male Sprague-Dawley rats were divided into 4 groups (n=8); control, high Fe diet (650 mg iron/kg), radiation (fractionated 3 Gy exposure from a Cs- 137 source) and combined high Fe diet + radiation exposure. Animals were euthanized 24h after the last treatment of radiation; livers were removed immediately and flash -frozen in liquid nitrogen. Expression of genes thought to be involved in redox homeostasis, drug metabolism and DNA damage repair was measured by RT-qPCR. Where possible, protein expression of the same genes was measured by western blotting. All data are expressed as % change in expression normalized to reference gene expression; comparisons were then made of each treatment group to the sham exposed/ normal diet control group. Data was considered significant at p< 0.5. RESULTS Among the redox homeostasis genes examined, metallothionein showed a significant down regulation in the radiation treated group (-3.85 fold) and a trend toward down regulation in the high Fe + rad group. Metallothionein is involved in the regulation of physiological metals and also has antioxidant activities. Among the drug metabolism genes examined, ATP binding cassette subfamily B (Abcb1b) gene expression increased more than 10-fold in both groups that received radiation treatments. This increased expression was also seen at the protein level. This ABC transporter carries many different compounds across cell membranes, including administered medications. The cytochrome P450 2E1 enzyme, a mixed-function oxidase that deactivates some medications and activates others, showed about a 2-fold increase in gene expression in both radiation-treated groups, with a trend toward increased expression at the protein level. Expression of epoxide hydrolase, which detoxifies polycyclic aromatic hydrocarbons, showed similar 2-fold increases. Among the DNA repair genes examined, expression of RAD51 was significantly down regulated (1.5 fold) in the radiation treated group. RAD51 is involved in repair of double-stranded DNA breaks. CONCLUSION This experiment used 2 different sources of physiological oxidative stress, administered separately and together, and examined their impacts on liver gene and protein expression. It is clear that significant changes occurred in expression of several genes and proteins in the radiation-treated animals. If the results from this ground analog of portions of the spaceflight environment hold true for the spaceflight environment itself, the physiological roles of the affected enzymes (drug transport and metabolism, redox homeostasis) could mean consequences in redox homeostasis or the pharmacokinetics of administered medications

The nuclear bile acid receptor FXR controls the liver derived tumor suppressor histidine-rich glycoprotein.

PubMed

Deuschle, Ulrich; Birkel, Manfred; Hambruch, Eva; Hornberger, Martin; Kinzel, Olaf; Perović-Ottstadt, Sanja; Schulz, Andreas; Hahn, Ulrike; Burnet, Michael; Kremoser, Claus

2015-06-01

The nuclear bile acid receptor Farnesoid X receptor (FXR) is strongly expressed in liver and intestine, controls bile acid and lipid homeostasis and exerts tumor-protective functions in liver and intestine. Histidine-rich glycoprotein (HRG) is an abundant plasma protein produced by the liver with the proposed function as a pattern recognition molecule involved in the clearance of immune complexes, necrotic cells and pathogens, the modulation of angiogenesis, the normalization of deranged endothelial vessel structure in tumors and tumor suppression. FXR recognition sequences were identified within a human HRG promoter fragment that mediated FXR/FXR-agonist dependent reporter gene activity in vitro. We show that HRG is a novel transcriptional target gene of FXR in human hepatoma cells, human upcyte® primary hepatocytes and 3D human liver microtissues in vitro and in mouse liver in vivo. Prolonged administration of the potent nonsteroidal FXR agonist PX20606 increases HRG levels in mouse plasma. Finally, daily oral administration of this FXR agonist for seven days resulted in a significant increase of HRG levels in the plasma of healthy human male volunteers during a clinical Phase I safety study. HRG might serve as a surrogate marker indicative of liver-specific FXR activation in future human clinical studies. Furthermore, potent FXR agonists might be beneficial in serious health conditions where HRG is reduced, for example, in hepatocellular carcinoma but also other solid cancers, liver failure, sepsis and pre-eclampsia. © 2014 UICC.

Anti-inflammatory properties of methylthioadenosine in experimental colitis

USDA-ARS?s Scientific Manuscript database

The methionine (Met) metabolic cycle is critical for normal cell functions. Met cycle disruption has been implicated in disease, such as alcoholic liver disease (ALD) and multiple sclerosis (MS). Studies in animal models of ALD and MS have shown that the Met metabolite methylthioadenosine (MTA) has ...

Effect of Pelargonium reniforme roots on alcohol-induced liver damage and oxidative stress.

PubMed

Adewusi, Emmanuel Adekanmi; Afolayan, Anthony Jide

2010-09-01

Ethnobotanical surveys conducted on Pelargonium reniforme Curtis (Geraniaceae) have shown that the aqueous root extracts are used to treat alcohol-induced liver damage. We evaluated the antioxidant properties of the extract and its effects on alcohol-induced hepatotoxicity using Wistar rats. Alcohol-induced hepatotoxicity studies were carried out by observing the effect of the aqueous root extract on some liver marker enzymes, bilirubin, and total protein after liver damage. The levels of some phenolic compounds were determined by standard methods. Also, the reducing power of the plant extract and its ability to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH*) and 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS*+) radicals were determined to evaluate its antioxidant activity. The results obtained show that the plant extract possessed significant antioxidant activity. It had a significant level of phenolic compounds, scavenged DPPH* and ABTS*+ radicals effectively, and demonstrated good reducing power. This may indicate that the plant contained compounds which can remove toxic metabolites following alcohol abuse. Serum analysis of animals treated with only ethanol showed a significant increase in the levels of liver marker enzymes and total and unconjugated bilirubin, while a significant decrease was observed in the levels of conjugated bilirubin and total proteins. Administration of the plant extract restored the levels of these markers to normal levels, and this indicates the ability of the plant extract to restore normal functioning of a damaged liver. The study shows that P. reniforme is a potential source of antioxidants and compounds which are useful in treating alcoholic liver damage.

[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.

Reactive oxygen species mediate human hepatocyte injury during hypoxia/reoxygenation.

PubMed

Bhogal, Ricky Harminder; Curbishley, Stuart M; Weston, Christopher J; Adams, David H; Afford, Simon C

2010-11-01

Increasing evidence shows that reactive oxygen species (ROS) may be critical mediators of liver damage during the relative hypoxia of ischemia/reperfusion injury (IRI) associated with transplant surgery or of the tissue microenvironment created as a result of chronic hepatic inflammation or infection. Much work has been focused on Kupffer cells or liver resident macrophages with respect to the generation of ROS during IRI. However, little is known about the contribution of endogenous hepatocyte ROS production or its potential impact on the parenchymal cell death associated with IRI and chronic hepatic inflammation. For the first time, we show that human hepatocytes isolated from nondiseased liver tissue and human hepatocytes isolated from diseased liver tissue exhibit marked differences in ROS production in response to hypoxia/reoxygenation (H-R). Furthermore, several different antioxidants are able to abrogate hepatocyte ROS-induced cell death during hypoxia and H-R. These data provide clear evidence that endogenous ROS production by mitochondria and nicotinamide adenine dinucleotide phosphate oxidase drives human hepatocyte apoptosis and necrosis during hypoxia and H-R and may therefore play an important role in any hepatic diseases characterized by a relatively hypoxic liver microenvironment. In conclusion, these data strongly suggest that hepatocytes and hepatocyte-derived ROS are active participants driving hepatic inflammation. These novel findings highlight important functional/metabolic differences between hepatocytes isolated from normal donor livers, hepatocytes isolated from normal resected tissue obtained during surgery for malignant neoplasms, and hepatocytes isolated from livers with end-stage disease. Furthermore, the targeting of hepatocyte ROS generation with antioxidants may offer therapeutic potential for the adjunctive treatment of IRI and chronic inflammatory liver diseases. © 2010 AASLD.

Association between macroscopic appearance of liver lesions and liver histology in dogs with splenic hemangiosarcoma: 79 cases (2004-2009).

PubMed

Clendaniel, Daphne C; Sivacolundhu, Ramesh K; Sorenmo, Karin U; Donovan, Taryn A; Turner, Avenelle; Arteaga, Theresa; Bergman, Philip J

2014-01-01

Medical records for 79 dogs with confirmed splenic hemangiosarcoma (HSA) following splenectomy were reviewed for information regarding either the presence or absence of macroscopic liver lesions and the histopathological characteristics of the liver. Only 29 of 58 dogs (50%) with grossly abnormal livers had HSA metastasis. No dogs with grossly normal livers had metastasis detected on liver pathology. Gross lesions in the liver such as multiple nodules, dark-colored nodules, and active bleeding nodules were highly associated with malignancy. For the dogs in this study, performing biopsy in a grossly normal liver was a low-yield procedure in dogs with splenic HSA.

Disease progression in Chinese chronic hepatitis C patients with persistently normal alanine aminotransaminase levels.

PubMed

Hui, C-K; Zhang, H-Y; Shek, T; Yao, H; Yueng, Y-H; Leung, K-W; Lai, S-T; Lai, J-Y; Leung, N; Lau, G K

2007-06-01

Although chronic hepatitis C virus-infected patients with persistently normal alanine aminotransaminase levels usually have mild liver disease, disease progression can still occur. However, it is uncertain which group of patients is at risk of disease progression. To examine the severity of liver disease on liver biopsy in Chinese patients with persistently normal alanine aminotransaminase levels, and their disease progression over time. Eighty-two patients with persistently normal alanine aminotransaminase levels were followed up longitudinally. The median time of follow-up was 8.1 years. Forty-seven of the 82 patients (57.3%) had a second liver biopsy. At the time of analysis, six of the 82 patients (7.3%) developed decompensated liver cirrhosis. Patients with an initial fibrosis stage F2 or F3 [6/23 (26.1%) vs. 0/59 (0%), P < 0.0001] or inflammatory grade A2 or A3 [5/40 (12.5%) vs. 1/42 (2.4%), P = 0.04] were more likely to develop decompensated liver cirrhosis. On multivariate analysis, initial fibrosis stage F2 or F3 was independently associated with progression to decompensated liver cirrhosis (relative risk 2.3, 95% confidence interval 0.03-2.5, P = 0.02). Chinese chronic hepatitis C virus patients with persistently normal alanine aminotransaminase levels with moderate to severe fibrosis at initial evaluation are more likely to develop decompensated liver cirrhosis.

EFFECT ON PERFUSION VALUES OF SAMPLING INTERVAL OF CT PERFUSION ACQUISITIONS IN NEUROENDOCRINE LIVER METASTASES AND NORMAL LIVER

PubMed Central

Ng, Chaan S.; Hobbs, Brian P.; Wei, Wei; Anderson, Ella F.; Herron, Delise H.; Yao, James C.; Chandler, Adam G.

2014-01-01

Objective To assess the effects of sampling interval (SI) of CT perfusion acquisitions on CT perfusion values in normal liver and liver metastases from neuroendocrine tumors. Methods CT perfusion in 16 patients with neuroendocrine liver metastases were analyzed by distributed parameter modeling to yield tissue blood flow, blood volume, mean transit time, permeability, and hepatic arterial fraction, for tumor and normal liver. CT perfusion values for the reference sampling interval of 0.5s (SI0.5) were compared with those of SI datasets of 1s, 2s, 3s and 4s, using mixed-effects model analyses. Results Increases in SI beyond 1s were associated with significant and increasing departures of CT perfusion parameters from reference values at SI0.5 (p≤0.0009). CT perfusion values deviated from reference with increasing uncertainty with increasing SIs. Findings for normal liver were concordant. Conclusion Increasing SIs beyond 1s yield significantly different CT perfusion parameter values compared to reference values at SI0.5. PMID:25626401

Small for Size and Flow (SFSF) syndrome: An alternative description for posthepatectomy liver failure.

PubMed

Golriz, Mohammad; Majlesara, Ali; El Sakka, Saroa; Ashrafi, Maryam; Arwin, Jalal; Fard, Nassim; Raisi, Hanna; Edalatpour, Arman; Mehrabi, Arianeb

2016-06-01

Small for Size Syndrome (SFSS) syndrome is a recognizable clinical syndrome occurring in the presence of a reduced mass of liver, which is insufficient to maintain normal liver function. A definition has yet to be fully clarified, but it is a common clinical syndrome following partial liver transplantation and extended hepatectomy, which is characterized by postoperative liver dysfunction with prolonged cholestasis and coagulopathy, portal hypertension, and ascites. So far, this syndrome has been discussed with focus on the remnant size of the liver after partial liver transplantation or extended hepatectomy. However, the current viewpoints believe that the excessive flow of portal vein for the volume of the liver parenchyma leads to over-pressure, sinusoidal endothelial damages and haemorrhage. The new hypothesis declares that in both extended hepatectomy and partial liver transplantation, progression of Small for Size Syndrome is not determined only by the "size" of the liver graft or remnant, but by the hemodynamic parameters of the hepatic circulation, especially portal vein flow. Therefore, we suggest the term "Small for Size and Flow (SFSF)" for this syndrome. We believe that it is important for liver surgeons to know the pathogenesis and manifestation of this syndrome to react early enough preventing non-reversible tissue damages. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Hepatocytes Polyploidization and Cell Cycle Control in Liver Physiopathology

PubMed Central

Gentric, Géraldine; Desdouets, Chantal; Celton-Morizur, Séverine

2012-01-01

Most cells in mammalian tissues usually contain a diploid complement of chromosomes. However, numerous studies have demonstrated a major role of “diploid-polyploid conversion” during physiopathological processes in several tissues. In the liver parenchyma, progressive polyploidization of hepatocytes takes place during postnatal growth. Indeed, at the suckling-weaning transition, cytokinesis failure events induce the genesis of binucleated tetraploid liver cells. Insulin signalling, through regulation of the PI3K/Akt signalling pathway, is essential in the establishment of liver tetraploidization by controlling cytoskeletal organisation and consequently mitosis progression. Liver cell polyploidy is generally considered to indicate terminal differentiation and senescence, and both lead to a progressive loss of cell pluripotency associated to a markedly decreased replication capacity. Although adult liver is a quiescent organ, it retains a capacity to proliferate and to modulate its ploidy in response to various stimuli or aggression (partial hepatectomy, metabolic overload (i.e., high copper and iron hepatic levels), oxidative stress, toxic insult, and chronic hepatitis etc.). Here we review the mechanisms and functional consequences of hepatocytes polyploidization during normal and pathological liver growth. PMID:23150829

Hepatocytes polyploidization and cell cycle control in liver physiopathology.

PubMed

Gentric, Géraldine; Desdouets, Chantal; Celton-Morizur, Séverine

2012-01-01

Most cells in mammalian tissues usually contain a diploid complement of chromosomes. However, numerous studies have demonstrated a major role of "diploid-polyploid conversion" during physiopathological processes in several tissues. In the liver parenchyma, progressive polyploidization of hepatocytes takes place during postnatal growth. Indeed, at the suckling-weaning transition, cytokinesis failure events induce the genesis of binucleated tetraploid liver cells. Insulin signalling, through regulation of the PI3K/Akt signalling pathway, is essential in the establishment of liver tetraploidization by controlling cytoskeletal organisation and consequently mitosis progression. Liver cell polyploidy is generally considered to indicate terminal differentiation and senescence, and both lead to a progressive loss of cell pluripotency associated to a markedly decreased replication capacity. Although adult liver is a quiescent organ, it retains a capacity to proliferate and to modulate its ploidy in response to various stimuli or aggression (partial hepatectomy, metabolic overload (i.e., high copper and iron hepatic levels), oxidative stress, toxic insult, and chronic hepatitis etc.). Here we review the mechanisms and functional consequences of hepatocytes polyploidization during normal and pathological liver growth.

Relevance of Endoplasmic Reticulum Stress Cell Signaling in Liver Cold Ischemia Reperfusion Injury

PubMed Central

Folch-Puy, Emma; Panisello, Arnau; Oliva, Joan; Lopez, Alexandre; Castro Benítez, Carlos; Adam, René; Roselló-Catafau, Joan

2016-01-01

The endoplasmic reticulum (ER) is involved in calcium homeostasis, protein folding and lipid biosynthesis. Perturbations in its normal functions lead to a condition called endoplasmic reticulum stress (ERS). This can be triggered by many physiopathological conditions such as alcoholic steatohepatitis, insulin resistance or ischemia-reperfusion injury. The cell reacts to ERS by initiating a defensive process known as the unfolded protein response (UPR), which comprises cellular mechanisms for adaptation and the safeguarding of cell survival or, in cases of excessively severe stress, for the initiation of the cell death program. Recent experimental data suggest the involvement of ERS in ischemia/reperfusion injury (IRI) of the liver graft, which has been considered as one of major problems influencing outcome after liver transplantation. The purpose of this review is to summarize updated data on the molecular mechanisms of ERS/UPR and the consequences of this pathology, focusing specifically on solid organ preservation and liver transplantation models. We will also discuss the potential role of ERS, beyond the simple adaptive response and the regulation of cell death, in the modification of cell functional properties and phenotypic changes. PMID:27231901

Hyperammonemic Coma—Barking Up the Wrong Tree

PubMed Central

Kruzel-Davila, Eti; Dori, Guy; Baron, Elzbieta; Bitterman, Haim

2007-01-01

Hepatic encephalopathy and myxedema coma share clinical features: coma, ascites, anemia, impaired liver functions, and a “metabolic” electroencephalogram (EEG). Hyperammonemia, a hallmark of hepatic encephalopathy, has also been described in hypothyroidism. Differentiation between the 2 conditions, recognition of their possible coexistence, and the consequent therapeutic implications are of utmost importance. We describe a case of an 82-year-old woman with a history of mild chronic liver disease who presented with hyperammonemic coma unresponsive to conventional therapy. Further investigation disclosed severe hypothyroidism. Thyroid hormone replacement resulted in gain of consciousness and normalization of hyperammonemia. In patients with an elevated ammonia level, altered mental status, and liver disease, who do not have a clear inciting event for liver disease decompensation, overwhelming evidence of hepatic decompensation, or who do not respond to appropriate therapy for hepatic encephalopathy, hypothyroidism should be considered and evaluated. PMID:17372808

[Effects of low intensity infra-red laser irradiation on ultrastructure and proliferation of liver cells in experimental hepatitis and cirrhosis].

PubMed

Baĭbekov, I M; Vorozheĭkin, V M; Artykov, Sh N

1992-04-01

With the aid of light, electron transmission and scanning electron microscopy and radioautography and stereometry, the influence of low-intensive laser irradiation (LILI) (infrared) was studied in normal rat liver and in experimental cirrhosis and hepatitis. It was revealed that arsenide-gallium laser irradiation causes the change of intracellular structure. These changes show the intensification on their specific function manifest in an increase of relative volume of intracellular structures. The changes of microvessels show the activation of microcirculation. The elevation of the index of the labelled nuclei testify to increased proliferation. The similar influences of LILI on the liver ultrastructure and proliferation in hepatitis and cirrhosis are accompanied by the reduction of the pathological changes of the liver--the hepatocytes oedema, granular, vacuolar and fatty dystrophy.

Cafeteria feeding induces interleukin-1beta mRNA expression in rat liver and brain.

PubMed

Hansen, M K; Taishi, P; Chen, Z; Krueger, J M

1998-06-01

intake affects gut-immune function and can provide a strong intestinal antigen challenge resulting in activation of host defense mechanisms in the digestive system. Previously, we showed that feeding rats a cafeteria diet increases non-rapid eye movement sleep by a subdiaphragmatic mechanism. Food intake and sleep regulation and the immune system share the regulatory molecule interleukin-1beta (IL-1beta). Thus this study examined the effects of a cafeteria diet on IL-1beta mRNA and IL-1 receptor accessory protein (IL-1RAP) mRNA expression in rat liver and brain. Rats were fed normal rat chow or a palatable diet consisting of bread, chocolate, and shortbread cookies (cafeteria diet). After 3 days, midway between the light period of the light-dark cycle, rats were killed by decapitation. Feeding rats a cafeteria diet resulted in increased IL-1beta mRNA expression in the liver and hypothalamus compared with rats fed only the normal rat chow. In addition, cafeteria feeding decreased IL-1RAP mRNA levels in the liver and brain stem. These results indicate that feeding has direct effects on cytokine production and together with other data suggest that the increased sleep that accompanies increased feeding may be the result of increased brain IL-1beta. These results further suggest that cytokine-to-brain communication may be important in normal physiological conditions, such as feeding, as well as being important during inflammatory responses.

Cognitive and emotional outcome after pediatric liver transplantation.

PubMed

Adebäck, Petra; Nemeth, Antal; Fischler, Björn

2003-10-01

The aim of the study was to evaluate the cognitive and emotional development after pediatric liver transplantation. A total of 21 patients, aged 4-16.9 yr (median 9.6 yr) were tested 1-9 yr (median 4.2 yr) after the transplantation. The pretransplant diagnoses included biliary atresia (eight patients), various metabolic diseases (n = 6), acute liver failure (n = 3), and miscellaneous (n = 4). The cognitive functions were tested with Wechsler preschool and primary scale of intelligence (WPPSI)-R or Wechsler intelligence scale for children (WISC)-III according to age. The Piers-Harris self-concept scale and the evaluation of human figure drawings according to Koppitz were used to detect emotional problems. All tests in all patients were performed by the same psychologist. A significantly lower result on cognitive tests was seen when compared with the expected normal values (p < 0.01). The number of patients with results within or under the lower normal range was higher than expected. Although the mean value of the Piers-Harris self-concept scale was normal, there was a large spread within the group. Indicators of emotional problems were found in the human figure drawings of 50% of the patients. To some extent, low cognitive scores coincided with low scores on self-concept scale and indicators of emotional difficulties. We conclude that the high degree of cognitive and emotional problems after liver transplantation is an important argument for routine psychologic follow-up and support in these patients.

Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues.

PubMed

Patel, Krupa J; Trédan, Olivier; Tannock, Ian F

2013-07-01

Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time-dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 μm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities.

Unusual Synchronous Methimazole-Induced Agranulocytosis and Severe Hepatotoxicity in Patient with Hyperthyroidism: A Case Report and Review of the Literature

PubMed Central

Yang, Jun; Zhang, Jun; Xu, Qin; Sheng, Guo-ping; Weng, Wan-wen; Dong, Meng-jie

2015-01-01

Context. To report a patient with hyperthyroidism who developed concurrent occurrence of agranulocytosis and severe hepatotoxicity after taking methimazole (MMI). Case. A 51-year-old Chinese male was diagnosed as hyperthyroidism with normal white blood count and liver function. After 4 weeks' treatment with MMI 20 mg/d, it developed to agranulocytosis and severe cholestatic hepatotoxicity. The patient's symptoms and laboratory abnormalities disappeared after the withdrawal of MMI; his white blood count and liver function recover to normal in 2 weeks and 5 weeks, respectively. 296 MBq dose of 131I was given to the patient 3 weeks after the withdrawal of MMI and his thyroid function was back to normal in 6 months. As we know through literature review, only 5 previous cases reported the synchronous ATD-induced agranulocytosis and severe hepatotoxicity in patients with hyperthyroidism. Methods. Review of the patient's clinical course. Literature review of cases of hyperthyroidism with agranulocytosis and severe hepatotoxicity demonstrated that these complications occurred after taking antithyroid drug (ATD). Conclusions. Patient with hyperthyroidism can have synchronous ATD-induced agranulocytosis and severe hepatotoxicity. This case is extremely rare, but the adverse effects with ATDs is clinically significant. The clinicians need to be careful about this and monitor biochemical of patients who take ATDs. PMID:26060496

Dietary glutamate reduces systemic but not intestinal leucine oxidation in protein malnourished piglets

USDA-ARS?s Scientific Manuscript database

The methionine (Met) metabolic cycle is critical for normal cell functions. Met cycle disruption has been implicated in disease, such as alcoholic liver disease (ALD) and multiple sclerosis (MS). Studies in animal models of ALD and MS have shown that the Met metabolite methylthioadenosine (MTA) has ...

Left Lobe Auxiliary Liver Transplantation for End-stage Hepatitis B Liver Cirrhosis.

PubMed

Wang, S-F; Chen, X-P; Chen, Z-S; Wei, L; Dong, S-L; Guo, H; Jiang, J-P; Teng, W-H; Huang, Z-Y; Zhang, W-G

2017-06-01

Auxiliary liver transplantation (ALT) for hepatitis B virus (HBV)-related liver cirrhosis previously showed poor results, because the native liver was a significant source of HBV recurrence and the graft could be rapidly destroyed by HBV infection in an immunosuppressive condition. Four patients with HBV-related liver cirrhosis were unable to undergo orthotopic liver transplantation because the only available grafts of left lobe were too small. Under entecavir-based anti-HBV treatment, they underwent ALT in which the recipient left liver was removed and the small left lobe graft was implanted in the corresponding space. The mean graft weight/recipient weight was 0.49% (range, 0.38%-0.55%). One year after transplantation, the graft sizes were increased to 273% and the remnant livers were decreased to 44%. Serum HBV DNA was persistently undetectable. Periodic graft biopsy showed no signs of tissue injury and negative immunostaining for hepatitis B surface antigen and hepatitis B core antigen. After a mean follow-up period of 21 months, all patients live well with normal graft function. Our study suggests that ALT for HBV-related liver cirrhosis is feasible under entecavir-based anti-HBV treatment. Successful application of small left livers in end-stage liver cirrhosis may significantly increase the pool of left liver grafts for adult patients. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Abnormal Chloride Homeostasis in the Substancia Nigra Pars Reticulata Contributes to Locomotor Deficiency in a Model of Acute Liver Injury

PubMed Central

Wei, Yan-Yan; Chen, Jing; Dou, Ke-Feng; Wang, Ya-Yun

2013-01-01

Background Altered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice. Methods Alterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE). The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed. Results In our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure. Conclusion Our data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure. PMID:23741482

Pharmacogenomics of drug-induced liver injury (DILI): Molecular biology to clinical applications.

PubMed

Kaliyaperumal, Kalaiyarasi; Grove, Jane I; Delahay, Robin M; Griffiths, William J H; Duckworth, Adam; Aithal, Guruprasad P

2018-05-21

A 21-year old woman was admitted to hospital with a two-week history of painless jaundice, fatigue and anorexia having previously been fit and well. One month prior to presentation, the patient had taken a five-day course of amoxicillin-clavulanic acid for an infected skin cyst. Otherwise, she was only on the oral contraceptive pill and reported minimal alcohol intake. On examination, she was deeply jaundiced, but alert and oriented with no asterixis. She had no stigmata of chronic liver disease, but hepatomegaly extending 3 cm from below the right subcostal margin was evident. Investigations showed: white cell count 13.4 × 10 9 /L (normal 3.6-9.3), haemoglobin 11.8 g/dl (normal 11-15), platelet count 356 × 10 9 /L (normal 170-420), sodium 138 mmol/L (normal 134-144), potassium 3.5 mmol/L (normal 3.5-5.0), creatinine 32 µmol/L (normal 40-75), albumin 30 g/L (normal 35-48), alanine aminotransferase 707 IU/L (normal 15-54), alkaline phosphatase 151 IU/L (normal 30-130), bilirubin 384 µmol/L (normal 7-31) and prothrombin time 27.2 s (normal 11.7-14). Screening for hepatitis A, B, C, E, Epstein-Barr virus, cytomegalovirus and autoimmune hepatitis was negative. Tests for anti-smooth muscle, antinuclear, and anti-liver-kidney microsomal-1 antibodies were negative; immunoglobulin levels and ceruloplasmin levels were normal. Liver ultrasonography demonstrated a liver of normal contour with no biliary dilatation, a normal spleen size and patent vessels. Liver biopsy revealed severe portal interface hepatitis with lobular inflammation and scant plasma cells. Her clinical condition deteriorated in the following days with prothrombin time and bilirubin rising to 56.6 s and 470 µmol/L, respectively. At follow-up after 11 days, her alanine aminotransferase level was 1,931 IU/L. She developed grade 2 hepatic encephalopathy 14 days after presentation, and was listed for a super-urgent liver transplant. Human leucocyte antigen (HLA) typing was performed as a part of preparatory investigations and showed the patient carried the HLA haplotype HLA-DRB1∗15:02-DQB1∗06:01. Following orthotopic transplantation of a deceased donor graft her explant histology revealed severe ongoing hepatitis with multi-acinar necrosis (Fig. 1A and B). This case raised a number of important questions about the diagnosis of drug-induced liver injury and tools available for clinicians to make the best decisions for patient care: In this Grand Rounds article, we will explore these questions, describing the pathophysiology, diagnostic and prognostic biomarkers, and clinical management of drug-induced liver injury. We will also discuss ongoing areas of uncertainty. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

A Fractal Analysis of CT Liver Images for the Discrimination of Hepatic Lesions: A Comparative Study

DTIC Science & Technology

2001-10-25

liver images in order to estimate their fractal dimension and to differentiate normal liver parenchyma from hepatocellular carcinoma . Four fractal...methods; thus discriminating up to 93% of the normal parenchyma and up to 82% of the hepatocellular carcinoma , correctly.

Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis.

PubMed

Romanelli, Roberto Giulio; Stasi, Cristina

2016-01-01

Cirrhosis is a diffuse pathophysiological state of the liver considered to be the final stage of various liver injuries, characterized by chronic necroinflammatory and fibrogenetic processes, with subsequent conversion of normal liver architecture into structurally abnormal nodules, dense fibrotic septa, concomitant parenchymal exaustment and collapse of the liver tissue. Alcoholic liver disease and chronic infections due to HBV and/or HCV constitute the main causes of liver cirrhosis worldwide. During a lag time of 15 to 30 years, chronic liver diseases can lead to liver cirrhosis and its complications. Active hepatic inflammation plays a pivotal role in the inflammation- necrosis-regeneration process, which eventually leads to liver cirrhosis and hepatocellular carcinoma. Prognosis of liver cirrhosis is highly variable and influenced by several variables, such as etiology, severity of liver disease, presence of complications and comorbidities. In advanced cirrhosis, survival decreases to one or two years. Correct advanced diagnosis and selected treatment with different molecules may help in understanding mechanisms of fibrogenesis, the driving forces of cirrhosis's pathogenesis, and the scrupulous approach to more effective therapeutic procedures. Prevention of fibrosis with further deterioration of liver function through specific treatments is always required, through the removal of the underlying causes of liver disease. Advanced liver disease, with subsequent complications, requires targeted treatment. Therefore, the aim of this review is to assess the diagnosis and treatment of liver cirrhosis on the pathophysiological bases, searching for relevant studies published in English using the PubMed database from 2011 to the present.

The therapeutic effects of bone marrow-derived mesenchymal stem cells and simvastatin in a rat model of liver fibrosis.

PubMed

Motawi, Tarek M K; Atta, Hazem M; Sadik, Nermin A H; Azzam, May

2014-01-01

Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. Studies concerning the capacity of mesenchymal stem cells (MSCs) and simvasatain (SIMV) to repair fibrotic tissues through reducing inflammation, collagen deposition, are still controversial. This study aimed to investigate the therapeutic efficacy of bone marrow (BM)-derived MSCs and SIMV on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats were divided into: normal, CCl4, CCl4/MSCs, CCl4/SIMV, CCl4/MSCs/SIMV, and SIMV groups. BM-derived MSCs were detected by RT-PCR of CD29 and were then infused into the tail vein of female rats that received CCl4 injection to induce liver fibrosis. Sex-determining region Y (SRY) gene on Y-chromosome gene was assessed by PCR to confirm homing of the male stem cells in liver tissue of the female recipients. Serum liver function tests, liver procollagens I and III, tissue inhibitors of metalloproteinase-1 (TIMP-1), endoglin, matrix metalloproteinase-1 (MMP-1) gene expressions, transforming growth factor-beta (TGF-β1) immunostaining, and histopathologicl examination were performed. MSCs and SIMV decreased liver procollagens I and III, TIMP-1 and endoglin gene expressions, TGF-β1 immunostaining, and serum liver function tests compared with the CCl4 group. MMP-1 expression was increased in the CCl4/MSCs group. Histopathological examination as well as fibrosis score supports the biochemical and molecular findings. It can be concluded that MSCs and SIMV were effective in the treatment of hepatic CCl4-induced fibrosis-rat model. Treatment with MSCs was superior to SIMV. This antifibrotic effect can be attributed to their effect on the MMPs/TIMPs balance which is central in fibrogenesis.

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.

Death receptor and mitochondria-mediated hepatocyte apoptosis underlies liver dysfunction in rats exposed to organic pollutants from drinking water

PubMed Central

Yang, Guanghong; Zhou, Zhiwei; Cen, Yanli; Gui, Xiaolin; Zeng, Qibing; Ao, Yunxia; Li, Qian; Wang, Shiran; Li, Jun; Zhang, Aihua

2015-01-01

Persistent organic pollutants in drinking water impose a substantial risk to the health of human beings, but the evidence for liver toxic effect and the underlying mechanism is scarce. This study aimed to examine the liver toxicity and elucidate the molecular mechanism of organic pollutants in drinking water in normal human liver cell line L02 cells and rats. The data showed that organic extraction from drinking water remarkably impaired rat liver function, evident from the increase in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase, and decrease in the serum level of total protein and albumin. Organic extraction dose-dependently induced apoptotic cell death in rat liver and L02 cells. Administration of rats with organic extraction promoted death receptor signaling pathway through the increase in gene and protein expression level of Fas and FasL. Treatment of rats with organic extraction also induced mitochondria-mediated apoptosis via increasing the expression level of proapoptotic protein, Bax, but decreasing the expression level of antiapoptotic protein, Bcl-2, resulting in an upregulation of cytochrome c and activation of caspase cascade at both transcriptional and post-transcriptional levels. Moreover, organic extraction enhanced rat liver glutathione S-transferases activity and reactive oxygen species generation, and upregulated aryl hydrocarbon receptor and glutathione S-transferase A1 at both transcriptional and translational levels. Collectively, the results indicate that organic extraction from drinking water impairs liver function, with the involvement of death receptor and mitochondria-mediated apoptosis in rats. The results provide evidence and molecular mechanisms for organic pollutants in drinking water-induced liver dysfunction, which may help prevent and treat organic extraction-induced liver injury. PMID:26316710

Death receptor and mitochondria-mediated hepatocyte apoptosis underlies liver dysfunction in rats exposed to organic pollutants from drinking water.

PubMed

Yang, Guanghong; Zhou, Zhiwei; Cen, Yanli; Gui, Xiaolin; Zeng, Qibing; Ao, Yunxia; Li, Qian; Wang, Shiran; Li, Jun; Zhang, Aihua

2015-01-01

Persistent organic pollutants in drinking water impose a substantial risk to the health of human beings, but the evidence for liver toxic effect and the underlying mechanism is scarce. This study aimed to examine the liver toxicity and elucidate the molecular mechanism of organic pollutants in drinking water in normal human liver cell line L02 cells and rats. The data showed that organic extraction from drinking water remarkably impaired rat liver function, evident from the increase in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase, and decrease in the serum level of total protein and albumin. Organic extraction dose-dependently induced apoptotic cell death in rat liver and L02 cells. Administration of rats with organic extraction promoted death receptor signaling pathway through the increase in gene and protein expression level of Fas and FasL. Treatment of rats with organic extraction also induced mitochondria-mediated apoptosis via increasing the expression level of proapoptotic protein, Bax, but decreasing the expression level of antiapoptotic protein, Bcl-2, resulting in an upregulation of cytochrome c and activation of caspase cascade at both transcriptional and post-transcriptional levels. Moreover, organic extraction enhanced rat liver glutathione S-transferases activity and reactive oxygen species generation, and upregulated aryl hydrocarbon receptor and glutathione S-transferase A1 at both transcriptional and translational levels. Collectively, the results indicate that organic extraction from drinking water impairs liver function, with the involvement of death receptor and mitochondria-mediated apoptosis in rats. The results provide evidence and molecular mechanisms for organic pollutants in drinking water-induced liver dysfunction, which may help prevent and treat organic extraction-induced liver injury.

Clinical predictors of silent but substantial liver fibrosis in primary Sjogren's syndrome.

PubMed

Lee, Sang-Won; Kim, Beom Kyung; Park, Jun Yong; Kim, Do Young; Ahn, Sang Hoon; Song, Jungsik; Park, Yong-Beom; Lee, Soo-Kon; Han, Kwang-Hyub; Kim, Seung Up

2016-07-01

To investigate the prevalence and the predictors of silent but substantial liver fibrosis in patients with primary Sjogren's syndrome (pSS). We enrolled 101 pSS patients with normal liver function and structures, and without significant liver diseases or other conditions affecting liver fibrosis. The European league against rheumatism (EULAR) SS patients reported index (ESSPRI) and the EULAR SS disease activity index (ESSDAI) were analyzed. Liver stiffness (LS) was measured using transient elastography and 7.4 kPa was determined as the cutoff value for significant liver fibrosis. The median age of patients (91women) was 53 years and the median LS value was 4.7 kPa. The median ESSPRI and ESSDAI showed no correlation with LS values. Twelve patients (11.9%) had significant liver fibrosis. In multivariate logistic regression, white blood cells count ≤4000.0/mm(3) (Odds ratio [OR] 9.821), serum albumin ≤3.8 mg/dL (OR 16.770) and aspartate aminotransferase (AST) ≥ 27.0 IU/L (OR 20.858) independently predicted silent but substantial liver fibrosis in pSS patients. The prevalence of silent but substantial liver fibrosis was 11.9% in pSS and its predictors were leukopenia, decreased serum albumin and increased AST levels.

Possible carcinogenic potential of dimethyl dimethoxy biphenyl dicarboxylate in experimental animals

PubMed Central

Botros, Sanaa Sabet; El-Lakkany, Naglaa Mohamed; Hammam, Olfat Ali; Sabra, Abdel-Naser Abdel-Aal; Taha, Alaa Awad

2016-01-01

Dimethyl dimethoxy biphenyl dicarboxylate (DDB) has been extensively used in the treatment of liver diseases accounting for 1–6% of the global disease burden. Cell replication, DNA synthesis, and proliferation, providing significant information about behavior of cells were examined in mice exposed to subchronic administration with DDB. Conventional liver functions specifically gamma-glutamyltransferase (γ-GT), a marker expressing liver canceration was also investigated. Normal mice were allocated into two groups each of 10 mice. The 1st and 2nd groups were treated with DDB in a dose of 50 mg/kg/day, 5 days/week for 1 month and 3 months, respectively. Comparable groups of normal mice were left without treatment as controls. Compared to normal control group, animals receiving DDB for 3 months showed marked elevations of both alanine aminotransferase and γ-GT, significant inhibition in cytochrome P450, a significant increase in the mean ploidy and 4C with moderate to marked increase in S-phase populations and the number of proliferating cell nuclear antigen-positive cells. In conclusion, this is the first report on the potential relationship between the subchronic administration of DDB and the increase in the hepatocyte proliferation, cell replication and DNA synthesis that may raise an alarm regarding possible DDB insult on the biological behavior of cells. PMID:27144153

Mitochondrial-related proteomic changes during obesity and fasting in mice are greater in the liver than skeletal muscles.

PubMed

Nesteruk, Monika; Hennig, Ewa E; Mikula, Michal; Karczmarski, Jakub; Dzwonek, Artur; Goryca, Krzysztof; Rubel, Tymon; Paziewska, Agnieszka; Woszczynski, Marek; Ledwon, Joanna; Dabrowska, Michalina; Dadlez, Michal; Ostrowski, Jerzy

2014-03-01

Although mitochondrial dysfunction is implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are not well established. We performed mitochondrial quantitative proteomic and whole transcriptome analysis followed by functional annotations within liver and skeletal muscles, using fasted and non-fasted 16- and 48-week-old high-fat diet (HFD)-fed and normal diet-fed (control group) wild-type C56BL/6J mice, and hyperphagic ob/ob and db/db obese mice. Our study identified 1,675 and 704 mitochondria-associated proteins with at least two peptides in liver and muscle, respectively. Of these, 221 liver and 44 muscle proteins were differentially expressed (adjusted p values ≤ 0.05) between control and all obese mice, while overnight fasting altered expression of 107 liver and 35 muscle proteins. In the liver, we distinguished a network of 27 proteins exhibiting opposite direction of expression changes in HFD-fed and hyperphagic mice when compared to control. The network centered on cytochromes P450 3a11 (Cyp3a11) and 4a14 (Cyp4a14), and fructose-bisphosphate aldolase B (Aldob) proteins which bridged proteins cluster involved in Metabolism of xenobiotics with proteins engaged in Fatty acid metabolism and PPAR signaling pathways. Functional annotations revealed that most of the hepatic molecular alterations, which characterized both obesity and fasting, related to different aspects of energy metabolism (such as Fatty acid metabolism, Peroxisome, and PPAR signaling); however, only a limited number of functional annotations could be selected from skeletal muscle data sets. Thus, our comprehensive molecular overview revealed that both obesity and fasting states induce more pronounced mitochondrial proteome changes in the liver than in the muscles.

Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression.

PubMed

Gonsebatt, M E; Del Razo, L M; Cerbon, M A; Zúñiga, O; Sanchez-Peña, L C; Ramírez, P

2007-09-01

Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 microM of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise 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

[Biochemical characterization of fractionated rat liver chromatin in experimental D-hypovitaminosis and after administration of steroidal drugs].

PubMed

Levitskiĭ, E L; Kholodova, Iu D; Gubskiĭ, Iu I; Primak, R G; Chabannyĭ, V N; Kindruk, N L; Mozzhukhina, T G; Lenchevskaia, L K; Mironova, V N; Saad, L M

1993-01-01

Marked changes in the structural and functional characteristics of liver nuclear chromatin fractions are observed under experimental D-hypovitaminosis, which differ in the degree of transcriptional activity. DNA-polymerase activity and activity of the fraction, enriched with RNA-polymerase I, increases in the active fraction. Free radical LPO reactions are modified in the chromatin fraction with low activity and to the less degree in the active one. Disturbances of chromatine structural properties are caused with the change in the protein and lipid components of chromatin. Administration of ecdysterone preparations (separately and together with vitamin D3) has a partial corrective effect on structural and functional organization of nuclear chromatine. At the action of ecdysterone normalization of LPO reactions modified by pathological changes is observed in the chromatin fraction with low activity and to the less degree in the active one. This kind of influence corrects to the less degree chromatin functional activity and quantitative and qualitative modifications of its protein component. Simultaneous influence of ecdysterone and vitamin D3 leads to the partial normalization of the biochemical indices studied (except for those which characterize LPO reactions) mainly in the active chromatin fraction.

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.

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.

Antimalarial Activity of Cocos nucifera Husk Fibre: Further Studies

PubMed Central

Adebayo, J. O.; Balogun, E. A.; Malomo, S. O.; Soladoye, A. O.; Olatunji, L. A.; Kolawole, O. M.; Oguntoye, O. S.; Babatunde, A. S.; Akinola, O. B.; Aguiar, A. C. C.; Andrade, I. M.; Souza, N. B.; Krettli, A. U.

2013-01-01

In this study, the antimalarial and toxicity potentials of husk fibre extracts of five Nigerian varieties of Cocos nucifera were evaluated in vitro. The only active extract fraction, West African Tall (WAT) ethyl acetate extract fraction, was then evaluated for its phytochemical constituents, antimalarial and toxicity potentials at varying doses (31.25–500 mg/kg body weight) using various organ function indices. The results revealed that WAT ethyl acetate extract fraction (WATEAEF) contained alkaloids, tannins, and flavonoids and was active against Plasmodium falciparum W2 strain maintained in continuous culture, with a selectivity index of 30.3. The same extract fraction was active in vivo against Plasmodium berghei NK65, causing more than 50% reduction in parasitaemia on days 4 and 6 after inoculation at various doses administered. WATEAEF did not significantly alter (P > 0.05) function indices of the liver and cardiovascular system at all doses administered but significantly increased (P < 0.05) plasma creatinine concentration at 250 and 500 mg/Kg body weight compared to controls. The results of this study suggest that WATEAEF possesses antimalarial activity and may not adversely affect normal liver function nor predispose subjects to cardiovascular diseases but may impair normal kidney function at higher doses. Further studies are underway to isolate the active principles. PMID:23983800

Antimalarial Activity of Cocos nucifera Husk Fibre: Further Studies.

PubMed

Adebayo, J O; Balogun, E A; Malomo, S O; Soladoye, A O; Olatunji, L A; Kolawole, O M; Oguntoye, O S; Babatunde, A S; Akinola, O B; Aguiar, A C C; Andrade, I M; Souza, N B; Krettli, A U

2013-01-01

In this study, the antimalarial and toxicity potentials of husk fibre extracts of five Nigerian varieties of Cocos nucifera were evaluated in vitro. The only active extract fraction, West African Tall (WAT) ethyl acetate extract fraction, was then evaluated for its phytochemical constituents, antimalarial and toxicity potentials at varying doses (31.25-500 mg/kg body weight) using various organ function indices. The results revealed that WAT ethyl acetate extract fraction (WATEAEF) contained alkaloids, tannins, and flavonoids and was active against Plasmodium falciparum W2 strain maintained in continuous culture, with a selectivity index of 30.3. The same extract fraction was active in vivo against Plasmodium berghei NK65, causing more than 50% reduction in parasitaemia on days 4 and 6 after inoculation at various doses administered. WATEAEF did not significantly alter (P > 0.05) function indices of the liver and cardiovascular system at all doses administered but significantly increased (P < 0.05) plasma creatinine concentration at 250 and 500 mg/Kg body weight compared to controls. The results of this study suggest that WATEAEF possesses antimalarial activity and may not adversely affect normal liver function nor predispose subjects to cardiovascular diseases but may impair normal kidney function at higher doses. Further studies are underway to isolate the active principles.

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.

Iron overload by Superparamagnetic Iron Oxide Nanoparticles is a High Risk Factor in Cirrhosis by a Systems Toxicology Assessment

NASA Astrophysics Data System (ADS)

Wei, Yushuang; Zhao, Mengzhu; Yang, Fang; Mao, Yang; Xie, Hang; Zhou, Qibing

2016-06-01

Superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent have been widely used in magnetic resonance imaging for tumor diagnosis and theranostics. However, there has been safety concern of SPIONs with cirrhosis related to excess iron-induced oxidative stress. In this study, the impact of iron overload by SPIONs was assessed on a mouse cirrhosis model. A single dose of SPION injection at 0.5 or 5 mg Fe/kg in the cirrhosis group induced a septic shock response at 24 h with elevated serum levels of liver and kidney function markers and extended impacts over 14 days including high levels of serum cholesterols and persistent low serum iron level. In contrast, full restoration of liver functions was found in the normal group with the same dosages over time. Analysis with PCR array of the toxicity pathways revealed the high dose of SPIONs induced significant expression changes of a distinct subset of genes in the cirrhosis liver. All these results suggested that excess iron of the high dose of SPIONs might be a risk factor for cirrhosis because of the marked impacts of elevated lipid metabolism, disruption of iron homeostasis and possibly, aggravated loss of liver functions.

Impact of splenic artery ligation after major hepatectomy on liver function, regeneration and viability.

PubMed

Carrapita, Jorge; Abrantes, Ana Margarida; Campelos, Sofia; Gonçalves, Ana Cristina; Cardoso, Dulce; Sarmento-Ribeiro, Ana Bela; Rocha, Clara; Santos, Jorge Nunes; Botelho, Maria Filomena; Tralhão, José Guilherme; Farges, Olivier; Barbosa, Jorge Maciel

2016-10-11

It was reported that prevention of acute portal overpressure in small-for-size livers by inflow modulation results in a better postoperative outcome. The aim is to investigate the impact of portal blood flow reduction by splenic artery ligation after major hepatectomy in a murine model. Forty-eight rats were subjected to an 85% hepatectomy or 85% hepatectomy and splenic artery ligation. Both groups were evaluated at 24, 48, 72 and 120 post-operative hours: liver function, regeneration and viability. All methods and experiments were carried out in accordance with Coimbra University guidelines. Splenic artery ligation produces viability increase after 24 h, induces a relative decrease in oxidative stress during the first 48 hours, allows antioxidant capacity increment after 24 h, which is reflected in a decrease of half-time normalized liver curve at 48 h and at 72 h and in an increase of mitotic index between 48 h and 72 h. Splenic artery ligation combined with 85% hepatectomy in a murine model, allows portal inflow modulation, promoting an increase in hepatocellular viability and regeneration, without impairing the function, probably by inducing a less marked elevation of oxidative stress at first 48 hours.

[Observation on the therapeutic effect of Lamivudin on chronic hepatitis B].

PubMed

Wen, Xiaofeng; Li, Xuemei; Xie, Houyu; Chen, Nian; Zeng, Wenfeng; Ru, Haiyun; Cui, Xaioping; Tang, Zhongmin

2002-12-01

To observe the therapeutic effect of Lamivudine on controlling hepatitis B virus DNA replication. The liver disease patients were divided into two groups, the treated group (n=64) was given Lamivudine 100 mg once a day for one year and was additionally given liver protection drugs according to their liver function, while the control group (n=30) was given common liver protection drugs. The blood routine test, liver function and the viral markers were detected at defined times. The results showed that after one year treatment of chronic hepatitis B with Lamivudine, the recovery rate of ALT was 90.7%, the negative conversion rate of HBV DNA was 73.1% showing a significant difference as compared with the control group (P<0.05). The negative seroconversion rate of HBeAg was 50%, HBeAg/anti HBe changing rate was 38.2%, that had no significant different as compared with the control group (P<0.05). The percentage for disease relapse and second elevation of ALT was 3.1% in therapeutic group that was significantly different from that of the control group (P<0.05). Two cases with severe hepatitis in the treated group were all alive. Lamivudine could effectively control HBV DNA replication, making ALT normal, it also could decrease the relapse rate of chronic hepatitis B and raise the survival rate of the patients with liver disease.

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.

Ischemic Preconditioning Increases the Tolerance of Fatty Liver to Hepatic Ischemia-Reperfusion Injury in the Rat

PubMed Central

Serafín, Anna; Roselló-Catafau, Joan; Prats, Neus; Xaus, Carme; Gelpí, Emilio; Peralta, Carmen

2002-01-01

Hepatic steatosis is a major risk factor in ischemia-reperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation. PMID:12163383

[Cholestatic icterus due to oral contraceptives].

PubMed

Pestel, M; Lambert, C; Jeanmougin, M

1973-03-01

A case report of cholestatic jaundice in a 25 year old woman, who had had jaundice at age 4 years, and had taken Stediril (a combined oral contraceptive) for 1 month, implicates either the pill or a possibly hereditary hyperlipidemia. The jaundice developed in 2 weeks with vomiting, epigastric pain, anorexia, then discolored urine and feces, and intense pruritus. On hospitalization the patient had moderate bilirubinemia (56 mg/1), low alkaline phosphatase (13 U.K.) and slightly high serum glutamate pyruvate transaminase (270 U.W.). There were elevated serum cholesterol (3 gm/1), triglycerides (2.05 gm/1), total lipids (10.6 gm/1), and a definitely increased pre-beta lipoprotein, suggesting hyperlipidemia type IV (Frederickson classification). Liver biopsy showed fibrosis of the portal spaces lymphocytic infiltration, canalicular and intrahepatocytic thrombi. On laparoscopy the liver had a regular lower border, normal volume color and surface. Albumin, prothrombin and flocculation tests were normal. The patient's jaundice lasted about 1 month, then liver function slowly improved, although pruritus remained intense. Probably this jaundice was due to oral contraceptives, in a patient predisposed either by jaundice in childhood or endogenous hyperlipidemia.

Label-free detection of liver cancer cells by aptamer-based microcantilever biosensor.

PubMed

Chen, Xuejuan; Pan, Yangang; Liu, Huiqing; Bai, Xiaojing; Wang, Nan; Zhang, Bailin

2016-05-15

Liver cancer is one of the most common and highly malignant cancers in the world. There are no effective therapeutic options if an early liver cancer diagnosis is not achieved. In this work, detection of HepG2 cells by label-free microcantilever array aptasensor was developed. The sensing microcantilevers were functionalized by HepG2 cells-specific aptamers. Meanwhile, to eliminate the interferences induced by the environment, the reference microcantilevers were modified with 6-mercapto-1-hexanol self-assembled monolayers. The aptasensor exhibits high specificity over not only human liver normal cells, but also other cancer cells of breast, bladder, and cervix tumors. The linear relation ranges from 1×10(3) to 1×10(5)cells/mL, with a detection limit of 300 cells/mL (S/N=3). Our work provides a simple method for detection of liver cancer cells with advantages in terms of simplicity and stability. Copyright © 2015 Elsevier B.V. All rights reserved.

Fractal and Fourier analysis of the hepatic sinusoidal network in normal and cirrhotic rat liver

PubMed Central

Gaudio, Eugenio; Chaberek, Slawomir; Montella, Andrea; Pannarale, Luigi; Morini, Sergio; Novelli, Gilnardo; Borghese, Federica; Conte, Davide; Ostrowski, Kazimierz

2005-01-01

The organization of the hepatic microvascular network has been widely studied in recent years, especially with regard to cirrhosis. This research has enabled us to recognize the distinctive vascular patterns in the cirrhotic liver, compared with the normal liver, which may explain the cause of liver dysfunction and failure. The aim of this study was to compare normal and cirrhotic rat livers by means of a quantitative mathematical approach based on fractal and Fourier analyses performed on photomicrographs and therefore on discriminant analysis. Vascular corrosion casts of livers belonging to the following three experimental groups were studied by scanning electron microscopy: normal rats, CCl4-induced cirrhotic rats and cirrhotic rats after ligation of the bile duct. Photomicrographs were taken at a standard magnification; these images were used for the mathematical analysis. Our experimental design found that use of these different analyses reaches an efficiency of over 94%. Our analyses demonstrated a higher complexity of the normal hepatic sinusoidal network in comparison with the cirrhotic network. In particular, the morphological changes were more marked in the animals with bile duct-ligation cirrhosis compared with animals with CCl4-induced cirrhosis. The present findings based on fractal and Fourier analysis could increase our understanding of the pathophysiological alterations of the liver, and may have a diagnostic value in future clinical research. PMID:16050897

Fructo-oligosaccharides and intestinal barrier function in a methionine-choline-deficient mouse model of nonalcoholic steatohepatitis.

PubMed

Matsumoto, Kotaro; Ichimura, Mayuko; Tsuneyama, Koichi; Moritoki, Yuki; Tsunashima, Hiromichi; Omagari, Katsuhisa; Hara, Masumi; Yasuda, Ichiro; Miyakawa, Hiroshi; Kikuchi, Kentaro

2017-01-01

Impairments in intestinal barrier function, epithelial mucins, and tight junction proteins have been reported to be associated with nonalcoholic steatohepatitis. Prebiotic fructo-oligosaccharides restore balance in the gastrointestinal microbiome. This study was conducted to determine the effects of dietary fructo-oligosaccharides on intestinal barrier function and steatohepatitis in methionine-choline-deficient mice. Three groups of 12-week-old male C57BL/6J mice were studied for 3 weeks; specifically, mice were fed a methionine-choline-deficient diet, a methionine-choline-deficient diet plus 5% fructo-oligosaccharides in water, or a normal control diet. Fecal bacteria, short-chain fatty acids, and immunoglobulin A (IgA) levels were investigated. Histological and immunohistochemical examinations were performed using mice livers for CD14 and Toll-like receptor-4 (TLR4) expression and intestinal tissue samples for IgA and zonula occludens-1 expression in epithelial tight junctions. The methionine-choline-deficient mice administered 5% fructo-oligosaccharides maintained a normal gastrointestinal microbiome, whereas methionine-choline-deficient mice without prebiotic supplementation displayed increases in Clostridium cluster XI and subcluster XIVa populations and a reduction in Lactobacillales spp. counts. Methionine-choline-deficient mice given 5% fructo-oligosaccharides exhibited significantly decreased hepatic steatosis (p = 0.003), decreased liver inflammation (p = 0.005), a decreased proportion of CD14-positive Kupffer cells (p = 0.01), decreased expression of TLR4 (p = 0.04), and increases in fecal short-chain fatty acid and IgA concentrations (p < 0.04) compared with the findings in methionine-choline-deficient mice that were not administered this prebiotic. This study illustrated that in the methionine-choline-deficient mouse model, dietary fructo-oligosaccharides can restore normal gastrointestinal microflora and normal intestinal epithelial barrier function, and decrease steatohepatitis. The findings support the role of prebiotics, such as fructo-oligosaccharides, in maintaining a normal gastrointestinal microbiome; they also support the need for further studies on preventing or treating nonalcoholic steatohepatitis using dietary fructo-oligosaccharides.

Baseline HBV load increases the risk of anti-tuberculous drug-induced hepatitis flares in patients with tuberculosis.

PubMed

Zhu, Chun-Hui; Zhao, Man-Zhi; Chen, Guang; Qi, Jun-Ying; Song, Jian-Xin; Ning, Qin; Xu, Dong

2017-02-01

Hepatitis associated anti-tuberculous treatment (HATT) has been a main obstacle in managing patients co-infected with Mycobacterium tuberculosis and hepatitis B virus (HBV). Therefore, we evaluated the factors related to the severity of adverse effects during HATT, especially those associated with liver failure. A retrospective study was carried out at Tongji Hospital from 2007 to 2012. Increases in serum transaminase levels of >3, 5, and 10 times the upper limit of normal (ULN) were used to define liver damage as mild, moderate, and severe, respectively. Patients with elevated total bilirubin (TBil) levels that were more than 10 times the ULN (>171 μmol/L) with or without decreased (<40%) prothrombin activity (PTA) were diagnosed with liver failure. A cohort of 87 patients was analyzed. The incidence of liver damage and liver failure was 59.8% (n=52) and 25.3% (n=22), respectively. The following variables were correlated with the severity of hepatotoxicity: albumin (ALB) levels, PTA, platelet counts (PLT), and the use of antiretroviral therapies (P<0.05). Hypo-proteinemia and antiretroviral therapy were significantly associated with liver failure, and high viral loads were a significant risk factor with an odds ratio (OR) of 2.066. Judicious follow-up of clinical conditions, liver function tests, and coagulation function, especially in patients with high HBV loads and hypoalbuminemia is recommended. It may be advisable to reconsider the use of antiviral drugs failure during the course of anti-tuberculous treatment of HBV infection patients to avoid the occurrence of furious liver failure.

Transient elastography as a noninvasive assessment tool for hepatopathies of different etiology in pediatric type 1 diabetes mellitus.

PubMed

Elkabbany, Zeinab A; Elbarbary, Nancy S; Ismail, Eman A; Mohamed, Nesrine A; Ragab, Dina; Abdel Alem, Shereen; Ezzat, Yasmine M; Maurice, Sarah S; Hashem, Noha U

2017-01-01

To identify the prevalence and effect of hepatopathies of different etiologies among pediatric patients with type 1 diabetes mellitus (T1DM) using transient elastography (TE) and its relation to glycemic control. One hundred T1DM patients were studied focusing on liver functions, fasting lipid profile, hemoglobin A1c (HbA1c), hepatitis C virus (HCV), serum immunoglobulins, autoimmune antibodies; anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and anti-liver kidney microsomal antibody (anti-LKM). Abdominal ultrasound was performed and TE was done for patients with HCV, positive autoimmune antibody and/or abnormal ultrasound findings. Thirty-one patients were found to have one or more hepatic abnormalities; clinical hepatomegaly in 8%, elevated alanine aminotransferase (ALT) in 10%, HCV in 6%, autoimmune hepatitis (AIH) in 11% (10 were positive for ASMA and 2 were positive for ANA while anti-LKM antibodies were negative) and abnormal hepatic ultrasound in 20% (12 non-alcoholic fatty liver disease, 5 AIH, 2 HCV, 1 Mauriac syndrome). Mean liver stiffness in those 31 patients was 7.0±2.1kPa (range, 3.1-11.8kPa); 24 were Metavir F0-F1, 7 were F2-F3 while none was F4. Type 1 diabetic patients with abnormal hepatic ultrasound had higher fasting blood glucose, HbA1c and total cholesterol than those with normal findings. Liver stiffness was significantly higher in patients with abnormal liver ultrasound compared with normal sonography. Liver stiffness was positively correlated to HbA1c and ALT. Hepatic abnormalities are prevalent in T1DM and related to poor metabolic control. TE provides a non-invasive method for detection of hepatopathy-induced fibrosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel Bioimaging Techniques of Metals by Laser Ablation Inductively Coupled Plasma Mass Spectrometry for Diagnosis Of Fibrotic and Cirrhotic Liver Disorders

PubMed Central

Gassler, Nikolaus; Bosserhoff, Anja K.; Becker, J. Sabine

2013-01-01

Background and Aims Hereditary disorders associated with metal overload or unwanted toxic accumulation of heavy metals can lead to morbidity and mortality. Patients with hereditary hemochromatosis or Wilson disease for example may develop severe hepatic pathology including fibrosis, cirrhosis or hepatocellular carcinoma. While relevant disease genes are identified and genetic testing is applicable, liver biopsy in combination with metal detecting techniques such as energy-dispersive X-ray spectroscopy (EDX) is still applied for accurate diagnosis of metals. Vice versa, several metals are needed in trace amounts for carrying out vital functions and their deficiency due to rapid growth, pregnancy, excessive blood loss, and insufficient nutritional or digestive uptake results in organic and systemic shortcomings. Established in situ techniques, such as EDX-ray spectroscopy, are not sensitive enough to analyze trace metal distribution and the quantification of metal images is difficult. Methods In this study, we developed a quantitative biometal imaging technique of human liver tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) in order to compare the distribution of selected metals in cryo-sections of healthy and fibrotic/cirrhotic livers. Results Most of the metals are homogeneous distributed within the normal tissue, while they are redirected within fibrotic livers resulting in significant metal deposits. Moreover, total iron and copper concentrations in diseased liver were found about 3-5 times higher than in normal liver samples. Conclusions Biometal imaging via LA-ICP-MS is a sensitive innovative diagnostic tool that will impact clinical practice in identification and evaluation of hepatic metal disorders and to detect subtle metal variations during ongoing hepatic fibrogenesis. PMID:23505552

Fuzzy logic algorithm for quantitative tissue characterization of diffuse liver diseases from ultrasound images.

PubMed

Badawi, A M; Derbala, A S; Youssef, A M

1999-08-01

Computerized ultrasound tissue characterization has become an objective means for diagnosis of liver diseases. It is difficult to differentiate diffuse liver diseases, namely cirrhotic and fatty liver by visual inspection from the ultrasound images. The visual criteria for differentiating diffused diseases are rather confusing and highly dependent upon the sonographer's experience. This often causes a bias effects in the diagnostic procedure and limits its objectivity and reproducibility. Computerized tissue characterization to assist quantitatively the sonographer for the accurate differentiation and to minimize the degree of risk is thus justified. Fuzzy logic has emerged as one of the most active area in classification. In this paper, we present an approach that employs Fuzzy reasoning techniques to automatically differentiate diffuse liver diseases using numerical quantitative features measured from the ultrasound images. Fuzzy rules were generated from over 140 cases consisting of normal, fatty, and cirrhotic livers. The input to the fuzzy system is an eight dimensional vector of feature values: the mean gray level (MGL), the percentile 10%, the contrast (CON), the angular second moment (ASM), the entropy (ENT), the correlation (COR), the attenuation (ATTEN) and the speckle separation. The output of the fuzzy system is one of the three categories: cirrhosis, fatty or normal. The steps done for differentiating the pathologies are data acquisition and feature extraction, dividing the input spaces of the measured quantitative data into fuzzy sets. Based on the expert knowledge, the fuzzy rules are generated and applied using the fuzzy inference procedures to determine the pathology. Different membership functions are developed for the input spaces. This approach has resulted in very good sensitivities and specificity for classifying diffused liver pathologies. This classification technique can be used in the diagnostic process, together with the history information, laboratory, clinical and pathological examinations.

Steatorrhea in patients with liver disease

PubMed Central

Williams, C. N.; Sidorov, J. J.

1971-01-01

Intestinal function was studied in 26 patients with seven types of acute and chronic liver disease, documented by liver biopsy. Steatorrhea, defined by a stool fat higher than 6 g. per day, was present in 18 of 23 consecutive patients studied, an incidence of 78.3%. Two patients with infectious hepatitis associated with steatorrhea studied previously were added and the 20 cases were analyzed. The malabsorption found was confined to fat and fat-soluble vitamins; stool excretion varied from 6.1 to 22 g. per day in the seven groups studied. No histological abnormality was seen on jejunal biopsy, serum vitamin B12, D-xylose and Schilling tests were normal, and no radiological findings associated with malabsorption were detected in the small bowel. It is concluded that steatorrhea is a common finding in a wide variety of acute and chronic liver diseases and cannot be attributed to a primary defect of the small bowel. PMID:5150072

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.

Severe chronic hepatitis secondary to prolonged use of ecstasy and cocaine.

PubMed

Payancé, Audrey; Scotto, Béatrice; Perarnau, Jean-Marc; de Muret, Anne; Bacq, Yannick

2013-11-01

Severe acute hepatotoxicity is a well known complication following the ingestion of ecstasy (3,4-methylenedioxymethamphetamine [MDMA] ecstasy). Hepatic dysfunction has also been reported after acute cocaine intoxication. However, chronic hepatitis after prolonged use of ecstasy and/or cocaine has rarely been reported. We report the case of a 27-year-old woman hospitalized with edema, ascites and severe liver failure (prothrombin rate 33%), following the use of ecstasy and cocaine over the previous 9 months. Clinical, biological, radiological and pathology findings were recorded at admission and over 8 years' follow-up. Liver biopsy showed architectural distortion caused by bridging fibrosis, proliferation of cholangioles, and lesions of active interface hepatitis. Other causes of acute and chronic liver disease were excluded. Magnetic resonance imaging showed marked liver fibrosis. After withdrawal of both substances clinical examination and liver function tests progressively normalized. Long-term monitoring with magnetic resonance imaging showed progressive regression of fibrosis. Use of ecstasy and cocaine may cause chronic hepatitis leading to marked liver fibrosis, which may regress after withdrawal of both substances. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Influence of diabetes on liver injury induced by antitubercular drugs and on silymarin hepatoprotection in rats.

PubMed

Srivastava, R K; Sharma, S; Verma, S; Arora, B; Lal, H

2008-12-01

Isoniazid, rifampicin and pyrazinamide during short-course chemotherapy for tuberculosis can result in liver injury. The coexistence of tuberculosis and diabetes is common in patients who receive inadequate treatment. The risk of hepatotoxicity from many toxicants is increased in diabetic rats. Silymarin provides protection against liver injury caused by many hepatotoxicants, including antitubercular drugs (ATDs). In the wake of increased severity of ATD-induced hepatotoxicity in diabetes we report here the results of a study on the influence of diabetes on silymarin hepatoprotection in rats. Rats with diabetes induced via intraperitoneally injected streptozotocin (50 mg/kg), nondiabetic rats and insulin-treated diabetic rats received isoniazid (7.5 mg/kg/day), rifampicin (10 mg/kg/day) and pyrazinamide (35 mg/kg/day) orally (p.o.) with or without silymarin (100 mg/kg/day p.o.) treatment for 45 days. Compared to nondiabetic rats, liver function tests and histological changes of liver revealed exaggerated liver injury in diabetic rats caused by ATDs which was evident by 5- to 8-fold increases in serum levels of marker enzymes (aspartate and alanine aminotransferase, alkaline phosphatase and gamma-glutamyltranspeptidase) and 1- to 2-fold increases in bilirubin accompanied by a 2-fold decrease in total serum proteins, intense fatty and inflammatory infiltrations, necrosis and fibrosis. Coadministration of silymarin provided protection against ATD hepatotoxicity in all animals. However, insulin-treated diabetic animals showed greater silymarin-induced hepatoprotection against ATD-induced liver injury, which was characterized by near normal levels of marker enzymes, an increase in total proteins and normal hepatic structure. These results thus indicate that diabetes exaggerates ATD-induced liver injury and attenuates silymarin-induced hepatoprotection. However, insulin treatment for diabetes offers greater silymarin-induced hepatoprotection against ATD-induced liver injury. Copyright (c) 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

Non-alcoholic Fatty Liver Disease (NAFLD)--A Review.

PubMed

Karim, M F; Al-Mahtab, M; Rahman, S; Debnath, C R

2015-10-01

Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in Hepatology clinics. It is closely related to the increased frequency of overweight or obesity. It has recognised association with metabolic syndrome. Central obesity, diabetes mellitus, dyslipidemia are commonest risk factors. Association with hepatitis C genotype 3 is also recognised. NAFLD is an important cause of cyptogenic cirrhosis of liver. It affects all populations and all age groups. Most patients with NAFLD are asymptomatic or vague upper abdominal pain. Liver function tests are mostly normal or mild elevation of aminotranferases. Histological features almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. Two hit hypothesis is prevailing theory for the development of NAFLD. Diagnosis is usually made by imaging tools like ultrasonogram which reveal a bright liver while liver biopsy is gold standard for diagnosis as well as differentiating simple fatty liver and non-alcoholic steatohepatitis (NASH). Prognosis is variable. Simple hepatic steatosis generally has a benign long-term prognosis. However, one to two third of NASH progress to fibrosis or cirrhosis and may have a similar prognosis as cirrhosis from other liver diseases. Treatment is mostly control of underlying disorders and dietary advice, exercise, insulin sensitizers, antioxidants, or cytoprotective agents. The prevalence of NAFLD is increasing. So it needs more research to address this problem.

Effect of hydroalcoholic extract of ginger on the liver of epileptic female rats treated with lamotrigine

PubMed Central

Poorrostami, Ameneh; Farokhi, Farah; Heidari, Reza

2014-01-01

Objective: Lamotrigine is an antiepileptic drug, widely used in the treatment of epilepsy; long-term use of this drug can cause hepatotoxicity. Zingiber officinale Roscoe (ginger) possesses antioxidant properties. In present research, the effect ofhydroalcoholic extract of ginger (HEG) on the liver of lamotrigine-treated epileptic rats was investigated Material and Methods: Forty-eight female Wistar rats were selected and allocated to 8 groups of 6 each. Group 1: Negative controls were treated with normal saline. Group 2: Positive controls were treated with lamotrigine (LTG) (10 mg/kg) daily by gavages for 4 consecutive weeks. Epilepsy was induced in treatment groups by i.p. injection of pentylenetetrazol (PTZ) (40 mg/kg). Group 3: Epileptic group received normal saline (10 ml/kg). Group 4: Epileptic group was treated with LTG (10 mg/kg). Groups 5 and 6: Epileptic groups received HEG (50 and 100 mg/kg). Groups 7 and 8: Epileptic groups received LTG and HEG (50 and 100 mg/kg). At the end of 28 days, blood samples were drawn and their livers were processed for light microscopy. Results: The mean values of TG, CHOL, AST, and ALT activity significantly rose (p<0.01) in groups 2, 3, and 4, while in rats treated with HEG (groups 5, 6, 7, and 8), the levels of liver enzymes significantly decreased (p<0.05) compared with epileptic group treated with lamotrigine (group 4). Histopathological changes of liver samples were comparable with respective control. Conclusion: These results suggest that hydroalcoholic extract of ginger improves liver function in lamotrigine-induced hepatotoxicity. PMID:25068142

Radiation hepatology of the rat: The effects of the proliferation stimulus induced by subtotal hepatectomy

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

Geraci, J.P.; Mariano, M.S.

1994-11-01

The effect of an 80 to 90% hepatectomy in stimulating proliferation immediately after irradiation of the liver was studied. A dose of 15 Gy was not lethal for animals with intact livers, but all animals with subtotal hepatectomies exposed to this dose died from apparent liver failure 28 to 60 days after exposure. To elucidate the mechanism for this mortality, plasma aspartate aminotransferase, retention of intravenous injected rose bengal, liver weight and liver hydroxyproline content were measured 0 to 90 days after 15 Gy irradiation of the liver to determine temporal changes in necrosis, function, mass and fibrosis, respectively, inmore » animals with either intact livers or livers with subtotal resection. Irradiation of the liver had no significant effect on these parameters in animals with intact livers. In subtotally hepatectomized animals the same radiation dose that suppressed liver mass restoration significantly increased hepatocyte necrosis within 7 days, which was followed by increased liver hydroxyproline concentration and hepatic dysfunction. This radiation-induced temporal change in hepatic dysfunction correlated with increased concentration of hydroxyproline but not with liver mass, indicating that liver fibrosis was the cause of hepatic dysfunction. Since similar sequelae are produced in intact livers after higher doses and longer intervals after irradiation, the proliferation stimulus induced by partial hepatectomy must accelerate the expression of damage and lower the radiation tolerance of the liver. However, in subtotally hepatectomized animals radiation-induced hepatocyte necrosis precedes fibrosis, whereas the reverse is normally true for animals with intact livers. 35 refs., 5 figs.« less

Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia.

PubMed

Cho, Jun-Ho; Kim, Goo-Young; Mansfield, Brian C; Chou, Janice Y

2018-05-08

Glycogen storage disease type Ia (GSD-Ia) deficient in glucose-6-phosphatase-α (G6Pase-α) is a metabolic disorder characterized by impaired glucose homeostasis and a long-term complication of hepatocellular adenoma/carcinoma (HCA/HCC). Mitochondrial dysfunction has been implicated in GSD-Ia but the underlying mechanism and its contribution to HCA/HCC development remain unclear. We have shown that hepatic G6Pase-α deficiency leads to downregulation of sirtuin 1 (SIRT1) signaling that underlies defective hepatic autophagy in GSD-Ia. SIRT1 is a NAD + -dependent deacetylase that can deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial integrity, biogenesis, and function. We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase-α-deficient livers impairs PGC-1α activity, leading to mitochondrial dysfunction. Here we show that the G6Pase-α-deficient livers display defective PGC-1α signaling, reduced numbers of functional mitochondria, and impaired oxidative phosphorylation. Overexpression of hepatic SIRT1 restores PGC-1α activity, normalizes the expression of electron transport chain components, and increases mitochondrial complex IV activity. We have previously shown that restoration of hepatic G6Pase-α expression normalized SIRT1 signaling. We now show that restoration of hepatic G6Pase-α expression also restores PGC-1α activity and mitochondrial function. Finally, we show that HCA/HCC lesions found in G6Pase-α-deficient livers contain marked mitochondrial and oxidative DNA damage. Taken together, our study shows that downregulation of hepatic SIRT1/PGC-1α signaling underlies mitochondrial dysfunction and that oxidative DNA damage incurred by damaged mitochondria may contribute to HCA/HCC development in GSD-Ia.

Cynanchum wilfordii Radix attenuates liver fat accumulation and damage by suppressing hepatic cyclooxygenase-2 and mitogen-activated protein kinase in mice fed with a high-fat and high-fructose diet.

PubMed

Jang, Seon-A; Lee, SungRyul; Sohn, Eun-Hwa; Yang, Jaehyuk; Park, Dae Won; Jeong, Yong Joon; Kim, Inhye; Kwon, Jung Eun; Song, Hae Seong; Cho, Young Mi; Meng, Xue; Koo, Hyun Jung; Kang, Se Chan

2016-09-01

Excessive consumption of fat and fructose augments the pathological progression of nonalcoholic fatty liver disease through hepatic fibrosis, inflammation, and hepatic de novo lipogenesis. We hypothesized that supplementation with Cynanchum wilfordii extract (CWE) decreases fat accumulation in the liver by suppressing cyclooxygenase-2 (COX-2), the nuclear translocation of nuclear factor κB (NF-κB), and p38 mitogen-activated protein kinase (MAPK). The beneficial effect of CWE was evaluated in a murine model of nonalcoholic fatty liver disease. Mice were fed either a normal diet or an atherogenic diet with fructose (ATHFR) in the presence or absence of CWE (50, 100, or 200 mg/kg; n=6/group). Treatment with ATHFR induced a hepatosplenomegaly-like condition (increased liver and spleen weight); this pathological change was attenuated in the presence of CWE. The ATHFR group exhibited impaired liver function, as evidenced by increased blood levels of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, fat accumulation in the liver, and lipid profiles. Supplementation of CWE (100 and 200 mg/kg, P<.05) ameliorated these impaired liver functions. Atherogenic diet with fructose increased the protein levels of COX-2 and p38 MAPK, as well as the nuclear translocation of NF-κB. These signaling pathways, which are associated with the inflammatory response, were markedly suppressed after CWE treatment (100 and 200 mg/kg). In summary, CWE supplementation reduced high-fat and high-fructose diet-induced fat accumulation and damage in the liver by suppressing COX-2, NF-κB, and p38 MAPK. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Safety evaluation of mercury based Ayurvedic formulation (Sidh Makardhwaj) on brain cerebrum, liver & kidney in rats

PubMed Central

Kumar, Gajendra; Srivastava, Amita; Sharma, Surinder Kumar; Gupta, Yogendra Kumar

2014-01-01

Background & objectives: Sidh Makardhwaj (SM) is a mercury based Ayurvedic formulation used in rheumatoid arthritis and neurological disorders. However, toxicity concerns due to mercury content are often raised. Therefore, the present study was carried out to evaluate the effect of SM on brain cerebrum, liver and kidney in rats. Methods: Graded doses of SM (10, 50, 100 mg/kg), mercuric chloride (1 mg/kg) and normal saline were administered orally to male Wistar rats for 28 days. Behavioural parameters were assessed on days 1, 7, 14 and 28 using Morris water maze, passive avoidance, elevated plus maze and rota rod. Liver and kidney function tests were done on day 28. Animals were sacrificed and brain cerebrum acetylcholinesterase activity, levels of malondialdehyde (MDA), reduced glutathione (GSH) in brain cerebrum, liver, kidney were estimated. The levels of mercury in brain cerebrum, liver and kidney were estimated and histopathology of these tissues was also performed. Results: SM in the doses used did not cause significant change in neurobehavioural parameters, brain cerebrum AChE activity, liver (ALT, AST, ALP bilirubin) and kidney (serum urea and creatinine) function tests as compared to control. The levels of mercury in brain cerebrum, liver, and kidney were found to be raised in dose dependent manner. However, the levels of MDA and GSH in these tissues did not show significant changes at doses of 10 and 50 mg/kg. Also, there was no histopathological change in cytoarchitecture of brain cerebrum, liver, and kidney tissues at doses of 10 and 50 mg/kg. Interpretation & conclusions: The findings of the present study suggest that Sidh Makardhwaj upto five times the equivalent human dose administered for 28 days did not show any toxicological effects on rat brain cerebrum, liver and kidney. PMID:24927349

Safety evaluation of mercury based Ayurvedic formulation (Sidh Makardhwaj) on brain cerebrum, liver & kidney in rats.

PubMed

Kumar, Gajendra; Srivastava, Amita; Sharma, Surinder Kumar; Gupta, Yogendra Kumar

2014-04-01

Sidh Makardhwaj (SM) is a mercury based Ayurvedic formulation used in rheumatoid arthritis and neurological disorders. However, toxicity concerns due to mercury content are often raised. Therefore, the present study was carried out to evaluate the effect of SM on brain cerebrum, liver and kidney in rats. Graded doses of SM (10, 50, 100 mg/kg), mercuric chloride (1 mg/kg) and normal saline were administered orally to male Wistar rats for 28 days. Behavioural parameters were assessed on days 1, 7, 14 and 28 using Morris water maze, passive avoidance, elevated plus maze and rota rod. Liver and kidney function tests were done on day 28. Animals were sacrificed and brain cerebrum acetylcholinesterase activity, levels of malondialdehyde (MDA), reduced glutathione (GSH) in brain cerebrum, liver, kidney were estimated. The levels of mercury in brain cerebrum, liver and kidney were estimated and histopathology of these tissues was also performed. SM in the doses used did not cause significant change in neurobehavioural parameters, brain cerebrum AChE activity, liver (ALT, AST, ALP bilirubin) and kidney (serum urea and creatinine) function tests as compared to control. The levels of mercury in brain cerebrum, liver, and kidney were found to be raised in dose dependent manner. However, the levels of MDA and GSH in these tissues did not show significant changes at doses of 10 and 50 mg/kg. Also, there was no histopathological change in cytoarchitecture of brain cerebrum, liver, and kidney tissues at doses of 10 and 50 mg/kg. The findings of the present study suggest that Sidh Makardhwaj upto five times the equivalent human dose administered for 28 days did not show any toxicological effects on rat brain cerebrum, liver and kidney.

Magnetic Targeting of Stem Cell Derivatives Enhances Hepatic Engraftment into Structurally Normal Liver

PubMed Central

Fagg, W. Samuel; Liu, Naiyou; Yang, Ming-Jim; Cheng, Ke; Chung, Eric; Kim, Jae-Sung; Wu, Gordon

2018-01-01

Attaining consistent robust engraftment in the structurally normal liver is an obstacle for cellular transplantation. Most experimental approaches to increase transplanted cells’ engraftment involve recipient-centered deleterious methods such as partial hepatectomy or irradiation which may be unsuitable in the clinic. Here, we present a cell-based strategy that increases engraftment into the structurally normal liver using a combination of magnetic targeting and proliferative endoderm progenitor (EPs) cells. Magnetic labeling has little effect on cell viability and differentiation, but in the presence of magnetic targeting, it increases the initial dwell time of transplanted EPs into the undamaged liver parenchyma. Consequently, greater cell retention in the liver is observed concomitantly with fewer transplanted cells in the lungs. These highly proliferative cells then significantly increase their biomass over time in the liver parenchyma, approaching nearly 4% of total liver cells 30 d after transplant. Therefore, the cell-based mechanisms of increased initial dwell time through magnetic targeting combined with high rate of proliferation in situ yield significant engraftment in the undamaged liver. PMID:29390880

Urinary metabolomics analysis identifies key biomarkers of different stages of nonalcoholic fatty liver disease

PubMed Central

Dong, Shu; Zhan, Zong-Ying; Cao, Hong-Yan; Wu, Chao; Bian, Yan-Qin; Li, Jian-Yuan; Cheng, Gen-Hong; Liu, Ping; Sun, Ming-Yu

2017-01-01

AIM To identify a panel of biomarkers that can distinguish between non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and explore molecular mechanism involved in the process of developing NASH from NAFLD. METHODS Biomarkers may differ during stages of NAFLD. Urine and blood were obtained from non-diabetic subjects with NAFLD and steatosis, with normal liver function (n = 33), from patients with NASH, with abnormal liver function (n = 45), and from healthy age and sex-matched controls (n = 30). Samples were subjected to metabolomic analysis to identify potential non-invasive biomarkers. Differences in urinary metabolic profiles were analyzed using liquid chromatography tandem mass spectrometry with principal component analysis and partial least squares-discriminate analysis. RESULTS Compared with NAFLD patients, patients with NASH had abnormal liver function and high serum lipid concentrations. Urinary metabonomics found differences in 31 metabolites between these two groups, including differences in nucleic acids and amino acids. Pathway analysis based on overlapping metabolites showed that pathways of energy and amino acid metabolism, as well as the pentose phosphate pathway, were closely associated with pathological processes in NAFLD and NASH. CONCLUSION These findings suggested that a panel of biomarkers could distinguish between NAFLD and NASH, and could help to determine the molecular mechanism involved in the process of developing NASH from NAFLD. Urinary biomarkers may be diagnostic in these patients and could be used to assess responses to therapeutic interventions. PMID:28487615

Elevated Liver Enzymes

MedlinePlus

Symptoms Elevated liver enzymes By Mayo Clinic Staff Elevated liver enzymes may indicate inflammation or damage to cells in the liver. Inflamed or ... than normal amounts of certain chemicals, including liver enzymes, into the bloodstream, which can result in elevated ...

Functional proteomics of nonalcoholic steatohepatitis: Mitochondrial proteins as targets of S-adenosylmethionine

PubMed Central

Santamaría, Enrique; Avila, Matías A.; Latasa, M. Ujue; Rubio, Angel; Martín-Duce, Antonio; Lu, Shelly C.; Mato, José M.; Corrales, Fernando J.

2003-01-01

Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A−/−) to study the proteome of the liver during the development of steatohepatitis. One hundred and seventeen protein spots, differentially expressed during the development of steatohepatitis, were selected and identified by peptide mass fingerprinting. Among them, 12 proteins were found to be affected from birth, when MAT1A−/− expression is switched on in WT mouse liver, to the rise of histological lesions, which occurs at ≈8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase β-subunit] have known roles in mitochondrial function. We show that the alteration in expression of PHB1 correlates with a loss of mitochondrial function. Experiments in isolated rat hepatocytes indicate that AdoMet regulates PHB1 content, thus suggesting ways by which steatohepatitis may be induced. Importantly, we found the expression of these mitochondrial proteins was abnormal in ob/ob mice and obese patients who are at risk for nonalcoholic steatohepatitis. PMID:12631701

Modeled Perfluorooctanoic Acid (PFOA) Exposure and Liver Function in a Mid-Ohio Valley Community.

PubMed

Darrow, Lyndsey A; Groth, Alyx C; Winquist, Andrea; Shin, Hyeong-Moo; Bartell, Scott M; Steenland, Kyle

2016-08-01

Perfluorooctanoic acid (PFOA or C8) has hepatotoxic effects in animals. Cross-sectional epidemiologic studies suggest PFOA is associated with liver injury biomarkers. We estimated associations between modeled historical PFOA exposures and liver injury biomarkers and medically validated liver disease. Participants completed surveys during 2008-2011 reporting demographic, medical, and residential history information. Self-reported liver disease, including hepatitis, fatty liver, enlarged liver and cirrhosis, was validated with healthcare providers. Alanine aminotransferase (ALT), γ-glutamyltransferase (GGT) and direct bilirubin, markers of liver toxicity, were obtained from blood samples collected in the C8 Health Project (2005-2006). Historically modeled PFOA exposure, estimated using environmental fate and transport models and participant residential histories, was analyzed in relation to liver biomarkers (n = 30,723, including 1,892 workers) and liver disease (n = 32,254, including 3,713 workers). Modeled cumulative serum PFOA was positively associated with ALT levels (p for trend < 0.0001), indicating possible liver toxicity. An increase from the first to the fifth quintile of cumulative PFOA exposure was associated with a 6% increase in ALT levels (95% CI: 4, 8%) and a 16% increased odds of having above-normal ALT (95% CI: odds ratio: 1.02, 1.33%). There was no indication of association with either elevated direct bilirubin or GGT; however, PFOA was associated with decreased direct bilirubin. We observed no evidence of an effect of cumulative exposure (with or without a 10-year lag) on all liver disease (n = 647 cases), nor on enlarged liver, fatty liver, and cirrhosis only (n = 427 cases). Results are consistent with previous cross-sectional studies showing association between PFOA and ALT, a marker of hepatocellular damage. We did not observe evidence that PFOA increases the risk of clinically diagnosed liver disease. Darrow LA, Groth AC, Winquist A, Shin HM, Bartell SM, Steenland K. 2016. Modeled perfluorooctanoic acid (PFOA) exposure and liver function in a Mid-Ohio Valley community. Environ Health Perspect 124:1227-1233; http://dx.doi.org/10.1289/ehp.1510391.

[Effect of American Ginseng Capsule on the liver oxidative injury and the Nrf2 protein expression in rats exposed by electromagnetic radiation of frequency of cell phone].

PubMed

Luo, Ya-ping; Ma, Hui-Rong; Chen, Jing-Wei; Li, Jing-Jing; Li, Chun-xiang

2014-05-01

To observe the effect of American Ginseng Capsule (AGC) on the liver oxidative injury and the Nrf2 protein expression in the liver tissue of rats exposed by 900 MHz cell phone electromagnetic radiation. Totally 40 male SD rats were randomly divided into the normal control group, the model group, the Shuifei Jibin Capsule (SJC) group, and the AGC group,10 in each group. Rats in the normal control group were not irradiated. Rats in the rest three groups were exposed by imitated 900 MHz cellular phone for 4 h in 12 consecutive days. Meanwhile, rats in the SJC group and the AGC group were intragastrically administrated with suspension of SJC and AGC (1 mL/200 g body weight) respectively. Normal saline was administered to rats in the normal control group and the model group. The histolomorphological changes of the liver tissue were observed by HE staining. Contents of malonic dialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX)were detected by colorimetry. The Nrf2 protein expression of hepatocytes was detected by immunohistochemical assay and Western blot. Compared with the normal control group, hepatocyte nucleus was atrophied or partially disappeared, the contents of liver MDA and Nrf2 protein obviously increased (P <0. 05, P <0. 01); contents of liver SOD and GSH decreased (P <0. 05) in the model group. Compared with the model group, karyopyknosis was obviously attenuated and approached to the normal level in the SJC group and the AGC group. The contents of liver MDA and Nrf2 protein expression decreased (P <0. 05), and the contents of liver SOD, GSH, and GSH-PX obviously increased (P < 0.05) in the SJC group. The contents of liver MDA and the Nrf2 protein expression decreased (P < 0.05), and contents of SOD and GSH obviously increased in the AGC group (P <0.01, P <0.05). The electromagnetic radiation induced by 900 MHz cell phone could affect the expression of Nrf2 protein, induce oxidative injury, and induce abnormal morphology of liver cells. SJC and AGC could promote the morphological recovery of the liver cells. Its mechanism might be related to affecting the expression of Nrf2 protein and attenuating oxidative damage of liver cells.

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.

Glycogen content in hepatocytes is related with their size in normal rat liver but not in cirrhotic one.

PubMed

Bezborodkina, Natalia N; Chestnova, Anna Yu; Vorobev, Mikhail L; Kudryavtsev, Boris N

2016-04-01

Hepatocytes differ from one another by the degree of the ploidy, size, position in the liver lobule, and level of the DNA-synthetic processes. It is believed, that the cell size exerts substantial influence on the metabolism of the hepatocytes and the glycogen content in them. The aim of the present study was to test this hypothesis. Dry weight of hepatocytes, their ploidy and glycogen content were determined in the normal and the cirrhotic rat liver. Liver cirrhosis in rats was produced by chronic inhalation of CCl4 vapours in the course of 6 months. A combined cytophotometric method was used. Dry weight of the cell, its glycogen and DNA content were successively measured on a mapped preparation. Hepatocytes of each ploidy class in the normal and the cirrhotic rat liver accumulated glycogen at the same rate. In the normal liver, there was a distinct correlation between the size of hepatocytes and glycogen content in them. This correlation was observed in each ploidy class, and was especially pronounced in the class of mononucleate tetraploid hepatocytes. In the cirrhotic liver, there was no correlation between the size of the cells and their glycogen content. The impairment of liver lobular structure probably explains the observed lack of correlation between hepatocyte size and their glycogen content in the cirrhotic liver. © 2016 International Society for Advancement of Cytometry. © 2016 International Society for Advancement of Cytometry.

Use of marginal grafts in deceased donor liver transplant: assessment of early outcomes.

PubMed

Godara, Rajesh; Naidu, C Sudeep; Rao, Pankaj P; Sharma, Sanjay; Banerjee, Jayant K; Saha, Anupam; Vijay, Kapileshwer

2014-03-01

Orthotopic liver transplantation has become a routinely applied therapy for an expanding group of patients with end-stage liver disease. Shortage of organs has led centers to expand their criteria for the acceptance of marginal donors. There is current debate about the regulation and results of liver transplantation using marginal grafts. The study included data of all patients who received deceased donor liver grafts between March 2007 to December 2011. Patients with acute liver failure, living donor transplantation, split liver transplantation, and retransplantation were excluded. Early allograft dysfunction, primary nonfunction, patient survival, and incidence of surgical complications were measured. A total of 33 patients were enrolled in this study. There were 20 marginal and 13 nonmarginal grafts. The two groups were well matched regarding age, sex and indication of liver transplantation, model for end-stage liver disease score, technique of transplant, requirement of vascular reconstruction, warm ischemia time, blood loss, mean operative time, etc. In our study, posttransplant peak level of liver enzymes, international normalization ratio, and bilirubin were not statistically significant in the marginal and nonmarginal group. Wound infection occurred in 10 % of marginal compared with 7.7 % of nonmarginal graft recipients (p > 0.05). In the marginal group, the incidences of vascular complications, hepatic artery thrombosis (four), and portal vein thrombosis (one) were not statistically significant compared to the nonmarginal group. Acute rejection was observed in a total of seven patients (21.2 %)-five (25 %) in the marginal group and two (15.4 %) in the nonmarginal graft recipients. Primary nonfunction occurred in three (9.1 %) patients-two (10 %) in the marginal and one (7.7 %) in the nonmarginal group. Average patient survival for the whole group was 91 % at 1 week, 87.8 % at 3 months, and 84.8 % at 6 months. Because organ scarcity persists, additional pressure will build to use a greater proportion of the existing donor pool. The study, although small, clearly indicates that marginal livers can assure a normal early functional recovery after transplantation.

Plasma disappearance of exogenous erythropoietin in mice under different experimental conditions.

PubMed

Lezón, C E; Martínez, M P; Conti, M I; Bozzini, C E

1998-06-01

Erythropoietin (EPO) is a glycoprotein hormone produced primarily in the kidneys and to a lesser extent in the liver that regulates red cell production. Most of the studies conducted in experimental animals to assess the role of EPO in the regulation of erythropoiesis were performed in mouse models. However, little is known about the in vivo metabolism of the hormone in this species. The present study was thus undertaken to measure the plasma tl/2 of radiolabeled recombinant human EPO (rh-EPO) in normal mice as well as in mice with altered erythrocyte production rates (EPR), plasma EPO (pEPO) titer, marrow responsiveness, red cell volume, or liver function. Adult CF-1 mice of both sexes were used throughout. For the EPO life-span studies, 30 mice in each experiment were intravenously injected with 600,000 cpm of 125l-rh-EPO and bled by cardiac puncture in groups of five every hour for 6 h. Trichloroacetic acid (TCA) was added to each plasma sample and the radioactivity in the precipitate measured in a gamma-counter. EPO, pEPO, marrow responsiveness, or red cell volume were altered by either injections of rh-EPO, 5-fluorouracil, or phenylhydrazine, or by bleeding, or red cell transfusion. Liver function was altered by CI4C administration. In the normal groups of mice, the estimated tl/2 was 182.75+/-14.4 (SEM) min. The estimated tl/2 of the other experimental groups was not significantly different from normal. These results, therefore, strongly suggest that the clearance rate of EPO in mice is not subjected to physiologic regulation and that pEPO titer can be really taken as the reflection of the EPO production rate, at least in the experimental conditions reported here.

An effective assessment of valproate sodium-induced hepatotoxicity with UPLC-MS and (1)HNMR-based metabonomics approach.

PubMed

Huo, Taoguang; Chen, Xi; Lu, Xiumei; Qu, Lianyue; Liu, Yang; Cai, Shuang

2014-10-15

Valproate sodium is one of the most prescribed antiepileptic drugs. However, valproate sodium has various side effects, especially its toxicity on liver. Current markers for toxicity reflect mostly the late stages of tissue damage; thus, more efficient methods for toxicity evaluation are desired. To evaluate the toxicity of valproate sodium on liver, we performed both UPLC-MS and (1)HNMR-based metabonomics analysis of serum samples from 34 epileptic patients (age: 42.0±18.6, 18 male/16 female) after valproate sodium treatment. Compared to conventional markers, the serum metabolic profiles provided clear distinction of the valproate sodium induced normal liver function and abnormal liver function in epileptic patients. Through multivariate statistical analysis, we identified marker metabolites associated with the hepatotoxicity induced by valproate sodium, such as glucose, lactate, acetoacetate, VLDL/LDL, lysophosphatidylcholines, phosphatidylcholines, choline, creatine, amino acids, N-acetyl glycoprotein, pyruvate and uric acid. This metabonomics approach may provide effective way to evaluate the valproate sodium-induced toxicity in a manner that can complement current measures. This approach is expected to find broader application in other drug-induced toxicity assessment. Copyright © 2014 Elsevier B.V. All rights reserved.

Hypervitaminosis A inducing intra-hepatic cholestasis--a rare case report.

PubMed

Ramanathan, Vivek S; Hensley, Gary; French, Samuel; Eysselein, Victor; Chung, David; Reicher, Sonya; Pham, Binh

2010-04-01

The use of over-the-counter supplements is commonplace in today's health conscious society. We present an unusual case of intrahepatic cholestasis caused by vitamin A intoxication. The patient consumed one Herbalife shake with two multivitamin tablets of the same brand for 12 years. When calculated this equated to more than the recommended daily allowance for vitamin A consumption. Deranged liver function tests were consistent with a cholestatic process. Liver biopsy was obtained and revealed features pathognomonic of vitamin A toxicity, without the usual fibrosis. When the supplements were ceased, his jaundice and alkaline phosphatase completely normalized. This case highlights the importance of health care providers documenting non-prescribed dietary supplements and considering them in the etiology of cholestatic liver disease. Copyright 2009 Elsevier Inc. All rights reserved.

[Role of FibroScan in liver fibrosis evaluation in patients with chronic hepatitis B virus infection and related influencing factors].

PubMed

Xie, Q X; Xu, N; Jiang, X P; Zhang, Y F; Zhang, Z H; Li, J B; Hu, X Y; Li, X

2016-09-20

Objective: To investigate the role of FibroScan(FS)in liver fibrosis evaluation in patients with chronic hepatitis B virus(HBV)infection and related influencing factors. Methods: A total of 313 patients with chronic HBV infection were enrolled, and liver tissue was obtained through ultrasound-guided"1-second fast tissue cutting". The liver stiffness measurement(LSM)was determined by FS, serum HBeAg and liver function were measured, and the patients' demographic data were recorded. The t -test was used for comparison of normally distributed data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed data between groups; the Spearman or Pearson correlation coefficient was used for correlation analysis; the ROC curve and AUC were used to evaluate the efficiency of FS in the diagnosis of liver fibrosis ≥S2. Results: LSM was positively correlated with liver inflammation grade and fibrosis stage( r = 0.428 and 0.402 in HBeAg-positive group and r = 0.296 and 0.283 in HBeAg-negative group, all P < 0.001). The correlation of LSM with sex, age, alanine aminotransferase(ALT)level, and total bilirubin(TBil)was affected by HBeAg status and ALT level, and LSM was only positively correlated with TBil in HBeAg-negative group( r = 0.298, P < 0.001). In patients with ALT ≥2×upper limit of normal(ULN), FS had a low efficiency in the diagnosis of liver fibrosis ≥S2(AUC < 0.75, P > 0.05), regardless of their HBeAg status. The cut-off values of FS in the diagnosis of liver fibrosis ≥S2 varied with ALT level and HBeAg status, and in the ALT <1×ULN and 1-2×ULN groups, the cut-off values of FS in the diagnosis of liver fibrosis ≥S2 in patients with positive and negative HBeAg were 5.85 kPa/7.3 kPa and 6.35 kPa/8.5 kPa, respectively. In the patients with positive HBeAg in ALT < 2×ULN group, LSM was positively correlated with age( r = 0.278, P = 0.014). FS had relatively high diagnostic efficiency in patients aged > 30 years(AUC = 0.867, P < 0.001)and low diagnostic efficiency in patients aged≤30 years(AUC = 0.632, P > 0.05). Conclusion: LSM is positively correlated with liver inflammation grade and fibrosis stage. The cut-off value of FS in the diagnosis of marked liver fibrosis is affected by age, ALT level, and HBeAg status. FS has low diagnostic efficiency in patients aged ≤30 years.

Nutrition and Liver Health.

PubMed

Jackson, Alan A

2017-01-01

Good clinical practice is based on a secure and accurate diagnosis. Poor nutrition is frequently associated with disorders of the liver, and a specific nutrition diagnosis is needed for providing best care and experiencing successful outcome. There is opportunity for better-structured approaches to making secure and consistent nutritional diagnoses in patients with liver disease. Nutrition is the set of integrated processes by which cells, tissues, organs and the whole body acquire the energy and nutrients to retain normal structure and perform the required functions. At the level of the whole body, this is achieved through dietary supply and the capacity of the body to transform the substrates and cofactors necessary for metabolism. All of these domains (diet, metabolic capacity, activity of the microbiome, body composition and the level of demand for energy and nutrients) are influenced by levels of physical activity and can vary according to physiological and pathological disease states. The liver plays a central role in establishing and maintaining these regulated processes. Its capacity to achieve and maintain these functional capabilities is established during one's early life. When these capabilities are exceeded and the ability to maintain the milieu interieur is compromised, ill-health supervenes. Stress tests that assess flow through gateway pathways can be used to determine the maximal capacity and functional reserve for critical functions. The inability of the liver to reliably integrate body lipid metabolism and the accumulation of abnormal lipid are obvious manifestations of impaired regulation both in situations of weight loss, for example, the fatty liver of severe malnutrition, and in situations of energy excess, as in non-alcoholic fatty liver disease. The use of stable isotopic probes and the more recent definition of the variability in the metabolome in different nutritional and pathological states indicate the great potential for clinical tools that would enable a more precise nutritional diagnosis, but these require systematic investigation and application. For the present, approaches that place emphasis on being able to control the metabolic state without exposing the liver to unnecessary metabolic stress remain the basis for successful nutritional support. © 2017 S. Karger AG, Basel.

Activation of RAS/ERK alone is insufficient to inhibit RXRα function and deplete retinoic acid in hepatocytes

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

Wang, Ai-Guo, E-mail: wangaiguotl@hotmail.com; Song, Ya-Nan; Chen, Jun

2014-09-26

Highlights: • The activation of RAS/ERK is insufficient to inhibit RXRα function and deplete RA. • The retinoid metabolism-related genes are down-regulated by ras oncogene. • The atRA has no effect on preventing hepatic tumorigenesis or curing the developed hepatic nodules. - Abstract: Activation of RAS/ERK signaling pathway, depletion of retinoid, and phosphorylation of retinoid X receptor alpha (RXRα) are frequent events found in liver tumors and thought to play important roles in hepatic tumorigenesis. However, the relationships among them still remained to be elucidated. By exploring the transgenic mouse model of hepatic tumorigenesis induced by liver-specific expression of H-ras12Vmore » oncogene, the activation of RAS/ERK, the mRNA expression levels of retinoid metabolism-related genes, the contents of retinoid metabolites, and phosphorylation of RXRα were determined. RAS/ERK signaling pathway was gradually and significantly activated in hepatic tumor adjacent normal liver tissues (P) and hepatic tumor tissues (T) of H-ras12V transgenic mice compared with normal liver tissues (Wt) of wild type mice. On the contrary, the mRNA expression levels of retinoid metabolism-related genes were significantly reduced in P and T compared with Wt. Interestingly, the retinoid metabolites 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (atRA), the well known ligands for nuclear transcription factor RXR and retinoic acid receptor (RAR), were significantly decreased only in T compared with Wt and P, although the oxidized polar metabolite of atRA, 4-keto-all-trans-retinoic-acid (4-keto-RA) was significantly decreased in both P and T compared with Wt. To our surprise, the functions of RXRα were significantly blocked only in T compared with Wt and P. Namely, the total protein levels of RXRα were significantly reduced and the phosphorylation levels of RXRα were significantly increased only in T compared with Wt and P. Treatment of H-ras12V transgenic mice at 5-week-old or 5-month-old with atRA had no effect on the prevention of tumorigenesis or cure of developed nodules in liver. These events imply that the depletion of 9cRA and atRA and the inhibition of RXRα function in hepatic tumors involve more complex mechanisms besides the activation of RAS/ERK pathway.« less

Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling.

PubMed

Scharin Täng, M; Redfors, B; Lindbom, M; Svensson, J; Ramunddal, T; Ohlsson, C; Shao, Y; Omerovic, E

2012-12-01

IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF-1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4 weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI. Copyright © 2012 Elsevier Ltd. All rights reserved.

The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease.

PubMed

King, Adrienne L; Mantena, Sudheer K; Andringa, Kelly K; Millender-Swain, Telisha; Dunham-Snary, Kimberly J; Oliva, Claudia R; Griguer, Corinne E; Bailey, Shannon M

2016-10-01

Mitochondrial dysfunction and bioenergetic stress play an important role in the etiology of alcoholic liver disease. Previous studies from our laboratory show that the primary methyl donor S-Adenosylmethionine (SAM) minimizes alcohol-induced disruptions in several mitochondrial functions in the liver. Herein, we expand on these earlier observations to determine whether the beneficial actions of SAM against alcohol toxicity extend to changes in the responsiveness of mitochondrial respiration to inhibition by nitric oxide (NO), induction of the mitochondrial permeability transition (MPT) pore, and the hypoxic state of the liver. For this, male Sprague-Dawley rats were pair-fed control and alcohol-containing liquid diets with and without SAM for 5 weeks and liver hypoxia, mitochondrial respiration, MPT pore induction, and NO-dependent control of respiration were examined. Chronic alcohol feeding significantly enhanced liver hypoxia, whereas SAM supplementation attenuated hypoxia in livers of alcohol-fed rats. SAM supplementation prevented alcohol-mediated decreases in mitochondrial state 3 respiration and cytochrome c oxidase activity. Mitochondria isolated from livers of alcohol-fed rats were more sensitive to calcium-mediated MPT pore induction (i.e., mitochondrial swelling) than mitochondria from pair-fed controls, whereas SAM treatment normalized sensitivity for calcium-induced swelling in mitochondria from alcohol-fed rats. Liver mitochondria from alcohol-fed rats showed increased sensitivity to NO-dependent inhibition of respiration compared with pair-fed controls. In contrast, mitochondria isolated from the livers of SAM treated alcohol-fed rats showed no change in the sensitivity to NO-mediated inhibition of respiration. Collectively, these findings indicate that the hepato-protective effects of SAM against alcohol toxicity are mediated, in part, through a mitochondrial mechanism involving preservation of key mitochondrial bioenergetic parameters and the attenuation of hypoxic stress. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Imaging follow-up after liver transplantation

PubMed Central

Rossi, Massimo; Mennini, Gianluca; Melandro, Fabio; Anzidei, Michele; De Vizio, Silvia; Koryukova, Kameliya; Catalano, Carlo

2016-01-01

Liver transplantation (LT) represents the best treatment for end-stage chronic liver disease, acute liver failure and early stages of hepatocellular carcinoma. Radiologists should be aware of surgical techniques to distinguish a normal appearance from pathological findings. Imaging modalities, such as ultrasound, CT and MR, provide for rapid and reliable detection of vascular and biliary complications after LT. The role of imaging in the evaluation of rejection and primary graft dysfunction is less defined. This article illustrates the main surgical anastomoses during LT, the normal appearance and complications of the liver parenchyma and vascular and biliary structures. PMID:27188846

THE CHEMISTRY OF THE LIVER IN ACUTE YELLOW ATROPHY

PubMed Central

Wells, H. Gideon

1907-01-01

From the liver of a young man who died of typical, " idiopathic" acute yellow atrophy of the liver, after an illness of six weeks, there were isolated and identified the following amino acids: Histidin, lysin, tyrosin, leucin, glycocoll, alanin, prolin, glutaminic acid, aspartic acid. These were found free in extracts of the liver, and presumably represent products of the autolysis of liver cells, although the amount of soluble non-protein nitrogen present in the extracts was so large as to suggest that there must be some other source for these substances. Small quantities of free proteoses and peptones, and of xanthin and hypoxanthin, were also found in the extracts. In the insoluble proteins of the liver the proportion of diamino acids was decreased slightly as compared with normal livers. The proportion of protein phosphorus was increased, probably because of active regenerative proliferation, while the sulphur was normal in amount. Iron was increased because of the large quantity of blood in the liver and the hematogenous pigmentation of the liver cells. Gelatigenous material was increased both absolutely and relatively, because of the loss of parenchyma and the proliferation of the stroma. The proportion of water to solids was much increased, there having been a loss of over two-thirds of the entire parenchymatous elements of the liver. The amount of fat, lecithin and cholesterin was not far from that normal for the liver. PMID:19867115

PERCUTANEOUS RADIOFREQUENCY ASSISTED LIVER PARTITION WITH PORTAL VEIN EMBOLIZATION FOR STAGED HEPATECTOMY (PRALPPS).

PubMed

Giménez, Mariano E; Houghton, Eduardo J; Davrieux, C Federico; Serra, Edgardo; Pessaux, Patrick; Palermo, Mariano; Acquafresca, Pablo A; Finger, Caetano; Dallemagne, Bernard; Marescaux, Jacques

2018-03-01

When a major hepatic resection is necessary, sometimes the future liver remnant is not enough to maintain sufficient liver function and patients are more likely to develop liver failure after surgery. To test the hypothesis that performing a percutaneous radiofrecuency liver partition plus percutaneous portal vein embolization (PRALPPS) for stage hepatectomy in pigs is feasible. Four pigs (Sus scrofa domesticus) both sexes with weights between 25 to 35 kg underwent percutaneous portal vein embolization with coils of the left portal vein. By contrasted CT, the difference between the liver parenchyma corresponding to the embolized zone and the normal one was identified. Immediately, using the fusion of images between ultrasound and CT as a guide, radiofrequency needles were placed percutaneouslyand then ablated until the liver partition was complete. Finally, hepatectomy was completed with a laparoscopic approach. All animals have survived the procedures, with no reported complications. The successful portal embolization process was confirmed both by portography and CT. In the macroscopic analysis of the pieces, the depth of the ablation was analyzed. The hepatic hilum was respected. On the other hand, the correct position of the embolization material on the left portal vein could be also observed. "Percutaneous radiofrequency assisted liver partition with portal vein embolization" (PRALLPS) is a feasible procedure.

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.

The influence of aminotransferase levels on liver stiffness assessed by Acoustic Radiation Force Impulse Elastography: a retrospective multicentre study.

PubMed

Bota, Simona; Sporea, Ioan; Peck-Radosavljevic, Markus; Sirli, Roxana; Tanaka, Hironori; Iijima, Hiroko; Saito, Hidetsugu; Ebinuma, Hirotoshi; Lupsor, Monica; Badea, Radu; Fierbinteanu-Braticevici, Carmen; Petrisor, Ana; Friedrich-Rust, Mireen; Sarrazin, Christoph; Takahashi, Hirokazu; Ono, Naofumi; Piscaglia, Fabio; Marinelli, Sara; D'Onofrio, Mirko; Gallotti, Anna; Salzl, Petra; Popescu, Alina; Danila, Mirela

2013-09-01

Acoustic Radiation Force Impulse Elastography is a new method for non-invasive evaluation of liver fibrosis. To evaluate the impact of elevated alanine aminotransferase levels on liver stiffness assessment by Acoustic Radiation Force Impulse Elastography. A multicentre retrospective study including 1242 patients with chronic liver disease, who underwent liver biopsy and Acoustic Radiation Force Impulse. Transient Elastography was also performed in 512 patients. The best Acoustic Radiation Force Impulse cut-off for predicting significant fibrosis was 1.29 m/s in cases with normal alanine aminotransferase levels and 1.44 m/s in patients with alanine aminotransferase levels>5 × the upper limit of normal. The best cut-off for predicting liver cirrhosis were 1.59 and 1.75 m/s, respectively. Acoustic Radiation Force Impulse cut-off for predicting significant fibrosis and cirrhosis were relatively similar in patients with normal alanine aminotransferase and in those with alanine aminotransferase levels between 1.1 and 5 × the upper limit of normal: 1.29 m/s vs. 1.36 m/s and 1.59 m/s vs. 1.57 m/s, respectively. For predicting cirrhosis, the Transient Elastography cut-offs were significantly higher in patients with alanine aminotransferase levels between 1.1 and 5 × the upper limit of normal compared to those with normal alanine aminotransferase: 12.3 kPa vs. 9.1 kPa. Liver stiffness values assessed by Acoustic Radiation Force Impulse and Transient Elastography are influenced by high aminotransferase levels. Transient Elastography was also influenced by moderately elevated aminotransferase levels. Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Modifying three-dimensional scaffolds from novel nanocomposite materials using dissolvable porogen particles for use in liver tissue engineering

PubMed Central

Fuller, Barry; Seldon, Clare; Davidson, Brian; Seifalian, Alexander

2013-01-01

Background: Although hepatocytes have a remarkable regenerative power, the rapidity of acute liver failure makes liver transplantation the only definitive treatment. Attempts to incorporate engineered three-dimensional liver tissue in bioartificial liver devices or in implantable tissue constructs, to treat or bridge patients to self-recovery, were met with many challenges, amongst which is to find suitable polymeric matrices. We studied the feasibility of utilising nanocomposite polymers in three-dimensional scaffolds for hepatocytes. Materials and methods: Hepatocytes (HepG2) were seeded on a flat sheet and in three-dimensional scaffolds made of a nanocomposite polymer (Polyhedral Oligomeric Silsesquioxane [POSS]-modified polycaprolactone urea urethane) alone as well as with porogen particles, i.e. glucose, sodium bicarbonate and sodium chloride. The scaffold architecture, cell attachment and morphology were studied with scanning electron microscopy, and we assessed cell viability and functionality. Results: Cell attachment to the scaffolds was demonstrated. The scaffold made with glucose particles as porogen showed a narrower range of pore size with higher porosity and better inter-pore communications and seemed to encourage near normal cell morphology. There was a steady increase of albumin secretion throughout the experiment while the control (monolayer cell culture) showed a steep decrease after day 7. At the end of the experiment, there was no significant difference in viability and functionality between the scaffolds and the control. Conclusion: In this initial study, porogen particles were used to modify the scaffolds produced from the novel polymer. Although there was no significance against the control in functionality and viability, the demonstrable attachment on scanning electron microscopy suggest potential roles for this polymer and in particular for scaffolds made with glucose particles in liver tissue engineering. PMID:22532408

Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function.

PubMed

Park, Jin Su; Park, Min-Chan; Park, Yong-Beom; Lee, Soo-Kon; Lee, Sang-Won

2014-01-01

We evaluated the effects of concurrent use of methotrexate and celecoxib on silent liver and kidney damages in rheumatoid arthritis (RA) patients. We enrolled 92 RA patients with normal laboratory results related to liver and kidney functions, who had received methotrexate and celecoxib concurrently over 6 months. Liver stiffness measurement (LSM) using transient elastography and ultrasonography were performed along with blood and urine tests. Estimated glomerular filtration rate (eGFR) was calculated by both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) equations. Initial eGFR represented kidney function at the time of the initiation of celecoxib. The cutoff for abnormal LSM values was adopted as 5.3 kPa. The optimal cutoff of each eGFR for abnormal LSM values was also calculated. The median age of patients was 55 years old (74 women). The median LSM was 4.4 kPa and the median eGFRs and median initial eGFRs ranged from 89 to 99 mL/min/1.73 m(2). The cumulative doses of methotrexate and celecoxib and their concurrent administration duration did not affect LSM values and eGFRs. Both eGFRs were significantly associated with LSM values. Patients with initial eGFR(CKD-EPI), initial eGFR(MDRD), and eGFR(CKD-EPI) below each optimal cutoff had significantly high risks for silent liver fibrosis (RR 9.4, 10.3, and 4.4, p < 0.001, respectively). Both initial eGFRs (CKD-EPI and MDRD) and eGFR (CKD-EPI) were significant predictors for the development of silent liver fibrosis in RA patients who had received methotrexate and celecoxib concurrently for at least 6 months.

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.

Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.

PubMed

Ko, Kwang Suk; Tomasi, Maria Lauda; Iglesias-Ara, Ainhoa; French, Barbara A; French, Samuel W; Ramani, Komal; Lozano, Juan José; Oh, Pilsoo; He, Lina; Stiles, Bangyan L; Li, Tony W H; Yang, Heping; Martínez-Chantar, M Luz; Mato, José M; Lu, Shelly C

2010-12-01

Prohibitin 1 (PHB1) is a highly conserved, ubiquitously expressed protein that participates in diverse processes including mitochondrial chaperone, growth and apoptosis. The role of PHB1 in vivo is unclear and whether it is a tumor suppressor is controversial. Mice lacking methionine adenosyltransferase 1A (MAT1A) have reduced PHB1 expression, impaired mitochondrial function, and spontaneously develop hepatocellular carcinoma (HCC). To see if reduced PHB1 expression contributes to the Mat1a knockout (KO) phenotype, we generated liver-specific Phb1 KO mice. Expression was determined at the messenger RNA and protein levels. PHB1 expression in cells was varied by small interfering RNA or overexpression. At 3 weeks, KO mice exhibit biochemical and histologic liver injury. Immunohistochemistry revealed apoptosis, proliferation, oxidative stress, fibrosis, bile duct epithelial metaplasia, hepatocyte dysplasia, and increased staining for stem cell and preneoplastic markers. Mitochondria are swollen and many have no discernible cristae. Differential gene expression revealed that genes associated with proliferation, malignant transformation, and liver fibrosis are highly up-regulated. From 20 weeks on, KO mice have multiple liver nodules and from 35 to 46 weeks, 38% have multifocal HCC. PHB1 protein levels were higher in normal human hepatocytes compared to human HCC cell lines Huh-7 and HepG2. Knockdown of PHB1 in murine nontransformed AML12 cells (normal mouse hepatocyte cell line) raised cyclin D1 expression, increased E2F transcription factor binding to cyclin D1 promoter, and proliferation. The opposite occurred with PHB1 overexpression. Knockdown or overexpression of PHB1 in Huh-7 cells did not affect proliferation significantly or sensitize cells to sorafenib-induced apoptosis. Hepatocyte-specific PHB1 deficiency results in marked liver injury, oxidative stress, and fibrosis with development of HCC by 8 months. These results support PHB1 as a tumor suppressor in hepatocytes. Copyright © 2010 American Association for the Study of Liver Diseases.

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.

Cardiolipin content is involved in liver mitochondrial energy wasting associated with cancer-induced cachexia without the involvement of adenine nucleotide translocase.

PubMed

Julienne, Cloé Mimsy; Tardieu, Marine; Chevalier, Stéphan; Pinault, Michelle; Bougnoux, Philippe; Labarthe, François; Couet, Charles; Servais, Stéphane; Dumas, Jean-François

2014-05-01

Cancer-induced cachexia describes the progressive skeletal muscle wasting associated with many cancers leading to shortened survival time in cancer patients. We previously reported that cardiolipin content and energy-wasting processes were both increased in liver mitochondria in a rat model of peritoneal carcinosis (PC)-induced cachexia. To increase the understanding of the cellular biology of cancer cachexia, we investigated the involvement of adenine nucleotide translocator (ANT) in mitochondrial energy-wasting processes in liver mitochondria of PC and pair-fed control rats and its interactions with cardiolipin in isolated liver mitochondria from healthy rats exposed to cardiolipin-enriched liposomes. We showed in this study that functional ANT content was decreased in liver mitochondria from PC rats but without any effects on the efficiency of ATP synthesis. Moreover, non-phosphorylating energy wasting was not affected by saturating concentrations of carboxyatractylate (CAT), a potent inhibitor of ANT, in liver mitochondria from PC rats. Decreased efficiency of ATP synthesis was found in normal liver mitochondria exposed to cardiolipin-enriched liposomes, with increased non-phosphorylating energy wasting, thus mimicking mitochondria from PC rats. However, the functional ANT content in these cardiolipin-enriched mitochondria was unchanged, although non-phosphorylating energy wasting was reduced by CAT-induced inhibition of ANT. Finally, non-phosphorylating energy wasting was increased in cardiolipin-enriched mitochondria with substrates for complexes 1 and 2, but not for complex 4. In conclusion, increased energy wasting measured in liver mitochondria from rats with cancer cachexia is dependent on cardiolipin but independent of ANT. Interactions between ANT and cardiolipin are modified when cancer cachexia occurs. Copyright © 2014 Elsevier B.V. All rights reserved.

The first Polish liver transplantation after Roux-en-Y gastric bypass surgery for morbid obesity: a case report and literature review.

PubMed

Marszałek, Rafał; Ziemiański, Paweł; Łągiewska, Beata; Pacholczyk, Marek; Domienik-Karłowicz, Justyna; Trzebicki, Janusz; Wierzbicki, Zbigniew; Jankowski, Krzysztof; Kosieradzki, Maciej; Wasiak, Dariusz; Jonas, Maurycy; Pruszczyk, Piotr; Durlik, Magdalena; Lisik, Wojciech; Chmura, Andrzej

2015-02-25

Morbid obesity is associated with liver pathology, most commonly non-alcoholic steatohepatitis (NASH) leading to cirrhosis. However, the morbid obesity impedes qualification for organ transplantation. We present a case report of a 56-year-old woman who underwent bariatric procedure followed by liver transplantation (LTx). Her initial weight was 130.2 kg (BMI 50.9 kg/m2). The patient had a history of arterial hypertension, diabetes, gonarthrosis, and obstructive sleep apnea syndrome and no history of alcohol abuse. She underwent Roux-en-Y gastric bypass (RYGB) procedure. The routine intraoperative liver biopsy revealed fibrosis (III°), steatosis (II°), and intra-acinar inflammation. The operation led to a substantial loss of weight. Two years after the surgery the patient was referred to the Transplantation Clinic of Department of General Surgery and Transplantology with suspicion of liver failure due to advanced cirrhosis, which could be a result of previously diagnosed NASH and, probably, excessive alcohol use after bariatric surgery. The patient was qualified for elective LTx, which was performed 3 years after the RYGB. Immediately before LTx, the patient's weight was 65 kg (BMI 25.4 kg/m²). The postoperative period was complicated by bleeding into the peritoneal cavity, which required reoperation. She also had renal failure, requiring renal replacement therapy. One year after LTx, she showed stable liver function with normal transaminases activity and bilirubin concentration, remission of diabetes, and good renal function. Steatohepatitis in morbidly obese patients may lead to cirrhosis. Bariatric procedure can be a bridge to liver transplantation for morbidly obese patients with advanced liver fibrosis.

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.

INHIBITION OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION BY PERFLUORINATED COMPOUNDS IN RAT LIVER AND DOLPHIN KIDNEY EPITHELIAL CELL LINES IN VITRO AND SPRAGUE-DAWLEY RATS IN VIVO

EPA Science Inventory

Abstract

Gap Junctional Intercellular Communication (GJIC) is the major pathway of intercellular signal transduction, and is, thus, important for normal cell growth and function. Recent studies have revealed a global distribution of some perfluorinated organic compounds e...

Pseudogynecomastia secondary to injection of heroin into breast tissue.

PubMed

Carlson, R H; Velez, R; Rivlin, R S

1978-03-01

A 50-year-old man who has a heroin addict developed bilateral, symmetrical swelling of the breasts as a result of injecting himself directly into the breasts for several years. Results of histologic examination of the breast tissue showed granulomatous inflammation and a foreign body reaction without gynecomastia or tumor. Liver and endocrine functions were generally normal.

Changing interdigestive migrating motor complex in rats under acute liver injury.

PubMed

Liu, Mei; Zheng, Su-Jun; Xu, Weihong; Zhang, Jianying; Chen, Yu; Duan, Zhongping

2014-01-01

Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC) is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by d-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders.

Electrochemical lesions in the rat liver support its potential for treatment of liver tumors.

PubMed

Wemyss-Holden, S A; Robertson, G S; Dennison, A R; de la M Hall, P; Fothergill, J C; Jones, B; Maddern, G J

2000-09-01

An effective therapy is needed for patients with surgically unresectable liver tumors who have very limited life expectancy. One possible treatment is electrochemical tumor necrosis. This study investigated the natural history of electrochemical lesions in the normal rat liver. A direct current generator, connected to platinum electrodes, was used to create controlled areas of liver necrosis. Animals were sacrificed 2 days, 2 weeks, 2 months, and 6 months after treatment and the macroscopic and histological appearance of the necrotic lesions was followed. No animal died as a result of electrolysis; postoperatively, all gained weight normally. Liver enzymes were significantly (P < 0.001) elevated after treatment, but returned to normal after a week. Two days after electrolysis, histology confirmed an ellipsoidal area of coagulative necrosis at the site of the electrode tip and commonly a segment of peripheral necrosis. After 2 weeks there was histological evidence of healing. By 6 months, very little necrotic tissue remained within a small fibrous scar. Electrolysis is a safe method for creating defined areas of liver necrosis that heal well with no associated mortality. This study supports the potential of electrolysis for treating patients with unresectable liver tumors. Copyright 2000 Academic Press.

A Secreted Form of the Asialoglycoprotein Receptor, sH2a, as a Novel Potential Noninvasive Marker for Liver Fibrosis

PubMed Central

Lurie, Yoav; Ron, Efrat; Santo, Moshe; Reif, Shimon; Elashvili, Irma; Bar, Lana; Lederkremer, Gerardo Z.

2011-01-01

Background and Aim The human asialoglycoprotein receptor is a membrane heterooligomer expressed exclusively in hepatocytes. A soluble secreted form, sH2a, arises, not by shedding at the cell surface, but by intracellular cleavage of its membrane-bound precursor, which is encoded by an alternatively spliced form of the receptor H2 subunit. Here we determined and report that sH2a, present at constant levels in serum from healthy individuals is altered upon liver fibrosis, reflecting the status of hepatocyte function. Methods We measured sH2a levels in serum using a monoclonal antibody and an ELISA assay that we developed, comparing with routine liver function markers. We compared blindly pretreatment serum samples from a cohort of 44 hepatitis C patients, which had METAVIR-scored biopsies, with 28 healthy individuals. Results sH2a levels varied minimally for the healthy individuals (150±21 ng/ml), whereas the levels deviated from this normal range increasingly in correlation with fibrosis stage. A simple algorithm combining sH2a levels with those of alanine aminotransferase allowed prediction of fibrosis stage, with a very high area under the ROC curve of 0.86. Conclusions sH2a has the potential to be a uniquely sensitive and specific novel marker for liver fibrosis and function. PMID:22096539

Serum-Free Medium and Mesenchymal Stromal Cells Enhance Functionality and Stabilize Integrity of Rat Hepatocyte Spheroids

PubMed Central

Bao, Ji; Fisher, James E.; Lillegard, Joseph B.; Wang, William; Amiot, Bruce; Yu, Yue; Dietz, Allan B.; Nahmias, Yaakov; Nyberg, Scott L.

2013-01-01

Long-term culture of hepatocyte spheroids with high ammonia clearance is valuable for therapeutic applications, especially the bioartificial liver. However, the optimal conditions are not well studied. We hypothesized that liver urea cycle enzymes can be induced by high protein diet and maintain on a higher expression level in rat hepatocyte spheroids by serum-free medium (SFM) culture and coculture with mesenchymal stromal cells (MSCs). Rats were feed normal protein diet (NPD) or high protein diet (HPD) for 7 days before liver digestion and isolation of hepatocytes. Hepatocyte spheroids were formed and maintained in a rocked suspension culture with or without MSCs in SFM or 10% serum-containing medium (SCM). Spheroid viability, kinetics of spheroid formation, hepatic functions, gene expression, and biochemical activities of rat hepatocyte spheroids were tested over 14 days of culture. We observed that urea cycle enzymes of hepatocyte spheroids can be induced by high protein diet. SFM and MSCs enhanced ammonia clearance and ureagenesis and stabilized integrity of hepatocyte spheroids compared to control conditions over 14 days. Hepatocytes from high protein diet-fed rats formed spheroids and maintained a high level of ammonia detoxification for over 14 days in a novel SFM. Hepatic functionality and spheroid integrity were further stabilized by coculture of hepatocytes with MSCs in the spheroid microenvironment. These findings have direct application to development of the spheroid reservoir bioartificial liver. PMID:23006214

Symbiotic formulation in experimentally induced liver fibrosis in rats: intestinal microbiota as a key point to treat liver damage?

PubMed

D'Argenio, Giuseppe; Cariello, Rita; Tuccillo, Concetta; Mazzone, Giovanna; Federico, Alessandro; Funaro, Annalisa; De Magistris, Laura; Grossi, Enzo; Callegari, Maria L; Chirico, Marilena; Caporaso, Nicola; Romano, Marco; Morelli, Lorenzo; Loguercio, Carmela

2013-05-01

Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis. CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P < 0.001 in all cases). Circulating levels of pro-inflammatory cytokine TNF-α were significantly increased in rats with liver fibrosis as compared with normal rats, while symbiotic treatment normalized the plasma levels of TNF-α and significantly enhanced anti-inflammatory cytokine IL 10. TNF-α, TGF-β, TLR4, TLR2, iNOS and α-SMA mRNA expression in the liver were up-regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls. Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis. © 2013 John Wiley & Sons A/S.

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.

Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/−-IRS-1+/− Double Heterozygous (IR-IRS1dh) Mice

PubMed Central

Franko, Andras; Kunze, Alexander; Böse, Marlen; von Kleist-Retzow, Jürgen-Christoph; Paulsson, Mats; Hartmann, Ursula; Wiesner, Rudolf J.

2017-01-01

Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR)+/−-insulin receptor substrate-1 (IRS-1)+/− double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver. PMID:28556799

Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/--IRS-1+/- Double Heterozygous (IR-IRS1dh) Mice.

PubMed

Franko, Andras; Kunze, Alexander; Böse, Marlen; von Kleist-Retzow, Jürgen-Christoph; Paulsson, Mats; Hartmann, Ursula; Wiesner, Rudolf J

2017-05-30

Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR) +/- -insulin receptor substrate-1 (IRS-1) +/- double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver.

Quantitative characterization of fatty liver disease using x-ray scattering

NASA Astrophysics Data System (ADS)

Elsharkawy, Wafaa B.; Elshemey, Wael M.

2013-11-01

Nonalcoholic fatty liver disease (NAFLD) is a dynamic condition in which fat abnormally accumulates within the hepatocytes. It is believed to be a marker of risk of later chronic liver diseases, such as liver cirrhosis and carcinoma. The fat content in liver biopsies determines its validity for liver transplantation. Transplantation of livers with severe NAFLD is associated with a high risk of primary non-function. Moreover, NAFLD is recognized as a clinically important feature that influences patient morbidity and mortality after hepatic resection. Unfortunately, there is a lack in a precise, reliable and reproducible method for quantification of NAFLD. This work suggests a method for the quantification of NAFLD. The method is based on the fact that fatty liver tissue would have a characteristic x-ray scattering profile with a relatively intense fat peak at a momentum transfer value of 1.1 nm-1 compared to a soft tissue peak at 1.6 nm-1. The fat content in normal and fatty liver is plotted against three profile characterization parameters (ratio of peak intensities, ratio of area under peaks and ratio of area under fat peak to total profile area) for measured and Monte Carlo simulated x-ray scattering profiles. Results show a high linear dependence (R2>0.9) of the characterization parameters on the liver fat content with a reported high correlation coefficient (>0.9) between measured and simulated data. These results indicate that the current method probably offers reliable quantification of fatty liver disease.

Basement Membrane Type IV Collagen and Laminin: An Overview of Their Biology and Value as Fibrosis Biomarkers of Liver Disease.

PubMed

Mak, Ki M; Mei, Rena

2017-08-01

Basement membranes provide structural support to epithelium, endothelium, muscles, fat cells, Schwann cells, and axons. Basement membranes are multifunctional: they modulate cellular behavior, regulate organogenesis, promote tissue repair, form a barrier to filtration and tumor metastasis, bind growth factors, and mediate angiogenesis. All basement membranes contain type IV collagen (Col IV), laminin, nidogen, and perlecan. Col IV and laminin self-assemble into two independent supramolecular networks that are linked to nidogen and perlecan to form a morphological discernable basement membrane/basal lamina. The triple helical region, 7S domain and NCI domain of Col IV, laminin and laminin fragment P1 have been evaluated as noninvasive fibrosis biomarkers of alcoholic liver disease, viral hepatitis, and nonalcoholic fatty liver disease. Elevated serum Col IV and laminin are related to degrees of fibrosis and severity of hepatitis, and may reflect hepatic basement membrane metabolism. But the serum assays have not been linked to disclosing the anatomical sites and lobular distribution of perisinusoidal basement membrane formation in the liver. Hepatic sinusoids normally lack a basement membrane, although Col IV is a normal matrix component of the space of Disse. In liver disease, laminin deposits in the space of Disse and codistributes with Col IV, forming a perisinusoidal basement membrane. Concomitantly, the sinusoidal endothelium loses its fenestrae and is transformed into vascular type endothelium. These changes lead to capillarization of hepatic sinusoids, a significant pathology that impairs hepatic function. Accordingly, codistribution of Col IV and laminin serves as histochemical marker of perisinusoidal basement membrane formation in liver disease. Anat Rec, 300:1371-1390, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Increased Expression Profile and Functionality of TLR6 in Peripheral Blood Mononuclear Cells and Hepatocytes of Morbidly Obese Patients with Non-Alcoholic Fatty Liver Disease.

PubMed

Arias-Loste, María Teresa; Iruzubieta, Paula; Puente, Ángela; Ramos, David; Santa Cruz, Carolina; Estébanez, Ángel; Llerena, Susana; Alonso-Martín, Carmen; San Segundo, David; Álvarez, Lorena; López Useros, Antonio; Fábrega, Emilio; López-Hoyos, Marcos; Crespo, Javier

2016-11-10

Current evidence suggests that gut dysbiosis drives obesity and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Toll-like receptor 2 (TLR2) and TLR6 specifically recognize components of Gram-positive bacteria. Despite the potential implications of TLR2 in NAFLD pathogenesis, the role of TLR6 has not been addressed. Our aim is to study a potential role of TLR6 in obesity-related NAFLD. Forty morbidly obese patients undergoing bariatric surgery were prospectively studied. Cell surface expression of TLR2 and TLR6 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated monocytes were cultured with specific TLR2/TLR6 agonists and intracellular production of cytokines was determined by flow-cytometry. In liver biopsies, the expression of TLR2 and TLR6 was analyzed by immunohistochemistry and cytokine gene expression using RT-qPCR. TLR6 expression in PBMCs from non-alcoholic steatohepatitis (NASH) patients was significantly higher when compared to those from simple steatosis. The production of pro-inflammatory cytokines in response to TLR2/TLR6 stimulation was also significantly higher in patients with lobular inflammation. Hepatocyte expression of TLR6 but not that of TLR2 was increased in NAFLD patients compared to normal liver histology. Deregulated expression and activity of peripheral TLR6 in morbidly obese patients can mirror the liver inflammatory events that are well known drivers of obesity-related NASH pathogenesis. Moreover, TLR6 is also significantly overexpressed in the hepatocytes of NAFLD patients compared to their normal counterparts. Thus, deregulated TLR6 expression may potentiate TLR2-mediated liver inflammation in NAFLD pathogenesis, and also serve as a potential peripheral biomarker of obesity-related NASH.

Effect of parenteral serum plant sterols on liver enzymes and cholesterol metabolism in a patient with short bowel syndrome.

PubMed

Hallikainen, Maarit; Huikko, Laura; Kontra, Kirsi; Nissinen, Markku; Piironen, Vieno; Miettinen, Tatu; Gylling, Helena

2008-01-01

Hepatobiliary complications are common during parenteral nutrition. Lipid moiety in commercially available solutions contains plant sterols. It is not known whether plant sterols in parenteral nutrition interfere with hepatic function in adults. We detected how different amounts of plant sterols in parenteral nutrition solution affected serum plant sterol concentrations and liver enzymes during a 1.5-year follow-up in a patient with short bowel syndrome. Serum lipid, plant sterol, and liver enzyme levels were measured regularly during the transition from Intralipid (100% soy-based intravenous fat emulsion) to ClinOleic (an olive oil-based intravenous fat emulsion with 80% olive oil, 20% soy oil and lower plant sterols); the lipid supply was also gradually increased from 20 to 35 g/d. Plant sterols in parenteral nutrition solution and serum were measured with gas-liquid chromatography. During infusion of soy-based intravenous fat emulsion (30 g/d, total plant sterols 87 mg/d), the concentrations of sitosterol, campesterol, and stigmasterol were 4361, 1387, and 378 microg/dL, respectively, and serum liver enzyme values were >or= 2.5 times above upper limit of normal. After changing to olive oil-based intravenous fat emulsion (20-35 g/d, plant sterols 37-65 mg/d), concentrations decreased to 2148 to 2251 microg/dL for sitosterol, 569-297 microg/dL for campesterol, and 95-55 microg/dL for stigmasterol. Concomitantly, liver enzyme values decreased to 1.4 to 1.8 times above upper limit of normal at the end of follow-up. The nutrition status of the patient improved. The amount of plant sterols in lipid emulsion affects serum liver enzyme levels more than the amount of lipid.

Impact of Graft Selection on Donor and Recipient Outcomes After Living Donor Liver Transplantation.

PubMed

Braun, Hillary J; Dodge, Jennifer L; Roll, Garrett R; Freise, Chris E; Ascher, Nancy L; Roberts, John P

2016-06-01

Balancing donor and recipient risks in living donor liver transplantation remains an issue of debate. This study assessed the impact of graft selection on outcomes and complications for left lobe (LL) versus right lobe (RL) donors and recipients. The medical records of donors and recipients, who underwent living donor liver transplantation at our institution between 2003 and 2015, were reviewed. For donors, we evaluated graft volume, residual liver volume per standard liver volume, length of hospital stay (LOS), complications, and readmissions. For recipients, we looked at graft and patient survival, graft function at postoperative days 7 and 14, graft volume, LOS, biliary complications, Model for End-Stage Liver Disease at transplant, and hepatitis C virus status. At 5 years posttransplant, there were no significant differences in graft survival for LL recipients (86% [95% confidence interval, 74-93]) compared with 82% (95% confidence interval, 69-89) for RL recipients (P = 0.85) or recipient survival (90% vs 84%; P = 0.44). In LL recipients, postoperative days 7 and 14 median international normalized ratio (1.5 and 1.2, respectively) and total bilirubin (4.6 and 2.7) were significantly greater compared with RL recipients (7 and 14 days international normalized ratio [1.2, P < 0.001; 1.1, P = 0.001] and total bilirubin (2.7, P = 0.001; 2.1, P = 0.05)). The LL recipients also had a significantly greater median LOS (14 vs 10, P = 0.008). Median donor LOS was significantly greater for RL donors (7 [interquartile range, 7-8] vs 7 [interquartile range, 6-7] days, P < 0.001). The RL and LL grafts provide comparable long-term outcomes in properly selected donor-recipient pairs and the appropriate use of LL grafts does not impact graft or patient survival at 5 years posttransplant.

Effects of an Agaricus blazei aqueous extract pretreatment on paracetamol-induced brain and liver injury in rats.

PubMed

Soares, Andréia A; de Oliveira, Andrea L; Sá-Nakanishi, Anacharis B; Comar, Jurandir F; Rampazzo, Ana P S; Vicentini, Fernando A; Natali, Maria R M; Gomes da Costa, Sandra M; Bracht, Adelar; Peralta, Rosane M

2013-01-01

The action of an Agaricus blazei aqueous extract pretreatment on paracetamol injury in rats was examined not only in terms of the classical indicators (e.g., levels of hepatic enzymes in the plasma) but also in terms of functional and metabolic parameters (e.g., gluconeogenesis). Considering solely the classical indicators for tissue damage, the results can be regarded as an indication that the A. blazei extract is able to provide a reasonable degree of protection against the paracetamol injury in both the hepatic and brain tissues. The A. blazei pretreatment largely prevented the increased levels of hepatic enzymes in the plasma (ASP, ALT, LDH, and ALP) and practically normalized the TBARS levels in both liver and brain tissues. With respect to the functional and metabolic parameters of the liver, however, the extract provided little or no protection. This includes morphological signs of inflammation and the especially important functional parameter gluconeogenesis, which was impaired by paracetamol. Considering these results and the long list of extracts and substances that are said to have hepatoprotective effects, it would be useful to incorporate evaluations of functional parameters into the experimental protocols of studies aiming to attribute or refute effective hepatoprotective actions to natural products.

Effects of an Agaricus blazei Aqueous Extract Pretreatment on Paracetamol-Induced Brain and Liver Injury in Rats

PubMed Central

Soares, Andréia A.; de Oliveira, Andrea L.; Sá-Nakanishi, Anacharis B.; Comar, Jurandir F.; Rampazzo, Ana P. S.; Vicentini, Fernando A.; Natali, Maria R. M.; Gomes da Costa, Sandra M.; Peralta, Rosane M.

2013-01-01

The action of an Agaricus blazei aqueous extract pretreatment on paracetamol injury in rats was examined not only in terms of the classical indicators (e.g., levels of hepatic enzymes in the plasma) but also in terms of functional and metabolic parameters (e.g., gluconeogenesis). Considering solely the classical indicators for tissue damage, the results can be regarded as an indication that the A. blazei extract is able to provide a reasonable degree of protection against the paracetamol injury in both the hepatic and brain tissues. The A. blazei pretreatment largely prevented the increased levels of hepatic enzymes in the plasma (ASP, ALT, LDH, and ALP) and practically normalized the TBARS levels in both liver and brain tissues. With respect to the functional and metabolic parameters of the liver, however, the extract provided little or no protection. This includes morphological signs of inflammation and the especially important functional parameter gluconeogenesis, which was impaired by paracetamol. Considering these results and the long list of extracts and substances that are said to have hepatoprotective effects, it would be useful to incorporate evaluations of functional parameters into the experimental protocols of studies aiming to attribute or refute effective hepatoprotective actions to natural products. PMID:23984368

A score model for the continuous grading of early allograft dysfunction severity.

PubMed

Pareja, Eugenia; Cortes, Miriam; Hervás, David; Mir, José; Valdivieso, Andrés; Castell, José V; Lahoz, Agustín

2015-01-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcomes. A lack of consensus on an EAD definition hinders comparisons of liver transplant outcomes and management of recipients among and within centers. We sought to develop a model for the quantitative assessment of early allograft function [Model for Early Allograft Function Scoring (MEAF)] after transplantation. A retrospective study including 1026 consecutive liver transplants was performed for MEAF score development. Multivariate data analysis was used to select a small number of postoperative variables that adequately describe EAD. Then, the distribution of these variables was mathematically modeled to assign a score for each actual variable value. A model, based on easily obtainable clinical parameters (ie, alanine aminotransferase, international normalized ratio, and bilirubin) and scoring liver function from 0 to 10, was built. The MEAF score showed a significant association with patient and graft survival at 3-, 6- and 12-month follow-ups. Hepatic steatosis and age for donors; cold/warm ischemia times and postreperfusion syndrome for surgery; and intensive care unit and hospital stays, Model for End-Stage Liver Disease and Child-Pugh scores, body mass index, and fresh frozen plasma transfusions for recipients were factors associated significantly with EAD. The model was satisfactorily validated by its application to an independent set of 200 patients who underwent liver transplantation at a different center. In conclusion, a model for the quantitative assessment of EAD severity has been developed and validated for the first time. The MEAF provides a more accurate graft function assessment than current categorical classifications and may help clinicians to make early enough decisions on retransplantation benefits. Furthermore, the MEAF score is a predictor of recipient and graft survival. The standardization of the criteria used to define EAD may allow reliable comparisons of recipients' treatments and transplant outcomes among and within centers. © 2014 American Association for the Study of Liver Diseases.

Liver grafts from selected older donors do not have significantly more ischaemia reperfusion injury

PubMed Central

Martins, Paulo N; Chang, Sue; Mahadevapa, Basant; Martins, Ann-Britt; Sheiner, Patricia

2011-01-01

Background There is a general concern that aged organs are more susceptible to ischaemia. In the light of recent proposals to change the liver allocation system by expanding regional sharing, it is feared that increased cold ischaemia time of grafts from older donors may reduce graft survival. The aim of this study was to correlate donor age and the patterns of ischaemia reperfusion injury and synthetic function early after liver transplantation. Methods We performed a retrospective study of first transplants using a single-centre electronic database. Patterns of liver injury (based on transaminases and post-reperfusion biopsy), synthetic function (international normalized ratio [INR]), and graft and patient survival in recipients receiving liver grafts from donors aged ≥65 years (group 1, n= 50) were compared with equivalent patterns in a matched cohort of recipients transplanted with grafts from donors aged <65 years (group 2, n= 50). Results There was no significant difference in transaminase levels from day 0 to day 6 after transplantation. When groups 1 and 2 were subdivided into two subgroups based on the duration of graft cold ischaemia time (<8 h and ≥8 h), there was no statistical difference in transaminase levels during the first 7 days. There were two cases (4%) of primary non-function in group 1 and one (2%) in group 2. Initial poor function did not differ significantly between the groups (26% vs. 24%; P= 0.81). In addition, there was no difference in histological changes in post-reperfusion biopsies (21% vs. 34%; P= 0.078) and rate of acute rejection episodes in the first year (30% vs. 32%; P= 0.99). There was no significant difference between groups 1 and 2 in 1-year patient and graft survivals (78% vs. 90% [P= 0.17]; 88% vs. 94% [P= 0.48], respectively). Conclusions Judiciously selected livers from aged donors are not associated with major increased susceptibility to ischaemia reperfusion injury. PMID:21309940

Increasing the donor pool: consideration of prehospital cardiac arrest in controlled donation after circulatory death for liver transplantation.

PubMed

Elaffandi, Ahmed H; Bonney, Glenn K; Gunson, Bridget; Scalera, Irene; Mergental, Hynek; Isaac, John R; Bramhall, Simon R; Mirza, Darius F; Perera, M Thamara P R; Muiesan, Paolo

2014-01-01

Donor warm ischemia has implications for outcomes after liver transplantation (LT) using organs from donation after circulatory death (DCD) donors. Prehospital cardiac arrest (PHCA) before donation may generate a further ischemic insult. The aim of this single-center study of 108 consecutive DCD LT procedures was to compare the outcomes of PHCA and non-PHCA cohorts. A review of a prospectively collected database of all DCD grafts transplanted between January 2007 and October 2011 was undertaken to identify donors who had sustained PHCA. The unit policy was to consider such donors when transaminase levels were ≤4 times the normal range and had an improving trend. Twenty-six of the 108 DCD transplants were from DCD donors with PHCA, and 82 were in the non-PHCA cohort. A comparative analysis of the PHCA and non-PHCA cohorts showed better short-term results (a low incidence of acute kidney injury) for the PHCA group but satisfactory long-term results for both groups with no significant differences in graft or patient survival between them. In conclusion, a careful donor selection policy for including PHCA DCD donors with normalized liver function tests or transaminase levels ≤ 4 times the norm resulted in successful transplantation and could boost the donor pool with no adverse outcomes. © 2013 American Association for the Study of Liver Diseases.

A complex of α6 integrin and E-cadherin drives liver metastasis of colorectal cancer cells through hepatic angiopoietin-like 6

PubMed Central

Marchiò, Serena; Soster, Marco; Cardaci, Sabrina; Muratore, Andrea; Bartolini, Alice; Barone, Vanessa; Ribero, Dario; Monti, Maria; Bovino, Paola; Sun, Jessica; Giavazzi, Raffaella; Asioli, Sofia; Cassoni, Paola; Capussotti, Lorenzo; Pucci, Piero; Bugatti, Antonella; Rusnati, Marco; Pasqualini, Renata; Arap, Wadih; Bussolino, Federico

2012-01-01

Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and α6 integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural α6 integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α6 integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC. PMID:23070965

Antibiotic tigecycline enhances cisplatin activity against human hepatocellular carcinoma through inducing mitochondrial dysfunction and oxidative damage

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

Tan, Jun; Song, Meijun; Zhou, Mi

Targeting mitochondrial metabolism has been recently demonstrated to be a promising therapeutic strategy for the treatment of various cancer. In this work, we demonstrate that antibiotic tigecycline is selectively against hepatocellular carcinoma (HCC) through inducing mitochondrial dysfunction and oxidative damage. Tigecycline is more effective in inhibiting proliferation and inducing apoptosis of HCC than normal liver cells. Importantly, tigecycline significantly enhances the inhibitory effects of chemotherapeutic drug cisplatin in HCC in vitro and in vivo. Mechanistically, tigecycline specifically inhibits mitochondrial translation as shown by the decreased protein levels of Cox-1 and -2 but not Cox-4 or Grp78, and increased mRNA levels of Cox-1more » and -2 but not Cox-4 in HCC cells exposed to tigecycline. In addition, tigecycline significantly induces mitochondrial dysfunction in HCC cells via decreasing mitochondrial membrane potential, complex I and IV activities, mitochondrial respiration and ATP levels. Tigecycline also increases levels of mitochondrial superoxide, hydrogen peroxide and ROS levels. Consistent with oxidative stress, oxidative damage on DNA, protein and lipid are also observed in tigecycline-treated cells. Importantly, antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of tigecycline, suggesting that oxidative stress is required for the action of tigecycline in HCC cells. We further show that HCC cells have higher level of mitochondrial biogenesis than normal liver cells which might explain the different sensitivity to tigecycline between HCC and normal liver cells. Our work is the first to demonstrate that tigecycline is a promising candidate for HCC treatment and highlight the therapeutic value of targeting mitochondrial metabolism in HCC. - Highlights: • Tigecycline selectively targets HCC in vitro and in vivo. • Tigecycline enhances HCC cell response to chemotherapeutic drug. • Tigecycline inhibits mitochondrial translation and functions in HCC cells. • Tigecycline induces oxidative stress and damage in HCC cells. • Mitochondrial biogenesis and respiration is higher in HCC than normal liver cells.« less

Update on liver transplants in Lebanon.

PubMed

Faraj, Walid; Haydar, Ali; Nounou, Ghina El; Naaj, Abdallah Abou El; Khoury, Ghattas; Jabbour, Samar; Khalife, Mohamed

2015-09-01

Objective-To review all liver transplants performed at the American University of Beirut Medical Center from 1998 to present. Materials and Methods-From 1998 to present, 21 liver transplants (15 into adults and 6 into children) were performed at the American University of Beirut Medical Center. Of the 21 transplants, 5 were living related liver transplants. Results-Patient survival was 76% at 1, 5, and 10 years. Five recipients died at a median of 9 (range, 1-56) days after transplant. Causes of death included 1 case of severe cellular rejection, 1 case of portal and hepatic artery thrombosis, 1 case of intraoperative cardiac arrest, and 2 cases of primary nonfunction. Two biliary complications and 2 major vascular complications also occurred. All 16 survivors are well, with normal findings on liver function tests at a median follow-up time of 93 (range, 10-185) months after transplant. Conclusions-Although our numbers are small, the 10-year survival rate is comparable to reported rates for other series around the world. Deceased organ donations must be encouraged so that we can perform more transplants. As a source of organs, living related liver transplant is important; however, it cannot replace deceased donation.

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.

Pretransplantation Cystatin C, but not Creatinine, Predicts 30-day Cardiovascular Events and Mortality in Liver Transplant Recipients With Normal Serum Creatinine Levels.

PubMed

Kwon, H-M; Moon, Y-J; Jung, K-W; Jun, I-G; Song, J-G; Hwang, G-S

2018-05-01

The connection between renal dysfunction and cardiovascular dysfunction has been consistently shown. In patients with liver cirrhosis, renal dysfunction shows a tight correlation with prognosis after liver transplantation (LT); therefore, precise renal assessment is mandatory. Cystatin C, a sensitive biomarker for assessing renal function, has shown superiority in detecting mild renal dysfunction compared to classical biomarker creatinine. In this study, we aimed to compare cystatin C and creatinine in predicting 30-day major cardiovascular events (MACE) and all-cause mortality in LT recipients with normal serum creatinine levels. Between May 2010 and October 2015, 1181 LT recipients (mean Model for End-stage Liver Disease score 12.1) with pretransplantation creatinine level ≤1.4 mg/dL were divided into tertiles according to each renal biomarker. The 30-day MACE was a composite of troponin I >0.2 ng/mL, arrhythmia, congestive heart failure, death, and cerebrovascular events. The highest tertile of cystatin C (≥0.95 mg/L) was associated with a higher risk for a 30-day MACE event (odds ratio: 1.62; 95% confidence interval: 1.07 to 2.48) and higher risk of death (hazard ratio: 1.96; 95% confidence interval: 1.04 to 3.67) than the lowest tertile (<0.74 mg/L) after multivariate adjustments. However, the highest tertile of creatinine level showed neither increasing MACE event rate nor worse survival rate compared with the lowest tertile (both insignificant after multivariate adjustment). Pretransplantation cystatin C is superior in risk prediction of MACE and all-cause mortality in LT recipients with normal creatinine, compared to creatinine. It would assist further risk stratification which may not be detected with creatinine. Copyright © 2018 Elsevier Inc. All rights reserved.

Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review.

PubMed

Reardon, Jillian; Hussaini, Trana; Alsahafi, Majid; Azalgara, Vladimir Marquez; Erb, Siegfried R; Partovi, Nilufar; Yoshida, Eric M

2016-09-28

Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited to minor gastrointestinal complaints (most often, diarrhea) and did not occur at increased frequency as compared to controls. As administration of bile acids was often limited to durations of 12 months or less, long-term side effects for non-cholestatic indications cannot be excluded. Conclusions: Based on the available literature, bile acids cannot be widely recommended for non-cholestatic liver diseases at present.

Evaluation of the 13C-octanoate breath test as a surrogate marker of liver damage in animal models.

PubMed

Shalev, Tamar; Aeed, Hussein; Sorin, Vladimir; Shahmurov, Mark; Didkovsky, Elena; Ilan, Yaron; Avni, Yona; Shirin, Haim

2010-06-01

Octanoate (also known as sodium octanoate), a medium-chain fatty acid metabolized in the liver, is a potential substrate for non-invasive breath testing of hepatic mitochondrial beta-oxidation. We evaluated the 13C-octanoate breath test (OBT) for assessing injury in acute hepatitis and two rat models of liver cirrhosis, first testing octanoate absorption (per os or intraperitoneally (i.p.)) in normal rats. We then induced acute hepatitis with thioacetamide (300 mg/kg/i.p., 24-h intervals). Liver injury end points were serum aminotransferase levels and 13C-OBT (24 and 48 h following initial injection). Thioacetamide (200 mg/kg/i.p., twice per week, 12 weeks) was used to induce liver cirrhosis. OBT and liver histological assessment were performed every 4 weeks. Bile duct ligation (BDL) was used to induce cholestatic liver injury. We completed breath tests with 13C-OBT and 13C-methacetin (MBID), liver biochemistry, and liver histology in BDL and sham-operated rats (baseline, 6, 14, 20 days post-BDL). Octanoate absorbs well by either route. Peak amplitudes and cumulative percentage dose recovered at 30 and 60 min (CPDR30/60), but not peak time, correlated with acute hepatitis. Fibrosis stage 3 at week 8 significantly correlated with each OBT parameter. Cholestatic liver injury (serum bilirubin, ALP, gamma-GT, liver histology) was associated with significant suppression of the maximal peak values and CPDR30/60, respectively (P<0.05),using MBID but not 13C-octanoate. OBT is sensitive for potentially evaluating liver function in rat models of acute hepatitis and thioacetamide-induced liver cirrhosis but not in cholestatic liver injury. The MBID test may be better for evaluation of cholestatic liver disease in this model.

Expression and function of the atypical cadherin FAT1 in chronic liver disease

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

Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E.

Highlights: Black-Right-Pointing-Pointer The expression of the atypical cadherin FAT1 is increased in chronic liver disease. Black-Right-Pointing-Pointer FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. Black-Right-Pointing-Pointer FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. Black-Right-Pointing-Pointer FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. -- Abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCsmore » are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NF{kappa}B activity. This transcription factor is critical for apoptosis resistance of HSCs, and consequently, we detected a higher apoptosis rate in FAT1 suppressed HSCs compared to control cells. Our findings suggest FAT1 as new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease.« less

[Undifferentiated (embryonal) sarcoma of the liver. Report of a case].

PubMed

Orozco, H; Mercado, M A; Takahashi, T; Chan, C; Quintanilla, L; Jiménez, M; Sosa, R; Esquivel, E

1991-01-01

A 15-year-old woman who was studied because an abdominal mass at the Instituto Nacional de la Nutricion Salvador Zubiran (INNSZ) is reported. The history revealed only malaise and mild abdominal pain. At physical exploration, an abdominal mass in the upper right quadrant was found. Liver function tests were normal. Abdominal ultrasound and computerized tomography revealed a large cystic mass of the right hepatic lobe. She underwent exploratory laparotomy. Intraoperative frozen sections of the biopsies demonstrated undifferentiated sarcoma of the liver, and an extended right trisegmentectomy was performed. Postoperative outcome was uneventful. Adjuvant treatment with doxorubicin and dacarbazine was given, and at six months of follow-up, the patient is alive without any evidence of recurrence. Clinical and histopathologic features of this rare malignant tumor are discussed, as well as the therapeutic choices.

Academic potential and cognitive functioning of long-term survivors after childhood liver transplantation.

PubMed

Ee, L C; Lloyd, O; Beale, K; Fawcett, J; Cleghorn, G J

2014-05-01

This cross-sectional study assessed intellect, cognition, academic function, behaviour, and emotional health of long-term survivors after childhood liver transplantation. Eligible children were >5 yr post-transplant, still attending school, and resident in Queensland. Hearing and neurocognitive testing were performed on 13 transplanted children and six siblings including two twin pairs where one was transplanted and the other not. Median age at testing was 13.08 (range 6.52-16.99) yr; time elapsed after transplant 10.89 (range 5.16-16.37) yr; and age at transplant 1.15 (range 0.38-10.00) yr. Mean full-scale IQ was 97 (81-117) for transplanted children and 105 (87-130) for siblings. No difficulties were identified in intellect, cognition, academic function, and memory and learning in transplanted children or their siblings, although both groups had reduced mathematical ability compared with normal. Transplanted patients had difficulties in executive functioning, particularly in self-regulation, planning and organization, problem-solving, and visual scanning. Thirty-one percent (4/13) of transplanted patients, and no siblings, scored in the clinical range for ADHD. Emotional difficulties were noted in transplanted patients but were not different from their siblings. Long-term liver transplant survivors exhibit difficulties in executive function and are more likely to have ADHD despite relatively intact intellect and cognition. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Successful living donor liver transplant in a child with Abernethy malformation with biliary atresia, ventricular septal defect and intrapulmonary shunting.

PubMed

Singhal, Ashish; Srivastava, Ajitabh; Goyal, Neerav; Vij, Vivek; Wadhawan, Manav; Bera, Motilal; Gupta, Subash

2009-12-01

Congenital portosystemic shunts are the anomalies in which the mesenteric venous drainage bypasses the liver and drains directly into the systemic circulation. This is a report of a rare case of LDLT in a four-yr old male child suffering with biliary atresia (post-failed Kasai procedure) associated with (i) a large congenital CEPSh from the spleno-mesentric confluence to the LHV, (ii) intrapulmonary shunts, (iii) perimembranous VSD. The left lobe graft was procured from the mother of the child. Recipient IVC and the shunt vessel were preserved during the hepatectomy, and the caval and shunt clamping were remarkably short while performing the HV and portal anastomosis. Post-operative course was uneventful; intrapulmonary shunts regressed within three months after transplantation and currently after 18 months following transplant child is doing well with normal liver functions. CEPSh has been extensively discussed and all the published cases of liver transplantation for CEPSh were reviewed.

Diagnostic value of diffusion weighted MRI and ADC in differential diagnosis of cavernous hemangioma of the liver.

PubMed

Tokgoz, Ozlem; Unlu, Ebru; Unal, Ilker; Serifoglu, Ismail; Oz, Ilker; Aktas, Elif; Caglar, Emrah

2016-03-01

To investigate the use of diffusion weighted magnetic resonance imaging (DWI) and the apparent diffusion coefficient (ADC) values in the diagnosis of hemangioma. The study population consisted of 72 patients with liver masses larger than 1 cm (72 focal lesions). DWI examination with a b value of 600 s/mm2 was carried out for all patients. After DWI examination, an ADC map was created and ADC values were measured for 72 liver masses and normal liver tissue (control group). The average ADC values of normal liver tissue and focal liver lesions, the "cut-off" ADC values, and the diagnostic sensitivity and specificity of the ADC map in diagnosing hemangioma, benign and malignant lesions were researched. Of the 72 liver masses, 51 were benign and 21 were malignant. Benign lesions comprised 38 hemangiomas and 13 simple cysts. Malignant lesions comprised 9 hepatocellular carcinomas, and 12 metastases. The highest ADC values were measured for cysts (3.782±0.53×10(-3) mm(2)/s) and hemangiomas (2.705±0.63×10(-3) mm(2)/s). The average ADC value of hemangiomas was significantly higher than malignant lesions and the normal control group (p<0.001). The average ADC value of cysts were significantly higher when compared to hemangiomas and normal control group (p<0.001). To distinguish hemangiomas from malignant liver lesions, the "cut-off" ADC value of 1.800×10(-3) mm(2)/s had a sensitivity of 97.4% and a specificity of 90.9%. To distinguish hemangioma from normal liver parenchyma the "cut-off" value of 1.858×10(-3) mm(2)/s had a sensitivity of 97.4% and a specificity of 95.7%. To distinguish benign liver lesions from malignant liver lesions the "cut-off" value of 1.800×10(-3) mm(2)/s had a sensitivity of 96.1% and a specificity of 90.0%. DWI and quantitative measurement of ADC values can be used in differential diagnosis of benign and malignant liver lesions and also in the diagnosis and differentiation of hemangiomas. When dynamic examination cannot distinguish cases with vascular metastasis and lesions from hemangioma, DWI and ADC values can be useful in the primary diagnosis and differential diagnosis. The technique does not require contrast material, so it can safely be used in patients with renal failure.

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.

Effect of hepatic impairment on the pharmacokinetics of a single dose of cilostazol.

PubMed

Bramer, S L; Forbes, W P

1999-01-01

The pharmacokinetic profiles of cilostazol and its metabolites following a single oral dose of cilostazol 100 mg were compared between individuals with impaired and normal liver function. The study was conducted as a single-centre, open-label, single dose pharmacokinetic and tolerability trial. 12 patients with impaired and compensated liver function were compared with 12 volunteers with normal liver function. Participants in each group were matched for gender, age and weight. Of the 12 patients with hepatic impairment examined in this study, 10 had mild impairment (Child-Pugh class A) and 2 had moderate impairment (Child-Pugh class B). Blood and urine were collected up to 144 hours after drug administration. Pharmacokinetics were determined by noncompartmental methods. Protein binding did not differ between the groups (95.2% healthy volunteers, 94.6% hepatically impaired patients). Mean +/- SD unbound oral clearance of cilostazol decreased by 8.6% because of hepatic impairment (3380 +/- 1400 ml/min in healthy volunteers, 3260 +/- 2030 ml/min in hepatically impaired patients). Total urinary excretion of metabolites was significantly higher in healthy volunteers (26 vs 17% of dose). Overall, the pharmacokinetics of cilostazol and its metabolites, OPC-13213 and OPC-13015, were not substantially different in those with mild and moderate hepatic disease compared with values in healthy volunteers. Except for terminal-phase disposition half-life and apparent terminal-phase volume of distribution for cilostazol, the ratios of geometric means of pharmacokinetic parameters for plasma cilostazol, OPC-13213 and OPC-13015 in those with hepatic impairment versus healthy volunteers were close to 100%. Based on the results of the pharmacokinetic analysis, dose adjustment in patients with mild hepatic impairment is not necessary. However, caution should be exercised when cilostazol is administered to patients with moderate or severe hepatic impairment.

Risk factors of hepatic dysfunction in patients with Graves’ hyperthyroidism and the efficacy of 131iodine treatment

PubMed Central

Wang, Renfei; Tan, Jian; Zhang, Guizhi; Zheng, Wei; Li, Chengxia

2017-01-01

Abstract Hepatic dysfunction is often observed in patients with Graves’ hyperthyroidism. The aims of this study were to investigate the risk factors for hepatic dysfunction and to analyze the efficacy of 131I (radioactive iodine-131) treatment. In total, 2385 patients with Graves’ hyperthyroidism (478 males, 1907 females; age 42.8 ± 13.5 years) were involved in our study. Of these, 1552 cases with hepatic dysfunction received 131I treatment. All clinical data were retrospectively reviewed to explore the risk factors associated with hepatic dysfunction using logistic regression analysis. Furthermore, we observed thyroid and liver function indices for the 1552 subjects at 3, 6 and 12 months after 131I treatment, in order to evaluate efficacy. Overall, 65% patients were affected by hepatic dysfunction. The most common abnormality was elevated alkaline phosphatase (ALP), of which the prevalence was 52.3%. The percentages of hepatocellular injury type, bile stasis, and mixed type were 45.8%, 32.4%, and 21.8%, respectively. Both univariate and multivariate analyses demonstrated that age, duration of Graves hyperthyroidism, free triiodothyronine (FT3)level, and thyrotrophin receptor antibody (TRAb) concentration were the most significant risk factors predicting hepatic dysfunction. Additionally, the patients with mild hepatic dysfunction, or hepatocellular injury type were more likely to attain normal liver function after 131I treatment. Furthermore, after 131I treatment, liver function was more likely to return to normal in the cured group of patients compared with the uncured group. Older patients and cases with a longer history of Graves’ hyperthyroidism, higher FT3 or TRAb concentration were more likely to be associated with hepatic dysfunction, and the prognosis of hepatic dysfunction was closely associated with the outcomes of Graves’ hyperthyroidism after 131I treatment. PMID:28151911

Liver stiffness and platelet count for identifying patients with compensated liver disease at low risk of variceal bleeding.

PubMed

Marot, Astrid; Trépo, Eric; Doerig, Christopher; Schoepfer, Alain; Moreno, Christophe; Deltenre, Pierre

2017-05-01

The 2015 Baveno VI guidelines recommend against performing upper gastrointestinal endoscopy in patients with compensated cirrhosis who have a liver stiffness <20 kPa and a platelet count >150 000/mm³ because of a low prevalence of varices at risk of bleeding in this population. The aim was to synthesize the available evidence on the usefulness of the combined use of liver stiffness and platelet count to identify patients without oesophageal varices. Meta-analysis of trials evaluating the usefulness of a given cut-off for liver stiffness and platelet count to rule out the presence of oesophageal varices. Fifteen studies were included. All studies excepting five used the Baveno VI criteria. Compared to patients with either high liver stiffness or low platelet count, those with low liver stiffness and normal platelet count had a lower risk of varices at risk of bleeding (OR=0.22, 95% CI=0.13-0.39, P<.001) with low heterogeneity between studies (I 2 =21%). They also had a lower risk of varices (OR=0.23, 95% CI=0.17-0.32, P<.001) with moderate heterogeneity between studies (I 2 =28%). In patients with low liver stiffness and normal platelet count, the pooled estimate rates for varices at risk of bleeding was 0.040 (95% CI=0.027-0.059) with low heterogeneity between studies (I 2 =3%). Patients with low liver stiffness and normal platelet count have a lower risk of varices than those with either high liver stiffness or low platelet count. Varices at risk of bleeding are found in no more than 4% of patients when liver stiffness is <20 kPa and platelet count is normal. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An Imaging Biomarker for Assessing Hepatic Function in Patients with Primary Sclerosing Cholangitis.

PubMed

Schulze, Jennifer; Lenzen, Henrike; Hinrichs, Jan B; Ringe, Burckhardt; Manns, Michael P; Wacker, Frank; Ringe, Kristina I

2018-05-15

We aimed to evaluate the potential of hepatobiliary phase magnetic resonance imaging (MRI) as parameter for assessment of hepatocellular function in patients with primary sclerosing cholangitis (PSC). We collected data from 111 patients (83 male, 28 female; median, 44 years old), from March 2012 through March 2016, with a confirmed diagnosis of PSC who underwent MRI evaluation before and after injection (hepatobiliary phase) of a hepatocyte-specific contrast agent (gadoxetate disodium). Signal intensities were measured in each liver segment. Mean relative enhancement values were calculated and correlated with findings from liver functions tests, prognostic scoring systems (model for end-stage liver disease [MELD] score; Mayo risk score; Amsterdam-Oxford-PSC score), abnormalities detected by endoscopic retrograde cholangiopancreatography (using the Amsterdam cholangiographic classification system), and clinical endpoints (liver transplantation, cholangiocarcinoma, liver-related death). Our primary aim was to associate relative enhancement values with liver function and patient outcomes. Most patients had moderate-stage disease and had intermediate levels of risk (median MELD score, 8 and median Mayo score, 0.27). Clinical endpoints were reached by 21 patients (6 developed cholangiocarcinoma, 8 underwent liver transplantation, and 7 patients died). The highest levels of correlations were observed for relative enhancement 20 min after contrast injection and level of alkaline phosphatase (r= -0.636), bilirubin (r= -0.646), albumin (r= 0.538); as well as international normalized ratio (r=0.456); MELD score (r= -0.587); Mayo risk score (r= -0.535), and Amsterdam-Oxford model score (r= -0.595) (P<.0001). Relative enhancement correlated with all clinical endpoints (all P<.05). A cutoff relative enhancement value of 0.65 identified patients with a clinical endpoint with 73.9% sensitivity 92.9% specificity (area under the receiver operating characteristic curve, 0.901; likelihood ratio, 10.34; P<.0001). In an analysis of 111 patients with PSC, we found MRI-measured relative enhancement, using a hepatocyte-specific contrast agent, to identify patients with clinical outcomes with 73.9% sensitivity 92.9% specificity. Long-term, multicenter studies are needed to further evaluate this marker of PSC progression. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Alternative Therapy and Abnormal Liver Function During Adjuvant Chemotherapy in Breast Cancer Patients

PubMed Central

Ahn, Jin-Hee; Kim, Sung-Bae; Yun, Mi Ra; Lee, Jung-Shin; Kang, Yoon-Koo

2004-01-01

Although hepatotoxicity has been rarely reported during adjuvant chemotherapy in breast cancer patients, we observed a high frequency in our patients who were also taking alternative agents. We therefore sought to determine the association between hepatotoxicity and alternative agents during adjuvant chemotherapy in breast cancer patients. All breast cancer patients were treated with the same chemotherapeutic regimen and had normal baseline liver function test (LFT). LFT was checked repeatedly during each cycle of chemotherapy. Patients showing LFT abnormalities were asked about use of alternative agents, and, after the end of chemotherapy, a questionnaire was administered to each patient on their use of alternative agents. Of 178 patients, 65 (36.5%) admitted using alternative therapy, and significantly more patients in this group developed LFT abnormalities (37/65, 56.9%) than those who denied taking alternative therapy (25/113, 22.1%, p=0.001). Although LFT abnormalities were mild to moderate and normalized in most patients after cessation of alternative agents, it remained a serious problem in one patient. In conclusion, alternative therapy may be one of the etiologies for abnormal LFT in breast cancer patients receiving adjuvant chemotherapy. PMID:15201506

Resetting the transcription factor network reverses terminal chronic hepatic failure

PubMed Central

Nishikawa, Taichiro; Bell, Aaron; Brooks, Jenna M.; Setoyama, Kentaro; Melis, Marta; Han, Bing; Fukumitsu, Ken; Handa, Kan; Tian, Jianmin; Kaestner, Klaus H.; Vodovotz, Yoram; Locker, Joseph; Soto-Gutierrez, Alejandro; Fox, Ira J.

2015-01-01

The cause of organ failure is enigmatic for many degenerative diseases, including end-stage liver disease. Here, using a CCl4-induced rat model of irreversible and fatal hepatic failure, which also exhibits terminal changes in the extracellular matrix, we demonstrated that chronic injury stably reprograms the critical balance of transcription factors and that diseased and dedifferentiated cells can be returned to normal function by re-expression of critical transcription factors, a process similar to the type of reprogramming that induces somatic cells to become pluripotent or to change their cell lineage. Forced re-expression of the transcription factor HNF4α induced expression of the other hepatocyte-expressed transcription factors; restored functionality in terminally diseased hepatocytes isolated from CCl4-treated rats; and rapidly reversed fatal liver failure in CCl4-treated animals by restoring diseased hepatocytes rather than replacing them with new hepatocytes or stem cells. Together, the results of our study indicate that disruption of the transcription factor network and cellular dedifferentiation likely mediate terminal liver failure and suggest reinstatement of this network has therapeutic potential for correcting organ failure without cell replacement. PMID:25774505

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 function tests abnormality and clinical severity of dengue infection in adult patients.

PubMed

Kittitrakul, Chatporn; Silachamroon, Udomsak; Phumratanaprapin, Weerapong; Krudsood, Srivicha; Wilairatana, Polrat; Treeprasertsuk, Sombat

2015-01-01

The clinical manifestations of dengue infection in the adult are different from those in children, i.e. having less prevalence to bleeding, and more commonly, abnormal liver function tests. The primary objective is to describe the clinical manifestations of dengue infection in adult patients. The secondary objective is to compare the clinical manifestations of dengue infection between the groups of normal and abnormal liver function tests in adult patients. Retrospective study was done in adults (age 15 years) dengue patients admitted at the Hospital for Tropical Diseases from 2000-2002. Dengue infection diagnosed by WHO clinical criteria 1997 with serological tests confirmed by ELISA test or Rapid Immunochromatographic test. Liver function test was recorded by day of fever. There were 127 adult dengue patients with mean age 26.4 ± 11.5 years. Classifications of dengue infection by WHO criteria were DF 4.7%, DHF grade 126.0%, DHF grade 2 63.0% and DHF grade 3 6.3%. Mean duration of fever clearance time was 6.0 ± 1.9 days but the fever lasted longer in cases of high-level transaminases (> 10 folds). The common presenting symptoms and signs were myalgia (95.9%), nausea/vomiting (87.7%), positive tourniquet test (77.2%), abdominal pain (42.7%), hepatomegaly (34.6%), and bleeding (20.5%). The ratio of AST and ALTwas 1.8:1. Abnormal AST and ALT were found in 88.2% and 69.3% of the patients, respectively. Patients with nausea/vomiting, petechiae or duration of fever > 7 days more frequently had abnormal transaminases. Abnormal AST during the febrile stage was associated with bleeding. High-level AST and ALT occurred in 11.0% and 7.0%, respectively. Shock was associated with high-level ALT during the febrile stage. Adult dengue patients commonly showed abnormal liver function tests and accounted for at least two-thirds of them. High-level ALT during the febrile stage showed association with shock.

Influence of Donor and Recipient CYP3A4, CYP3A5, and ABCB1 Genotypes on Clinical Outcomes and Nephrotoxicity in Liver Transplant Recipients.

PubMed

Debette-Gratien, Marilyne; Woillard, Jean-Baptiste; Picard, Nicolas; Sebagh, Mylène; Loustaud-Ratti, Véronique; Sautereau, Denis; Samuel, Didier; Marquet, Pierre

2016-10-01

This study investigated the influence of the CYP3A4*22, CYP3A5*3, and ABCB1 exons 12, 21, and 26 polymorphisms in donors and recipients on clinical outcomes and renal function in 170 liver transplant patients on cyclosporin A (CsA) or tacrolimus (Tac). Allelic discrimination assays were used for genotyping. Multivariate time-dependent Cox proportional hazard models, multiple linear regression using the generalized estimating equation and linear mixed-effect models were used for statistical analysis. Expression of CYP3A5 by either or both the donor and the recipient was significantly associated with lower Tac, but not CsA, dose-normalized trough levels. In the whole population, graft loss was only significantly associated with longer exposure to high calcineurin inhibitor (CNI) concentrations (hazard ratio, 6.93; 95% confidence interval, 2.13-22.55), P = 0.00129), whereas in the Tac subgroup, the risk of graft loss was significantly higher in recipient CYP3A5*1 expressers (hazard ratio, 3.39; 95% confidence interval, 1.52-7.58; P = 0.0028). Renal function was significantly associated with: (1) baseline modification of diet in renal disease (β = 0.51 ± 0.05; P < 0.0001); (2) duration of patient follow-up (per visit, β = -0.98 ± 0.22; P < 0.0001); and (3) CNI exposure (per quantile increase, β = -2.42 ± 0.59; P < 0.0001). No genetic factor was associated with patient survival, acute rejection, liver function test results, recurrence of viral or other initial liver disease, or renal function. This study confirms the effect of CYP3A5*3 on tacrolimus dose requirement in liver transplantation and shows unexpected associations between the type of, and exposure to, CNI and either chronic rejection or graft loss. None of the genetic polymorphisms studied had a noticeable impact on renal function degradation at 10 years.

Liver transplantation from a deceased donor with β-thalassemia intermedia is not contraindicated: A case report.

PubMed

Gumus, Ersin; Abbasoglu, Osman; Tanyel, Cahit; Gumruk, Fatma; Ozen, Hasan; Yuce, Aysel

2017-05-01

The use of extended criteria donors who might have previously been deemed unsuitable is an option to increase the organ supply for transplantation. This report presents a pediatric case of a successful liver transplantation from a donor with β-thalassemia intermedia. A patient, 6-year-old female, with a diagnosis of cryptogenic liver cirrhosis underwent deceased donor liver transplantation from a thalassemic donor. Extreme hyperferritinemia was detected shortly after transplantation. The most probable cause of hyperferritinemia was iron overload secondary to transplantation of a hemosiderotic liver. Hepatocellular injury due to acute graft rejection might have contributed to elevated ferritin levels by causing release of stored iron from the hemosiderotic liver graft. Iron chelation and phlebotomy therapies were started simultaneously in the early postoperative period to avoid iron-related organ toxicity and transplant failure. Follow-up with monthly phlebotomies after discharge yielded a favorable outcome with normal transplant functions. Thalassemia intermedia patients can be candidates of liver donors to decrease pretransplant waitlist mortality. After transplantation of a hemosiderotic liver, it is important to monitor the recipient in terms of iron overload and toxicity. Early attempts to lower iron burden including chelation therapy and/or phlebotomy should be considered to avoid organ toxicity and transplant failure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

Deregulated Methionine Adenosyltransferase α1, c-Myc and Maf Proteins Interplay Promotes Cholangiocarcinoma Growth in Mice and Humans

PubMed Central

Yang, Heping; Liu, Ting; Wang, Jiaohong; Li, Tony W.H.; Fan, Wei; Peng, Hui; Krishnan, Anuradha; Gores, Gregory J.; Mato, Jose M.; Lu, Shelly C.

2016-01-01

We reported c-Myc induction drives cholestatic liver injury and cholangiocarcinoma (CCA) in mice. We also showed induction of Maf proteins (MafG and c-Maf) contributed to cholestatic liver injury, whereas S-adenosylmethionine (SAMe) administration was protective. Here we determined whether there is interplay between c-Myc, Maf proteins and methionine adenosyltransferase α1 (MATα1), which is responsible for SAMe biosynthesis in liver. We used bile duct ligation (BDL) and lithocholic acid (LCA) treatment in mice as chronic cholestasis models, a murine CCA model, human CCA cell lines KMCH and Huh-28, human liver cancer HepG2, and human CCA specimens to study gene and protein expression, protein-protein interactions, molecular mechanisms and functional outcomes. We found c-Myc, MATα1 (encoded by MAT1A), MafG and c-Maf interact with each other directly. MAT1A expression fell in hepatocytes and bile duct epithelial cells during chronic cholestasis and in murine and human CCA. The opposite occurred with c-Myc, MafG and c-Maf expression. MATα1 interacts mainly with Mnt in normal liver but this switches to c-Maf, MafG and c-Myc in cholestatic livers and CCA. Promoter regions of these genes have E-boxes that are bound by MATα1 and Mnt in normal liver and benign bile duct epithelial cells that switched to c-Myc, c-Maf and MafG in cholestasis and CCA cells. E-box positively regulates c-Myc, MafG and c-Maf, but it negatively regulates MAT1A. MATα1 represses whereas c-Myc, MafG and c-Maf enhance E-box-driven promoter activity. Knocking down MAT1A or overexpressing MafG or c-Maf enhanced CCA growth and invasion in vivo. Conclusion We have uncovered a novel interplay between MATα1, c-Myc and Maf proteins and their deregulation during chronic cholestasis may facilitate CCA oncogenesis. PMID:26969892

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.

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.

Liver myofibroblasts of murine origins express mesothelin: Identification of novel rat mesothelin splice variants*

PubMed Central

G. Lavoie, Elise; Dranoff, Jonathan A.

2017-01-01

Liver myofibroblasts are specialized effector cells that drive hepatic fibrosis, a hallmark process of chronic liver diseases, leading to progressive scar formation and organ failure. Liver myofibroblasts are increasingly recognized as heterogeneous with regards to their origin, phenotype, and functions. For instance, liver myofibroblasts express cell markers that are universally represented such as, ItgαV and Pdgfrβ, or restricted to a given subpopulation such as, Lrat exclusively expressed in hepatic stellate cells, and Gpm6a in mesothelial cells. To study liver myofibroblasts in vitro, we have previously generated and characterized a SV40-immortalized polyclonal rat activated portal fibroblast cell line called RGF-N2 expressing multiple mesothelin mRNA transcripts. Mesothelin, a cell-surface molecule expressed in normal mesothelial cells and overexpressed in several cancers such as, mesothelioma and cholangiocarcinoma, was recently identified as a key regulator of portal myofibroblast proliferation, and fibrosis progression in the setting of chronic cholestatic liver disease. Here, we identify novel mesothelin splice variants expressed in rat activated portal fibroblasts. RGF-N2 portal fibroblast cDNA was used as template for insertion of hemagglutinin tag consensus sequence into the complete open reading frame of rat mesothelin variant coding sequences by extension PCR. Purified amplicons were subsequently cloned into an expression vector for in vitro translation and transfection in monkey COS7 fibroblasts, before characterization of fusion proteins by immunoblot and immunofluorescence. We show that rat activated portal fibroblasts, hepatic stellate cells, and cholangiocarcinoma cells express wild-type mesothelin and additional splice variants, while mouse activated hepatic stellate cells appear to only express wild-type mesothelin. Notably, rat mesothelin splice variants differ from the wild-type isoform by their protein properties and cellular distribution in transfected COS7 fibroblasts. We conclude that mesothelin is a marker of activated murine liver myofibroblasts. Mesothelin gene expression and regulation may be critical in liver myofibroblasts functions and fibrosis progression. PMID:28898276

Gallium-68 DOTATOC PET/CT In Vivo Characterization of Somatostatin Receptor Expression in the Prostate

PubMed Central

Gajić, Milan M.; Obradović, Vladimir B.; Baum, Richard P.

2014-01-01

Abstract Aim: The aim was to investigate somatostatin receptor (sstr) expression in normal prostate by determining the maximum standardized uptake value (SUVmax) of 68Ga-DOTATOC PET/CT in neuroendocrine tumor (NET) patients, without NET involvement of the prostate gland, for establishing the reference standard. Methods: Sixty-four NET patients underwent 68Ga-DOTATOC PET/CT. SUVmax of the prostate gland, normal liver, testes, and gluteus muscles were evaluated. The prostate gland size was measured. Statistical analysis was performed using dedicated software (SPSS13). Results: Mean/median 68Ga-DOTATOC SUVmax values were as follows: normal prostate 2.6±0.0, slightly enlarged prostate 4.2±1.6, prostatic hypertrophy 4.9±1.6, prostatic hyperplasia 5.0±1.5, prostate cancer 9.5±2.1, normal liver 7.3±1.8, testes 1.8±0.5, and gluteus 1.0±0.2. The normal prostate gland had three times less sstr expression than normal liver tissue. Strong correlation was found between patient age and sstr expression in prostate/prostate size. No significant difference existed in sstr expression between prostatic hypertrophy and hyperplasia. Much higher sstr expression was found in prostatic cancer compared with normal prostate. Conclusion: 68Ga-DOTATOC PET/CT defines the baseline sstr uptake in prostate not affected by NET (significantly lower than in the liver). Higher values were established in prostatic hyperplasia and hypertrophy. Only concomitant prostate cancer was associated with higher SUVmax in comparison with non-neoplastic liver. PMID:24450327

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.

Dimethylethanolamine does not prevent liver failure in phosphatidylethanolamine N-methyltransferase-deficient mice fed a choline-deficient diet.

PubMed

Waite, Kristin A; Vance, Dennis E

2004-03-22

Mice that lack phosphatidylethanolamine-N-methyltransferase (PEMT) and are fed a choline-deficient (CD) diet suffer severe liver damage and do not survive. Since phosphatidyldimethylethanolamine (PDME) has physical properties similar to those of phosphatidylcholine (PC), we hypothesized that dimethylethanolamine (DME) would be converted into PDME that might substitute for PC, and therefore abrogate the liver damage in the Pemt -/- mice fed a CD diet. We fed Pemt -/- mice either a CD diet, a CD diet supplemented with choline, or a CD diet supplemented with DME (CD + DME). Pemt -/- mice fed the CD diet developed severe liver failure by 4 days while CD + DME-fed mice developed severe liver failure by 5 days. The hepatic PC level in choline-supplemented (CS) mice was 67 +/- 4 nmol/mg protein, whereas the PC content was reduced in CD- and CD + DME-fed mice (49 +/- 3 and 30 +/- 3 nmol/mg protein, respectively). Upon supplementation of the CD diet with DME the amount of hepatic PDME was 81 +/- 9 nmol/mg protein so that the hepatic content of PC + PDME combined was 111 nmol/mg protein. Moreover, plasma apolipoprotein B100 and Al levels were markedly lower in mice fed the CD + DME diet compared to mice fed the CS diet, as was the plasma content of PC. Thus, despite replacement of the deficit in hepatic PC with PDME in Pemt -/- mice fed a CD diet, normal liver function was not restored. We conclude that although PC and PDME exhibit similar physical properties, the three methyl groups of choline are required for hepatic function in mice.

Peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP) but not PPAR-interacting protein (PRIP) is required for nuclear translocation of constitutive androstane receptor in mouse liver.

PubMed

Guo, Dongsheng; Sarkar, Joy; Ahmed, Mohamed R; Viswakarma, Navin; Jia, Yuzhi; Yu, Songtao; Sambasiva Rao, M; Reddy, Janardan K

2006-08-25

The constitutive androstane receptor (CAR) regulates transcription of phenobarbital-inducible genes that encode xenobiotic-metabolizing enzymes in liver. CAR is localized to the hepatocyte cytoplasm but to be functional, it translocates into the nucleus in the presence of phenobarbital-like CAR ligands. We now demonstrate that adenovirally driven EGFP-CAR, as expected, translocates into the nucleus of normal wild-type hepatocytes following phenobarbital treatment under both in vivo and in vitro conditions. Using this approach we investigated the role of transcription coactivators PBP and PRIP in the translocation of EGFP-CAR into the nucleus of PBP and PRIP liver conditional null mouse hepatocytes. We show that coactivator PBP is essential for nuclear translocation of CAR but not PRIP. Adenoviral expression of both PBP and EGFP-CAR restored phenobarbital-mediated nuclear translocation of exogenously expressed CAR in PBP null livers in vivo and in PBP null primary hepatocytes in vitro. CAR translocation into the nucleus of PRIP null livers resulted in the induction of CAR target genes such as CYP2B10, necessary for the conversion of acetaminophen to its hepatotoxic intermediate metabolite, N-acetyl-p-benzoquinone imine. As a consequence, PRIP-deficiency in liver did not protect from acetaminophen-induced hepatic necrosis, unlike that exerted by PBP deficiency. These results establish that transcription coactivator PBP plays a pivotal role in nuclear localization of CAR, that it is likely that PBP either enhances nuclear import or nuclear retention of CAR in hepatocytes, and that PRIP is redundant for CAR function.

PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis

PubMed Central

Méndez-Lucas, Andrés; Duarte, João; Sunny, Nishanth E.; Satapati, Santhosh; He, TianTeng; Fu, Xiaorong; Bermúdez, Jordi; Burgess, Shawn C.; Perales, Jose C.

2013-01-01

Background & Aims Hepatic gluconeogenesis helps maintain systemic energy homeostasis by compensating for discontinuities in nutrient supply. Liver specific deletion of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) abolishes gluconeogenesis from mitochondrial substrates, deregulates lipid metabolism and affects TCA cycle. While, mouse liver almost exclusively expresses PEPCK-C, humans equally present a mitochondrial isozyme (PEPCK-M). Despite clear relevance to human physiology, the role of PEPCK-M and its gluconeogenic potential remain unknown. Here, we test the significance of PEPCK-M in gluconeogenesis and TCA cycle function in liver-specific PEPCK-C knockout and WT mice. Methods The effects of the overexpression of PEPCK-M were examined by a combination of tracer studies and molecular biology techniques. Partial PEPCK-C re-expression was used as a positive control. Metabolic fluxes were evaluated in isolated livers by NMR using 2H and 13C tracers. Gluconeogenic potential, together with metabolic profiling, were investigated in vivo and in primary hepatocytes. Results PEPCK-M expression partially rescued defects in lipid metabolism, gluconeogenesis and TCA cycle function impaired by PEPCK-C deletion, while ~10% re-expression of PEPCK-C normalized most parameters. When PEPCK-M was expressed in the presence of PEPCK-C, the mitochondrial isozyme amplified total gluconeogenic capacity, suggesting autonomous regulation of oxaloacetate to phosphoenolpyruvate fluxes by the individual isoforms. Conclusions We conclude that PEPCK-M has gluconeogenic potential per se, and cooperates with PEPCK-C to adjust gluconeogenic/TCA flux to changes in substrate or energy availability, hinting at a role in the regulation of glucose and lipid metabolism in human liver. PMID:23466304

Normal and Fibrotic Rat Livers Demonstrate Shear Strain Softening and Compression Stiffening: A Model for Soft Tissue Mechanics

PubMed Central

Cao, Xuan; van Oosten, Anne; Shenoy, Vivek B.; Janmey, Paul A.; Wells, Rebecca G.

2016-01-01

Tissues including liver stiffen and acquire more extracellular matrix with fibrosis. The relationship between matrix content and stiffness, however, is non-linear, and stiffness is only one component of tissue mechanics. The mechanical response of tissues such as liver to physiological stresses is not well described, and models of tissue mechanics are limited. To better understand the mechanics of the normal and fibrotic rat liver, we carried out a series of studies using parallel plate rheometry, measuring the response to compressive, extensional, and shear strains. We found that the shear storage and loss moduli G’ and G” and the apparent Young's moduli measured by uniaxial strain orthogonal to the shear direction increased markedly with both progressive fibrosis and increasing compression, that livers shear strain softened, and that significant increases in shear modulus with compressional stress occurred within a range consistent with increased sinusoidal pressures in liver disease. Proteoglycan content and integrin-matrix interactions were significant determinants of liver mechanics, particularly in compression. We propose a new non-linear constitutive model of the liver. A key feature of this model is that, while it assumes overall liver incompressibility, it takes into account water flow and solid phase compressibility. In sum, we report a detailed study of non-linear liver mechanics under physiological strains in the normal state, early fibrosis, and late fibrosis. We propose a constitutive model that captures compression stiffening, tension softening, and shear softening, and can be understood in terms of the cellular and matrix components of the liver. PMID:26735954

Relation of Insulin Resistance and Liver Fibrosis Progression in Patients with Chronic Hepatitis C Virus Infection

PubMed Central

Mohamed, Hassan R; Abdel-Azziz, Mohamed Yaqoot; Zalata, Kkaled Refaat; Abdel-Razik, Ahmed M M

2009-01-01

Background: Hepatitis C virus (HCV) infection can predispose to the development of insulin resistance before diabetes occurs. Such a potential link is particularly cogent in light of recent data indicate that diabetes may be associated with increased hepatic fibrosis progression in patients with chronic HCV infection. The aim of the study is to determine the prevalence of insulin resistance in non diabetic patients with chronic hepatitis C and its relation to liver fibrosis. Methods: Thirty eight patients with chronic liver diseases. They subdivided into 2 groups; chronic hepatitis C (CHC) with elevated liver enzymes and CHC with normal liver enzymes. Age and sex matched 12 healthy subjects as control group. All subjects were subjected to Careful history and copmlete examination with stress upon symptoms and signs of chronic liver diseases. Investigations include liver function tests; viral markers (Anti HCV antibodies & PCR for HCV). Serum fasting glucose; serum fasting insulin; homeostasis model assessment (HOMA), liver biopsy and abdominal ultrasound. Results: No correlation between viral load and hepatic fibrosis in HCV infected patients. Liver fibrosis is considerably higher among HCV patients with elevated serum transaminase levels. Insulin resistance is present in HCV infected cases compared with control group and it is positively correlated with liver fibrosis. Conclusion: The present data support the hypothesis that insulin resistance may increase the rate of fibrosis progression in non diabetic patients with chronic HCV. Follow up of hyperinsulinemia by serial measurement of HOMA test in non diabetic HCV infected patients may be a biochemical indicator for progression of liver fibrosis. PMID:21475535

Alpha fetoprotein - series (image)

MedlinePlus

... normal levels of AFP may be due to: Cancer in testes, ovaries, biliary (liver secretion) tract, stomach, or pancreas Cirrhosis of the liver Liver cancer Malignant teratoma Recovery from hepatitis Problems during pregnancy ...

Transient diabetes insipidus in pregnancy

PubMed Central

Gunawardana, Kavinga; Grossman, Ashley

2015-01-01

Summary Gestational diabetes insipidus (DI) is a rare complication of pregnancy, usually developing in the third trimester and remitting spontaneously 4–6 weeks post-partum. It is mainly caused by excessive vasopressinase activity, an enzyme expressed by placental trophoblasts which metabolises arginine vasopressin (AVP). Its diagnosis is challenging, and the treatment requires desmopressin. A 38-year-old Chinese woman was referred in the 37th week of her first single-gestation due to polyuria, nocturia and polydipsia. She was known to have gestational diabetes mellitus diagnosed in the second trimester, well-controlled with diet. Her medical history was unremarkable. Physical examination demonstrated decreased skin turgor; her blood pressure was 102/63 mmHg, heart rate 78 beats/min and weight 53 kg (BMI 22.6 kg/m2). Laboratory data revealed low urine osmolality 89 mOsmol/kg (350–1000), serum osmolality 293 mOsmol/kg (278–295), serum sodium 144 mmol/l (135–145), potassium 4.1 mmol/l (3.5–5.0), urea 2.2 mmol/l (2.5–6.7), glucose 3.5 mmol/l and HbA1c 5.3%. Bilirubin, alanine transaminase, alkaline phosphatase and full blood count were normal. The patient was started on desmopressin with improvement in her symptoms, and normalisation of serum and urine osmolality (280 and 310 mOsmol/kg respectively). A fetus was delivered at the 39th week without major problems. After delivery, desmopressin was stopped and she had no further evidence of polyuria, polydipsia or nocturia. Her sodium, serum/urine osmolality at 12-weeks post-partum were normal. A pituitary magnetic resonance imaging (MRI) revealed the neurohypophyseal T1-bright spot situated ectopically, with a normal adenohypophysis and infundibulum. She remains clinically well, currently breastfeeding, and off all medication. This case illustrates some challenges in the diagnosis and management of transient gestational DI. Learning points Gestational DI is a rare complication of pregnancy occurring in two to four out of 100 000 pregnancies. It usually develops at the end of the second or third trimester of pregnancy and remits spontaneously 4–6 weeks after delivery. Gestational DI occurrence is related to excessive vasopressinase activity, an enzyme expressed by placental trophoblasts during pregnancy, which metabolises AVP. Its activity is proportional to the placental weight, explaining the higher vasopressinase activity in third trimester or in multiple pregnancies. Vasopressinase is metabolised by the liver, which most likely explains its higher concentrations in pregnant women with hepatic dysfunction, such acute fatty liver of pregnancy, HELLP syndrome, hepatitis and cirrhosis. Therefore, it is important to assess liver function in patients with gestational DI, and to be aware of the risk of DI in pregnant women with liver disease. Serum and urine osmolality are essential for the diagnosis, but other tests such as serum sodium, glucose, urea, creatinine, liver function may be informative. The water deprivation test is normally not recommended during pregnancy because it may lead to significant dehydration, but a pituitary MRI should be performed at some point to exclude lesions in the hypothalamo-pituitary region. These patients should be monitored for vital signs, fluid balance, body weight, fetal status, renal and liver function, and treated with desmopressin. The recommended doses are similar or slightly higher than those recommended for central DI in non-pregnant women, and should be titrated individually. PMID:26524979

Transient diabetes insipidus in pregnancy.

PubMed

Marques, Pedro; Gunawardana, Kavinga; Grossman, Ashley

2015-01-01

Gestational diabetes insipidus (DI) is a rare complication of pregnancy, usually developing in the third trimester and remitting spontaneously 4-6 weeks post-partum. It is mainly caused by excessive vasopressinase activity, an enzyme expressed by placental trophoblasts which metabolises arginine vasopressin (AVP). Its diagnosis is challenging, and the treatment requires desmopressin. A 38-year-old Chinese woman was referred in the 37th week of her first single-gestation due to polyuria, nocturia and polydipsia. She was known to have gestational diabetes mellitus diagnosed in the second trimester, well-controlled with diet. Her medical history was unremarkable. Physical examination demonstrated decreased skin turgor; her blood pressure was 102/63 mmHg, heart rate 78 beats/min and weight 53 kg (BMI 22.6 kg/m(2)). Laboratory data revealed low urine osmolality 89 mOsmol/kg (350-1000), serum osmolality 293 mOsmol/kg (278-295), serum sodium 144 mmol/l (135-145), potassium 4.1 mmol/l (3.5-5.0), urea 2.2 mmol/l (2.5-6.7), glucose 3.5 mmol/l and HbA1c 5.3%. Bilirubin, alanine transaminase, alkaline phosphatase and full blood count were normal. The patient was started on desmopressin with improvement in her symptoms, and normalisation of serum and urine osmolality (280 and 310 mOsmol/kg respectively). A fetus was delivered at the 39th week without major problems. After delivery, desmopressin was stopped and she had no further evidence of polyuria, polydipsia or nocturia. Her sodium, serum/urine osmolality at 12-weeks post-partum were normal. A pituitary magnetic resonance imaging (MRI) revealed the neurohypophyseal T1-bright spot situated ectopically, with a normal adenohypophysis and infundibulum. She remains clinically well, currently breastfeeding, and off all medication. This case illustrates some challenges in the diagnosis and management of transient gestational DI. Gestational DI is a rare complication of pregnancy occurring in two to four out of 100 000 pregnancies. It usually develops at the end of the second or third trimester of pregnancy and remits spontaneously 4-6 weeks after delivery.Gestational DI occurrence is related to excessive vasopressinase activity, an enzyme expressed by placental trophoblasts during pregnancy, which metabolises AVP. Its activity is proportional to the placental weight, explaining the higher vasopressinase activity in third trimester or in multiple pregnancies.Vasopressinase is metabolised by the liver, which most likely explains its higher concentrations in pregnant women with hepatic dysfunction, such acute fatty liver of pregnancy, HELLP syndrome, hepatitis and cirrhosis. Therefore, it is important to assess liver function in patients with gestational DI, and to be aware of the risk of DI in pregnant women with liver disease.Serum and urine osmolality are essential for the diagnosis, but other tests such as serum sodium, glucose, urea, creatinine, liver function may be informative. The water deprivation test is normally not recommended during pregnancy because it may lead to significant dehydration, but a pituitary MRI should be performed at some point to exclude lesions in the hypothalamo-pituitary region.These patients should be monitored for vital signs, fluid balance, body weight, fetal status, renal and liver function, and treated with desmopressin. The recommended doses are similar or slightly higher than those recommended for central DI in non-pregnant women, and should be titrated individually.

Boron attenuates malathion-induced oxidative stress and acetylcholinesterase inhibition in rats.

PubMed

Coban, Funda Karabag; Ince, Sinan; Kucukkurt, Ismail; Demirel, Hasan Huseyin; Hazman, Omer

2015-10-01

Organophosphorus compounds cause oxidative stress and lead to alterations in antioxidant status in organisms. In this study, the effects of subchronic exposure to malathion and the protective effects of boron (B) were evaluated in 48 Wistar rats, which were divided equally into six groups. For 28 d, the control group received a normal diet and tap water, the corn oil group received a normal diet and 0.5 mL of corn oil by gastric gavage and the malathion group received a normal diet and malathion (100 mg/kg/d) by gastric gavage. During the same period, each of the three other groups received a different dosage of B (5, 10 and 20 mg/kg/d, respectively) and malathion (100 mg/kg/d) by gastric gavage. Malathion administration during the period increased malondialdehyde, nitric oxide and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, as well as markers of liver function, yet decreased acetylcholinesterase, reduced glutathione, superoxide dismutase, and catalase activities in blood, liver, kidney and brain tissues. Administration of B in a dose-dependent manner also reversed malathion-induced oxidative stress, lipid peroxidation (LPO) and antioxidant enzyme activity. Moreover, B exhibited protective action against malathion-induced histopathological changes in liver, kidney and brain tissues. These results demonstrate that, if used in a dose-dependent manner, B decreases malathion-induced oxidative stress, enhances the antioxidant defense mechanism and regenerates tissues in rats.

Increased peripheral CD4+ regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C.

PubMed

Langhans, Bettina; Nischalke, Hans Dieter; Krämer, Benjamin; Hausen, Annekristin; Dold, Leona; van Heteren, Peer; Hüneburg, Robert; Nattermann, Jacob; Strassburg, Christian P; Spengler, Ulrich

2017-05-01

CD4 + regulatory T cells (Tregs) expand during chronic hepatitis C virus (HCV) infection, inhibit antiviral immunity and promote fibrosis. Direct-acting antiviral agents (DAA) have revolutionized HCV therapy. However, it is unclear if Tregs are normalized after DAA-induced HCV elimination. We analyzed Tregs before (baseline), at end of therapy (EOT), 12 and 24weeks (SVR12, SVR24) and long-term (51±14weeks) after EOT in 26 genotype-1-infected patients who were successfully treated with sofosbuvir (SOF) plus interferon (IFN)/ribavirin (n=12) and IFN-free DAA regimens (SOF plus daclatasvir or simeprevir; n=14). Frequency, phenotype and suppressor function of peripheral Foxp3 + CD25 + CD4 + T cells were studied by multi-color flow cytometry and co-culture inhibition assays. Frequencies and activation status of Foxp3 + CD25 + CD4 + T cells remained elevated above those of normal controls in both treatment groups even long-term after HCV elimination. Co-culture assays indicated a dose-response relationship for functional inhibition of autologous CD4 + effector T cells and confirmed that activation of Tregs remained largely unchanged over the observation period. Unlike IFN-free regimens, SOF plus IFN/ribavirin induced a transiently increased frequency of Foxp3 + CD25 + CD4 + T cells at EOT (5.0% at baseline to 6.1% at EOT; p=0.001). These Foxp3 + CD25 + CD4 + T cells co-expressed the activation markers glycoprotein A repetitions predominant (GARP; p=0.012) and tumor necrosis factor receptor superfamily, member 4 (OX-40; p=0.001) but showed unchanged in vitro inhibitory activity. Although IFN-based DAA therapy induced transient expansion of activated Foxp3 + CD25 + CD4 + T cells, neither IFN-based nor IFN-free DAA regimens normalized frequencies and activation status of Tregs one year after viral elimination. Persistence of immunosuppressive Tregs may thus contribute to complications of liver disease even long-term after HCV cure. In chronic hepatitis C virus (HCV) infection, CD4 + regulatory T cells (Tregs) can reduce antiviral immune responses, promote liver fibrosis and may increase the risk for liver cancer, because they gradually expand during disease. Modern direct-acting antiviral agents (DAA) can "cure" hepatitis C in almost all treated patients. However, our study shows that DAA do not normalize the increased frequency and activation status of Tregs even long-term after HCV elimination. Tregs may persistently modulate functions of the immune system even after "cure" of hepatitis C. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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.

Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt

PubMed Central

Abdel-Moneim, Adel; Morsy, Basant M.; Mahmoud, Ayman M.; Abo-Seif, Mohamed A.; Zanaty, Mohamed I.

2013-01-01

Hepatitis C is a major global health burden and Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. The current study was designed to evaluate the beneficial therapeutic effects of ethanolic extracts of Nigella sativa, Zingiber officinale and their mixture in Egyptian HCV patients. Sixty volunteer patients with proven HCV and fifteen age matched healthy subjects were included in this study. Exclusion criteria included patients on interferon alpha (IFN-α) therapy, infection with hepatitis B virus, drug-induced liver diseases, advanced cirrhosis, hepatocellular carcinoma (HCC) or other malignancies, blood picture abnormalities and major severe illness. Liver function enzymes, albumin, total bilirubin, prothrombin time and concentration, international normalized ratio, alpha fetoprotein and viral load were all assessed at baseline and at the end of the study. Ethanolic extracts of Nigella sativa and Zingiber officinale were prepared and formulated into gelatinous capsules, each containing 500 mg of Nigella sativa and/or Zingiber officinale. Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study. Both extracts as well as their mixture significantly ameliorated the altered viral load, alpha fetoprotein, liver function parameters; with more potent effect for the combined therapy. In conclusion, administration of Nigella sativa and/or Zingiber officinale ethanolic extracts to HCV patients exhibited potential therapeutic benefits via decreasing viral load and alleviating the altered liver function, with more potent effect offered by the mixture. PMID:27298610

Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt.

PubMed

Abdel-Moneim, Adel; Morsy, Basant M; Mahmoud, Ayman M; Abo-Seif, Mohamed A; Zanaty, Mohamed I

2013-01-01

Hepatitis C is a major global health burden and Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. The current study was designed to evaluate the beneficial therapeutic effects of ethanolic extracts of Nigella sativa, Zingiber officinale and their mixture in Egyptian HCV patients. Sixty volunteer patients with proven HCV and fifteen age matched healthy subjects were included in this study. Exclusion criteria included patients on interferon alpha (IFN-α) therapy, infection with hepatitis B virus, drug-induced liver diseases, advanced cirrhosis, hepatocellular carcinoma (HCC) or other malignancies, blood picture abnormalities and major severe illness. Liver function enzymes, albumin, total bilirubin, prothrombin time and concentration, international normalized ratio, alpha fetoprotein and viral load were all assessed at baseline and at the end of the study. Ethanolic extracts of Nigella sativa and Zingiber officinale were prepared and formulated into gelatinous capsules, each containing 500 mg of Nigella sativa and/or Zingiber officinale. Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study. Both extracts as well as their mixture significantly ameliorated the altered viral load, alpha fetoprotein, liver function parameters; with more potent effect for the combined therapy. In conclusion, administration of Nigella sativa and/or Zingiber officinale ethanolic extracts to HCV patients exhibited potential therapeutic benefits via decreasing viral load and alleviating the altered liver function, with more potent effect offered by the mixture.

Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial.

PubMed

Rogers, Zora R; Wang, Winfred C; Luo, Zhaoyu; Iyer, Rathi V; Shalaby-Rana, Eglal; Dertinger, Stephen D; Shulkin, Barry L; Miller, John H; Files, Bea; Lane, Peter A; Thompson, Bruce W; Miller, Scott T; Ware, Russell E

2011-03-03

We evaluated spleen function in 193 children with sickle cell anemia 8 to 18 months of age by (99m)Tc sulfur-colloid liver-spleen scan and correlated results with clinical and laboratory parameters, including 2 splenic biomarkers: pitted cell counts (PIT) and quantitative Howell-Jolly bodies (HJB) enumerated by flow cytometry. Loss of splenic function began before 12 months of age in 86% of infants in association with lower total or fetal hemoglobin and higher white blood cell or reticulocyte counts, reinforcing the need for early diagnosis and diligent preventive care. PIT and HJB correlated well with each other and liver-spleen scan results. Previously described biomarker threshold values did define patients with abnormal splenic function, but our data suggest that normal spleen function is better predicted by PIT of ≤1.2% or HJB ≤55/10(6) red blood cells and absent function by PIT ≥4.5% or HJB ≥665/10(6). HJB is methodologically advantageous compared with PIT, but both are valid biomarkers of splenic function. This trial was registered at www.clinicaltrials.gov as #NCT00006400. © 2011 by The American Society of Hematology

Image-guided intervention in the coagulopathic patient.

PubMed

Kohli, Marc; Mayo-Smith, William; Zagoria, Ronald; Sandrasegaran, Kumar

2016-04-01

Determining practice parameters for interventional procedures is challenging due to many factors including unreliable laboratory tests to measure bleeding risk, variable usage of standardized terminology for adverse events, poorly defined standards for administration of blood products, and the growing numbers of anticoagulant and antiplatelet medications. We aim to address these and other issues faced by radiologists performing invasive procedures through a review of available literature, and experiential guidance from three academic medical centers. We discuss the significant limitations with respect to using prothrombin-time and international normalized ratio to measure bleeding risk, especially in patients with synthetic defects due to liver function. Factors affecting platelet function including the impact of uremia; recent advances in laboratory testing, including platelet function testing; and thromboelastography are also discussed. A review of the existing literature of fresh-frozen plasma replacement therapy is included. The literature regarding comorbidities affecting coagulation including malignancy, liver failure, and uremia are also reviewed. Finally, the authors present a set of recommendations for laboratory thresholds, corrective transfusions, as well as withholding and restarting medications.

Upper gastrointestinal bleeding: an ammoniagenic and catabolic event due to the total absence of isoleucine in the haemoglobin molecule.

PubMed

Olde Damink, S W; Dejong, C H; Deutz, N E; van Berlo, C L; Soeters, P B

1999-06-01

Upper gastrointestinal bleeding causes increased urea concentrations in patients with normal liver function and high ammonia concentrations in patients with impaired liver function. This ammoniagenesis may precipitate encephalopathy. The haemoglobin molecule is unique because it lacks the essential amino acid isoleucine and has high amounts of leucine and valine. Upper gastrointestinal bleeding therefore presents the gut with protein of very low biologic value, which may be the stimulus to induce a cascade of events culminating in net catabolism. This may influence the function of rapidly dividing cells and short half-life proteins. We hypothesize that, following a variceal bleed in a cirrhotic patient, the lack of isoleucine in blood protein is the cause of the exaggerated ammoniagenesis and catabolism. We propose that intravenous administration of isoleucine may serve as a simple therapeutic that transforms blood protein in a balanced protein, resulting in only a short-lived rise in ammonia and urea production, and preventing interference with protein synthesis.

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.

The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis

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

Cheng, Yahui; Tian, Yuanyao; Xia, Jialu

Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl{sub 4}-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl{sub 4}-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantlymore » decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis. - Highlights: • CCl{sub 4} treatment triggered a mixed M1/M2 macrophage phenotype in fibrosis. • Lower expression of PTEN in murine M2 macrophages in vivo and vitro. • PTEN modulates M2 macrophages activation via PI3K/Akt/STAT6 signaling. • Provide a new cellular target modulate macrophage mediated hepatic fibrosis.« less

Assessment of tumor vascularization with functional computed tomography perfusion imaging in patients with cirrhotic liver disease.

PubMed

Li, Jin-Ping; Zhao, De-Li; Jiang, Hui-Jie; Huang, Ya-Hua; Li, Da-Qing; Wan, Yong; Liu, Xin-Ding; Wang, Jin-E

2011-02-01

Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and early diagnosis is critical for patient outcome. In patients with HCC, it is mostly based on liver cirrhosis, developing from benign regenerative nodules and dysplastic nodules to HCC lesions, and a better understanding of its vascular supply and the hemodynamic changes may lead to early tumor detection. Angiogenesis is essential for the growth of primary and metastatic tumors due to changes in vascular perfusion, blood volume and permeability. These hemodynamic and physiological properties can be measured serially using functional computed tomography perfusion (CTP) imaging and can be used to assess the growth of HCC. This study aimed to clarify the physiological characteristics of tumor angiogenesis in cirrhotic liver disease by this fast imaging method. CTP was performed in 30 volunteers without liver disease (control subjects) and 49 patients with liver disease (experimental subjects: 27 with HCC and 22 with cirrhosis). All subjects were also evaluated by physical examination, laboratory screening and Doppler ultrasonography of the liver. The diagnosis of HCC was made according to the EASL criteria. All patients underwent contrast-enhanced ultrasonography, pre- and post-contrast triple-phase CT and CTP study. A mathematical deconvolution model was applied to provide hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic arterial index (HAI), hepatic arterial perfusion (HAP) and hepatic portal perfusion (HPP) data. The Mann-Whitney U test was used to determine differences in perfusion parameters between the background cirrhotic liver parenchyma and HCC and between the cirrhotic liver parenchyma with HCC and that without HCC. In normal liver, the HAP/HVP ratio was about 1/4. HCC had significantly higher HAP and HAI and lower HPP than background liver parenchyma adjacent to the HCC. The value of HBF at the tumor rim was significantly higher than that in the controls. HBF, HBV, HAI, HAP and HPP, but not MTT and PS, were significantly higher in the cirrhotic liver parenchyma involved with HCC than those of the controls. Perfusion parameters were not significantly different between the controls and the cirrhotic liver parenchyma not involved with HCC. CTP can clearly distinguish tumor from cirrhotic liver parenchyma and controls and can provide quantitative information about tumor-related angiogenesis, which can be used to assess tumor vascularization in cirrhotic liver disease.

Integrated analysis of microRNA and gene expression profiles reveals a functional regulatory module associated with liver fibrosis.

PubMed

Chen, Wei; Zhao, Wenshan; Yang, Aiting; Xu, Anjian; Wang, Huan; Cong, Min; Liu, Tianhui; Wang, Ping; You, Hong

2017-12-15

Liver fibrosis, characterized with the excessive accumulation of extracellular matrix (ECM) proteins, represents the final common pathway of chronic liver inflammation. Ever-increasing evidence indicates microRNAs (miRNAs) dysregulation has important implications in the different stages of liver fibrosis. However, our knowledge of miRNA-gene regulation details pertaining to such disease remains unclear. The publicly available Gene Expression Omnibus (GEO) datasets of patients suffered from cirrhosis were extracted for integrated analysis. Differentially expressed miRNAs (DEMs) and genes (DEGs) were identified using GEO2R web tool. Putative target gene prediction of DEMs was carried out using the intersection of five major algorithms: DIANA-microT, TargetScan, miRanda, PICTAR5 and miRWalk. Functional miRNA-gene regulatory network (FMGRN) was constructed based on the computational target predictions at the sequence level and the inverse expression relationships between DEMs and DEGs. DAVID web server was selected to perform KEGG pathway enrichment analysis. Functional miRNA-gene regulatory module was generated based on the biological interpretation. Internal connections among genes in liver fibrosis-related module were determined using String database. MiRNA-gene regulatory modules related to liver fibrosis were experimentally verified in recombinant human TGFβ1 stimulated and specific miRNA inhibitor treated LX-2 cells. We totally identified 85 and 923 dysregulated miRNAs and genes in liver cirrhosis biopsy samples compared to their normal controls. All evident miRNA-gene pairs were identified and assembled into FMGRN which consisted of 990 regulations between 51 miRNAs and 275 genes, forming two big sub-networks that were defined as down-network and up-network, respectively. KEGG pathway enrichment analysis revealed that up-network was prominently involved in several KEGG pathways, in which "Focal adhesion", "PI3K-Akt signaling pathway" and "ECM-receptor interaction" were remarked significant (adjusted p<0.001). Genes enriched in these pathways coupled with their regulatory miRNAs formed a functional miRNA-gene regulatory module that contains 7 miRNAs, 22 genes and 42 miRNA-gene connections. Gene interaction analysis based on String database revealed that 8 out of 22 genes were highly clustered. Finally, we experimentally confirmed a functional regulatory module containing 5 miRNAs (miR-130b-3p, miR-148a-3p, miR-345-5p, miR-378a-3p, and miR-422a) and 6 genes (COL6A1, COL6A2, COL6A3, PIK3R3, COL1A1, CCND2) associated with liver fibrosis. Our integrated analysis of miRNA and gene expression profiles highlighted a functional miRNA-gene regulatory module associated with liver fibrosis, which, to some extent, may provide important clues to better understand the underlying pathogenesis of liver fibrosis. Copyright © 2017. Published by Elsevier B.V.

Surgical treatment of a rare primary renal carcinoid tumor with liver metastasis

PubMed Central

Gedaly, Roberto; Jeon, Hoonbae; Johnston, Thomas D; McHugh, Patrick P; Rowland, Randall G; Ranjan, Dinesh

2008-01-01

Background Carcinoid tumors are characteristically low grade malignant neoplasms with neuroendocrine differentiation that arise in various body sites, most commonly the lung and gastrointestinal tract, but less frequently the kidneys, breasts, ovaries, testes, prostate and other locations. We report a case of a carcinoid of renal origin with synchronous single liver metastases on radiological studies. Case presentation A 45 year-old patient who presented with abdominal pain was found on CT scan to have lesions in the right ovary, right kidney, and left hepatic lobe. CA-125, CEA, and CA 19-9 were within normal limits, as were preoperative liver function tests and renal function. Biopsy of the liver mass demonstrated metastatic neuroendocrine tumor. At laparotomy, the patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, radical right nephrectomy with lymphadenectomy, and left hepatectomy. Pathology evaluation reported a right ovarian borderline serous tumor, well-differentiated neuroendocrine carcinoma of the kidney (carcinoid) with 2 positive retroperitoneal lymph nodes, and a single liver metastasis. Immunohistochemistry revealed that this lesion was positive for synaptophysin and CD56, but negative for chromogranin as well as CD10, CD7, and CD20, consistent with a well-differentiated neuroendocrine tumor. She is doing well one year after her initial surgery, with no evidence of tumor recurrence. Conclusion Early surgical intervention, together with careful surveillance and follow-up, can achieve successful long-term outcomes in patients with this rare malignancy. PMID:18430248

Why to compare absolute numbers of mitochondria.

PubMed

Schmitt, Sabine; Schulz, Sabine; Schropp, Eva-Maria; Eberhagen, Carola; Simmons, Alisha; Beisker, Wolfgang; Aichler, Michaela; Zischka, Hans

2014-11-01

Prompted by pronounced structural differences between rat liver and rat hepatocellular carcinoma mitochondria, we suspected these mitochondrial populations to differ massively in their molecular composition. Aiming to reveal these mitochondrial differences, we came across the issue on how to normalize such comparisons and decided to focus on the absolute number of mitochondria. To this end, fluorescently stained mitochondria were quantified by flow cytometry. For rat liver mitochondria, this approach resulted in mitochondrial protein contents comparable to earlier reports using alternative methods. We determined similar protein contents for rat liver, heart and kidney mitochondria. In contrast, however, lower protein contents were determined for rat brain mitochondria and for mitochondria from the rat hepatocellular carcinoma cell line McA 7777. This result challenges mitochondrial comparisons that rely on equal protein amounts as a typical normalization method. Exemplarily, we therefore compared the activity and susceptibility toward inhibition of complex II of rat liver and hepatocellular carcinoma mitochondria and obtained significant discrepancies by either normalizing to protein amount or to absolute mitochondrial number. Importantly, the latter normalization, in contrast to the former, demonstrated a lower complex II activity and higher susceptibility toward inhibition in hepatocellular carcinoma mitochondria compared to liver mitochondria. These findings demonstrate that solely normalizing to protein amount may obscure essential molecular differences between mitochondrial populations. Copyright © 2014 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Exertional heat stroke and acute liver failure: a late dysfunction

PubMed Central

Carvalho, Ana Sofia; Rodeia, Simão C; Silvestre, Joana; Póvoa, Pedro

2016-01-01

Heat stroke (HS) is defined as a severe elevation of core body temperature along with central nervous system dysfunction. Exertional heat stroke (EHS) with acute liver failure (ALF) is a rare condition. The authors report the case of a 25-year-old man with a history of cognitive enhancers’ intake who developed hyperthermia and neurological impairment while running an outdoor marathon. The patient was cooled and returned to normal body temperature after 6 h. He subsequently developed ALF and was transferred to the intensive care unit. Over-the-counter drug intake may have been related to heat intolerance and contributed to the event. The patient was successfully treated with conservative measures. In the presence of EHS, it is crucial to act promptly with aggressive total body cooling, in order to prevent progression of the clinical syndrome. Liver function must also be monitored, since it can be a late organ dysfunction. PMID:26969359

Fabrication of nanoparticles using Annona squamosa leaf and assessment of its effect on liver (Hep G2) cancer cell line

NASA Astrophysics Data System (ADS)

Vanitha, V.; Hemalatha, S.; Pushpabharathi, N.; Amudha, P.; Jayalakshmi, M.

2017-04-01

Annona squamosa is a fruit bearing plant possesses potent bioactive compounds in all its part. In this present investigation iron oxide nanoparticle was synthesized from hydroethanol extract of Annona squamosa leaves at 60°C temperature. Production of iron oxide nanoparticles in extraction is detected by UV-V spectrophotometer, Scanning electron microscopy was employed to analyse the structure of nanoparticles. Fourier transform infrared spectroscopy (FT-IR) analysis were performed, in order to determine the functional groups on Annona squamosa leaves extract. The synthesized Fe3O4 NPs shows potential cytotoxicity against liver carcinoma cell line (HepG2), and there is no toxicity on the normal liver cell line. Our reports confirmed that the Annona squamosa leaf is a very good eco-friendly and nontoxic bioreductant for the synthesis of Iron oxide nanoparticle and opens up further opportunities for fabrication of drugs towards cancer therapy.

[Common intralobular microcirculatory module peculliarities in cholestasis in white rats].

PubMed

Sulaberidze, G D; Kardzvia, D Dzh; Kikalishvili, L A; Khomeriki, Ts T

2006-03-01

The dynamics of intralobular microcirculatory module transformation in cholestasis was investigated. The liver tissues of 54 white Wistar rats were studied by Histology, TEM, TEM after injection of 1% Pb(NO(3))(3), vie common bile duct (CBD), SEM of corrosion casts prepared after methylmethacrylate injection vie CBD. It is demonstrated that liver is the basis of microcirculation of 4 different liquids: blood, bile, connective tissue liquid and lymph. Accordingly, in normal condition 4 different well formed compartments bordered from each-others by different types of cells exist. In the yearly stages of cholestasis (3-6 days) the function of bile drainage is partially overtaken by lymph pathways. This is accompanied by the beginning of the destruction of structures bordering above-mentioned microcirculatory beds. In the later stages of cholestasis (12-18 days) the final disorganization of microcirculatory compartments with mixture of all liquids is observed. It is accompanied by increased dystrophy of liver cells population.

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 ...

The impact of weight changes on nonalcoholic Fatty liver disease in adult men with normal weight.

PubMed

Cho, Ji-Young; Chung, Tae-Heum; Lim, Kyoung-Mo; Park, Hee-Jin; Jang, Jung-Mi

2014-09-01

Although it is known that losing weight has an effect on the treatment of non-alcoholic fatty liver disease, the studies that show how losing weight affects the non-alcoholic fatty liver disease for the normal weight male adults are limited so far. In this study, we set body mass index as criteria and investigated how the weight changes for 4 years makes an impact on the risk of non-alcoholic fatty liver disease for the male adults who have the normal body mass index. From January to December of 2004, among the normal weight male adults who had general check-up at the Health Promotion Center of Ulsan University Hospital, 180 people (average age, 47.4 ± 4.61 years) who were diagnosed with fatty liver through abdominal ultrasonography were included in this study and were observed according to the variety of data and ultrasonography after 4 years (2008). People who had a history of drinking more than 140 g of alcohol per week or who had a past medical history were excluded from the analysis. The weight change of subjects was calculated using the formula 'weight change = weight of 2008 (kg) - weight of 2004 (kg)' and classified into three groups, loss group (≤-3.0 kg), stable group (-2.9 to 2.9 kg), and gain group (≥3.0 kg). The odds for disappearance of non-alcoholic fatty liver disease in those three different groups were compared. Among 180 subjects, compared with stable group (67.2%, 121 subjects), loss group (11.7%, 21 subjects) showed 18.37-fold increase in the odds of disappearance of non-alcoholic fatty liver disease (95% confidence interval [CI], 4.34 to 77.80) and gain group (21.1%, 38 subjects) showed 0.28-fold decrease in the odds of disappearance of non-alcoholic fatty liver disease (95% CI, 0.10 to 0.83). Even for the normal weight people, losing weight has an effect on the improvement of non-alcoholic fatty liver disease.

Extrapolation of Normal Tissue Complication Probability for Different Fractionations in Liver Irradiation

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

Tai An; Erickson, Beth; Li, X. Allen

2009-05-01

Purpose: The ability to predict normal tissue complication probability (NTCP) is essential for NTCP-based treatment planning. The purpose of this work is to estimate the Lyman NTCP model parameters for liver irradiation from published clinical data of different fractionation regimens. A new expression of normalized total dose (NTD) is proposed to convert NTCP data between different treatment schemes. Method and Materials: The NTCP data of radiation- induced liver disease (RILD) from external beam radiation therapy for primary liver cancer patients were selected for analysis. The data were collected from 4 institutions for tumor sizes in the range of of 8-10more » cm. The dose per fraction ranged from 1.5 Gy to 6 Gy. A modified linear-quadratic model with two components corresponding to radiosensitive and radioresistant cells in the normal liver tissue was proposed to understand the new NTD formalism. Results: There are five parameters in the model: TD{sub 50}, m, n, {alpha}/{beta} and f. With two parameters n and {alpha}/{beta} fixed to be 1.0 and 2.0 Gy, respectively, the extracted parameters from the fitting are TD{sub 50}(1) = 40.3 {+-} 8.4Gy, m =0.36 {+-} 0.09, f = 0.156 {+-} 0.074 Gy and TD{sub 50}(1) = 23.9 {+-} 5.3Gy, m = 0.41 {+-} 0.15, f = 0.0 {+-} 0.04 Gy for patients with liver cirrhosis scores of Child-Pugh A and Child-Pugh B, respectively. The fitting results showed that the liver cirrhosis score significantly affects fractional dose dependence of NTD. Conclusion: The Lyman parameters generated presently and the new form of NTD may be used to predict NTCP for treatment planning of innovative liver irradiation with different fractionations, such as hypofractioned stereotactic body radiation therapy.« less

 Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis.

PubMed

Hilscher, Moira; Enders, Felicity B; Carey, Elizabeth J; Lindor, Keith D; Tabibian, James H

2016-01-01

 Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.

Morphologic examination of CD3-CD4(bright) cells in rat liver.

PubMed

Yamamoto, Satoshi; Sato, Yosinobu; Abo, Toru; Hatakeyama, Katsuyosi

2002-01-01

Recently, we found CD3-CD4(bright) cells with comparative specificity for normal rat liver. In the current study, we investigated the type and form of both CD3-CD4(bright) cells and CD3-CD4(dull) cells in the rat liver. The surface phenotype of hepatic mononuclear cells in Lewis rats was identified by using monoclonal antibodies including anti-CD4, anti-CD3, and antimacrophage in conjunction with two- or three-color immunofluorescence analysis. CD3-CD4(bright) cells and CD3-CD4(dull) cells were examined morphologically using May-Giemsa staining and scanning electron microscopy. The distribution of CD3-CD4(bright) cells and CD3-CD4(dull) cells 48 hours after intravenous administration of liposome-encapsulated dichloromethylene diphosphate was also investigated. In comparison to CD3-CD4(dull) cells, CD3-CD4(bright) cells were slightly larger macrophages with abundant cytoplasmic granules, being present with comparative specificity for normal rat liver and showing negligible effects by intravenous liposome-encapsulated dichloromethylene diphosphate administration. These data suggest that in normal young rat liver these CD3-CD4(dull) and CD3-CD4(bright) cells may be dendritic cells and Kupffer cells that shift from the liver to the spleen or vice versa. These cells may also be able to locally proliferate in liver or spleen due to changes in the developing liver.

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

Erinjeri, Joseph P., E-mail: erinjerj@mskcc.org; Deodhar, Ajita; Thornton, Raymond H.

Hepatic encephalopathy is considered a contraindication to hepatic artery embolization. We describe a patient with a well-differentiated neuroendocrine tumor metastatic to the liver with refractory hepatic encephalopathy and normal liver function tests. The encephalopathy was refractory to standard medical therapy with lactulose. The patient's mental status returned to baseline after three hepatic artery embolization procedures. Arteriography and ultrasound imaging before and after embolization suggest that the encephalopathy was due to arterioportal shunting causing hepatofugal portal venous flow and portosystemic shunting. In patients with a primary or metastatic well-differentiated neuroendocrine tumor whose refractory hepatic encephalopathy is due to portosystemic shunting (rathermore » than global hepatic dysfunction secondary to tumor burden), hepatic artery embolization can be performed safely and effectively.« less

Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review

PubMed Central

Reardon, Jillian; Hussaini, Trana; Alsahafi, Majid; Azalgara, Vladimir Marquez; Erb, Siegfried R.; Partovi, Nilufar; Yoshida, Eric M.

2016-01-01

Abstract Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited to minor gastrointestinal complaints (most often, diarrhea) and did not occur at increased frequency as compared to controls. As administration of bile acids was often limited to durations of 12 months or less, long-term side effects for non-cholestatic indications cannot be excluded. Conclusions: Based on the available literature, bile acids cannot be widely recommended for non-cholestatic liver diseases at present. PMID:27777888

Liver tumor boundaries identified intraoperatively using real-time indocyanine green fluorescence imaging.

PubMed

Zhang, Ya-Min; Shi, Rui; Hou, Jian-Cun; Liu, Zi-Rong; Cui, Zi-Lin; Li, Yang; Wu, Di; Shi, Yuan; Shen, Zhong-Yang

2017-01-01

Clear delineation between tumors and normal tissues is ideal for real-time surgical navigation imaging. We investigated applying indocyanine green (ICG) fluorescence imaging navigation using an intraoperative administration method in liver resection. Fifty patients who underwent liver resection were divided into two groups based on clinical situation and operative purpose. In group I, sizes of superficial liver tumors were determined; tiny tumors were identified. In group II, the liver resection margin was determined; real-time navigation was performed. ICG was injected intravenously at the beginning of the operation; the liver surface was observed with a photodynamic eye (PDE). Liver resection margins were determined using PDE. Fluorescence contrast between normal liver and tumor tissues was obvious in 32 of 35 patients. A boundary for half the liver or specific liver segments was determined in nine patients by examining the portal vein anatomy after ICG injection. Eight small tumors not observed preoperatively were detected; the smallest was 2 mm. ICG fluorescence imaging navigation is a promising, simple, and safe tool for routine real-time intraoperative imaging during hepatic resection and clinical exploration in hepatocellular carcinoma, enabling high sensibility for identifying liver resection margins and detecting tiny superficial tumors.

A study of hepatic lesions in broiler chickens at processing plants in Saskatchewan

PubMed Central

Hutchison, Thomas W.S.; Riddell, Craig

1990-01-01

A detailed descriptive study was done on broiler chickens with abnormal livers found at processing. Two syndromes were evident: those birds with enlarged, pale, firm livers, designated hepatosis, with Clostridium perfringens type A often isolated; and ascitic birds with cobblestone-appearing livers. Livers with hepatosis had marked proliferation of bile ducts; ascitic livers had normal architecture. Hearts from birds with ascites had elevated right ventricular/total ventricular weight ratios, whereas hearts from normal birds and birds with hepatosis did not. Two isolates of C. perfringens produced necrotic enteritis in experimental birds; an attempt to reproduce hepatosis with these isolates was unsuccessful. ImagesFigure 1.Figure 2.Figure 3.Figure 4.Figure 5.Figure 6.Figure 7. PMID:17423489

A knowledge-based approach to automated planning for hepatocellular carcinoma.

PubMed

Zhang, Yujie; Li, Tingting; Xiao, Han; Ji, Weixing; Guo, Ming; Zeng, Zhaochong; Zhang, Jianying

2018-01-01

To build a knowledge-based model of liver cancer for Auto-Planning, a function in Pinnacle, which is used as an automated inverse intensity modulated radiation therapy (IMRT) planning system. Fifty Tomotherapy patients were enrolled to extract the dose-volume histograms (DVHs) information and construct the protocol for Auto-Planning model. Twenty more patients were chosen additionally to test the model. Manual planning and automatic planning were performed blindly for all twenty test patients with the same machine and treatment planning system. The dose distributions of target and organs at risks (OARs), along with the working time for planning, were evaluated. Statistically significant results showed that automated plans performed better in target conformity index (CI) while mean target dose was 0.5 Gy higher than manual plans. The differences between target homogeneity indexes (HI) of the two methods were not statistically significant. Additionally, the doses of normal liver, left kidney, and small bowel were significantly reduced with automated plan. Particularly, mean dose and V15 of normal liver were 1.4 Gy and 40.5 cc lower with automated plans respectively. Mean doses of left kidney and small bowel were reduced with automated plans by 1.2 Gy and 2.1 Gy respectively. In contrast, working time was also significantly reduced with automated planning. Auto-Planning shows availability and effectiveness in our knowledge-based model for liver cancer. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Circulating AIM as an Indicator of Liver Damage and Hepatocellular Carcinoma in Humans

PubMed Central

Yamazaki, Tomoko; Mori, Mayumi; Arai, Satoko; Tateishi, Ryosuke; Abe, Masanori; Ban, Mihoko; Nishijima, Akemi; Maeda, Maki; Asano, Takeharu; Kai, Toshihiro; Izumino, Kiyohiro; Takahashi, Jun; Aoyama, Kayo; Harada, Sei; Takebayashi, Toru; Gunji, Toshiaki; Ohnishi, Shin; Seto, Shinji; Yoshida, Yukio; Hiasa, Yoichi; Koike, Kazuhiko; Yamamura, Ken-ichi; Inoue, Ken-ichiro; Miyazaki, Toru

2014-01-01

Background Hepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC. Methods and Findings Here we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99±1.8 µg/ml in men and 6.06±2.1 µg/ml in women. AIM levels were significantly augmented in the younger generation (20s–40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis. Conclusion AIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease. PMID:25302503

Image patch-based method for automated classification and detection of focal liver lesions on CT

NASA Astrophysics Data System (ADS)

Safdari, Mustafa; Pasari, Raghav; Rubin, Daniel; Greenspan, Hayit

2013-03-01

We developed a method for automated classification and detection of liver lesions in CT images based on image patch representation and bag-of-visual-words (BoVW). BoVW analysis has been extensively used in the computer vision domain to analyze scenery images. In the current work we discuss how it can be used for liver lesion classification and detection. The methodology includes building a dictionary for a training set using local descriptors and representing a region in the image using a visual word histogram. Two tasks are described: a classification task, for lesion characterization, and a detection task in which a scan window moves across the image and is determined to be normal liver tissue or a lesion. Data: In the classification task 73 CT images of liver lesions were used, 25 images having cysts, 24 having metastasis and 24 having hemangiomas. A radiologist circumscribed the lesions, creating a region of interest (ROI), in each of the images. He then provided the diagnosis, which was established either by biopsy or clinical follow-up. Thus our data set comprises 73 images and 73 ROIs. In the detection task, a radiologist drew ROIs around each liver lesion and two regions of normal liver, for a total of 159 liver lesion ROIs and 146 normal liver ROIs. The radiologist also demarcated the liver boundary. Results: Classification results of more than 95% were obtained. In the detection task, F1 results obtained is 0.76. Recall is 84%, with precision of 73%. Results show the ability to detect lesions, regardless of shape.

Ultrasonographically visible hepatic location in clinically normal horses.

PubMed

Johns, I C; Miles, A

2016-06-01

Ultrasound is widely used for evaluating horses with suspected liver dysfunction. Although a change in size is considered suggestive of pathology, no clear guidelines exist to define the hepatic ultrasonographically visible locations (HUVL) in horses. The aim of the study was to describe the HUVL in normal horses and determine whether this is altered by signalment, height, weight and body condition score (BCS). Prospective observational study. Bilateral ultrasonographic evaluation was performed in 58 clinically normal horses with no history of hepatic disease. The most cranial/caudal intercostal spaces (ICS), total number of ICS in which the liver was visualised and the ventral extent of the liver were recorded. Liver was visualised on the right in 56/58 horses (97%), the left in 41/58 (71%) and on both sides in 39/58 (67%). The most cranial ICS was 5 (right) or 4 (left) and the most caudal was 16 (right) or 11 (left). Liver was visualised in ICS 0-11 (right) and ICS 0-5 (left). Liver was not visualised ventral to the costochondral junction. There was no significant effect of sex, breed, height, weight or BCS on HUVL. Liver was visible in significantly fewer ICS on the right in horses aged 24 years and older (median ICS 3.5) compared with younger horses (median ICS 7; P = 0.016). These findings suggest that the liver should be consistently visualised on the right side, but absence of ultrasonographically visible liver on the left is unlikely to be clinically relevant. Liver dimensions may be decreased in older horses. © 2016 Australian Veterinary Association.

IL-6-Mediated Activation of Stat3α Prevents Trauma/Hemorrhagic Shock-Induced Liver Inflammation

PubMed Central

Moran, Ana; Thacker, Stephen A.; Arikan, Ayse Akcan; Mastrangelo, Mary-Ann A.; Wu, Yong; Yu, Bi; Tweardy, David J.

2011-01-01

Trauma complicated by hemorrhagic shock (T/HS) is the leading cause of morbidity and mortality in the United States for individuals under the age of 44 years. Initial survivors are susceptible to developing multiple organ failure (MOF), which is thought to be caused, at least in part, by excessive or maladaptive activation of inflammatory pathways. We previously demonstrated in rodents that T/HS results in liver injury that can be prevented by IL-6 administration at the start of resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required, and the mechanism(s) for the IL-6 protective effect have not been reported. In the experiments described here, we demonstrated that the extent of liver inflammation induced by T/HS depends on the duration of hypotension and requires resuscitation. We established that IL-6 administration at the start of resuscitation is capable of completely reversing liver inflammation and is associated with increased Stat3 activation. Global assessment of the livers showed that the main effect of IL-6 was to normalize the T/HS-induced inflammation transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver inflammation and to normalize the T/HS-induced liver inflammation transcriptome. Genetic deletion of a Stat3β, a naturally occurring, dominant-negative isoform of the Stat3, attenuated T/HS-induced liver inflammation, confirming a role for Stat3, especially Stat3α, in preventing T/HS-mediated liver inflammation. Thus, T/HS-induced liver inflammation depends on the duration of hypotension and requires resuscitation; IL-6 administration at the start of resuscitation reverses T/HS-induced liver inflammation, through activation of Stat3α, which normalized the T/HS-induced liver inflammation transcriptome. PMID:21738667

Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats.

PubMed

Singh, Hem; Prakash, Atish; Kalia, A N; Majeed, Abu Bakar Abdul

2016-10-01

Previously explored combination therapies mostly involved the use of bioactive molecules. It is believed that herbal compounds containing multiple plant products have synergistic hepatoprotective effects and could enhance the desired actions. To investigate the combination of ethanolic fruits extract of Solanum xanthocarpum (SX) and Juniperus communis (JC) against Paracetamol (PCM) and Azithromycin (AZM) induced liver toxicity in rats. Liver toxicity was induced by combine oral administration of PCM (250 mg/kg) and AZM (200 mg/kg) for 7 days in Wistar rats. Fruit extract of SX (200 and 400 mg/kg) and JC (200 and 400 mg/kg) were administered daily for 14 days. The hepatoprotective activity was assessed using liver functional test, oxidative parameters and histopathological examination. The results demonstrated that combine administration of AZM and PCM significantly produced liver toxicity by increasing the serum level of hepatic enzymes and oxidative parameters in liver of rats. Histopathological examination also indicated that AZM and PCM produced liver damage in rats. Chronic treatment of SX and JC extract significantly and dose-dependently attenuated the liver toxicity by normalizing the biochemical factors and no gross histopathological changes were observed in liver of rats. Furthermore, combine administration of lower dose of SX and JC significantly potentiated their hepatoprotective effect which was significant as compared to their effect per se. The results clearly indicated that SX and JC extract has hepatoprotective potential against AZM and PCM induced liver toxicity due to their synergistic anti-oxidant properties.

Successful transplantation of donor organs from a hemlock poisoning victim.

PubMed

Foster, Preston F; McFadden, Robert; Trevino, Raul; Galliardt, Scott; Kopczewski, Lea Ann; Gugliuzza, Kristene; Gonzalez, Zulma; Wright, Francis

2003-09-15

The poison hemlock plant (Conium maculatum) has been a known poison since early in human history, most notably as the agent used for the execution/suicide of Socrates in ancient Greece. No experience has been reported regarding the suitability of a hemlock victim's organs for transplantation. This report documents successful transplantation of the liver, kidney, and pancreas from a 14-year-old girl who died of anoxic encephalopathy from asphyxia after the accidental ingestion of fresh hemlock while on a nature hike. Predonation laboratory values were not remarkable, and liver and kidney biopsy results were normal. All organs in the three recipients had immediate function, and no recipient had any clinical evidence of transmitted toxin. All recipients are well, with functioning transplants at greater than 6 months after transplantation. Poison hemlock intoxication does not seem to be a contraindication to organ donation.

Oral versus intravenous paracetamol: which is better in closure of patent ductus arteriosus in very low birth weight infants?

PubMed

Sancak, Selim; Gokmen Yildirim, Tulin; Topcuoglu, Sevilay; Yavuz, Taner; Karatekin, Guner; Ovali, Fahri

2016-01-01

To compare the efficacy of oral and intravenous paracetamol for closure of hemodynamically significant patent ductus arteriosus (HSPDA) in very low birth weight (VLBW) preterm infants. Eighteen VLBW infants with HSPDA treated with either intravenous (n = 10) or oral (n = 8) paracetamol at 60 mg/kg/d for three consecutive days were analysed retrospectively. Ductal closure rate and evaluation of liver function tests were the major outcomes. After two courses of treatment, HSPDA closure rate was higher in oral paracetamol group than that in the intravenous paracetamol group (88% versus 70%), but it was not statistically significant (p = 0.588). Liver function tests were normal after the treatment. Although it was not statistically significant, the cumulative closure rates were higher in oral paracetamol group than those in the intravenous group. Larger trials are needed to confirm these data.

In vivo quantification of motion in liver parenchyma and its application in shistosomiasis tissue characterization

NASA Astrophysics Data System (ADS)

Badawi, Ahmed M.; Hashem, Ahmed M.; Youssef, Abou-Bakr M.; Abdel-Wahab, Mohamed F.

1995-03-01

Schistosomiasis is a major problem in Egypt, despite an active control program it is estimated to exist in about 1/3 of the population. Deposition of less functioning fibrous tissues in the liver is the major contributory factor to the hepatic pathology. Fibrous tissues consist of a complex array of connective matrix material and a variety of collagen isotopes. As a result of an increased stromal density (collagen content), the parenchyma became more ectogenic and less elastic (hard). In this study we investigated the effect of cardiac mechanical impulses from the heart and aorta on the kinetics of the liver parenchyma. Under conditions of controlled patient movements and suspended respiration, a 30 frame per second of 588 X 512 ultrasound images (cineloop, 32 pels per cm) are captured from an aTL ultrasound machine then digitized. The image acquisition is triggered by the R wave of the ECG of the patient. The motion that has a forced oscillation form in the liver parenchyma is quantified by tracking of small box (20 - 30 pels) in 16 directions for all the successive 30 frames. The tracking was done using block matching techniques (the max correlation between boxes in time, frequency domains, and the minimum SAD (sum absolute difference) between boxes). The motion is quantified for many regions at different positions within the liver parenchyma for 80 cases of variable degrees of schisto., cirrhotic livers, and for normal livers. The velocity of the tissue is calculated from the displacement (quantified motion), time between frames, and the scan time for the ultrasound scanner. We found that the motion in liver parenchyma is small in the order of very few millimeters, and the attenuation of the mechanical wave for one ECG cycle is higher in the schisto. and cirrhotic livers than in the normal ones. Finally quantification of motion in liver parenchyma due to cardiac impulses under controlled limb movement and respiration may be of value in the characterization of schisto. (elasticity based not scattering based). This value could be used together with the wide varieties of quantitative tissue characterization parameters for pathology differentiation and for differentiating subclasses of cirrhosis as well as the determination of the extent of bilharzial affection.

Brainstem evoked response audiometry: an investigatory tool in detecting hepatic encephalopathy in decompensated chronic liver disease.

PubMed

Kabali, Balasubramanian; Velayutham, Gowri; Kapali, Suresh Chander

2014-01-01

It is estimated that globally there is a marked increase in liver disease with reports of rising morbidity and mortality, particularly in younger age groups. Brainstem auditory evoked potential (BAEP) was recorded in 60 decompensated chronic liver disease (DCLD) subjects who fulfilled the selection criteria and compared to 60 age and gender matched healthy subjects with normal liver functions. DCLD subjects were divided into two inter groups based on presence or absence of hepatic encephalopathy (HE). Group 1 comprises of 30 subjects of grade- I HE and Group 2 included 30 subjects without hepatic encephalopathy (NHE). Absolute and interpeak wave latencies were measured. Results were analysed by student independent t- test using SPSS software 11 version. Statistical significance was tested using P value. From the present study it can be concluded that the central nervous system is involved in liver cirrhosis evidenced by an abnormal BAEP latencies parameters. This shows that there may be progressive demyelination occurring along with axonal loss or dysfunction in liver cirrhosis HE. This study suggests that periodic evaluation of cirrhotic individuals to such test will help in monitoring the progress of encephalopathy. The prime goal of this study is early diagnosis and initiation of treatment before the onset of coma can reduce the fatality rate.

Long-term exposure to a butter-rich diet induces mild-to-moderate steatosis in Chang liver cells and Swiss albino mice models.

PubMed

Nalloor, Thomas John Philip; Kumar, Nitesh; Narayanan, Kasinathan; Palanimuthu, Vasanth Raj

2017-05-01

Butter is one of the widely used fats present in the diet. However, there is no satisfactory study available that evaluates the effect of a high-fat diet containing butter as the principal fat on the development of non-alcoholic fatty liver disease (NAFLD). In the present study, butter was used for the development of steatosis in Chang liver cells in an in vitro study and Swiss albino mice in an in vivo study. In vitro steatosis was established, and butter was compared with oleic acid in Chang liver cells using an oil red O (ORO)-based colorimetric assay. In the in vivo study, a butter-rich special diet was fed for 15 weeks to mice, who showed no significant change in body weight. The expression pattern of phosphatase and tensin homolog (PTEN) and miR-21 was compared by reverse transcriptase-PCR. Special diet-fed animals showed downregulated PTEN compared to normal diet-fed animals, while levels of miR-21 remained the same. Elevations in biochemical parameters, viz., triglycerides and liver function tests showed symptoms of onset of NAFLD. Histophathological study of livers of test animals confirmed mild-to-moderate degree of NAFLD.

Morphological and functional characterization of non-alcoholic fatty liver disease induced by a methionine-choline-deficient diet in C57BL/6 mice.

PubMed

Itagaki, Hiroko; Shimizu, Kazuhiko; Morikawa, Shunichi; Ogawa, Kenji; Ezaki, Taichi

2013-01-01

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), appears to be increasingly common worldwide. Its histopathology and the effects of nutrition on liver function have not been fully determined. To elucidate the cellular mechanisms of NAFLD induced by a methionine-choline-deficient (MCD) diet in mice. Particular focus was placed on the role of phagocytic cells. Male C57BL/6 mice were fed an MCD diet for 30 weeks. A recovery model was also established wherein a normal control diet was provided for 2 weeks after a period of 8, 16, or 30 weeks. Mice fed the MCD diet for ≥ 2 weeks exhibited severe steatohepatitis with elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Steatohepatitis was accompanied by the infiltration of CD68-positive macrophages (Kupffer cells). The severity of steatohepatitis increased in the first 16 weeks but was seen to lessen by week 30. Fibrosis began to develop at 10 weeks and continued thereafter. Steatohepatitis and elevated serum hepatic enzyme concentrations returned to normal levels after switching the diet back to the control within the first 16 weeks, but fibrosis and CD68-positive macrophages remained. The histopathological changes and irreversible fibrosis seen in this model were caused by prolonged feeding of an MCD diet. These results were accompanied by changes in the activity of CD68-positive cells with temporary elevation of CCL-2, MMP-13, and MMP-9 levels, all of which may trigger early steatohepatitis and late fibrosis through phagocytosis-associated MMP induction.

Protein Degradation in Normal and Beige (Chediak-Higashi) Mice

PubMed Central

Lyons, Robert T.; Pitot, Henry C.

1978-01-01

The beige mouse, C57BL/6 (bg/bg), is an animal model for the Chediak-Higashi syndrome in man, a disease characterized morphologically by giant lysosomes in most cell types. Half-lives for the turnover of [14C]bicarbonate-labeled total soluble liver protein were determined in normal and beige mice. No significant differences were observed between the normal and mutant strain for both rapidly and slowly turning-over classes of proteins. Glucagon treatment during the time-course of protein degradation had similar effects on both normal and mutant strains and led to the conclusion that the rate of turnover of endogenous intracellular protein in the beige mouse liver does not differ from normal. The rates of uptake and degradation of an exogenous protein were determined in normal and beige mice by intravenously injecting 125I-bovine serum albumin and following, in peripheral blood, the loss with time of phosphotungstic acid-insoluble bovine serum albumin and the parallel appearance of phosphotungstic acid-soluble (degraded) material. No significant differences were observed between beige and normal mice in the uptake by liver lysosomes of 125I-bovine serum albumin (t½ = 3.9 and 2.8 h, respectively). However, it was found that lysosomes from livers of beige mice released phosphotungstic acid-soluble radioactivity at a rate significantly slower than normal (t½ = 6.8 and 3.1 h, respectively). This defect in beige mice could be corrected by chronic administration of carbamyl choline (t½ = 3.5 h), a cholinergic agonist which raises intracellular cyclic GMP levels. However, no significant differences between normal and beige mice were observed either in the ability of soluble extracts of liver and kidney to bind [3H]cyclic GMP in vitro or in the basal levels of cyclic AMP in both tissues. The relevance of these observations to the presumed biochemical defect underlying the Chediak-Higashi syndrome is discussed. PMID:202611

Treatment of Rats with Apocynin Has Considerable Inhibitory Effects on Arylamine N-Acetyltransferase Activity in the Liver.

PubMed

Francis, Sheena; Laurieri, Nicola; Nwokocha, Chukwuemeka; Delgoda, Rupika

2016-05-31

The effect of apocynin on the activity of arylamine N-acetyltransferases (NATs) in excised liver samples was examined using eighteen Sprague-Dawley rats. Three groups of six animals each were fed a normal diet alone or a treatment of 50 or 100 mg/kg/day of apocynin via gavages for eight (8) weeks. Chronic in vivo administration of apocynin led to significant (p < 0.001) reduction of in vitro liver NAT activity up to 93% as compared with untreated rats (18.80 ± 2.10 μmols p-anisidine/min/μg liver protein). In vitro exposure of untreated liver homogenates to apocynin led to a dose-dependent inhibition of NAT activity with IC50 = 0.69 ± 0.02 mM. In silico modelling of apocynin tautomers and radical species into human NAT crystal structures supported the hypothesis that thiol functionalities in NAT enzymes may be crucial in apocynin binding. The involvement of human NAT enzymes in different pathological conditions, such as cancer, has encouraged the research for selective NAT inhibitors in both humans and animal models with possible chemopreventive properties.

A complex of α6 integrin and E-cadherin drives liver metastasis of colorectal cancer cells through hepatic angiopoietin-like 6.

PubMed

Marchiò, Serena; Soster, Marco; Cardaci, Sabrina; Muratore, Andrea; Bartolini, Alice; Barone, Vanessa; Ribero, Dario; Monti, Maria; Bovino, Paola; Sun, Jessica; Giavazzi, Raffaella; Asioli, Sofia; Cassoni, Paola; Capussotti, Lorenzo; Pucci, Piero; Bugatti, Antonella; Rusnati, Marco; Pasqualini, Renata; Arap, Wadih; Bussolino, Federico

2012-11-01

Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and α(6) integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural α(6) integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α(6) integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC. Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity.

PubMed

Bowen, David G; Zen, Monica; Holz, Lauren; Davis, Thomas; McCaughan, Geoffrey W; Bertolino, Patrick

2004-09-01

Hepatic immunobiology is paradoxical: although the liver possesses unusual tolerogenic properties, it is also the site of effective immune responses against multiple pathogens and subject to immune-mediated pathology. The mechanisms underlying this dichotomy remain unclear. Following previous work demonstrating that the liver may act as a site of primary T cell activation, we demonstrate here that the balance between immunity and tolerance in this organ is established by competition for primary activation of CD8+ T cells between the liver and secondary lymphoid tissues, with the immune outcome determined by the initial site of activation. Using a transgenic mouse model in which antigen is expressed within both liver and lymph nodes, we show that while naive CD8+ T cells activated within the lymph nodes were capable of mediating hepatitis, cells undergoing primary activation within the liver exhibited defective cytotoxic function and shortened half-life and did not mediate hepatocellular injury. The implications of these novel findings may pertain not only to the normal maintenance of peripheral tolerance, but also to hepatic allograft tolerance and the immunopathogenesis of chronic viral hepatitis.

Evaluation of the antitumor activity of platinum nanoparticles in the treatment of hepatocellular carcinoma induced in rats.

PubMed

Medhat, Amina; Mansour, Somaya; El-Sonbaty, Sawsan; Kandil, Eman; Mahmoud, Mustafa

2017-07-01

This study aimed to evaluate the antitumor activity of platinum nanoparticles compared with cis-platin both in vitro and in vivo in the treatment of hepatocellular carcinoma induced in rats. The treatment efficacy of platinum nanoparticles was evaluated by measuring antioxidant activities against oxidative stress caused by diethylnitrosamine in liver tissue. The measurements included reduced glutathione content and superoxide dismutase activity, as well as malondialdehyde level. Liver function tests were also determined, in addition to the evaluation of serum alpha-fetoprotein, caspase-3, and cytochrome c in liver tissue. Total RNA extraction from liver tissue samples was also done for the relative quantification of B-cell lymphoma 2, matrix metallopeptidase 9, and tumor protein p53 genes. Histopathological examination was also performed for liver tissue. Results showed that platinum nanoparticles are more potent than cis-platin in treatment of hepatocellular carcinoma induced by diethylnitrosamine in rats as it ameliorated the investigated parameters toward normal control animals. These findings were well appreciated with histopathological studies of diethylnitrosamine group treated with platinum nanoparticles, suggesting that platinum nanoparticles can serve as a good therapeutic agent for the treatment of hepatocellular carcinoma which should attract further studies.

Is liver perfusion CT reproducible? A study on intra- and interobserver agreement of normal hepatic haemodynamic parameters obtained with two different software packages.

PubMed

Bretas, Elisa Almeida Sathler; Torres, Ulysses S; Torres, Lucas Rios; Bekhor, Daniel; Saito Filho, Celso Fernando; Racy, Douglas Jorge; Faggioni, Lorenzo; D'Ippolito, Giuseppe

2017-10-01

To evaluate the agreement between the measurements of perfusion CT parameters in normal livers by using two different software packages. This retrospective study was based on 78 liver perfusion CT examinations acquired for detecting suspected liver metastasis. Patients with any morphological or functional hepatic abnormalities were excluded. The final analysis included 37 patients (59.7 ± 14.9 y). Two readers (1 and 2) independently measured perfusion parameters using different software packages from two major manufacturers (A and B). Arterial perfusion (AP) and portal perfusion (PP) were determined using the dual-input vascular one-compartmental model. Inter-reader agreement for each package and intrareader agreement between both packages were assessed with intraclass correlation coefficients (ICC) and Bland-Altman statistics. Inter-reader agreement was substantial for AP using software A (ICC = 0.82) and B (ICC = 0.85-0.86), fair for PP using software A (ICC = 0.44) and fair to moderate for PP using software B (ICC = 0.56-0.77). Intrareader agreement between software A and B ranged from slight to moderate (ICC = 0.32-0.62) for readers 1 and 2 considering the AP parameters, and from fair to moderate (ICC = 0.40-0.69) for readers 1 and 2 considering the PP parameters. At best there was only moderate agreement between both software packages, resulting in some uncertainty and suboptimal reproducibility. Advances in knowledge: Software-dependent factors may contribute to variance in perfusion measurements, demanding further technical improvements. AP measurements seem to be the most reproducible parameter to be adopted when evaluating liver perfusion CT.

Low Platelet to White Blood Cell Ratio Indicates Poor Prognosis for Acute-On-Chronic Liver Failure.

PubMed

Jie, Yusheng; Gong, Jiao; Xiao, Cuicui; Zhu, Shuguang; Zhou, Wenying; Luo, Juan; Chong, Yutian; Hu, Bo

2018-01-01

Background. Platelet to white blood cell ratio (PWR) was an independent prognostic predictor for outcomes in some diseases. However, the prognostic role of PWR is still unclear in patients with hepatitis B related acute-on-chronic liver failure (ACLF). In this study, we evaluated the clinical performances of PWR in predicting prognosis in HBV-related ACLF. Methods. A total of 530 subjects were recruited, including 97 healthy controls and 433 with HBV-related ACLF. Liver function, prothrombin time activity (PTA), international normalized ratio (INR), HBV DNA measurement, and routine hematological testing were performed at admission. Results . At baseline, PWR in patients with HBV-related ACLF (14.03 ± 7.17) was significantly decreased compared to those in healthy controls (39.16 ± 9.80). Reduced PWR values were clinically associated with the severity of liver disease and the increased mortality rate. Furthermore, PWR may be an inexpensive, easily accessible, and significant independent prognostic index for mortality on multivariate analysis (HR = 0.660, 95% CI: 0.438-0.996, p = 0.048) as well as model for end-stage liver disease (MELD) score. Conclusions . The PWR values were markedly decreased in ACLF patients compared with healthy controls and associated with severe liver disease. Moreover, PWR was an independent prognostic indicator for the mortality rate in patients with ACLF. This investigation highlights that PWR comprised a useful biomarker for prediction of liver severity.

A non-human primate model of human radiation-induced venocclusive liver disease and hepatocyte injury

PubMed Central

Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro; Roy-Chowdhury, Jayanta; Locker, Joseph; Abe, Michio; Enke, Charles A.; Baranowska-Kortylewicz, Janina; Solberg, Timothy D.; Guha, Chandan; Fox, Ira J.

2014-01-01

Background Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Since the characteristic venocclusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic venocclusive disease. Methods We performed a dose escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results At doses ≥40Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses where radiation-induced liver disease was mild or non-existent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions The cynomolgus monkey, as the first animal model of human venocclusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury. PMID:24315566

The Hippo-YAP Pathway Regulates 3D Organ Formation and Homeostasis.

PubMed

Ishihara, Erika; Nishina, Hiroshi

2018-04-17

The vertebrate body shape is formed by the specific sizes and shapes of its resident tissues and organs, whose alignments are essential for proper functioning. To maintain tissue and organ shape, and thereby function, it is necessary to remove senescent, transformed, and/or damaged cells, which impair function and can lead to tumorigenesis. However, the molecular mechanisms underlying three-dimensional (3D) organ formation and homeostasis are not fully clear. Yes-associated protein (YAP) is a transcriptional co-activator that is involved in organ size control and tumorigenesis. Recently, we reported that YAP is essential for proper 3D body shape through regulation of cell tension by using a unique medaka fish mutant, hirame ( hir ). In Madin–Darby canine kidney (MDCK) epithelial cells, active YAP-transformed cells are eliminated apically when surrounded by normal cells. Furthermore, in a mosaic mouse model, active YAP-expressing damaged hepatocytes undergo apoptosis and are eliminated from the liver. Thus, YAP functions in quantitative and quality control in organogenesis. In this review, we describe the various roles of YAP in vertebrates, including in the initiation of liver cancer.

Sphincterotomy in patients with gallstones, elevated LFTs and a normal CBD on ERCP.

PubMed

Siddique, Iqbal; Mohan, Krishna; Khajah, Abdulkareem; Hasan, Fuad; Memon, Anjum; Kalaoui, Maher; al-Shamali, Mohammad; Patty, Istvan; al-Nakib, Basil

2003-01-01

To determine whether an endoscopic sphincterotomy affects outcome in patients with symptomatic gallstones, elevated liver function tests and a normal common bile duct on endoscopic retrograde cholangiopancreatogram. A total of 163 patients with symptomatic gallstones and elevated liver function tests, and found to have a normal common bile duct on endoscopic retrograde cholangiopancreatogram were included in the study. Endoscopic sphincterotomy was performed in 78 (47.8%) patients, while 85 (52.1%) patients did not have an endoscopic sphincterotomy. The two groups were compared for detection of small unseen common bile duct stones/debris, endoscopic retrograde cholangiopancreatogram related complications, and biliary complications after cholecystectomy. Small common bile duct stones/debris were recovered in 11/43 (25.5%) patients who had instrumentation of the common bile duct performed after endoscopic sphincterotomy. Common bile duct instrumentation was not performed in any of the patients without endoscopic sphincterotomy. No patient had any biliary complication after cholecystectomy, both in the immediate postoperative period and on a follow-up of 37.5 +/- 13.6 months (range 17-66). Endoscopic retrograde cholangiopancreatogram related complications occurred in 8 patients who had an endoscopic sphincterotomy and in 2 without endoscopic sphincterotomy (p < 0.05). Performing an endoscopic sphincterotomy in these patients increases the detection of small unseen common bile duct stones/debris without changing the clinical outcome after cholecystectomy. It also increases the endoscopic retrograde cholangiopancreatogram related complication rate, and therefore may not be necessary.

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.

Prevention and reversal of intestinal failure-associated liver disease in premature infants with short bowel syndrome using intravenous fish oil in combination with omega-6/9 lipid emulsions.

PubMed

Lilja, Helene Engstrand; Finkel, Yigael; Paulsson, Mattias; Lucas, Steven

2011-07-01

Although premature infants with short bowel syndrome are at the highest risk of developing intestinal failure-associated liver disease (IFALD), they have great capacity for intestinal growth and adaptation if IFALD can be prevented. Conventional soybean oil-based intravenous lipid emulsions have been associated with IFALD. This study presents data on 5 premature neonates with short bowel syndrome treated with a combination of parenteral fish oil- and olive/soybean-based lipid emulsion for periods ranging between 7 and 17 months. Despite an enteral tolerance of less than 50% in 4 of these patients during their first year of life, direct bilirubin levels normalized while on this combination of ClinOleic (Baxter, Maurepas, France)/Omegaven (Fresenius Kabi, Bad Homburg, Germany) at a 1:1 ratio. None of our patients developed irreversible IFALD even though all of them were premature, had undergone multiple major surgical procedures, and had experienced several episodes of sepsis. Thus far, we have not seen any adverse effects of this mixed lipid emulsion in these preterm infants. All 5 patients are growing and developing well and have normal liver function. Copyright © 2011 Elsevier Inc. All rights reserved.

[IMPORTANCE OF SHEAR WAVE ELASTOGRAPHY OF LIVERS IN PRACTICALLY HEALTHY PREGNANT WOMEN].

PubMed

Sariyeva, E; Salahova, S; Bayramov, N

2017-01-01

Pulse-wave elastography (SWE) that is one of the mostly used methods in the recent years holds important place in assessment of liver fibrosis. However there is no exact information on the results of liver elastography in healthy pregnant women in the world literature. The aim of the study was to investigate theSWE parameters of liver elastography in practically healthy pregnant women. The subject of the research was 50 practically healthy pregnant women within 18-45 years old (mean age 27.7±0.7). The pregnant women with genital and extragenital diseases were not included to the research. The research work was executed in the II Department of Obstetrics and Gynecology of Azerbaijan Medical University. SWE of liver in pregnant women was conducted in the I Department of Surgical Diseases of Azerbaijan Medical University through Supersonic Aixplorer Multi Wave device presented by the Scientific Development Foundation under the President of the Azerbaijan Republic. The obtained tissue hardness indicators are assessed under METAVIR scale. The results of the research showed that the measures of liver in practically healthy pregnant women are normal, edges flat, its echogenicity mainly normal, echostructure of its parenchyma homogenous, hardness was F0-F1 (normal) under METAVIR scale, fibrosis not observed. The obtained results were processed by variational (power average, percentile distribution) and correlation (ρ-Spearman) analyzes using the statistical package SPSS-20. A statistical study of the distribution of liver density in healthy women showed that the average density was 4,43±0,01 with 95% confidence interval (4,23 - 4,63). The histogram of distribution of liver density in practically healthy women belongs to the family of normal distributions with coefficients of variation coefficient (16.3%), asymmetry (-0.861±0.337) and excess (-0.068±0.662). Correlation analysis in healthy women did not reveal a reliable relationship between age and liver density (ρ=0.082, p=0.571), but a significant inverse correlation was found between the body mass index (BMI) and liver density (ρ=-0.317; p=0.025). Easy application, non-invasiveness, maximum exactness within the real time, repeatedly application of procedure and no risk to fetus by Shear Wave elastography of liver allow applying this method in pregnant women. Study of liver elasticity in pregnant women allows assessing the grades of hepatic fibrosis and differentiating liver disease.

Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia.

PubMed

Crouser, Elliott D; Julian, Mark W; Huff, Jennifer E; Joshi, Mandar S; Bauer, John A; Gadd, Martha E; Wewers, Mark D; Pfeiffer, Douglas R

2004-02-01

This study was designed to determine the role played by the mitochondrial permeability transition in the pathogenesis of mitochondrial damage and dysfunction in a representative systemic organ during the acute phase of endotoxemia. A well-established, normotensive feline model was employed to determine whether pretreatment with cyclosporine A, a potent inhibitor of the mitochondrial permeability transition, normalizes mitochondrial ultrastructural injury and dysfunction in the liver during acute endotoxemia. The Ohio State University Medical Center research laboratory. Random source, adult, male conditioned cats. Hemodynamic resuscitation and maintenance of acid-base balance and tissue oxygen availability were provided, as needed, to minimize the potentially confounding effects of tissue hypoxia and/or acidosis on the experimental results. Treatment groups received isotonic saline vehicle (control; n = 6), lipopolysaccharide (3.0 mg/kg, intravenously; n = 8), or cyclosporine A (6.0 mg/kg, intravenously; n = 6) or tacrolimus (FK506, 0.1 mg/kg, intravenously; n = 4) followed in 30 mins by lipopolysaccharide (3.0 mg/kg, intravenously). Liver samples were obtained 4 hrs posttreatment, and mitochondrial ultrastructure, function, and cytochrome c, Bax, and ceramide contents were assessed. As expected, significant mitochondrial injury was apparent in the liver 4 hrs after lipopolysaccharide treatment, despite maintenance of regional tissue oxygen availability. Namely, mitochondria demonstrated high-amplitude swelling and exhibited altered respiratory function. Cyclosporine A pretreatment attenuated lipopolysaccharide-induced mitochondrial ultrastructural abnormalities and normalized mitochondrial respiratory control, reflecting protection against inner mitochondrial membrane damage. However, an abnormal permeability of outer mitochondrial membranes to cytochrome c was observed in all lipopolysaccharide-treated groups and was associated with increased mitochondrial concentrations of Bax and ceramide. These studies confirm that liver mitochondria are early targets of injury during endotoxemia and that inner and outer mitochondrial membrane damage occurs through different mechanisms. Inner mitochondrial membrane damage appears to relate to the mitochondrial permeability transition, whereas outer mitochondrial membrane damage can occur independent of the mitochondrial permeability transition. Preliminary evidence suggests that Bax may participate in lipopolysaccharide-induced outer mitochondrial membrane damage, but further investigations are needed to confirm this.

Effects of chronic copper exposure during early life in rhesus monkeys.

PubMed

Araya, Magdalena; Kelleher, Shannon L; Arredondo, Miguel A; Sierralta, Walter; Vial, María Teresa; Uauy, Ricardo; Lönnerdal, Bo

2005-05-01

Whether infants regulate copper absorption and the potential effects of excess copper in early life remain poorly defined. The objective of the study was to assess copper retention, liver copper content, and liver function in infant rhesus monkeys fed infant formula containing 6.6 mg Cu/L. From birth to 5 mo of age, infant rhesus monkeys were fed formula that was supplemented with copper (0.6 mg Cu/L; n = 5) or not supplemented (n = 4). In all animals, weight and crown-rump length (by anthropometry), hemoglobin, hematocrit, plasma ceruloplasmin activity, and zinc and copper concentrations were measured monthly (birth to 6 mo) and at 8 and 12 mo. When the animals were 1, 5, and 8 mo old, liver copper and metallothionein concentrations, liver histology (by light and electron microscopy), and the number of Kupffer cells were assessed, and 67Cu retention was measured. Liver function was assessed by measurement of plasma alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase activities and protein, albumin, bilirubin, and blood urea nitrogen concentrations. 67Cu retention was 19.2% and 10.9% after 1 and 5 mo of copper treatment, respectively, compared with approximately 75% in controls at age 2 mo. At age 8 mo, 67Cu retention was 22.9% in copper-treated animals and 31.5% in controls. Liver histology remained normal by light microscopy, with mild ultrastructural signs of cell damage at 5 mo. Liver copper concentration was 4711, 1139, and 498 microg/g dry tissue at 1, 5, and 8 mo, respectively, in copper-treated animals and 250 microg/g at 2 mo in controls. Measurements could not be completed in all animals. No clinical evidence of copper toxicity was observed. Copper absorption was down-regulated; increases in liver copper content at ages 1 and 5 mo did not result in histologic damage. Ultrastructural changes at age 5 mo could signal early cellular damage.

Expression of hepatic lipid droplets is decreased in the nitrofen model of congenital diaphragmatic hernia.

PubMed

Takahashi, Hiromizu; Kutasy, Balazs; Friedmacher, Florian; Takahashi, Toshiaki; Puri, Prem

2016-02-01

Prenatal mortality in newborn infants with congenital diaphragmatic hernia (CDH) has been attributed to increased amounts of liver hernia ion through the diaphragmatic defect. Antenatal studies in human and rodent fetus with CDH further demonstrated a contribution of the developing liver in the pathogenesis of CDH. The abnormal hepatic growth in experimental animal models, therefore, indicates a disruption of normal liver development in CDH. However, the underlying structural, histological and functional changes in the liver of animals with CDH remain unclear. We design this study to test the hypothesis that the morphological and cellular liver development is altered in the nitrogen-induced CDH model. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Livers and chest were harvested on D21 and divided into two groups: control (n = 8), nitrofen with CDH (CDH, n = 8). Haematoxylin-eosin (Straub et al. Histopathology 68:617-631, 2013) staining was performed to evaluate underlying morphological changes. Apoptosis was checked by using TUNEL staining and apoptotic cell number was counted on 16-16 slides in 25 fields by two independent viewers. Hepatic lipid droplet expressions were evaluated by hepatic adipose differentiation-related protein (ARDP) expression. Compared to controls markedly increased hypertrophy was seen in CDH group. Significantly increased apoptotic cell numbers were detected in CDH group compared to controls (5.1 ± 1.5 vs 2.1 ± 0.6) (p < 0.05). The relative mRNA expression levels of ARDP were significantly reduced in CDH group compared to controls. Immunohistochemistry showed markedly decreased hepatic ADRP immunoreactivity in CDH fetuses compared to controls. Our findings provide strong evidence of hepatic hypertrophy and increased cell apoptosis in the liver of nitrofen-induced CDH. These morphological changes may affect liver lipid droplet expression function.

A 27-Year Experience With Surgical Treatment of Budd-Chiari Syndrome

PubMed Central

Orloff, Marshall J.; Daily, Pat O.; Orloff, Susan L.; Girard, Barbara; Orloff, Mark S.

2000-01-01

Objective To determine the effects of surgical portal decompression in Budd-Chiari syndrome (BCS) on survival, quality of life, shunt patency, liver function, portal hemodynamics, and hepatic morphology during periods ranging from 3.5 to 27 years. Summary Background Data Experiments in the authors’ laboratory showed that surgical portal decompression reversed the deleterious effects of BCS on the liver. This study was aimed at determining whether similar benefit could be obtained in patients with BCS. Methods From 1972 to 1999, the authors conducted prospective studies of the treatment of 60 patients with BCS who were divided into three groups: the first had occlusion confined to the hepatic veins treated by direct side-to-side portacaval shunt (SSPCS); the second had occlusion involving the inferior vena cava (IVC) treated by a portal decompressive procedure that bypassed the obstructed IVC; and the third group, who had advanced cirrhosis and hepatic decompensation and were referred too late for treatment by portal decompression, required orthotopic liver transplantation. Results In the 32 patients with BCS resulting from hepatic vein occlusion alone, SSPCS had a surgical death rate of 3%, and 94% of the patients were alive 3.5 to 27 years after surgery. All 31 survivors remained free of ascites and almost all had normal liver function. No patient with a patent shunt had encephalopathy. The SSPCS remained patent in all but one patient. Liver biopsies showed no evidence of congestion or necrosis, and 48% of the biopsies were diagnosed as normal. Mesoatrial shunt was performed in eight patients with BCS caused by IVC thrombosis. All patients survived surgery, but five subsequently developed thrombosis of the synthetic graft and died. Because of the poor results, mesoatrial shunt was abandoned. Instead, a high-flow combination shunt was introduced, consisting of SSPCS combined with a cavoatrial shunt (CAS) through a Gore-Tex graft. There were no surgical or long-term deaths among 10 patients who underwent combined SSPCS and CAS, and the shunts functioned effectively during 4 to 16 years of follow-up. Ten patients with advanced cirrhosis were referred too late to benefit from surgical portal decompression, and they were approved and listed for orthotopic liver transplantation. Three patients died of liver failure while awaiting a transplant, and four patients died after the transplant. The 1- and 5-year survival rates were 40% and 30%, respectively. Conclusions SSPCS in BCS with hepatic vein occlusion alone results in reversal of liver damage, correction of hemodynamic disturbances, prolonged survival, and good quality of life when performed early in the course of BCS. Similarly good results are obtained with combined SSPCS and CAS in patients with BCS resulting from IVC occlusion. In contrast, mesoatrial shunt has been discontinued in the authors’ program because of an unacceptable incidence of graft thrombosis and death. In patients with advanced cirrhosis from long-standing, untreated BCS, orthotopic liver transplantation is the only hope of relief and results in the salvage of some patients. The key to long survival in BCS is prompt diagnosis and treatment by portal decompression. PMID:10973384

[Congenital portosystemic shunt. The Abernethy malformation].

PubMed

Avila, L F; Luis, A L; Encinas, J L; Hernández, F; Olivares, P; Fernández Cuadrado, J; Hierro, L; Jara, P; López Santamaría, M; Tovar, J A

2006-10-01

Congenital portosystemic shunt (CEPS) is a rare condition that was first reported by John Abernethy in 1793. Two types of CEPS are described: type I (side to end anastomosis) or congenital absence of the portal vein, and type II (side to side anastomosis) with portal vein supply partially conserved. Type I CEPS is usually seen in girls and associates multiple malformations as polysplenia, malrotation, and cardiac anomalies. Type II is even rarer with no sex preference and no malformations associated. Hepatic encephalopathy is a common complication of both types in adulthood. Liver transplantation is the only effective treatment for symptomatic type I CEPS. A therapeutic approach for type II could be surgical closure of the shunt. To analyse our experience in diagnosis and management of portosystemic shunts. We report 4 cases of CEPS (3 type I and 1 type II) diagnosed between January-1997 and March-2005 in our department. We present 4 patients with ages at diagnosis ranging from 0 to 28 months, 3 type I CEPS (2 boys and 1 girl) and 1 boy type II. The type I girl was prenatally diagnosed at 12 weeks of gestation. Initial clinical signs in type 1 boys were splenomegaly and hypersplenism, both with normal pondo-statural growth. No polysplenia or cardiac anomalies were assessed. One of them presented mild developmental delay, dismorphic features and facial telangiectasias. He had normal coagulation tests with chronic hepatic dysfunction (high transaminases) and regenerative nodular lesions were seen by imaging techniques. The other type I patient had hypoprothrombinemia, tendency to capillary bleeding (haematomas and epistaxis) with preserved liver function. Both patients have developed mild portal hypertension and present steatosis signs at liver biopsy. The type I girl presents a 21 trisomy and associates a cardiac anomaly (interauricular communication). Her hepatic function test are normal but liver calcifications can be seen by ultrasound. Type II child associates hypospadias but he has no clinical sigh or symptom related to the shunt. In our three cases diagnosis was suggested by conventional and Doppler ultrasound and confirmed by angio-resonance imaging. All our patients are included in a meticulous clinical and radiological follow-up with no need of surgical treatment for the shunt until now. Although diagnosis of these malformations could be casual we have to think about CEPS in children presenting unspecific liver disease. Magnetic angio-resonance imaging is actually the best diagnosis methods for CEPS. These patients have a high risk for developing hepatic encephalopathy and portal hypertension, so a careful follow-up is required although surgery is not usually needed until adulthood.

Finding the optimal dose of vitamin K1 to treat vitamin K deficiency and to avoid anaphylactoid reactions.

PubMed

Mi, Yan-Ni; Ping, Na-Na; Li, Bo; Xiao, Xue; Zhu, Yan-Bing; Cao, Lei; Ren, Jian-Kang; Cao, Yong-Xiao

2017-10-01

Vitamin K1 injection induces severe dose-related anaphylactoid reactions and overdose for the treatment of vitamin K deficiency. We aimed to find an optimal and small dose of vitamin K1 injection to treat vitamin K deficiency and avoid anaphylactoid reactions in animal. Rats were administered a vitamin K-deficient diet and gentamicin to establish vitamin K deficiency model. Behaviour tests were performed in beagle dogs to observe anaphylactoid reactions. The results showed an increased protein induced by vitamin K absence or antagonist II (PIVKA-II) levels, a prolonging of prothrombin time (PT) and activated partial thromboplastin time (APTT) and a decrease in vitamin K-dependent coagulation factor (F) II, VII, IX and X activities in the model group. In vitamin K1 0.01 mg/kg group, the liver vitamin K1 levels increased fivefold and the liver vitamin K2 levels increased to the normal amount. Coagulation markers PT, APTT, FVII and FIX activities returned to normal. Both in the 0.1 and 1.0 mg/kg vitamin K1 groups, coagulation functions completely returned to normal. Moreover, the amount of liver vitamin K1 was 40 (0.1 mg/kg) or 100 (1.0 mg/kg) times as in normal. Vitamin K2 was about 4 (0.1 mg/kg) or 5 (1.0 mg/kg) times as the normal amount. There was no obvious anaphylactoid symptom in dogs with the dose of 0.03 mg/kg, which is equivalent to the dose of 0.01 mg/kg in rats. These results demonstrated that a small dose of vitamin K1 is effective to improve vitamin K deficiency and to prevent anaphylactoid reactions, simultaneously. © 2017 Société Française de Pharmacologie et de Thérapeutique.

Evaluation of Hepatoprotective Effect of Curcumin on Liver Cirrhosis Using a Combination of Biochemical Analysis and Magnetic Resonance-Based Electrical Conductivity Imaging

PubMed Central

Kyung, Eun Jung; Kim, Hyun Bum; Hwang, Eun Sang; Lee, Seok; Choi, Bup Kyung; Lim, Sang Moo; Kwon, Oh In

2018-01-01

In oriental medicine, curcumin is used to treat inflammatory diseases, and its anti-inflammatory effect has been reported in recent research. In this feasibility study, the hepatoprotective effect of curcumin was investigated using a rat liver cirrhosis model, which was induced with dimethylnitrosamine (DMN). Together with biochemical analysis, we used a magnetic resonance-based electrical conductivity imaging method to evaluate tissue conditions associated with a protective effect. The effects of curcumin treatment and lactulose treatment on liver cirrhosis were compared. Electrical conductivity images indicated that liver tissues damaged by DMN showed decreased conductivity compared with normal liver tissues. In contrast, cirrhotic liver tissues treated with curcumin or lactulose showed increased conductivity than tissues in the DMN-only group. Specifically, conductivity of cirrhotic liver after curcumin treatment was similar to that of normal liver tissues. Histological staining and immunohistochemical examination showed significant levels of attenuated fibrosis and decreased inflammatory response after both curcumin and lactulose treatments compared with damaged liver tissues by DMN. The conductivity imaging and biochemical examination results indicate that curcumin's anti-inflammatory effect can prevent the progression of irreversible liver dysfunction. PMID:29887757

The 57Fe hyperfine interactions in iron storage proteins in liver and spleen tissues from normal human and two patients with mantle cell lymphoma and acute myeloid leukemia: a Mössbauer effect study

NASA Astrophysics Data System (ADS)

Oshtrakh, M. I.; Alenkina, I. V.; Vinogradov, A. V.; Konstantinova, T. S.; Semionkin, V. A.

2015-04-01

Study of human spleen and liver tissues from healthy persons and two patients with mantle cell lymphoma and acute myeloid leukemia was carried out using Mössbauer spectroscopy with a high velocity resolution. Small variations in the 57Fe hyperfine parameters for normal and patient's tissues were detected and related to small variations in the 57Fe local microenvironment in ferrihydrite cores. The differences in the relative parts of more crystalline and more amorphous core regions were also supposed for iron storage proteins in normal and patients' spleen and liver tissues.

Damage to enteric neurons occurs in mice that develop fatty liver disease but not diabetes in response to a high-fat diet.

PubMed

Rivera, L R; Leung, C; Pustovit, R V; Hunne, B L; Andrikopoulos, S; Herath, C; Testro, A; Angus, P W; Furness, J B

2014-08-01

Disorders of gastrointestinal functions that are controlled by enteric neurons commonly accompany fatty liver disease. Established fatty liver disease is associated with diabetes, which itself induces enteric neuron damage. Here, we investigate the relationship between fatty liver disease and enteric neuropathy, in animals fed a high-fat, high-cholesterol diet in the absence of diabetes. Mice were fed a high-fat, high-cholesterol diet (21% fat, 2% cholesterol) or normal chow for 33 weeks. Liver injury was assessed by hematoxylin and eosin, picrosirius red staining, and measurement of plasma alanine aminotransaminase (ALT). Quantitative immunohistochemistry was performed for different types of enteric neurons. The mice developed steatosis, steatohepatitis, fibrosis, and a 10-fold increase in plasma ALT, indicative of liver disease. Oral glucose tolerance was unchanged. Loss and damage to enteric neurons occurred in the myenteric plexus of ileum, cecum, and colon. Total numbers of neurons were reduced by 15-30% and neurons expressing nitric oxide synthase were reduced by 20-40%. The RNA regulating protein, Hu, became more concentrated in the nuclei of enteric neurons after high-fat feeding, which is an indication of stress on the enteric nervous system. There was also disruption of the neuronal cytoskeletal protein, neurofilament medium. Enteric neuron loss and damage occurs in animals with fatty liver disease in the absence of glucose intolerance. The enteric neuron damage may contribute to the gastrointestinal complications of fatty liver disease. © 2014 John Wiley & Sons Ltd.

Idiopathic liver function test abnormality in pregnancy is associated with assisted reproduction techniques.

PubMed

Kopylov, Uri; Avidan, Benjamin; Papageorgiou, Neofytos P; Katz, Lior H; Sivan, Eyal; Zimlichman, Eyal; Hussein, Haya; Maor, Yaakov

2013-02-01

To examine the prevalence, etiology, risk factors, and outcomes of liver abnormality in pregnancy, in a tertiary medical center, and to study the potential impact of artificial reproduction techniques (ART) on the incidence and the outcome of pregnancy-related liver abnormality. A retrospective case-control study using an electronic database and patients' files. Tertiary referral center. Women in the third trimester of pregnancy who were hospitalized for delivery. None. Development of significant elevation of alanine aminotransferase (ALT ≥ 100 IU/L). Secondary outcomes included development of maternal and fetal complications. The upper limit of normal of ALT was ≥ 1.5 times and it occurred in 440 (1.6%) pregnancies; of those, 228 (0.8%) had ALT ≥ 100 IU/L. The etiology of significant liver test abnormality was idiopathic in 47% of patients. Compared with spontaneous pregnancies (295/23,793), ART was significantly associated with liver test abnormality (145/4, 520). The presence of ALT ≥ 100 IU/L in the third trimester was associated with higher rates of cesarean sections, prematurity, low birthweight, and fetal complications. A definite etiology was not determined in about half of pregnancy-associated liver test abnormality. The ART was significantly associated with liver test elevation. Significant liver test abnormality in the third trimester may have an impact on maternal and fetal/neonatal outcomes. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. 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.

IL-8 signaling is up regulated in alcoholic hepatitis and DDC fed mice with Mallory Denk Bodies (MDBs) present

PubMed Central

Liu, Hui; French, Barbara A.; Nelson, Tyler J.; Li, Jun; Tillman, Brittany; French, Samuel W.

2015-01-01

Chemokines and their receptors are involved in oncogenesis and in tumor progression, invasion, and metastasis. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. The chemokine CXCL8, also known as interleukin-8 (IL-8), is a proinflammatory molecule that has functions within the tumor microenvironment. Deregulation of IL-8 signaling is shown to play pivotal roles in tumorigenesis and progression. Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. By comparing AH livers where MDBs had formed with normal livers, there were significant changes of IL-8 signaling by RNA sequencing (RNA-Seq) analyses. Real-time PCR analysis of CXCR2 further shows a 6-fold up regulation in AH livers and a 26-fold up regulation in the livers of DDC re-fed mice. IL-8 mRNA was also significantly up regulated in AH livers and DDC re-fed mice livers. This indicates that CXCR2 and IL-8 may be crucial for liver MDB formation. MDB containing balloon hepatocytes in AH livers had increased intensity of staining of the cytoplasm for both CXCR2 and IL-8. Over expression of IL-8 leads to an increase of the mitogen activated protein kinase (MAPK) cascade and exacerbates the inflammatory cycle. These observations constitute a demonstration of the altered regulation of IL-8 signaling in the livers of AH and mice fed DDC where MDBs formed, providing further insight into the mechanism of MDB formation mediated by IL-8 signaling in AH. PMID:26260904

IL-8 signaling is up-regulated in alcoholic hepatitis and DDC fed mice with Mallory Denk Bodies (MDBs) present.

PubMed

Liu, Hui; French, Barbara A; Nelson, Tyler J; Li, Jun; Tillman, Brittany; French, Samuel W

2015-10-01

Chemokines and their receptors are involved in oncogenesis and in tumor progression, invasion, and metastasis. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. The chemokine CXCL8, also known as interleukin-8 (IL-8), is a proinflammatory molecule that has functions within the tumor microenvironment. Deregulation of IL-8 signaling is shown to play pivotal roles in tumorigenesis and progression. Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. By comparing AH livers where MDBs had formed with normal livers, there were significant changes of IL-8 signaling by RNA sequencing (RNA-Seq) analyses. Real-time PCR analysis of CXCR2 further shows a 6-fold up-regulation in AH livers and a 26-fold up-regulation in the livers of DDC re-fed mice. IL-8 mRNA was also significantly up-regulated in AH livers and DDC re-fed mice livers. This indicates that CXCR2 and IL-8 may be crucial for liver MDB formation. MDB containing balloon hepatocytes in AH livers had increased intensity of staining of the cytoplasm for both CXCR2 and IL-8. Overexpression of IL-8 leads to an increase of the mitogen activated protein kinase (MAPK) cascade and exacerbates the inflammatory cycle. These observations constitute a demonstration of the altered regulation of IL-8 signaling in the livers of AH and mice fed DDC where MDBs formed, providing further insight into the mechanism of MDB formation mediated by IL-8 signaling in AH. Copyright © 2015 Elsevier Inc. All rights reserved.

Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis.

PubMed

Wahlin, Staffan; Aschan, Johan; Björnstedt, Mikael; Broomé, Ulrika; Harper, Pauline

2007-01-01

We report the case of a middle-age patient presenting with severe progressive protoporphyric cholestasis. To halt further progression of liver disease, medical treatment was given aimed at different mechanisms possibly causing cholestasis in erythropoietic protoporphyria. Within eighty days, liver biochemistry completely normalized and liver histology markedly improved. Bone marrow transplantation was performed to prevent relapse of cholestatic liver disease by correcting the main site of protoporphyrin overproduction. Thirty-three months after cholestatic presentation and ten months after bone marrow transplantation, liver and porphyrin biochemistry remains normal. The patient is in excellent condition and photosensitivity is absent. The theoretical role of each treatment used to successfully reverse cholestasis and the role of bone marrow transplantation in erythropoietic protoporphyria are discussed. Medical treatment can resolve hepatic abnormalities in protoporphyric cholestasis. Bone marrow transplantation achieves phenotypic reversal and may offer protection from future protoporphyric liver disease.

Based on surface-enhanced Raman spectroscopy analysis of serum albumin in different stages of liver disease for early screening primary liver cancer

NASA Astrophysics Data System (ADS)

Liao, Fadian; Ruan, Qiuyong; Lin, Juqiang; Lin, Jinyong; Zeng, Yongyi; Li, Ling; Huang, Zufang; Liu, Nenrong; Chen, Rong

2014-09-01

Despite the introduction of high-technology methods of detection and diagnosis, screening of primary liver cancer (PLC) remains imperfect. To diagnosis PLC earlier, Surface-enhanced Raman spectroscopy (SERS) coupled with cellulose-acetate membrane electrophoresis were introduced to separate human serum albumin and SERS spectra. Three groups (15 normal persons' samples, 17 hepatitis/cirrhosis samples, 15 cases of PLC) of serum albumin were tested. Silver colloid was used to obtain SERS spectra of human serum albumin. Principal component analysis (PCA) and linear discriminant analysis (LDA) were also employed for statistical analysis. The mean Raman spectra of three groups and the difference spectra of any two suggested that the albumin has changed in liver patients. Compared to normal groups, some Raman peaks have shifted or even disappeared in hepatitis/cirrhosis and PLCs groups. The sensitivity and specificity between PLCs and normal groups is 80% and 93.3%. Among hepatitis/cirrhosis and normal groups, the sensitivity is 88.2% and specificity is also 93.3%. Besides, the sensitivity and specificity between PLCs and hepatitis/cirrhosis groups is 86.7% and 76.5%. All the above data and results indicated that early screening of PLC is potential by SERS in different stages of liver disease before cancer occurs.

Icariin Ameliorate Thiram-Induced Tibial Dyschondroplasia via Regulation of WNT4 and VEGF Expression in Broiler Chickens

PubMed Central

Zhang, Hui; Mehmood, Khalid; Li, Kun; Rehman, Mujeeb U.; Jiang, Xiong; Huang, Shucheng; Wang, Lei; Zhang, Lihong; Tong, Xiaole; Nabi, Fazul; Yao, Wangyuan; Iqbal, Muhammad K.; Shahzad, Muhammad; Li, Jiakui

2018-01-01

Tibial dyschondroplasia (TD) is main bone problem in fast growing poultry birds that effect proximal growth plate (GP) of tibia bone. TD is broadly defined as non-vascularized and non-mineralized, and enlarged GP with tibia bone deformation and lameness. Icariin (Epimedium sagittatum) is a traditional Chinese medicine, which is commonly practiced in the treatment of various bone diseases. Recently, many researcher reports about the beneficial effects of icariin in relation to various types of bone conditions but no report is available about promoting effect of icariin against TD. Therefore, current study was conducted to explore the ameliorating effect of icariin in thiram-induced TD chickens. A total of 180 broiler chicks were equally distributed in three groups; control, TD induced by thiram (50 mg/kg), and icariin group (treated with icariin @10 mg/kg). All groups were administered with normal standard diet ad libitum regularly until the end of experiment. The wingless-type member 4 (WNT4) and vascular endothelial growth factor (VEGF) genes and proteins expression were analyzed by quantitative real-time polymerase chain reaction and western blot analysis respectively. Tibial bone parameters, physiological changes in serum, antioxidant enzymes, and chicken growth performance were determined to assess advantage and protective effect of the medicine in broiler chicken. The expression of WNT4 was decreased while VEGF increased significantly (P < 0.05) in TD affected chicks. TD enhanced the GP, lameness, and irregular chondrocytes, while reduced the liver function, antioxidant enzymes in liver, and performance of chickens. Icariin treatment up-regulated WNT4 and down-regulated VEGF gene and protein expressions significantly (P < 0.05), restored the GP width, increased growth performance, corrected liver functions and antioxidant enzymes levels in liver, and mitigated the lameness in broiler chickens. In conclusion, icariin administration recovered GP size, normalized performance and prevented lameness significantly. Therefore, icariin treatments are encouraged to reduce the incidence of TD in broiler chickens. PMID:29527166

[Expressions and significance of TLR2 and TLR4 in Kupffer cells of tree shrews chronically infected with hepatitis B virus].

PubMed

Ruan, Ping; Yang, Chun; Su, Jianjia; Ou, Chao; Cao, Ji; Luo, Chengpiao; Tang, Yanping; Qin, Hong; Sun, Wen; Li, Yuan

2014-07-01

To investigate the mRNA expression levels of Toll-like receptors 2 (TLR2) and TLR4 in Kupffer cells of tree shrews that were chronically infected with hepatitis B virus (HBV), and the effects of these receptors on the function of Kupffer cells. The tree shrews were divided into tree shrews proved with chronic HBV infection, tree shrews suspected with chronic HBV infection, and normal control tree shrews without hepatitis B vaccination. The samples of serum and liver biopsy were collected periodically, and the levels of HBV DNA in serum and liver tissues were detected by fluorescence-based quantitative real-time PCR (qRT-PCR). Meanwhile, Kupffer cells were isolated from the biopsied liver tissues, and then purified and primarily cultured. Afterwards, qRT-PCR was applied to detect the mRNA expression levels of TLR2, TLR4 and TNF-α in the Kupffer cells. Cell migration assay and lysosome-specific fluorescent probe were adopted to analyze the effects of TLR2 and TLR4 on the migration capacity of Kupffer cells and the quantity of lysosomes in these cells. The mRNA expression levels of TLR2 and TLR4 in tree shrews proved with chronic HBV infection were lower than those in the ones suspected with chronic HBV infection and normal controls without hepatitis B vaccination (P<0.05), and these expression levels were all negatively correlated with the level of HBV DNA in liver tissues of the animals (P<0.05), but were positively correlated with the number of migrated Kupffer cells, the density of lysosomes and the mRNA expression level of TNF-α (P<0.05). TLR2 and TLR4 in Kupffer cells may play important roles in the chronic process of hepatic pathological changes in tree shrews infected with HBV through their influence on the function of Kupffer cells.

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.

Controlled cell morphology and liver-specific function of engineered primary hepatocytes by fibroblast layer cell densities.

PubMed

Sakai, Yusuke; Koike, Makiko; Kawahara, Daisuke; Hasegawa, Hideko; Murai, Tomomi; Yamanouchi, Kosho; Soyama, Akihiko; Hidaka, Masaaki; Takatsuki, Mitsuhisa; Fujita, Fumihiko; Kuroki, Tamotsu; Eguchi, Susumu

2018-03-05

Engineered primary hepatocytes, including co-cultured hepatocyte sheets, are an attractive to basic scientific and clinical researchers because they maintain liver-specific functions, have reconstructed cell polarity, and have high transplantation efficiency. However, co-culture conditions regarding engineered primary hepatocytes were suboptimal in promoting these advantages. Here we report that the hepatocyte morphology and liver-specific function levels are controlled by the normal human diploid fibroblast (TIG-118 cell) layer cell density. Primary rat hepatocytes were plated onto TIG-118 cells, previously plated 3 days before at 1.04, 5.21, and 26.1×10 3  cells/cm 2 . Hepatocytes plated onto lower TIG-118 cell densities expanded better during the early culture period. The hepatocytes gathered as colonies and only exhibited small adhesion areas because of the pushing force from proliferating TIG-118 cells. The smaller areas of each hepatocyte result in the development of bile canaliculi. The highest density of TIG-118 cells downregulated albumin synthesis activity of hepatocytes. The hepatocytes may have undergone apoptosis associated with high TGF-β1 concentration and necrosis due to a lack of oxygen. These occurrences were supported by apoptotic chromatin condensation and high expression of both proteins HIF-1a and HIF-1b. Three types of engineered hepatocyte/fibroblast sheets comprising different TIG-118 cell densities were harvested after 4 days of hepatocyte culture and showed a complete cell sheet format without any holes. Hepatocyte morphology and liver-specific function levels are controlled by TIG-118 cell density, which helps to design better engineered hepatocytes for future applications such as in vitro cell-based assays and transplantable hepatocyte tissues. Copyright © 2018 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Changes in arginase isoenzymes pattern in human hepatocellular carcinoma

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

Chrzanowska, Alicja; Krawczyk, Marek; Baranczyk-Kuzma, Anna

2008-12-12

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide affecting preferentially patients with liver cirrhosis. The studies were performed on tissues obtained during surgery from 50 patients with HCC, 40 with liver cirrhosis and 40 control livers. It was found that arginase activity in HCC was nearly 5- and 15-fold lower than in cirrhotic and normal livers, respectively. Isoenzymes AI (so-called liver-type arginase) and AII (extrahepatic arginase) were identified by Western blotting in all studied tissues, however the amount of AI, as well as the expression of AI-mRNA were lower in HCC, in comparison with normal liver, andmore » those of AII were significantly higher. Since HCC is arginine-dependent, and arginine is essential for cells growth, the decrease of AI may preserve this amino acid within tumor cells. Concurrently, the rise of AII can increase the level of polyamines, compounds crucial for cells proliferation. Thus, both arginase isoenzymes seem to participate in liver cancerogenesis.« less

Non-cirrhotic portal fibrosis at a tertiary care centre in South India.

PubMed

Mukta, V; Panicker, Lakshmi C; Sivamani, Kalaimani; Goel, Amit; Basu, Debdutta; Dhanapathi, Halnayak

2017-01-01

Non-cirrhotic portal fibrosis (NCPF) is one of the important causes of upper gastrointestinal haemorrhage in patients in tropical countries. The aim of this study was to describe the clinical and laboratory profile of 68 patients with NCPF. NCPF is defined as liver disease with: (1) evidence of portal hypertension; (2) a liver biopsy showing no cirrhosis or a Tc-labelled sulphur colloid scan showing a pattern suggestive of NCPF; and (3) a patent splenoportal axis. The clinical, laboratory and demographic features of 68 patients with such criteria were studied and analysed. NCPF was common in women (73.5%) in the fourth decade of life. The median duration of illness was 24 months (range, 1 month-28 years). Patients presented to hospital with the sensation of a mass in the abdomen (50%) or with haematemesis (26.5%). They had splenomegaly (95.6%) and thrombocytopenia (88.2%). The majority of patients had normal liver function tests. Abdominal ultrasonography showed increased periportal and peri gallbladder echoes (72%), spontaneous collaterals (41.2%) and ascites (19.1%). Liver biopsy revealed portal venous sclerosis (76.3%) and periportal fibrosis (55.3%). Tc-labelled sulphur colloid scan was suggestive of NCPF in the remaining 30 cases. NCPF is common in South India. Transient ascites occurs due to decompensation of liver function after variceal bleeding and in long standing cases of NCPF. Our study used Tc-sulphur scan for diagnosing NCPF in patients where liver biopsy was contraindicated in view of severe thrombocytopenia; however, the diagnostic utility of Tc-sulphur nuclear scan to diagnose NCPF in patients with severe hypersplenism needs to be further evaluated in future studies. © The Author(s) 2016.

Vitamin B12 supplement alleviates N'-nitrosodimethylamine-induced hepatic fibrosis in rats.

PubMed

Ahmad, Areeba; Afroz, Nishat; Gupta, Umesh D; Ahmad, Riaz

2014-01-10

Abstract Context: Altered vitamin B 12 levels have been correlated with hepatotoxicity; however, further evidence is required to establish its protective role. Objective: To evaluate the effects of vitamin B 12 supplement in protecting N'-nitrosodimethylamine (NDMA)-induced hepatic fibrosis in Wistar rats. Materials and methods: Hepatic fibrosis was induced by administering NDMA in doses of 10 mg/kg body weight thrice a week for 21 days. Another group received equal doses (10 mg/kg body weight) of vitamin B 12 subsequent to NDMA treatment. Animals from either group were sacrificed weekly from the start of the treatment along with their respective controls. Progression of hepatic fibrosis, in addition to the effect of vitamin B 12 , was assessed biochemically for liver function biomarkers, liver glycogen, hydroxyproline (HP) and B 12 reserves along with histopathologically by hematoxylin and eosin (H & E) as well immunohistochemical staining for α-SMA expression. Results and discussion: Elevation in the levels of aminotransferases, SALP, total bilirubin and HP was observed in NDMA treated rats, which was concomitant with remarkable depletion in liver glycogen and B 12 reserves (p < 0.05). Liver biopsies also demonstrated disrupted lobular architecture, collagen amassing and intense fibrosis by NDMA treatment. Immunohistochemical staining showed the presence of activated stellate cells that was dramatically increased up to day 21 in fibrotic rats. Following vitamin B 12 treatment, liver function biomarkers, glycogen contents and hepatic vitamin B 12 reserves were restored in fibrotic rats, significantly. Vitamin B 12 administration also facilitated restoration of normal liver architecture. Conclusion: These findings provide interesting new evidence in favor of protective role for vitamin B 12 against NDMA-induced hepatic fibrosis in rats.

The association between content of the elements S, Cl, K, Fe, Cu, Zn and Br in normal and cirrhotic liver tissue from Danes and Greenlandic Inuit examined by dual hierarchical clustering analysis.

PubMed

Laursen, Jens; Milman, Nils; Pind, Niels; Pedersen, Henrik; Mulvad, Gert

2014-01-01

Meta-analysis of previous studies evaluating associations between content of elements sulphur (S), chlorine (Cl), potassium (K), iron (Fe), copper (Cu), zinc (Zn) and bromine (Br) in normal and cirrhotic autopsy liver tissue samples. Normal liver samples from 45 Greenlandic Inuit, median age 60 years and from 71 Danes, median age 61 years. Cirrhotic liver samples from 27 Danes, median age 71 years. Element content was measured using X-ray fluorescence spectrometry. Dual hierarchical clustering analysis, creating a dual dendrogram, one clustering element contents according to calculated similarities, one clustering elements according to correlation coefficients between the element contents, both using Euclidian distance and Ward Procedure. One dendrogram separated subjects in 7 clusters showing no differences in ethnicity, gender or age. The analysis discriminated between elements in normal and cirrhotic livers. The other dendrogram clustered elements in four clusters: sulphur and chlorine; copper and bromine; potassium and zinc; iron. There were significant correlations between the elements in normal liver samples: S was associated with Cl, K, Br and Zn; Cl with S and Br; K with S, Br and Zn; Cu with Br. Zn with S and K. Br with S, Cl, K and Cu. Fe did not show significant associations with any other element. In contrast to simple statistical methods, which analyses content of elements separately one by one, dual hierarchical clustering analysis incorporates all elements at the same time and can be used to examine the linkage and interplay between multiple elements in tissue samples. Copyright © 2013 Elsevier GmbH. All rights reserved.

SR-BI as target in atherosclerosis and cardiovascular disease - A comprehensive appraisal of the cellular functions of SR-BI in physiology and disease.

PubMed

Hoekstra, Menno

2017-03-01

High-density lipoprotein (HDL) is considered an anti-atherogenic lipoprotein species due to its role in reverse cholesterol transport. HDL delivers cholesterol esters to the liver through selective uptake by scavenger receptor class B type I (SR-BI). In line with the protective role for HDL in the context of cardiovascular disease, studies in mice and recently also in humans have shown that a disruption of normal SR-BI function predisposes subjects to the development of atherosclerotic lesions and cardiovascular disease. Although SR-BI function has been studied primarily in the liver, it should be acknowledged that the SR-BI protein is expressed in multiple tissues and cell types across the body, albeit at varying levels between the different tissues. Given that SR-BI is widely expressed throughout the body, multiple cell types and tissues can theoretically contribute to the atheroprotective effect of SR-BI. In this review the different functions of SR-BI in normal physiology are highlighted and the (potential) consequences of cell type-specific disruption of SR-BI function for atherosclerosis and cardiovascular disease susceptibility discussed. It appears that hepatocyte and platelet SR-BI inhibit respectively the development of atherosclerotic lesions and thrombosis, suggesting that SR-BI located on these cell compartments should be regarded as being a protective factor in the context of cardiovascular disease. The relative contribution of SR-BI present on endothelial cells, steroidogenic cells, adipocytes and macrophages to the pathogenesis of atherosclerosis and cardiovascular disease remains less clear, although proper SR-BI function in these cells does appear to influence multiple processes that impact on cardiovascular disease susceptibility. Copyright © 2017 The Author. Published by Elsevier B.V. All rights reserved.

Identification of a differentially-expressed gene in fatty liver of overfeeding geese.

PubMed

Zhao, Ayong; Tang, Huachun; Lu, Sufang; He, Ruiguo

2007-09-01

In response to overfeeding, geese develop fatty liver. To understand the fattening mechanism, mRNA differential display reverse transcription PCR was used to study the gene expression differences between French Landes grey geese and Xupu white geese in conditions of overfeeding and normal feeding. One gene was found to be up-regulated in the fatty liver in both breeds, and it has a 1797 bp cDNA with 83% identity to chicken SELENBP1. The sequence analysis revealed that its open reading frame of 1413 bp encodes a protein of 471 amino acids, which contains a putative conserved domain of 56 kDa selenium binding protein with high homology to its homologues of chicken (95%), rat (86%), mouse (84%), human (86%), monkey (86%), dog (86%), and cattle (86%). The function of this protein has been briefly reviewed based on published information. In tissue expression analysis, the expression of geese SELENBP1 mRNA was found to be higher in liver or kidney than in other tested tissues. The results showed that overfeeding could increase the mRNA expression level of geese SELENBP1.

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

Accumulation of hydroxyl lipids and 4-hydroxy-2-hexenal in live fish infected with fish diseases.

PubMed

Tanaka, Ryusuke; Shigeta, Kazuhiro; Sugiura, Yoshimasa; Hatate, Hideo; Matsushita, Teruo

2014-04-01

Hydroxy lipids (L-OH) and 4-hydroxy-2-hexenal (HHE) levels as well as other parameters such as lipid level, lipid class, fatty acid composition, and other aldehydes levels in the liver of diseased fish were investigated. Although significant differences in lipid level, lipid class, fatty acid composition, and other aldehyde levels were not always observed between normal and diseased fish, L-OH and HHE levels were significantly higher in the liver of the diseased fish than in that of the normal fish cultured with the same feeds under the same conditions. In the liver of puffer fish (Fugu rubripes) infected with Trichodina, L-OH and HHE levels significantly increased from 25.29±5.04 to 47.70 ± 5.27 nmol/mg lipid and from 299.79±25.25 to 1,184.40±60.27 nmol/g tissue, respectively. When the levels of HHE and other aldehydes in the liver of the normal and diseased puffer fish were plotted, a linear relationship with a high correlation coefficient was observed between HHE and propanal (r2=0.9447). Increased L-OH and HHE levels in the liver of the diseased fish and a high correlation between HHE and propanal in the liver of the normal and diseased fish were also observed in flat fish (Paralichthys olivaceus) infected with streptococcus, yellowtail (Seriola quinqueradiata) infected with jaundice, and amberjack (S. purpurascens) infected with Photobacterium damselae subsp. piscicida.

Angiogenesis and proliferation of bile duct enhances ischemic tolerance in rats with cirrhosis

PubMed Central

Zhang, Zhiqiang; Li, Zhennan; Zou, Chen; Zhang, Jingjing; Zhu, Yi; Miao, Yi

2015-01-01

Background/aims: Primary biliary cirrhosis (PBC), an autoimmune disease of the liver, is marked by slow progressive destruction of bile ducts. These patients with PBC often undergo orthotopic liver transplantation (OLT). Ischemic bile duct lesion (IBDL) is a major source of morbidity and even mortality after OLT. Cirrhosis of the liver has a higher tolerance to ischemia than a normal liver, but the mechanism remains unknown. Angiogenesis and proliferation of bile duct often responses in bile duct ischemia, which may enhance ischemic tolerance in patients with cirrhosis. Methodology: To test the hypothesis, a rat model with cirrhosis was established. Biochemical indexes of ischemic severity were measured including total bilirubin (TBIL) and direct bilirubin (DBIL). Immunohistochemical assay was performed for Ki67 (a biomarker for the proliferation of bile duct) and CD34 (a biomarker of angiogenesis). Results: The levels were lower for TBIL and DBIL in the bile duct from rat model with cirrhosis than that from a normal rat after ischemic surgery (P < 0.05). The levels were higher for Ki67 and CD34 from a rat model with cirrhosis than that from a normal rat after ischemic surgery (P < 0.05). Conclusions: The results suggest that a liver with cirrhosis has a better ischemic tolerance than a normal liver. Angiogenesis and proliferation of bile duct enhances ischemic tolerance in rats with cirrhosis. More research on the pathogenesis of IBDLs is needed for developing more specific preventive or therapeutic strategies. PMID:26550120

Spatial Distribution of Iron Within the Normal Human Liver Using Dual-Source Dual-Energy CT Imaging.

PubMed

Abadia, Andres F; Grant, Katharine L; Carey, Kathleen E; Bolch, Wesley E; Morin, Richard L

2017-11-01

Explore the potential of dual-source dual-energy (DSDE) computed tomography (CT) to retrospectively analyze the uniformity of iron distribution and establish iron concentration ranges and distribution patterns found in healthy livers. Ten mixtures consisting of an iron nitrate solution and deionized water were prepared in test tubes and scanned using a DSDE 128-slice CT system. Iron images were derived from a 3-material decomposition algorithm (optimized for the quantification of iron). A conversion factor (mg Fe/mL per Hounsfield unit) was calculated from this phantom study as the quotient of known tube concentrations and their corresponding CT values. Retrospective analysis was performed of patients who had undergone DSDE imaging for renal stones. Thirty-seven patients with normal liver function were randomly selected (mean age, 52.5 years). The examinations were processed for iron concentration. Multiple regions of interest were analyzed, and iron concentration (mg Fe/mL) and distribution was reported. The mean conversion factor obtained from the phantom study was 0.15 mg Fe/mL per Hounsfield unit. Whole-liver mean iron concentrations yielded a range of 0.0 to 2.91 mg Fe/mL, with 94.6% (35/37) of the patients exhibiting mean concentrations below 1.0 mg Fe/mL. The most important finding was that iron concentration was not uniform and patients exhibited regionally high concentrations (36/37). These regions of higher concentration were observed to be dominant in the middle-to-upper part of the liver (75%), medially (72.2%), and anteriorly (83.3%). Dual-source dual-energy CT can be used to assess the uniformity of iron distribution in healthy subjects. Applying similar techniques to unhealthy livers, future research may focus on the impact of hepatic iron content and distribution for noninvasive assessment in diseased subjects.

Evaluation of the hepatoprotective effect of combination between hinokiflavone and Glycyrrhizin against CCl4 induced toxicity in rats.

PubMed

Abdel-Kader, Maged S; Abulhamd, Ashraf T; Hamad, Abubaker M; Alanazi, Abdullah H; Ali, Rizwan; Alqasoumi, Saleh I

2018-05-01

Liver diseases are one of the fatal syndromes due to the vital role of the liver. Most of the effective treatment of liver conditions are of natural origin. Silymarin (SI) is the standard drug used for treatment of impaired liver functions. Two natural compounds possessing promising liver protection and with different chemical structures namely; the bioflavonoid hinokiflavone (HF) isolated from Junipers phoenicea family Cupressaceae and the sweet saponin Glycyrrhizin (GL) present in  Glycyrrhiza glabra  (liquorice) were selected for the current study. Since the two compounds are of different nature, they may act by different mechanisms and express synergistic effect. Combination of the two compounds using to dose levels were challenged with single doses of HF, GL and SI as well. The comparison was monitored via measuring serum biochemical parameters including, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltranspeptidase (GGT), alkaline phosphatase (ALP) and total bilirubin, tissue parameters such as MDA, NP-SH and TP, histopathological study using light and electron microscope. Protective effect on kidney was also monitored histopathologically and biochemically through observing the levels of LDH, creatinine, creatinine-kinase, urea and uric acid. The combinations of HF and GL showed protective effect more than the used single doses of HF and GL alone. However, SI was superior to the used combination in the two used doses in all the measured parameters. The liver and kidney cells appearance under normal and electron microscope showed that SI treated groups showed almost normal cells with slight toxic signs. Cells from group treated with the higher doses of the combination of HF and GL showed slight signs of intoxication under light and electron microscope indicating good level of protection. Although the combination of HF and GL expressed good protection in the higher dose, however, the combination did not exceed the protective effect of SI.

Efficiency of herbal medicine Dai-kenchu-to on portal blood flow in rat models.

PubMed

Muraoka, Izumi; Takatsuki, Mitsuhisa; Soyama, Akihiko; Yamaguchi, Izumi; Tanaka, Shiro; Tanaka, Takayuki; Kinoshita, Ayaka; Hara, Takanobu; Kuroki, Tamotsu; Eguchi, Susumu

2015-09-01

To clarify the influence of Dai-Kenchu-To (DKT) on portal blood flow (PBF), PBF was continuously measured with Doppler ultrasound. Normal liver rats were divided into a DKT 90 mg/kg, DKT 270 mg/kg administered group, and control, while cirrhotic liver rats were divided into a DKT-LC 90 mg/kg administered group and Control-LC. The PBF was measured after the administration of either DKT or water for 60 min by laser Doppler flowmetry system. The PBF in the DKT 90 increased approximately 10 min after DKT was administrated, and elevated levels were maintained for approximately 10 min. A comparison of the increase in PBF by the calculating the area under the curve (AUC) revealed that flow was significantly higher in the DKT 90 compared to either the control or the DKT 270 (p < 0.05). The cirrhotic liver group showed stable PBF in both the DKT-LC and Control-LC. The AUC, revealed no significant difference between the DKT-LC and Control-LC. DKT induced an increase in PBF in normal livers; however, its effects were insufficient to increase PBF in the cirrhotic livers. No increase in the portal blood flow in the cirrhotic liver rats was probably the result of the cirrhotic liver, which had fibrotic change, and, therefore, may not have had sufficient compliance to accept the increasing blood flow volume from the intestinal tract. We suggested DKT has the potential to protect the liver by increasing PBF when the liver has either normal or mild to moderate dysfunction.

Radiopaque biodegradable stent for duct-to-duct biliary reconstruction in pigs.

PubMed

Tanimoto, Yoshisato; Tashiro, Hirotaka; Mikuriya, Yoshihiro; Kuroda, Shintaro; Hashimoto, Masakazu; Kobayashi, Tsuyoshi; Taniura, Tokunori; Ohdan, Hideki

2016-06-01

Biliary stricture is a common cause of morbidity after liver transplantation. We previously developed a duct-to-duct biliary anastomosis technique using a biodegradable stent tube and confirmed the feasibility and safety of biliary stent use. However, the duration and mechanism of biliary stent absorption in the common bile duct remain unclear. Radiopaque biodegradable biliary stents were created using a copolymer of L-lactide and ε-caprolactone (70: 30) and coated with barium sulfate. Stents were surgically implanted in the common bile duct of 11 pigs. Liver function tests and computed tomography (CT) scans were performed postoperatively, and autopsies were conducted 6 months after biliary stent implantation. After the surgery, all 11 pigs had normal liver function and survived without any significant complications such as biliary leakage. A CT scan at 2 months post-procedure showed that the biliary stents were located in the hilum of the liver. The stents were not visible by CT scan at the 6-month follow-up examination. The surgical implantation of radiopaque biodegradable biliary stents in biliary surgery represents a new option for duct-to-duct biliary reconstruction. This technique appears to be feasible and safe and is not associated with any significant biliary complications. The advantage of coated biliary stent use is that it may be visualized using abdominal radiography such as CT.

Usefulness of chemical-shift MRI in discriminating increased liver echogenicity in glycogenosis.

PubMed

Pozzato, C; Dall'asta, C; Radaelli, G; Torcoletti, M; Formenti, A; Riva, E; Cornalba, G; Pontiroli, A E

2007-11-01

Glycogen storage diseases are inherited defects which cause accumulation of glycogen in the tissues. Hepatic steatosis is defined as accumulation of fat within hepatocytes. On sonography, liver shows increased echogenicity both in glycogen storage diseases and steatosis. Liver hyperechogenicity in glycogen storage diseases may depend on accumulation of glycogen and/or fat. Chemical-shift magnetic resonance imaging can discriminate tissues only containing water from those containing both fat and water. The primary aim of the present study was to evaluate the usefulness of liver chemical-shift magnetic resonance imaging for detecting liver steatosis in patients with metabolic impairment due to glycogen storage diseases. Twelve patients with type I (n=8) or type III (n=4) glycogen storage diseases were studied and compared to 12 obese-overweight subjects with known liver steatosis. As control group 12 lean normal voluntary subjects were recruited. Liver was evaluated by sonography and chemical-shift magnetic resonance imaging to calculate hepatic fat fraction. A significant difference in echogenicity between patients with glycogen storage diseases and normal subjects was observed (p<0.05), while this difference was not present between overweight-obese and glycogen storage diseases patients. On the contrary, fat fraction was similar between glycogen storage diseases patients and normal subjects and different between glycogen storage diseases patients and overweight-obese (p<0.05). The present data suggest that chemical-shift magnetic resonance imaging may exclude fat deposition as a cause of liver hyperechogenicity in subjects with glycogen storage diseases.

Expression of the serine/threonine kinase hSGK1 in chronic viral hepatitis.

PubMed

Fillon, Sophie; Klingel, Karin; Wärntges, Simone; Sauter, Martina; Gabrysch, Sabine; Pestel, Sabine; Tanneur, Valerie; Waldegger, Siegfried; Zipfel, Annette; Viebahn, Richard; Häussinger, Dieter; Bröer, Stefan; Kandolf, Reinhard; Lang, Florian

2002-01-01

The human serine/threonine kinase hSGK1 is expressed ubiquitously with highest transcript levels in pancreas and liver. This study has been performed to determine the hSGK1 distribution in normal liver and its putative role in fibrosing liver disease. HSGK1-localization was determined by in situ hybridization, regulation of hSGK1-transcription by Northern blotting, fibronectin synthesis and hSGK1 phosphorylation by Western blotting. In normal liver hSGK1 was mainly transcribed by Kupffer cells. In liver tissue from patients with chronic viral hepatitis, hSGK1 transcript levels were excessively high in numerous activated Kupffer cells and inflammatory cells localized within fibrous septum formations. HSGK1 transcripts were also detected in activated hepatic stellate cells. Accordingly, Western blotting revealed that tissue from fibrotic liver expresses excessive hSGK1 protein as compared to normal liver. TGF-beta1 (2 ng/ml) increases hSGK1 transcription in both human U937 macro-phages and HepG2 hepatoma cells. H(2)O(2) (0.3 mM) activated hSGK1 and increased fibronectin formation in HepG2 cells overexpressing hSGK1 but not in HepG2 cells expressing the inactive mutant hSGK1(K127R). In conclusion hSGK1 is upregulated by TGF-beta1 during hepatitis and may contribute to enhanced matrix formation during fibrosing liver disease. Copyright 2002 S. Karger AG, Basel

Fluorescence detection of malignant liver tumors using 5-aminolevulinic acid-mediated photodynamic diagnosis: principles, technique, and clinical experience.

PubMed

Inoue, Yoshihiro; Tanaka, Ryo; Komeda, Koji; Hirokawa, Fumitoshi; Hayashi, Michihiro; Uchiyama, Kazuhisa

2014-07-01

Photoactive drugs selectively accumulate in malignant tissue specimens and cause drug-induced fluorescence. Photodynamic diagnosis (PDD) and fluorescence can distinguish normal from malignant tissue. From May 2012 to September 2013, a total of 70 patients underwent hepatic resections using 5-ALA-mediated PDD for liver tumors at our hospital. 5-ALA fluorescence was detected in all hepatocellular carcinoma cases with serosa invasion. In liver metastasis from colorectal cancer cases with serosa invasion, 18 patients (85.7 %) were detected, and three patients (14.2 %) whose tumors showed complete response to neoadjuvant chemotherapy showed no fluorescence. Both superficial and deep malignant liver tumors were detected with 92.5 % sensitivity. Using 5-ALA-mediated PDD, tumors remaining at the cut surface and postoperative bile leakage were less frequent than in our previous hepatic resections using conventional white-light observation. Moreover, all malignant liver tumors were completely removed with a clear microscopic margin using 5-ALA, with a significant difference in resection margin width between 5-ALA-mediated PDD (6.7 ± 6.9 mm) and white-light observation (9.2 ± 7.0 mm; p = 0.0083). With the detection of malignant liver tumors, residual tumor and bile leakage at the cut surface of the remnant liver were improved by PDD with 5-ALA. This procedure may provide greater sensitivity than the conventional procedure. Furthermore, 5-ALA-mediated PDD can ensure histological clearance regardless of the resection margin and preserve as much liver parenchyma as possible in patients with impaired liver function.

Hepatocyte-Specific Expression of Human Lysosome Acid Lipase Corrects Liver Inflammation and Tumor Metastasis in lal−/− Mice

PubMed Central

Du, Hong; Zhao, Ting; Ding, Xinchun; Yan, Cong

2016-01-01

The liver is a major organ for lipid synthesis and metabolism. Deficiency of lysosomal acid lipase (LAL; official name Lipa, encoded by Lipa) in mice (lal−/−) results in enlarged liver size due to neutral lipid storage in hepatocytes and Kupffer cells. To test the functional role of LAL in hepatocyte, hepatocyte-specific expression of human LAL (hLAL) in lal−/− mice was established by cross-breeding of liver-activated promoter (LAP)–driven tTA transgene and (tetO)7-CMV-hLAL transgene with lal−/− knockout (KO) (LAP-Tg/KO) triple mice. Hepatocyte-specific expression of hLAL in LAP-Tg/KO triple mice reduced the liver size to the normal level by decreasing lipid storage in both hepatocytes and Kupffer cells. hLAL expression reduced tumor-promoting myeloid-derived suppressive cells in the liver of lal−/− mice. As a result, B16 melanoma metastasis to the liver was almost completely blocked. Expression and secretion of multiple tumor-promoting cytokines or chemokines in the liver were also significantly reduced. Because hLAL is a secretory protein, lal−/− phenotypes in other compartments (eg, blood, spleen, and lung) also ameliorated, including systemic reduction of myeloid-derived suppressive cells, an increase in CD4+ and CD8+ T and B lymphocytes, and reduced B16 melanoma metastasis in the lung. These results support a concept that LAL in hepatocytes is a critical metabolic enzyme in controlling neutral lipid metabolism, liver homeostasis, immune response, and tumor metastasis. PMID:26212911

THE RELATION OF THE LIVER TO FAT METABOLISM

PubMed Central

Drury, D. R.; McMaster, Philip D.

1929-01-01

Fat combustion is carried on adequately in rabbits deprived of the liver or brought into a condition of extreme liver insufficiency. Even 24 hours after hepatectomy fat combustion goes on as well as in the normal animal. Evidently the liver plays no essential part in the breaking down of fat. PMID:19869581

Effects of Bauhinia forficata Tea on Oxidative Stress and Liver Damage in Diabetic Mice

PubMed Central

Salgueiro, Andréia Caroline Fernandes; da Silva, Marianne Pires; Mendez, Andreas Sebastian Loureiro; Zemolin, Ana Paula Pegoraro; Posser, Thaís; Puntel, Robson Luiz; Puntel, Gustavo Orione

2016-01-01

This study was designed to evaluate the effects of Bauhinia forficata Link subsp. pruinosa (BF) tea on oxidative stress and liver damage in streptozotocin (STZ)-induced diabetic mice. Diabetic male mice have remained 30 days without any treatment. BF treatment started on day 31 and continued for 21 days as a drinking-water substitute. We evaluated (1) BF chemical composition; (2) glucose levels; (3) liver/body weight ratio and liver transaminases; (4) reactive oxygen species (ROS), lipid peroxidation, and protein carbonylation in liver; (5) superoxide dismutase (SOD) and catalase (CAT) activities in liver; (6) δ-aminolevulinate dehydratase (δ-ALA-D) and nonprotein thiols (NPSH) in liver; (7) Nrf2, NQO-1, and HSP70 levels in liver and pancreas. Phytochemical analyses identified four phenols compounds. Diabetic mice present high levels of NQO-1 in pancreas, increased levels of ROS and lipid peroxidation in liver, and decrease in CAT activity. BF treatment normalized all these parameters. BF did not normalize hyperglycemia, liver/body weight ratio, aspartate aminotransferase, protein carbonyl, NPSH levels, and δ-ALA-D activity. The raised oxidative stress seems to be a potential mechanism involved in liver damage in hyperglycemic conditions. Our results indicated that BF protective effect could be attributed to its antioxidant capacity, more than a hypoglycemic potential. PMID:26839634