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

Evaluation of abnormal liver function tests.

PubMed

Agrawal, Swastik; Dhiman, Radha K; Limdi, Jimmy K

2016-04-01

Incidentally detected abnormality in liver function tests is a common situation encountered by physicians across all disciplines. Many of these patients do not have primary liver disease as most of the commonly performed markers are not specific for the liver and are affected by myriad factors unrelated to liver disease. Also, many of these tests like liver enzyme levels do not measure the function of the liver, but are markers of liver injury, which is broadly of two types: hepatocellular and cholestatic. A combination of a careful history and clinical examination along with interpretation of pattern of liver test abnormalities can often identify type and aetiology of liver disease, allowing for a targeted investigation approach. Severity of liver injury is best assessed by composite scores like the Model for End Stage Liver Disease rather than any single parameter. In this review, we discuss the interpretation of the routinely performed liver tests along with the indications and utility of quantitative tests. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Non-invasive assessment of the liver using imaging

NASA Astrophysics Data System (ADS)

Thorling Thompson, Camilla; Wang, Haolu; Liu, Xin; Liang, Xiaowen; Crawford, Darrell H.; Roberts, Michael S.

2016-12-01

Chronic liver disease causes 2,000 deaths in Australia per year and early diagnosis is crucial to avoid progression to cirrhosis and end stage liver disease. There is no ideal method to evaluate liver function. Blood tests and liver biopsies provide spot examinations and are unable to track changes in function quickly. Therefore better techniques are needed. Non-invasive imaging has the potential to extract increased information over a large sampling area, continuously tracking dynamic changes in liver function. This project aimed to study the ability of three imaging techniques, multiphoton and fluorescence lifetime imaging microscopy, infrared thermography and photoacoustic imaging, in measuring liver function. Collagen deposition was obvious in multiphoton and fluorescence lifetime imaging in fibrosis and cirrhosis and comparable to conventional histology. Infrared thermography revealed a significantly increased liver temperature in hepatocellular carcinoma. In addition, multiphoton and fluorescence lifetime imaging and photoacoustic imaging could both track uptake and excretion of indocyanine green in rat liver. These results prove that non-invasive imaging can extract crucial information about the liver continuously over time and has the potential to be translated into clinic in the assessment of liver disease.

Prediction of postoperative outcome after hepatectomy with a new bedside test for maximal liver function capacity.

PubMed

Stockmann, Martin; Lock, Johan F; Riecke, Björn; Heyne, Karsten; Martus, Peter; Fricke, Michael; Lehmann, Sina; Niehues, Stefan M; Schwabe, Michael; Lemke, Arne-Jörn; Neuhaus, Peter

2009-07-01

To validate the LiMAx test, a new bedside test for the determination of maximal liver function capacity based on C-methacetin kinetics. To investigate the diagnostic performance of different liver function tests and scores including the LiMAx test for the prediction of postoperative outcome after hepatectomy. Liver failure is a major cause of mortality after hepatectomy. Preoperative prediction of residual liver function has been limited so far. Sixty-four patients undergoing hepatectomy were analyzed in a prospective observational study. Volumetric analysis of the liver was carried out using preoperative computed tomography and intraoperative measurements. Perioperative factors associated with morbidity and mortality were analyzed. Cutoff values of the LiMAx test were evaluated by receiver operating characteristic. Residual LiMAx demonstrated an excellent linear correlation with residual liver volume (r = 0.94, P < 0.001) after hepatectomy. The multivariate analysis revealed LiMAx on postoperative day 1 as the only predictor of liver failure (P = 0.003) and mortality (P = 0.004). AUROC for the prediction of liver failure and liver failure related death by the LiMAx test was both 0.99. Preoperative volume/function analysis combining CT volumetry and LiMAx allowed an accurate calculation of the remnant liver function capacity prior to surgery (r = 0.85, P < 0.001). Residual liver function is the major factor influencing the outcome of patients after hepatectomy and can be predicted preoperatively by a combination of LiMAx and CT volumetry.

Assessment of functional liver reserve: old and new in 99mTc-sulfur colloid scintigraphy.

PubMed

Matesan, Manuela M; Bowen, Stephen R; Chapman, Tobias R; Miyaoka, Robert S; Velez, James W; Wanner, Michele F; Nyflot, Matthew J; Apisarnthanarax, Smith; Vesselle, Hubert J

2017-07-01

A semiquantitative assessment of hepatic reticuloendothelial system function using colloidal particles scintigraphy has been proposed previously as a surrogate for liver function evaluation. In this article, we present an updated method for the overall assessment of technetium-99m (Tc)-sulfur colloid (SC) biodistribution that combines information from planar and attenuation-corrected Tc-SC single-photon emission computed tomography (SPECT) images. The imaging protocol described here was developed as an easy-to-implement method to assess overall and regional liver function changes associated with chronic liver disease. Thirty patients with chronic liver disease and primary liver cancers underwent Tc-SC whole-body planar imaging and upper-abdomen SPECT/computed tomography (CT) imaging before external beam radiation therapy. Liver plus spleen and bone marrow counts as a fraction of whole-body total counts were calculated from SC planar imaging. Attenuation correction Tc-SC images were rigidly coregistered with treatment planning CT images that contained liver and spleen regions-of-interest. Ratios of total liver counts to total spleen counts were obtained from the aligned Tc-SC SPECT and CT images, and were subsequently used to separate liver plus spleen counts obtained on the planar images. This hybrid SPECT/CT and planar scintigraphy approach yielded an updated estimation of whole-body SC distribution. These biodistribution estimates were compared with historical data for reference. Statistical associations of Tc-SC biodistribution to liver function parameters and liver disease scoring systems (Child-Pugh) were evaluated by Spearman rank correlation. Percentages of Tc-SC uptake ranged from 19.3 to 77.3% for the liver; 3.4 to 40.7% for the spleen; and 19.0 to 56.7% for the bone marrow. Spearman's correlation coefficient showed a significant statistical association between Child-Pugh score and bone marrow uptake at 0.55 (P≤0.05), liver uptake at 0.71 (P≤0.001), spleen uptake at 0.56 (P≤0.05), and spleen plus bone marrow uptake at 0.71 (P≤0.001). There was also a good correlation of SC uptake percentages with individual quantitative liver function components such as albumin and total bilirubin, and qualitative liver function components (varices, portal hypertension, ascites). For albumin: r=0.64 (P<0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P<0.001) compared with splenic uptake percentage, and r=0.45 (P≤0.05) compared with bone marrow uptake percentage. We describe a novel liver function quantitative assessment method that combines whole-body planar images and SPECT/CT attenuation-corrected images of Tc-SC distribution. Attenuation-corrected SC images provide valuable regional liver function information, which is a unique feature compared with other imaging methods available. The results of our study indicate that the Tc-SC uptake by the liver, spleen, and bone marrow correlates with liver function parameters in patients with diffuse liver disease and the correlation with liver disease severity is slightly better for liver uptake percentages than for individual values of bone marrow and spleen uptake percentages.

Liver Transplant

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Benign Liver Tumors

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Progression of Liver Disease

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Future remnant liver function as predictive factor for the hypertrophy response after portal vein embolization.

PubMed

Cieslak, Kasia P; Huisman, Floor; Bais, Thomas; Bennink, Roelof J; van Lienden, Krijn P; Verheij, Joanne; Besselink, Marc G; Busch, Olivier R C; van Gulik, Thomas M

2017-07-01

Preoperative portal vein embolization is widely used to increase the future remnant liver. Identification of nonresponders to portal vein embolization is essential because these patients may benefit from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which induces a more powerful hypertrophy response. 99m Tc-mebrofenin hepatobiliary scintigraphy is a quantitative method for assessment of future remnant liver function with a calculated cutoff value for the prediction of postoperative liver failure. The aim of this study was to analyze future remnant liver function before portal vein embolization to predict sufficient functional hypertrophy response after portal vein embolization. Sixty-three patients who underwent preoperative portal vein embolization and computed tomography imaging were included. Hepatobiliary scintigraphy was performed to determine pre-portal vein embolization and post-portal vein embolization future remnant liver function. Receiver operator characteristic analysis of pre-portal vein embolization future remnant liver function was performed to identify patients who would meet the post-portal vein embolization cutoff value for sufficient function (ie, 2.7%/min/m 2 ). Mean pre-portal vein embolization future remnant liver function was 1.80% ± 0.45%/min/m 2 and increased to 2.89% ± 0.97%/min/m 2 post-portal vein embolization. Receiver operator characteristic analysis in 33 patients who did not receive chemotherapy revealed that a pre-portal vein embolization future remnant liver function of ≥1.72%/min/m 2 was able to identify patients who would meet the safe future remnant liver function cutoff value 3 weeks after portal vein embolization (area under the curve = 0.820). The predictive value was less pronounced in 30 patients treated with neoadjuvant chemotherapy (area under the curve = 0.618). A total of 45 of 63 patients underwent liver resection, of whom 5 of 45 developed postoperative liver failure; 4 of 5 patients had a post-portal vein embolization future remnant liver function below the cutoff value for safe resection. When selecting patients for portal vein embolization, future remnant liver function assessed with hepatobiliary scintigraphy can be used as a predictor of insufficient functional hypertrophy after portal vein embolization, especially in nonchemotherapy patients. These patients are potential candidates for ALPPS. Copyright © 2017 Elsevier Inc. All rights reserved.

Dynamic gadoxetate-enhanced MRI for the assessment of total and segmental liver function and volume in primary sclerosing cholangitis.

PubMed

Nilsson, Henrik; Blomqvist, Lennart; Douglas, Lena; Nordell, Anders; Jacobsson, Hans; Hagen, Karin; Bergquist, Annika; Jonas, Eduard

2014-04-01

To evaluate dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) for the assessment of global and segmental liver volume and function in patients with primary sclerosing cholangitis (PSC), and to explore the heterogeneous distribution of liver function in this patient group. Twelve patients with primary sclerosing cholangitis (PSC) and 20 healthy volunteers were examined using DHCE-MRI with Gd-EOB-DTPA. Segmental and total liver volume were calculated, and functional parameters (hepatic extraction fraction [HEF], input relative blood-flow [irBF], and mean transit time [MTT]) were calculated in each liver voxel using deconvolutional analysis. In each study subject, and incongruence score (IS) was constructed to describe the mismatch between segmental function and volume. Among patients, the liver function parameters were correlated to bile duct obstruction and to established scoring models for liver disease. Liver function was significantly more heterogeneously distributed in the patient group (IS 1.0 versus 0.4). There were significant correlations between biliary obstruction and segmental functional parameters (HEF rho -0.24; irBF rho -0.45), and the Mayo risk score correlated significantly with the total liver extraction capacity of Gd-EOB-DTPA (rho -0.85). The study demonstrates a new method to quantify total and segmental liver function using DHCE-MRI in patients with PSC. Copyright © 2013 Wiley Periodicals, Inc.

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.

Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction.

PubMed

Cortes, Miriam; Pareja, Eugenia; García-Cañaveras, Juan C; Donato, M Teresa; Montero, Sandra; Mir, Jose; Castell, José V; Lahoz, Agustín

2014-09-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD. A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients. A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n=4). A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Causes of altered liver function tests - the role of alpha-1 antitrypsin.

PubMed

Stollenwerk, J; Schepke, M; Biecker, E

2016-09-01

Altered liver function tests are a common finding in clinical practice. Our retrospective study aimed to identify the diagnoses in a non-selected cohort of patients with altered liver tests and to investigate whether alpha-1 antitrypsin genotyping should be part of the diagnostic workup. 501 patients who were admitted to our outpatient clinic for further evaluation of altered liver function tests were included in the study. The patients underwent a standardized diagnostic program with history taking, physical examination, laboratory tests and ultrasonography. Liver biopsy was performed if appropriate. More than 50 % of the patients had nonalcoholic fatty liver disease. Alcoholic and drug-induced liver injury were found in 8.6 % and 7 % of patients, respectively. Chronic hepatitis B and C, autoimmune liver disease and inherited causes of liver disease made up for approximately 16 % of the diagnoses. The remaining patients were diagnosed with kryptogenic liver disease or had miscellaneous diagnoses. In 3.7 % of the genotyped patients, the alpha-1 antitrypsin genotype PiMZ was found. Nonalcoholic fatty liver disease is nowadays the most frequent cause of altered liver tests. Alcoholic liver disease might be underrepresented in our study since these patients less often seek medical attention or the diagnosis is already made by the primary care physician. Drug-induced liver injury was found in more patients than expected and might therefore be underdiagnosed in practice. The alpha-1 antitrypsin genotype PiMZ was found in absence of other possible causes of liver disease, indicating that the PiMZ genotype is itself a risk factor for liver disease. Genotyping for alpha-1 antitrypsin should therefore be done when other causes for altered liver function tests have been ruled out. © Georg Thieme Verlag KG Stuttgart · New York.

[Definition of surgical degree of freedom by functional anatomy in liver resection surgery].

PubMed

Kraus, T W; Golling, M; Klar, E

2001-07-01

Liver resections have developed to very complex and differentiated operations, clearly adapted to individual anatomical and physiological conditions. In parallel, perioperative morbidity has been dramatically reduced. Intraoperative strict consideration of various details of hepatic anatomy, particularly of functional liver anatomy, has proved to be of particular importance when liver surgery reaches indication and technical limits. The term "functional anatomy" stands for a form of hepatic substructurization, which is primarily based on the existence of hemodynamically independent regions of liver parenchyma. A selection of some of the most important details and facts of functional liver anatomy and secondary derived guidelines for surgical strategy and technique is presented in an overview, with special focus on liver resection.

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.

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.

Liver Function Assessment Using Technetium 99m-Galactosyl Single-Photon Emission Computed Tomography/CT Fusion Imaging: A Prospective Trial.

PubMed

Okabayashi, Takehiro; Shima, Yasuo; Morita, Sojiro; Shimada, Yasuhiro; Sumiyoshi, Tatsuaki; Sui, Kenta; Iwata, Jun; Iiyama, Tatsuo

2017-12-01

The prediction of postoperative liver function remains a largely subjective practice based on CT volumetric analysis. However, future liver volume after a hepatectomy is not the only factor that contributes to postoperative liver function and outcomes. In this prospective trial, 185 consecutive patients who underwent liver operations between 2014 and 2015 were studied. Volumetric and functional rates of remnant liver were measured using technetium 99m-galactosyl human serum albumin single-photon emission computed tomography/CT fusion imaging to evaluate post-hepatectomy remnant liver function. Remnant indocyanine green clearance rate using galactosyl (KGSA) (KGSA × functional rate) was used to predict future remnant liver function. Hepatectomy was considered safe for patients with remnant KGSA values ≥0.05, and the primary end point was to determine the accuracy and reliability of this criteria. The prediction of the 90-day major complication and mortality rates was assessed. Median hospital stay was 9 days and median ICU stay was 1 day, with only 1 in-hospital death (90-day mortality rate 0.5%). Overall morbidity rate evaluated according to the Clavien-Dindo classification was 9%. For post-hepatectomy liver failure definitions, the International Study Group of Liver Surgery definition was fulfilled in 14 patients (8%), with the majority being grade B (50%), compared with 2 patients (1%) fulfilling the "50-50" criteria, and 0 patients (0%) fulfilling the Peak Bili >7 criteria. Results of this study showed that remnant KGSA provided information that allowed us to predict remnant liver function. This information will be important for surgeons when deciding on a treatment plan for patients with liver diseases. (ClinicalTrials.gov ID: NCT02013895). Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Bioengineered transplantable porcine livers with re-endothelialized vasculature.

PubMed

Ko, In Kap; Peng, Li; Peloso, Andrea; Smith, Charesa J; Dhal, Abritee; Deegan, Daniel B; Zimmerman, Cindy; Clouse, Cara; Zhao, Weixin; Shupe, Thomas D; Soker, Shay; Yoo, James J; Atala, Anthony

2015-02-01

Donor shortage remains a continued challenge in liver transplantation. Recent advances in tissue engineering have provided the possibility of creating functional liver tissues as an alternative to donor organ transplantation. Small bioengineered liver constructs have been developed, however a major challenge in achieving functional bioengineered liver in vivo is the establishment of a functional vasculature within the scaffolds. Our overall goal is to bioengineer intact livers, suitable for transplantation, using acellular porcine liver scaffolds. We developed an effective method for reestablishing the vascular network within decellularized liver scaffolds by conjugating anti-endothelial cell antibodies to maximize coverage of the vessel walls with endothelial cells. This procedure resulted in uniform endothelial attachment throughout the liver vasculature extending to the capillary bed of the liver scaffold and greatly reduced platelet adhesion upon blood perfusion in vitro. The re-endothelialized livers, when transplanted to recipient pigs, were able to withstand physiological blood flow and maintained for up to 24 h. This study demonstrates, for the first time, that vascularized bioengineered livers, of clinically relevant size, can be transplanted and maintained in vivo, and represents the first step towards generating engineered livers for transplantation to patients with end-stage liver failure. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PubMed

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

2016-02-01

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

Nadolol for lithium tremor in the presence of liver damage.

PubMed

Dave, M; Langbart, M M

1994-03-01

Lithium-induced tremor classically responds to treatment with propranolol. Since it is metabolized in the liver, propranolol may not be the drug of choice in those patients who have compromised liver function or who are recovering from prior liver diseases. Another nonselective beta-adrenergic blocker, nadolol, has no hepatic biotransformation. We present here the first case report of successful treatment of lithium-induced tremor with nadolol, which was selected because the patient had compromised liver function. The patient's liver function tests remained stable with the therapy.

Liver Ischemic Preconditioning (IPC) Improves Intestinal Microbiota Following Liver Transplantation in Rats through 16s rDNA-Based Analysis of Microbial Structure Shift

PubMed Central

Lu, Haifeng; Chen, Xinhua; Jiang, Jianwen; Liu, Hui; He, Yong; Ding, Songming; Hu, Zhenhua; Wang, Weilin; Zheng, Shusen

2013-01-01

Background Ischemia-reperfusion (I/R) injury is associated with intestinal microbial dysbiosis. The “gut-liver axis” closely links gut function and liver function in health and disease. Ischemic preconditioning (IPC) has been proven to reduce I/R injury in the surgery. This study aims to explore the effect of IPC on intestinal microbiota and to analyze characteristics of microbial structure shift following liver transplantation (LT). Methods The LT animal models of liver and gut IPC were established. Hepatic graft function was assessed by histology and serum ALT/AST. Intestinal barrier function was evaluated by mucosal ultrastructure, serum endotoxin, bacterial translocation, fecal sIgA content and serum TNF-α. Intestinal bacterial populations were determined by quantitative PCR. Microbial composition was characterized by DGGE and specific bacterial species were determined by sequence analysis. Principal Findings Liver IPC improved hepatic graft function expressed as ameliorated graft structure and reduced ALT/AST levels. After administration of liver IPC, intestinal mucosal ultrastructure improved, serum endotoxin and bacterial translocation mildly decreased, fecal sIgA content increased, and serum TNF-α decreased. Moreover, liver IPC promoted microbial restorations mainly through restoring Bifidobacterium spp., Clostridium clusters XI and Clostridium cluster XIVab on bacterial genus level. DGGE profiles indicated that liver IPC increased microbial diversity and species richness, and cluster analysis demonstrated that microbial structures were similar and clustered together between the NC group and Liver-IPC group. Furthermore, the phylogenetic tree of band sequences showed key bacteria corresponding to 10 key band classes of microbial structure shift induced by liver IPC, most of which were assigned to Bacteroidetes phylum. Conclusion Liver IPC cannot only improve hepatic graft function and intestinal barrier function, but also promote restorations of intestinal microbiota following LT, which may further benefit hepatic graft by positive feedback of the “gut-liver axis”. PMID:24098410

Liver ischemic preconditioning (IPC) improves intestinal microbiota following liver transplantation in rats through 16s rDNA-based analysis of microbial structure shift.

PubMed

Ren, Zhigang; Cui, Guangying; Lu, Haifeng; Chen, Xinhua; Jiang, Jianwen; Liu, Hui; He, Yong; Ding, Songming; Hu, Zhenhua; Wang, Weilin; Zheng, Shusen

2013-01-01

Ischemia-reperfusion (I/R) injury is associated with intestinal microbial dysbiosis. The "gut-liver axis" closely links gut function and liver function in health and disease. Ischemic preconditioning (IPC) has been proven to reduce I/R injury in the surgery. This study aims to explore the effect of IPC on intestinal microbiota and to analyze characteristics of microbial structure shift following liver transplantation (LT). The LT animal models of liver and gut IPC were established. Hepatic graft function was assessed by histology and serum ALT/AST. Intestinal barrier function was evaluated by mucosal ultrastructure, serum endotoxin, bacterial translocation, fecal sIgA content and serum TNF-α. Intestinal bacterial populations were determined by quantitative PCR. Microbial composition was characterized by DGGE and specific bacterial species were determined by sequence analysis. Liver IPC improved hepatic graft function expressed as ameliorated graft structure and reduced ALT/AST levels. After administration of liver IPC, intestinal mucosal ultrastructure improved, serum endotoxin and bacterial translocation mildly decreased, fecal sIgA content increased, and serum TNF-α decreased. Moreover, liver IPC promoted microbial restorations mainly through restoring Bifidobacterium spp., Clostridium clusters XI and Clostridium cluster XIVab on bacterial genus level. DGGE profiles indicated that liver IPC increased microbial diversity and species richness, and cluster analysis demonstrated that microbial structures were similar and clustered together between the NC group and Liver-IPC group. Furthermore, the phylogenetic tree of band sequences showed key bacteria corresponding to 10 key band classes of microbial structure shift induced by liver IPC, most of which were assigned to Bacteroidetes phylum. Liver IPC cannot only improve hepatic graft function and intestinal barrier function, but also promote restorations of intestinal microbiota following LT, which may further benefit hepatic graft by positive feedback of the "gut-liver axis".

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.

Hemochromatosis

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Galactosemia

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Alagille Syndrome

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Newborn Jaundice

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Reye Syndrome

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Liver Function Assessment by Magnetic Resonance Imaging.

PubMed

Ünal, Emre; Akata, Deniz; Karcaaltincaba, Musturay

2016-12-01

Liver function assessment by hepatocyte-specific contrast-enhanced magnetic resonance imaging is becoming a new biomarker. Liver function can be assessed by T1 mapping (reduction rate) and signal intensity measurement (relative enhancement ratio) before and after GD-EOB-DTPA (gadoxetic acid) administration, as alternative to Tc-99m galactosyl serum albumin scintigraphy, 99m Tc-labeled mebrofenin scintigraphy, and indocyanine green clearance test. Magnetic resonance imaging assessment of liver function can enable diagnosis of cirrhosis, nonalcoholic fatty liver disease associated fibrosis and steatohepatitis, primary sclerosing cholangitis, toxic hepatitis, and chemotherapy and radiotherapy-related changes, which may be only visible on hepatobiliary phase images. Simple visual assessment of signal intensity at hepatobiliary phase images is important for the diagnosis of different patterns of liver dysfunction including diffuse, lobar, segmental, and subsegmental forms. Furthermore, preoperative assessment of liver function is feasible before oncologic hepatic surgery, which may be important to prevent posthepatectomy liver failure and to estimate future remnant volume. Functional magnetic resonance cholangiography obtained by T1-weighted images at hepatobiliary phase can allow diagnosis of acalculous cholecystitis, biliary leakage, bile reflux to the stomach, sphincter of oddi dysfunction, and lesions with communication to biliary tree. Functional information can be easily obtained when Gd-EOB-DTPA is used for liver magnetic resonance imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

[Liver diseases in the elderly].

PubMed

Bruguera, Miguel

2014-11-01

Liver diseases in the elderly have aroused less interest than diseases of other organs, since the liver plays a limited role in aging. There are no specific liver diseases of old age, but age-related anatomical and functional modifications of the liver cause changes in the frequency and clinical behavior of some liver diseases compared with those in younger patients. This review discusses the most important features of liver function in the healthy elderly population, as well as the features of the most prevalent liver diseases in this age group, especially the diagnostic approach to the most common liver problems in the elderly: asymptomatic elevation of serum transaminases and jaundice. Copyright © 2014 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

[Effect of fenicaberan on liver function in patients with chronic noncalculous cholecystitis].

PubMed

Skroban, N V

1989-06-01

The author studied the effect of fenicaberan on the functional state of the liver in 34 patients with chronic noncalculous cholecystitis. It was found that fenicaberan favours improvement of the functional state of the liver but complete normalization of all liver values indicates necessity continuation of treatment in outpatient conditions.

Impact of Liver Indicators on Clinical Outcome in Patients Undergoing Transcatheter Aortic Valve Implantation.

PubMed

Wendt, Daniel; Kahlert, Philipp; Canbay, Ali; Knipp, Stephan; Thoenes, Martin; Cremer, Gordina; Al-Rashid, Fadi; Jánosi, Rolf-Alexander; El-Chilali, Karim; Kamler, Markus; El Gabry, Mohamed; Marx, Philipp; Dohle, Daniel Sebastian; Tsagakis, Konstantinos; Benedik, Jaroslav; Gerken, Guido; Rassaf, Tienush; Jakob, Heinz; Thielmann, Matthias

2017-10-01

Liver dysfunction increases death and morbidity after cardiac operations. There are currently no data evaluating liver function in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed therefore to evaluate our TAVR results in regard to liver function. A total of 640 consecutive TAVR patients were evaluated. Of those, 11 patients presented with chronic liver disease before TAVR. The Model for End-Stage Liver Disease score was used to measure liver function in these patients. The primary study end point was 30-day mortality in patients presenting with liver dysfunction. Secondary study end point was liver enzymes after TAVR. The mean Model for End-Stage Liver Disease score in patients with chronic liver disease was 16.8 ± 6.2 (median, 18; range, 7 to 26). The 30-day mortality was 9.1% (57 of 629) in patients presenting without liver disease and 9.1% (1 of 11) in patients with liver disease (p = 1.00). Patients with chronic liver disease showed significantly higher preoperative levels of γ-glutamyl transpeptidase (p < 0.001). After TAVR, we observed a significant increase in alanine aminotransferase on postoperative day 3 compared with preoperative values (p < 0.001), accompanied by a decrease in albumin (p < 0.001). Liver cirrhosis per se is not considered as a contraindication for cardiac operations. In the present study, we did not observe a higher 30-day mortality rate in liver cirrhotic patients undergoing TAVR, suggesting TAVR as a feasible alternative with acceptable outcomes in patients with chronic liver disease. Moreover, the present study is the first to evaluate liver variables in patients undergoing TAVR. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Ob/ob Mouse Livers Show Decreased Oxidative Phosphorylation Efficiencies and Anaerobic Capacities after Cold Ischemia

PubMed Central

Tagaloa, Sherry; Zhang, Linda; Dare, Anna J.; MacDonald, Julia R.; Yeong, Mee-Ling; Bartlett, Adam S. J. R.; Phillips, Anthony R. J.

2014-01-01

Background Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. Methods Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity. Results Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers. Conclusions Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor livers. PMID:24956382

Neutrophil gelatinase‐associated lipocalin level is a prognostic factor for survival in rat and human chronic liver diseases

PubMed Central

Yoshikawa, Kyoko; Iwasa, Motoh; Kojima, Shinichi; Yoshizawa, Naohiko; Tempaku, Mina; Sugimoto, Ryosuke; Yamamoto, Norihiko; Sugimoto, Kazushi; Kobayashi, Yoshinao; Hasegawa, Hiroshi; Takei, Yoshiyuki

2017-01-01

Chronic liver disease patients often have complications, such as hepatocellular carcinoma (HCC) and acute bacterial infection. Model for end‐stage liver disease and Child‐Pugh scores are useful prognostic factors for chronic liver diseases but not for all chronic conditions, such as HCC. Our investigative aim targeted the prognostic abilities of neutrophil gelatinase‐associated lipocalin (NGAL) in rat and human chronic liver diseases. Blood NGAL levels were measured by enzyme‐linked immunosorbent assay in rats with cirrhosis and 96 patients with chronic liver disease and HCC. We examined the correlation between blood NGAL levels and liver functions as well as survival. In our rat model, liver NGAL expression was assessed by immunostaining, real‐time quantitative polymerase chain reaction, and immunoblot. In rats with cirrhosis, blood NGAL levels were continuously and significantly elevated in the deceased group and were significantly correlated with liver functions. Liver NGAL, toll‐like receptor 4, and interleukin‐6 levels were increased in the deceased group compared to the survival group. Blood NGAL levels were significantly correlated with liver NGAL levels, indicating blood NGAL was derived from the liver. In patients with chronic liver disease, blood NGAL levels were associated with liver function and renal function. Blood NGAL levels were significantly increased in patients with chronic liver disease with HCC compared to without HCC. For the survival group, 38 out of 96 patients were dead in the average follow‐up period of 9.9 months. The patients with blood NGAL ≤119 ng/mL had significantly longer rates of survival compared to patients with blood NGAL >119 ng/mL. Conclusion: Blood NGAL predicts the survival rate in rat and human chronic liver diseases. Our findings suggest blood NGAL may be prognostic of survival in chronic liver diseases complicated by HCC. (Hepatology Communications 2017;1:946–956) PMID:29404502

Primary Sclerosing Cholangitis (PSC)

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Type I Glycogen Storage Disease

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Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting

PubMed Central

Selden, Clare; Spearman, Catherine Wendy; Kahn, Delawir; Miller, Malcolm; Figaji, Anthony; Erro, Eloy; Bundy, James; Massie, Isobel; Chalmers, Sherri-Ann; Arendse, Hiram; Gautier, Aude; Sharratt, Peter; Fuller, Barry; Hodgson, Humphrey

2013-01-01

Liver failure is an increasing problem. Donor-organ shortage results in patients dying before receiving a transplant. Since the liver can regenerate, alternative therapies providing temporary liver-support are sought. A bioartificial-liver would temporarily substitute function in liver failure buying time for liver regeneration/organ-procurement. Our aim: to develop a prototype bioartificial-liver-machine (BAL) comprising a human liver-derived cell-line, cultured to phenotypic competence and deliverable in a clinical setting to sites distant from its preparation. The objective of this study was to determine whether its use would improve functional parameters of liver failure in pigs with acute liver failure, to provide proof-of-principle. HepG2cells encapsulated in alginate-beads, proliferated in a fluidised-bed-bioreactor providing a biomass of 4–6×1010cells, were transported from preparation-laboratory to point-of-use operating theatre (6000miles) under perfluorodecalin at ambient temperature. Irreversible ischaemic liver failure was induced in anaesthetised pigs, after portal-systemic-shunt, by hepatic-artery-ligation. Biochemical parameters, intracranial pressure, and functional-clotting were measured in animals connected in an extracorporeal bioartificial-liver circuit. Efficacy was demonstrated comparing outcomes between animals connected to a circuit containing alginate-encapsulated cells (Cell-bead BAL), and those connected to circuit containing alginate capsules without cells (Empty-bead BAL). Cells of the biomass met regulatory standards for sterility and provenance. All animals developed progressive liver-failure after ischaemia induction. Efficacy of BAL was demonstrated since animals connected to a functional biomass (+ cells) had significantly smaller rises in intracranial pressure, lower ammonia levels, more bilirubin conjugation, improved acidosis and clotting restoration compared to animals connected to the circuit without cells. In the +cell group, human proteins accumulated in pigs' plasma. Delivery of biomass using a short-term cold-chain enabled transport and use without loss of function over 3days. Thus, a fluidised-bed bioreactor containing alginate-encapsulated HepG2cell-spheroids improved important parameters of acute liver failure in pigs. The system can readily be up-scaled and transported to point-of-use justifying development at clinical scale. PMID:24367515

Integration of technologies for hepatic tissue engineering.

PubMed

Nahmias, Yaakov; Berthiaume, Francois; Yarmush, Martin L

2007-01-01

The liver is the largest internal organ in the body, responsible for over 500 metabolic, regulatory, and immune functions. Loss of liver function leads to liver failure which causes over 25,000 deaths/year in the United States. Efforts in the field of hepatic tissue engineering include the design of bioartificial liver systems to prolong patient's lives during liver failure, for drug toxicity screening and for the study of liver regeneration, ischemia/reperfusion injury, fibrosis, viral infection, and inflammation. This chapter will overview the current state-of-the-art in hepatology including isolated perfused liver, culture of liver slices and tissue explants, hepatocyte culture on collagen "sandwich" and spheroids, coculture of hepatocytes with non-parenchymal cells, and the integration of these culture techniques with microfluidics and reactor design. This work will discuss the role of oxygen and medium composition in hepatocyte culture and present promising new technologies for hepatocyte proliferation and function. We will also discuss liver development, architecture, and function as they relate to these culture techniques. Finally, we will review current opportunities and major challenges in integrating cell culture, bioreactor design, and microtechnology to develop new systems for novel applications.

Evaluation of liver function using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging based on a three-dimensional volumetric analysis system.

PubMed

Kudo, Masashi; Gotohda, Naoto; Sugimoto, Motokazu; Kobayashi, Tatsushi; Kojima, Motohiro; Takahashi, Shinichiro; Konishi, Masaru; Hayashi, Ryuichi

2018-06-02

Magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) is a diagnostic modality for liver tumors. Three-dimensional (3D) volumetric analysis systems using EOB-MRI data are used to simulate liver anatomy for surgery. This study was conducted to investigate clinical utility of a 3D volumetric analysis system on EOB-MRI to evaluate liver function. Between August 2014 and December 2015, 181 patients underwent laboratory and radiological exams as standardized preoperative evaluation for liver surgery. The liver-spleen contrast-enhanced ratio (LSR) was measured by a semi-automated 3D volumetric analysis system on EOB-MRI. First, the inter-evaluator variability of the calculated LSR was evaluated. Additionally, a subset of liver surgical specimens was evaluated histologically by using immunohistochemical staining. Finally, the correlations between the LSR and grading systems of liver function, laboratory data, or histological findings were analyzed. The inter-evaluator correlation coefficient of the measured LSR was 0.986. The mean LSR was significantly correlated with the Child-Pugh score (p = 0.014) and the ALBI score (p < 0.001). Significant correlations were also observed between the LSR and indocyanine green retention rate at 15 min (r = - 0.601, p < 0.001), between the LSR and liver fibrosis stage (r = - 0.556, p < 0.001), and between the LSR and liver steatosis grade (r = - 0.396, p < 0.001). The LSR calculated by a 3D volumetric analysis system on EOB-MRI was highly reproducible and was shown to be correlated with liver function parameters and liver histology. These data suggest that this imaging modality can be a reliable tool to evaluate liver function.

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

PubMed

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

2015-12-01

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

Alcoholic liver disease.

PubMed

Penny, Steven M

2013-01-01

In the United States, approximately 100,000 deaths are attributed to alcohol abuse each year. In 2009, the World Health Organization listed alcohol use as one of the leading causes of the global burden of disease and injury. Alcoholic liver disease, a direct result of chronic alcohol abuse, insidiously destroys the normal functions of the liver. The end result of the disease, cirrhosis, culminates in a dysfunctional and diffusely scarred liver. This article discusses the clinical manifestations, imaging considerations, and treatment of alcoholic liver disease and cirrhosis. Normal liver function, liver hemodynamics, the disease of alcoholism, and the deleterious effects of alcohol also are reviewed.

The bioimpedance analysis of a parenchyma of a liver in the conditions of its extensive resection in experiment

NASA Astrophysics Data System (ADS)

Agibalov, D. Y.; Panchenkov, D. N.; Chertyuk, V. B.; Leonov, S. D.; Astakhov, D. A.

2017-01-01

The liver failure which is result of disharmony of functionality of a liver to requirements of an organism is the main reason for unsatisfactory results of an extensive resection of a liver. However, uniform effective criterion of definition of degree of a liver failure it isn’t developed now. One of data acquisition methods about a morfo-functional condition of internals is the bioimpedance analysis (BIA) based on impedance assessment (full electric resistance) of a biological tissue. Measurements of an impedance are used in medicine and biology for the characteristic of physical properties of living tissue, studying of the changes bound to a functional state and its structural features. In experimental conditions we carried out an extensive resection of a liver on 27 white laboratory rats of the Vistar line. The comparative characteristic of data of a bioimpedansometriya in intraoperative and after the operational period with the main existing methods of assessment of a functional condition of a liver was carried out. By results of the work performed by us it is possible to claim that the bioimpedance analysis of a liver on the basis of an invasive bioimpedansometriya allows to estimate morphological features and functional activity of a liver before performance of an extensive resection of a liver. The data obtained during scientific work are experimental justification for use of an impedansometriya during complex assessment of functional reserves of a liver. Preliminary data of clinical approbation at a stage of introduction of a technique speak about rather high informational content of a bioimpedansometriya. The subsequent analysis of efficiency of the invasive bioimpedance analysis of a liver requires further accumulation of clinical data. However even at this stage the method showed the prospect for further use in clinical surgical hepathology.

Chronic DON exposure and acute LPS challenge: effects on porcine liver morphology and function.

PubMed

Renner, Lydia; Kahlert, Stefan; Tesch, Tanja; Bannert, Erik; Frahm, Jana; Barta-Böszörményi, Anikó; Kluess, Jeannette; Kersten, Susanne; Schönfeld, Peter; Rothkötter, Hermann-Josef; Dänicke, Sven

2017-08-01

The aim of the present study was to examine the role of chronic deoxynivalenol (DON) exposition on the liver morphology and function in combination with pre- and post-hepatic lipopolysaccharide (LPS) stress in young pigs fed for 4 weeks with a DON-contaminated diet (4.59 mg/kg feed). At the end of the experiment, LPS (7.5 μg/kg BW) was administered for 1 h pre-hepatically (Vena portae hepatis) or post-hepatically (Vena jugularis). Liver morphology was macroscopically checked and showed haemorrhage in all LPS groups, significantly higher relative liver weights, accompanied by marked oedema in the gallbladder wall. Histological changes were judged by a modified histology activity index (HAI). Liver HAI score was significantly increased in all LPS groups compared to placebo, primarily due to neutrophil infiltration and haemorrhage. DON feed alone was without effect on the liver HAI. Liver function was characterized by (i) hepatic biochemical markers, (ii) mitochondrial respiration and (iii) Ca 2+ accumulation capacity of isolated mitochondria. Clinical chemical parameters characterizing liver function were initially (<3 h) slightly influenced by LPS. After 3 h, bilirubin and alkaline phosphatase were increased significantly, in DON-fed, jugular-infused LPS group. Respiration and Ca 2+ accumulation capacity of isolated liver mitochondria was not impaired by chronic DON exposure, acute LPS challenge or combined treatments. DON-contaminated feed did not change macroscopy and histology of the liver, but modified the function under LPS stress. The different function was not linked to modifications of liver mitochondria.

Liver cell therapy and tissue engineering for transplantation.

PubMed

Vacanti, Joseph P; Kulig, Katherine M

2014-06-01

Liver transplantation remains the only definitive treatment for liver failure and is available to only a tiny fraction of patients with end-stage liver diseases. Major limitations for the procedure include donor organ shortage, high cost, high level of required expertise, and long-term consequences of immune suppression. Alternative cell-based liver therapies could potentially greatly expand the number of patients provided with effective treatment. Investigative research into augmenting or replacing liver function extends into three general strategies. Bioartificial livers (BALs) are extracorporeal devices that utilize cartridges of primary hepatocytes or cell lines to process patient plasma. Injection of liver cell suspensions aims to foster organ regeneration or provide a missing metabolic function arising from a genetic defect. Tissue engineering recreates the organ in vitro for subsequent implantation to augment or replace patient liver function. Translational models and clinical trials have highlighted both the immense challenges involved and some striking examples of success. Copyright © 2014. Published by Elsevier Inc.

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha.

PubMed

Desai, Seema S; Tung, Jason C; Zhou, Vivian X; Grenert, James P; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M; Chang, Tammy T

2016-07-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275). © 2016 by the American Association for the Study of Liver Diseases.

Prognostic value of enzymatic liver function for the estimation of short-term survival of liver transplant candidates: a prospective study with the LiMAx test.

PubMed

Jara, Maximilian; Malinowski, Maciej; Lüttgert, Katja; Schott, Eckart; Neuhaus, Peter; Stockmann, Martin

2015-01-01

LiMAx has been recently proposed as a new quantitative liver function test. Thus, we aimed to evaluate the diagnostic ability of LiMAx to assess short-term survival in liver transplant candidates and compare its performance to the model for end-stage liver disease (MELD) and indocyanine green plasma disappearance rate (ICG-PDR). Liver function of 167 chronic liver failure patients without hepatocellular carcinoma was prospectively investigated when they were evaluated for liver transplantation. Primary study endpoints were liver-related death within 6 months of follow-up. Within 6 months of follow-up, 18 patients died and 36 underwent liver transplantation. Median LiMAx results on evaluation day were significantly lower in patients who died (99 μg/kg/h vs. 55 μg/kg/h; P = 0.024), while median ICG-PDR results did not differ within both groups (4.4%/min vs. 3.5%/min; P = 0.159). LiMAx showed a higher negative predictive value (NPV: 0.93) as compared with ICG-PDR (NPV: 0.90) and the MELD (NPV: 0.91) in predicting risk of death within 6 months. In conclusion, LiMAx provides good prognostic information of liver transplant candidates. In particular, patients who are not at risk of death can be identified reliably by measuring actual enzymatic liver function capacity. © 2014 Steunstichting ESOT.

Hepatobiliary magnetic resonance imaging in patients with liver disease: correlation of liver enhancement with biochemical liver function tests.

PubMed

Kukuk, Guido M; Schaefer, Stephanie G; Fimmers, Rolf; Hadizadeh, Dariusch R; Ezziddin, Samer; Spengler, Ulrich; Schild, Hans H; Willinek, Winfried A

2014-10-01

To evaluate hepatobiliary magnetic resonance imaging (MRI) using Gd-EOB-DTPA in relation to various liver function tests in patients with liver disorders. Fifty-one patients with liver disease underwent Gd-EOB-DTPA-enhanced liver MRI. Based on region-of-interest (ROI) analysis, liver signal intensity was calculated using the spleen as reference tissue. Liver-spleen contrast ratio (LSCR) and relative liver enhancement (RLE) were calculated. Serum levels of total bilirubin, gamma glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), serum albumin level (AL), prothrombin time (PT), creatinine (CR) as well as international normalised ratio (INR) and model for end-stage liver disease (MELD) score were tested for correlation with LSCR and RLE. Pre-contrast LSCR values correlated with total bilirubin (r = -0.39; p = 0.005), GGT (r = -0.37; p = 0.009), AST (r = -0.38; p = 0.013), ALT (r = -0.29; p = 0.046), PT (r = 0.52; p < 0.001), GLDH (r = -0.55; p = 0.044), INR (r = -0.42; p = 0.003), and MELD Score (r = -0.53; p < 0.001). After administration of Gd-EOB-DTPA bilirubin (r = -0.45; p = 0.001), GGT (r = -0.40; p = 0.004), PT (r = 0.54; p < 0.001), AST (r = -0.46; p = 0.002), ALT (r = -0.31; p = 0.030), INR (r = -0.45; p = 0.001) and MELD Score (r = -0.56; p < 0.001) significantly correlated with LSCR. RLE correlated with bilirubin (r = -0.40; p = 0.004), AST (r = -0.38; p = 0.013), PT (r = 0.42; p = 0.003), GGT (r = -0.33; p = 0.020), INR (r = -0.36; p = 0.011) and MELD Score (r = -0.43; p = 0.003). Liver-spleen contrast ratio and relative liver enhancement using Gd-EOB-DTPA correlate with a number of routinely used biochemical liver function tests, suggesting that hepatobiliary MRI may serve as a valuable biomarker for liver function. The strongest correlation with liver enhancement was found for the MELD Score. • Relative enhancement (RLE) of Gd-EOB-DTPA is related to biochemical liver function tests. • Correlation of RLE with bilirubin, ALT, AST, GGT, INR and MELD Score is reverse. • The correlation of relative liver enhancement with prothrombin time is positive. • AST, ALT, GLDH, prothrombin time, INR and MELD Score correlate with pre-contrast liver-spleen contrast ratio. • Such biomarkers may help to evaluate liver function.

TH-A-9A-04: Incorporating Liver Functionality in Radiation Therapy Treatment Planning

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

Wu, V; Epelman, M; Feng, M

2014-06-15

Purpose: Liver SBRT patients have both variable pretreatment liver function (e.g., due to degree of cirrhosis and/or prior treatments) and sensitivity to radiation, leading to high variability in potential liver toxicity with similar doses. This work aims to explicitly incorporate liver perfusion into treatment planning to redistribute dose to preserve well-functioning areas without compromising target coverage. Methods: Voxel-based liver perfusion, a measure of functionality, was computed from dynamic contrast-enhanced MRI. Two optimization models with different cost functions subject to the same dose constraints (e.g., minimum target EUD and maximum critical structure EUDs) were compared. The cost functions minimized were EUDmore » (standard model) and functionality-weighted EUD (functional model) to the liver. The resulting treatment plans delivering the same target EUD were compared with respect to their DVHs, their dose wash difference, the average dose delivered to voxels of a particular perfusion level, and change in number of high-/low-functioning voxels receiving a particular dose. Two-dimensional synthetic and three-dimensional clinical examples were studied. Results: The DVHs of all structures of plans from each model were comparable. In contrast, in plans obtained with the functional model, the average dose delivered to high-/low-functioning voxels was lower/higher than in plans obtained with its standard counterpart. The number of high-/low-functioning voxels receiving high/low dose was lower in the plans that considered perfusion in the cost function than in the plans that did not. Redistribution of dose can be observed in the dose wash differences. Conclusion: Liver perfusion can be used during treatment planning potentially to minimize the risk of toxicity during liver SBRT, resulting in better global liver function. The functional model redistributes dose in the standard model from higher to lower functioning voxels, while achieving the same target EUD and satisfying dose limits to critical structures. This project is funded by MCubed and grant R01-CA132834.« less

Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis.

PubMed

Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

2016-12-14

To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. Liver stiffness was measured in sixty-eight rabbits with CCl 4 -induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. LSM by ElastPQ was significantly correlated with histologic fibrosis stage ( r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl 4 -induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy.

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.

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

PubMed

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

2013-08-01

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

Circulating lipocalin 2 is neither related to liver steatosis in patients with non-alcoholic fatty liver disease nor to residual liver function in cirrhosis.

PubMed

Meier, Elisabeth M; Pohl, Rebekka; Rein-Fischboeck, Lisa; Schacherer, Doris; Eisinger, Kristina; Wiest, Reiner; Krautbauer, Sabrina; Buechler, Christa

2016-09-01

Lipocalin 2 (LCN2) is induced in the injured liver and associated with inflammation. Aim of the present study was to evaluate whether serum LCN2 is a non-invasive marker to assess hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD) or residual liver function in patients with liver cirrhosis. Therefore, LCN2 was measured by ELISA in serum of 32 randomly selected patients without fatty liver (controls), 24 patients with ultrasound diagnosed NAFLD and 42 patients with liver cirrhosis mainly due to alcohol. Systemic LCN2 was comparable in patients with liver steatosis, those with liver cirrhosis and controls. LCN2 negatively correlated with bilirubin in both cohorts. In cirrhosis, LCN2 was not associated with more advanced liver injury defined by the CHILD-PUGH score and model for end-stage liver disease score. Resistin but not C-reactive protein or chemerin positively correlated with LCN2. LCN2 levels were not increased in patients with ascites or patients with esophageal varices. Consequently, reduction of portal pressure by transjugular intrahepatic portosystemic shunt did not affect LCN2 levels. Hepatic venous blood (HVS), portal venous blood and systemic venous blood levels of LCN2 were similar. HVS LCN2 was unchanged in patients with end-stage liver cirrhosis compared to those with well-compensated disease arguing against increased hepatic release. Current data exclude that serum LCN2 is of any value as steatosis marker in patients with NAFLD and indicator of liver function in patients with alcoholic liver cirrhosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Expression of Enzymes that Metabolize Medications

NASA Technical Reports Server (NTRS)

Wotring, Virginia E.; Peters, C. P.

2012-01-01

Most pharmaceuticals are metabolized by the liver. Clinically-used medication doses are given with normal liver function in mind. A drug overdose can result if the liver 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.

Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus.

PubMed

Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

2016-09-14

The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.

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

PubMed

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

2016-07-01

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

Assessment of hepatic function decline after stereotactic body radiation therapy for primary liver cancer.

PubMed

Toesca, Diego A S; Osmundson, Evan C; von Eyben, Rie; Shaffer, Jenny L; Koong, Albert C; Chang, Daniel T

This study aims to determine how the albumin-bilirubin (ALBI) score compares with the Child-Pugh (CP) score for assessing liver function following stereotactic body radiation therapy (SBRT). In total, 60 patients, 40 with hepatocellular carcinoma (HCC) and 20 with cholangiocarcinoma (CCA), were treated with SBRT. Liver function panels were obtained before and at 1, 3, 6, and 12 months after SBRT. Laboratory values were censored after locoregional recurrence, further liver-directed therapies, or liver transplant. A significant decline in hepatic function occurred after SBRT for HCC patients only (P = .001 by ALBI score; P < .0001 by CP score). By converting radiation doses to biologically equivalent doses by using a standard linear quadratic model using α/β of 10, the strongest dosimetric predictor of liver function decline for HCC was the volume of normal liver irradiated by a dose of 40 Gy when assessing liver function by the ALBI score (P = .07), and the volume of normal liver irradiated by a dose of 20 Gy by using the CP score (P= .0009). For CCA patients, the volume of normal liver irradiated by a dose of 40 Gy remained the strongest dosimetric predictor when using the ALBI score (P = .002), but no dosimetric predictor was significant using the CP score. Hepatic function decline correlated with worse overall survival for HCC (by ALBI, P = .0005; by CP, P < .0001) and for CCA (by ALBI, P = NS; by CP, P = .008). ALBI score was similarly able to predict hepatic function decline compared with CP score, and both systems correlated with survival. Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

The impact of longitudinal intestinal lengthening and tailoring on liver function in short bowel syndrome.

PubMed

Reinshagen, K; Zahn, K; Buch, C von; Zoeller, M; Hagl, C I; Ali, M; Waag, K-L

2008-08-01

Short bowel syndrome is a functional or anatomic loss of major parts of the small bowel leading to severe malnutrition. The limiting factor for the survival of these patients remains parenteral nutrition-related liver damage leading to end-stage liver failure. Longitudinal intestinal lengthening and tailoring (LILT) has been proven to enhance peristalsis, to decrease bacterial overgrowth and to extend the mucosal contact time for the absorption of nutrients. The aim of this study was to show the impact of LILT on the development of parenteral nutrition-related liver damage. A cohort of 55 patients with short bowel syndrome managed with LILT in our institution between 1987 and 2007 was retrospectively reviewed. LILT was performed at a mean age of 24 months (range 4 - 150 months). Mean follow-up time was 83.76 months (range 5 - 240 months). We obtained reliable data from 31 patients with regard to liver enzymes and function parameters in blood samples before LILT and at the present time. Liver biopsy was performed in 14 patients prior to LILT. Liver enzymes ALAT (mean 121 U/l), ASAT (mean 166 U/l) and bilirubin (mean 2.49 mg/dl) were elevated preoperatively in 27/31 children. After the lengthening procedure, ALAT (mean 50 U/l), ASAT (mean 63 U/l) and bilirubin (mean 1.059 mg/dl) normalized except in 5 of 8 patients who could not be weaned from parenteral nutrition after LILT. Liver function parameters such as the international normal ratio (INR) were slightly elevated in 5/31 patients. Albumin was generally low, probably due to parenteral nutrition. Liver biopsy was performed in 14 patients preoperatively, showing 4 patients with low-grade, 6 patients with intermediate and 4 patients with high-grade fibrosis. End-stage liver disease with cirrhosis was an exclusion criterion for LILT. All patients with liver fibrosis showed a normalization of liver enzymes when they were weaned from parenteral nutrition. But patients with higher grade liver fibrosis tend to develop more complications perioperatively. After LILT, all patients with liver fibrosis who could be weaned from parenteral nutrition showed a normalization of liver enzymes. Preoperative liver biopsy is mandatory in order to differentiate reversible liver fibrosis from end-stage liver disease. A higher grade of liver fibrosis and elevated INR has been shown to be a sensitive parameter for peri- and postoperative complications.

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.

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

PubMed

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

2015-01-01

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

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

PubMed

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

2012-04-01

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

Does adjuvant radiotherapy suppress liver regeneration after partial hepatectomy?

PubMed

Choi, Jin-Hwa; Kim, Kyubo; Chie, Eui Kyu; Jang, Jin-Young; Kim, Sun Whe; Oh, Do-Youn; Im, Seock-Ah; Kim, Tae-You; Bang, Yung-Jue; Ha, Sung W

2009-05-01

To analyze the influence of the adjuvant radiotherapy (RT) on the liver regeneration and liver function after partial hepatectomy (PH). Thirty-four patients who underwent PH for biliary tract cancer between October 2003 and July 2005 were reviewed. Hemihepatectomy was performed in 14 patients and less extensive surgery in 20. Of the patients, 19 patients had no adjuvant therapy (non-RT group) and 15 underwent adjuvant RT by a three-dimensional conformal technique (RT group). Radiation dose range was 40 to 50 Gy (median, 40 Gy). Liver volume on computed tomography and the results of liver function tests at 1, 4, 12, 24, and 52 weeks after PH were compared between the RT and non-RT groups. The preoperative characteristics were identical for both groups. During the interval between Weeks 4 and 12 when adjuvant RT was delivered in the RT group, the increase in liver volume was significantly smaller in the RT group than non-RT group (22.9 +/- 38.3cm(3) and 81.5 +/- 75.6cm(3), respectively, p = 0.007). However, the final liver volume measured at 1 year after PH did not differ between the two groups (p = 0.878). Liver function tests were comparable for both groups. The resection extent and original liver volume was independent factors for final liver volume measured at 1 year after PH. In this study, adjuvant RT delayed the liver regeneration process after PH, but the volume difference between the two study groups became nonsignificant after 1 year. Adjuvant RT had no additional adverse effect on liver function after PH.

Transport Advances in Disposable Bioreactors for Liver Tissue Engineering

NASA Astrophysics Data System (ADS)

Catapano, Gerardo; Patzer, John F.; Gerlach, Jörg Christian

Acute liver failure (ALF) is a devastating diagnosis with an overall survival of approximately 60%. Liver transplantation is the therapy of choice for ALF patients but is limited by the scarce availability of donor organs. The prognosis of ALF patients may improve if essential liver functions are restored during liver failure by means of auxiliary methods because liver tissue has the capability to regenerate and heal. Bioartificial liver (BAL) approaches use liver tissue or cells to provide ALF patients with liver-specific metabolism and synthesis products necessary to relieve some of the symptoms and to promote liver tissue regeneration. The most promising BAL treatments are based on the culture of tissue engineered (TE) liver constructs, with mature liver cells or cells that may differentiate into hepatocytes to perform liver-specific functions, in disposable continuous-flow bioreactors. In fact, adult hepatocytes perform all essential liver functions. Clinical evaluations of the proposed BALs show that they are safe but have not clearly proven the efficacy of treatment as compared to standard supportive treatments. Ambiguous clinical results, the time loss of cellular activity during treatment, and the presence of a necrotic core in the cell compartment of many bioreactors suggest that improvement of transport of nutrients, and metabolic wastes and products to or from the cells in the bioreactor is critical for the development of therapeutically effective BALs. In this chapter, advanced strategies that have been proposed over to improve mass transport in the bioreactors at the core of a BAL for the treatment of ALF patients are reviewed.

Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis

PubMed Central

Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

2016-01-01

AIM To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. METHODS Liver stiffness was measured in sixty-eight rabbits with CCl4-induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. RESULTS LSM by ElastPQ was significantly correlated with histologic fibrosis stage (r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. CONCLUSION ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl4-induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy. PMID:28028365

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

Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery

NASA Astrophysics Data System (ADS)

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

2000-02-01

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

Function of GATA Factors in the Adult Mouse Liver

PubMed Central

Zheng, Rena; Rebolledo-Jaramillo, Boris; Zong, Yiwei; Wang, Liqing; Russo, Pierre; Hancock, Wayne; Stanger, Ben Z.; Hardison, Ross C.; Blobel, Gerd A.

2013-01-01

GATA transcription factors and their Friend of Gata (FOG) cofactors control the development of diverse tissues. GATA4 and GATA6 are essential for the expansion of the embryonic liver bud, but their expression patterns and functions in the adult liver are unclear. We characterized the expression of GATA and FOG factors in whole mouse liver and purified hepatocytes. GATA4, GATA6, and FOG1 are the most prominently expressed family members in whole liver and hepatocytes. GATA4 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) identified 4409 occupied sites, associated with genes enriched in ontologies related to liver function, including lipid and glucose metabolism. However, hepatocyte-specific excision of Gata4 had little impact on gross liver architecture and function, even under conditions of regenerative stress, and, despite the large number of GATA4 occupied genes, resulted in relatively few changes in gene expression. To address possible redundancy between GATA4 and GATA6, both factors were conditionally excised. Surprisingly, combined Gata4,6 loss did not exacerbate the phenotype resulting from Gata4 loss alone. This points to the presence of an unusually robust transcriptional network in adult hepatocytes that ensures the maintenance of liver function. PMID:24367609

Generation, characterization and potential therapeutic applications of mature and functional hepatocytes from stem cells.

PubMed

Zhang, Zhenzhen; Liu, Jianfang; Liu, Yang; Li, Zheng; Gao, Wei-Qiang; He, Zuping

2013-02-01

Liver cancer is the sixth most common tumor in the world and the majority of patients with this disease usually die within 1 year. The effective treatment for end-stage liver disease (also known as liver failure), including liver cancer or cirrhosis, is liver transplantation. However, there is a severe shortage of liver donors worldwide, which is the major handicap for the treatment of patients with liver failure. Scarcity of liver donors underscores the urgent need of using stem cell therapy to the end-stage liver disease. Notably, hepatocytes have recently been generated from hepatic and extra-hepatic stem cells. We have obtained mature and functional hepatocytes from rat hepatic stem cells. Here, we review the advancements on hepatic differentiation from various stem cells, including hepatic stem cells, embryonic stem cells, the induced pluripotent stem cells, hematopoietic stem cells, mesenchymal stem cells, and probably spermatogonial stem cells. The advantages, disadvantages, and concerns on differentiation of these stem cells into hepatic cells are highlighted. We further address the methodologies, phenotypes, and functional characterization on the differentiation of numerous stem cells into hepatic cells. Differentiation of stem cells into mature and functional hepatocytes, especially from an extra-hepatic stem cell source, would circumvent the scarcity of liver donors and human hepatocytes, and most importantly it would offer an ideal and promising source of hepatocytes for cell therapy and tissue engineering in treating liver disease. Copyright © 2012 Wiley Periodicals, Inc.

Plants Consumption and Liver Health

PubMed Central

He, Qing

2015-01-01

The liver is a very important organ with a lot of functions for the host to survive. Dietary components are essential for and can be beneficial or detrimental to the healthy or diseased liver. Plants food is an essential part of the human diet and comprises various compounds which are closely related to liver health. Selected food plants can provide nutritional and medicinal support for liver disease. At the present, the knowledge of the effects of plants on the liver is still incomplete. The most urgent task at the present time is to find the best dietary and medicinal plants for liver health in an endless list of candidates. This review article updates the knowledge about the effects of plants consumption on the health of the liver, putting particular emphasis on the potential beneficial and harmful impact of dietary and medicinal plants on liver function. PMID:26221179

Orchestrating liver development.

PubMed

Gordillo, Miriam; Evans, Todd; Gouon-Evans, Valerie

2015-06-15

The liver is a central regulator of metabolism, and liver failure thus constitutes a major health burden. Understanding how this complex organ develops during embryogenesis will yield insights into how liver regeneration can be promoted and how functional liver replacement tissue can be engineered. Recent studies of animal models have identified key signaling pathways and complex tissue interactions that progressively generate liver progenitor cells, differentiated lineages and functional tissues. In addition, progress in understanding how these cells interact, and how transcriptional and signaling programs precisely coordinate liver development, has begun to elucidate the molecular mechanisms underlying this complexity. Here, we review the lineage relationships, signaling pathways and transcriptional programs that orchestrate hepatogenesis. © 2015. Published by The Company of Biologists Ltd.

Ad Integrum Functional and Volumetric Recovery in Right Lobe Living Donors: Is It Really Complete 1 Year After Donor Hepatectomy?

PubMed

Duclos, J; Bhangui, P; Salloum, C; Andreani, P; Saliba, F; Ichai, P; Elmaleh, A; Castaing, D; Azoulay, D

2016-01-01

The partial liver's ability to regenerate both as a graft and remnant justifies right lobe (RL) living donor liver transplantation. We studied (using biochemical and radiological parameters) the rate, extent of, and predictors of functional and volumetric recovery of the remnant left liver (RLL) during the first year in 91 consecutive RL donors. Recovery of normal liver function (prothrombin time [PT] ≥70% of normal and total bilirubin [TB] ≤20 µmol/L), liver volumetric recovery, and percentage RLL growth were analyzed. Normal liver function was regained by postoperative day's 7, 30, and 365 in 52%, 86%, and 96% donors, respectively. Similarly, mean liver volumetric recovery was 64%, 71%, and 85%; whereas the percentage liver growth was 85%, 105%, and 146%, respectively. Preoperative PT value (p = 0.01), RLL/total liver volume (TLV) ratio (p = 0.03), middle hepatic vein harvesting (p = 0.02), and postoperative peak TB (p < 0.01) were predictors of early functional recovery, whereas donor age (p = 0.03), RLL/TLV ratio (p = 0.004), and TLV/ body weight ratio (p = 0.02) predicted early volumetric recuperation. One-year post-RL donor hepatectomy, though functional recovery occurs in almost all (96%), donors had incomplete restoration (85%) of preoperative total liver volume. Modifiable predictors of regeneration could help in better and safer donor selection, while continuing to ensure successful recipient outcomes. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Kupffer Cell Metabolism and Function

PubMed Central

Nguyen-Lefebvre, Anh Thu; Horuzsko, Anatolij

2015-01-01

Kupffer cells are resident liver macrophages and play a critical role in maintaining liver functions. Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections. Under pathological conditions, they are activated by different components and can differentiate into M1-like (classical) or M2-like (alternative) macrophages. The metabolism of classical or alternative activated Kupffer cells will determine their functions in liver damage. Special functions and metabolism of Kupffer cells suggest that they are an attractive target for therapy of liver inflammation and related diseases, including cancer and infectious diseases. Here we review the different types of Kupffer cells and their metabolism and functions in physiological and pathological conditions. PMID:26937490

Gut microbial balance and liver transplantation: alteration, management, and prediction.

PubMed

Tian, Xinyao; Yang, Zhe; Luo, Fangzhou; Zheng, Shusen

2018-04-01

Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia-reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation.

Sexual dysfunction in chronic liver disease: is liver transplantation an effective cure?

PubMed

Burra, Patrizia; Germani, Giacomo; Masier, Annalisa; De Martin, Eleonora; Gambato, Martina; Salonia, Andrea; Bo, Patrizio; Vitale, Alessandro; Cillo, Umberto; Russo, Francesco Paolo; Senzolo, Marco

2010-06-27

The goal of liver transplantation is not only to ensure patient long-term survival but also to offer the opportunity to achieve psychologic and physical integrity. Quality of life after liver transplantation may be affected by unsatisfactory sexual function. Before liver transplantation, sexual dysfunction and sex hormone disturbances are reported in men and women mainly due to abnormality of physiology of the hypothalamic-pituitary-gonadal axis and, in some cases, origin of liver disease. Successful liver transplantation should theoretically restore hormonal balance and improve sexual function both in men and women, thus improving the reproductive performance. However, after transplantation, up to 25% of patients report persistent sexual dysfunction, and approximately one third of patients describe the appearance of de novo sexual dysfunction. Despite the described high prevalence of this condition, epidemiologic data are relatively scant. Further studies on pathophysiology and risk factors in the field of sexual function after liver transplantation along with new strategies to support and inform patients on the waiting list and after surgery are needed.

Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells

PubMed Central

Tokita, Daisuke; Sumpter, Tina L.; Raimondi, Giorgio; Zahorchak, Alan F.; Wang, Zhiliang; Nakao, Atsunori; Mazariegos, George V.; Abe, Masanori; Thomson, Angus W.

2008-01-01

Background/Aims The liver is comparatively rich in plasmacytoid (p) dendritic cells (DC),- innate immune effector cells that are also thought to play key roles in the induction and regulation of adaptive immunity. Methods Liver and spleen pDC were purified from fms-like tyrosine kinase ligand-reated control or lipopolysaccharide-injected C57BL/10 mice. Flow cytometric and molecular biologic assays were used to characterize their function and interaction with naturally-occurring regulatory T cells (Treg). Results While IL-10 production was greater for freshly-isolated liver compared with splenic pDC, the former produced less bioactive IL-12p70. Moreover, liver pDC expressed a low Delta4/Jagged1 Notch ligand ratio, skewed towards T helper 2 cell differentiation/cytokine production, and promoted allogeneic CD4+ T cell apoptosis. T cell proliferation in response to liver pDC was, however, enhanced by blocking IL-10 function at the initiation of cultures. In the absence of naturally occurring CD4+CD25+ regulatory T cells, similar levels of T cell proliferation were induced by liver and spleen pDC and the pro-apoptotic activity of liver pDC was reversed. Conclusion The inferior T cell allostimulatory activity of in vivo-stimulated liver pDC may depend on the presence and function of Treg, a property that may contribute to inherent liver tolerogenicity. PMID:18926588

Correlation of four potential biomarkers of liver fibrosis with liver function and grade of hepatic fibrosis in a neonatal cholestatic rat model.

PubMed

Tang, Ning; Zhang, Yaping; Liu, Zeyu; Ai, Xuemei; Liang, Qinghong

2017-07-01

The present study investigated the correlation between four serum biomarkers of liver fibrosis, liver function and pathological hepatic fibrosis grade in neonatal cholestatic rats. A total of 38 Sprague‑Dawley rats, aged 3 weeks, were randomly assigned to the experimental group (EG), control group (CG) and the blank control group (BCG). EG received intragastric administration of 1% α‑naphthylisothiocyanate, 75 mg/kg, to induce acute cholestasis liver injury, CG and BCG were set as control groups. Blood samples from all groups were collected 48 h following the procedure. The levels of liver function markers, and four biomarkers of liver fibrosis in serum, were measured and sections of liver tissue were stained for pathological analysis. The results of the present study demonstrated that the degree of hepatic fibrosis in EG, in the serum levels or by pathological analysis, was markedly more evident compared with the CG. Several indices of four biomarkers for liver fibrosis in serum were identified and correlated with the levels of liver function markers. The pathological hepatic fibrosis grade was correlated with γ‑glutamyl transferase (γ‑GT) and Hyaluronic acid (HA). Therefore, HA and γ‑GT were positively correlated with the grade of hepatic fibrosis, indicating their efficacy as biomarkers of infantile cholestatic hepatic fibrosis.

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

PubMed

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

2014-02-05

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

Primary biliary cirrhosis

MedlinePlus

... stools Itching Poor appetite and weight loss As liver function worsens, symptoms may include: Fluid buildup in the ... your liver is working properly: Albumin blood test Liver function tests (serum alkaline phosphatase is most important) Prothrombin ...

Stopping Liver Cancer's Rogue COP | Center for Cancer Research

Cancer.gov

Liver cancer is the fourth most common cancer type and the third leading cause of cancer death worldwide. Many liver tumors are actually metastases, tumors seeded in the liver by cancer cells from another organ, but hepatocellular carcinomas (HCCs), the most common liver tumors, are a heterogeneous family of cancers that arise in hepatocytes, the functional cells of the liver.

Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis

PubMed Central

Li, Yan; Farooq, Muhammad; Sheng, Donglai; Chandramouli, Chanchal; Lan, Tian; Mahajan, Nilesh K.; Kini, R. Manjunatha; Hong, Yunhan; Lisowsky, Thomas; Ge, Ruowen

2012-01-01

Augmenter of Liver Regeneration (ALR) is a sulfhydryl oxidase carrying out fundamental functions facilitating protein disulfide bond formation. In mammals, it also functions as a hepatotrophic growth factor that specifically stimulates hepatocyte proliferation and promotes liver regeneration after liver damage or partial hepatectomy. Whether ALR also plays a role during vertebrate hepatogenesis is unknown. In this work, we investigated the function of alr in liver organogenesis in zebrafish model. We showed that alr is expressed in liver throughout hepatogenesis. Knockdown of alr through morpholino antisense oligonucleotide (MO) leads to suppression of liver outgrowth while overexpression of alr promotes liver growth. The small-liver phenotype in alr morphants results from a reduction of hepatocyte proliferation without affecting apoptosis. When expressed in cultured cells, zebrafish Alr exists as dimer and is localized in mitochondria as well as cytosol but not in nucleus or secreted outside of the cell. Similar to mammalian ALR, zebrafish Alr is a flavin-linked sulfhydryl oxidase and mutation of the conserved cysteine in the CxxC motif abolishes its enzymatic activity. Interestingly, overexpression of either wild type Alr or enzyme-inactive AlrC131S mutant promoted liver growth and rescued the liver growth defect of alr morphants. Nevertheless, alr C131S is less efficacious in both functions. Meantime, high doses of alr MOs lead to widespread developmental defects and early embryonic death in an alr sequence-dependent manner. These results suggest that alr promotes zebrafish liver outgrowth using mechanisms that are dependent as well as independent of its sulfhydryl oxidase activity. This is the first demonstration of a developmental role of alr in vertebrate. It exemplifies that a low-level sulfhydryl oxidase activity of Alr is essential for embryonic development and cellular survival. The dose-dependent and partial suppression of alr expression through MO-mediated knockdown allows the identification of its late developmental role in vertebrate liver organogenesis. PMID:22292055

All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells.

PubMed

Werner, Melanie; Driftmann, Sabrina; Kleinehr, Kathrin; Kaiser, Gernot M; Mathé, Zotlan; Treckmann, Juergen-Walter; Paul, Andreas; Skibbe, Kathrin; Timm, Joerg; Canbay, Ali; Gerken, Guido; Schlaak, Joerg F; Broering, Ruth

2015-01-01

Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen. Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity. Cell preparation yielded the following cell counts per gram of liver tissue: 2.0 ± 0.4 × 10(7) hepatocytes, 1.8 ± 0.5 × 10(6 )Kupffer cells, 4.3 ± 1.9 × 10(5) liver sinusoidal endothelial cells, and 3.2 ± 0.5 × 10(5) stellate cells. Hepatocytes were identified by albumin (95.5 ± 1.7%) and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5 ± 1.2%) and exhibited phagocytic activity, as determined with 1 μm latex beads. Endothelial cells were CD146(+) (97.8 ± 1.1%) and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1 ± 1.5%). These cells further exhibited retinol (vitamin A)-mediated autofluorescence. Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease.

Evaluation of liver function using gadoxetate disodium (Gd-EOB-DTPA) enhanced MR imaging

NASA Astrophysics Data System (ADS)

Yamada, Akira; Hara, Takeshi; Li, Feng; Doi, Kunio

2010-03-01

Indocyanine green (ICG) is widely used for its clearance test in the evaluation of liver function. Gadoxetate disodium (Gd-EOB-DTPA) is a targeted MR contrast agent partially taken up by hepatocytes. The objective of this study was to evaluate the feasibility of an estimation of the liver function corresponding to plasma disappearance rate of indocyanine green (ICG-PDR) by use of the signal intensity of the liver alone in Gd-EOB-DTPA enhanced MR imaging (EOB-MRI). We evaluated fourteen patients who had EOB-MRI and ICG clearance test within 1 month. 2D-GRE T1 weighted images were obtained at pre contrast, 3 min (equilibrium phase) and 20 min (hepatobiliary phase) after the intravenous administration of Gd-EOB-DTPA, and the mean signal intensity of the liver was measured. The correlation between ICG-PDR and many parameters derived from the signal intensity of the liver in EOB-MRI was evaluated. The correlation coefficient between ICG-PDR and many parameters derived from the signal intensity of the liver in EOBMRI was low and not significant. The estimation of the liver function corresponding to ICG-PDR by use of the signal intensity of the liver alone in EOB-MRI would not be reliable.

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

PubMed

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

2013-01-01

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

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.

Impact of pretransplant renal function on survival after liver transplantation.

PubMed

Gonwa, T A; Klintmalm, G B; Levy, M; Jennings, L S; Goldstein, R M; Husberg, B S

1995-02-15

To determine the effect of pretransplant liver function on survival following orthotopic liver transplantation and to quantify the effects of cyclosporine administration on long-term renal function in patients undergoing liver transplant, we performed an analysis of a prospectively maintained database. Data from 569 consecutive patients undergoing liver transplantation alone who were treated with CsA for immunosuppression were used for this study. Actuarial graft and patient survival rates were calculated using Kaplan-Meier statistics. Glomerular filtration rates, serum creatinine, and the use of various immunosuppressives were analyzed for this study. The initial analysis demonstrated that patients presenting for liver transplant with hepatorenal syndrome have a significantly decreased acturial patient survival after liver transplant at 5 years compared with patients without hepatorenal syndrome (60% vs. 68%, P < 0.03). Patients with hepatorenal syndrome recovered their renal function after liver transplant. Patients who had hepatorenal syndrome were sicker and required longer stays in the intensive care unit, longer hospitalizations, and more dialysis treatments after transplantation compared with patients who did not have hepatorenal syndrome. The incidence of end-stage renal disease after liver transplantation in patients who had hepatorenal syndrome was 7%, compared with 2% in patients who did not have hepatorenal syndrome. To more fully examine the effect of pretransplant renal function on posttransplant survival, the non-hepatorenal syndrome patients were divided into quartiles depending upon their pretransplant renal function. The patients with the lowest pretransplant renal function had the same survival as the patients with the highest pretransplant renal function. In addition, there was no increased incidence of acute or chronic rejection in any of the groups. The patients with the lower pretransplant renal function were treated with more azathioprine to maintain renal function and had a negligible decrease in glomerular filtration rate following transplant. Conversely, patients with the highest level of renal function pretransplant had a 40% decline in renal function in the first year, but maintained stable renal function up to 4 years after transplant. We conclude that pretransplant renal function other than hepato-renal syndrome has no effect on patient survival after orthotopic liver transplant. Renal function after liver transplant is stable after an initial decline, despite continued administration of CsA.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in Liver Metabolic Gene Expression after Radiation Exposure

NASA Technical Reports Server (NTRS)

Peters, C. P.; Wotring, Virginia E.

2012-01-01

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 any effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments.

Quantitative PET of liver functions

PubMed Central

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

2018-01-01

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

Quantitative PET of liver functions.

PubMed

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

2018-01-01

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

Design of liver functional reserve monitor based on three-wavelength from IR to NIR.

PubMed

Ye, Fuli; Zhan, Huimiao; Shi, Guilian

2018-05-04

The preoperative evaluation of liver functional reserve is very important to determine the excision of liver lobe for the patients with liver cancer. There already exist many effective evaluation methods, but these ones have many disadvantages such as large trauma, complicated process and so on. Therefore, it is essential to develop a fast, accurate and simple detection method of liver functional reserve for the practical application in the clinical engineering field. According to the principle of spectrophotometry, this paper proposes a detection method of liver functional reserve based on three-wavelength from infrared light (IR) to near-infrared light (NIR), in which the artery pulse, the vein pulse and the move of tissue are taken into account. By using near-infrared photoelectric sensor technology and excreting experiment of indocyanine green, a minimally invasive, fast and simple testing equipment is designed in this paper. The testing result shows this equipment can greatly reduce the interference from human body and ambient, realize continuous and real-time detection of arterial degree of blood oxygen saturation and liver functional reserve.

Functions of autophagy in normal and diseased liver

PubMed Central

Czaja, Mark J.; Ding, Wen-Xing; Donohue, Terrence M.; Friedman, Scott L.; Kim, Jae-Sung; Komatsu, Masaaki; Lemasters, John J.; Lemoine, Antoinette; Lin, Jiandie D.; Ou, Jing-hsiung James; Perlmutter, David H.; Randall, Glenn; Ray, Ratna B.; Tsung, Allan; Yin, Xiao-Ming

2013-01-01

Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases. PMID:23774882

Platelets: No longer bystanders in liver disease

PubMed Central

Adams, David H.; Watson, Steve P.; Lalor, Patricia F.

2016-01-01

Growing lines of evidence recognize that platelets play a central role in liver homeostasis and pathobiology. Platelets have important roles at every stage during the continuum of liver injury and healing. These cells contribute to the initiation of liver inflammation by promoting leukocyte recruitment through sinusoidal endothelium. They can activate effector cells, thus amplifying liver damage, and by modifying the hepatic cellular and cytokine milieu drive both hepatoprotective and hepatotoxic processes. Conclusion: In this review we summarize how platelets drive such pleiotropic actions and attempt to reconcile the paradox of platelets being both deleterious and beneficial to liver function; with increasingly novel methods of manipulating platelet function at our disposal, we highlight avenues for future therapeutic intervention in liver disease. (Hepatology 2016;64:1774‐1784) PMID:26934463

Bioartificial liver: current status.

PubMed

Pless, G; Sauer, I M

2005-11-01

Liver failure remains a life-threatening syndrome. With the growing disparity between the number of suitable donor organs and the number of patients awaiting transplantation, efforts have been made to optimize the allocation of organs, to find alternatives to cadaveric liver transplantation, and to develop extracorporeal methods to support or replace the function of the failing organ. An extracorporeal liver support system has to provide the main functions of the liver: detoxification, synthesis, and regulation. The understanding that the critical issue of the clinical syndrome in liver failure is the accumulation of toxins not cleared by the failing liver led to the development of artificial filtration and adsorption devices (artificial liver support). Based on this hypothesis, the removal of lipophilic, albumin-bound substances, such as bilirubin, bile acids, metabolites of aromatic amino acids, medium-chain fatty acids, and cytokines, should be beneficial to the clinical course of a patient in liver failure. Artificial detoxification devices currently under clinical evaluation include the Molecular Adsorbent Recirculating System (MARS), Single-Pass Albumin Dialysis (SPAD), and the Prometheus system. The complex tasks of regulation and synthesis remain to be addressed by the use of liver cells (bioartificial liver support). The Extracorporeal Liver Assist Device (ELAD), HepatAssist, Modular Extracorporeal Liver Support system (MELS), and the Amsterdam Medical Center Bioartificial Liver (AMC-BAL) are bioartificial systems. This article gives a brief overview on these artificial and bioartificial devices and discusses remaining obstacles.

Preservation of Cell Structure, Metabolism, and Biotransformation Activity of Liver-On-Chip Organ Models by Hypothermic Storage.

PubMed

Gröger, Marko; Dinger, Julia; Kiehntopf, Michael; Peters, Frank T; Rauen, Ursula; Mosig, Alexander S

2018-01-01

The liver is a central organ in the metabolization of nutrition, endogenous and exogenous substances, and xenobiotic drugs. The emerging organ-on-chip technology has paved the way to model essential liver functions as well as certain aspects of liver disease in vitro in liver-on-chip models. However, a broader use of this technology in biomedical research is limited by a lack of protocols that enable the short-term preservation of preassembled liver-on-chip models for stocking or delivery to researchers outside the bioengineering community. For the first time, this study tested the ability of hypothermic storage of liver-on-chip models to preserve cell viability, tissue morphology, metabolism and biotransformation activity. In a systematic study with different preservation solutions, liver-on-chip function can be preserved for up to 2 d using a derivative of the tissue preservation solution TiProtec, containing high chloride ion concentrations and the iron chelators LK614 and deferoxamine, supplemented with polyethylene glycol (PEG). Hypothermic storage in this solution represents a promising method to preserve liver-on-chip function for at least 2 d and allows an easier access to liver-on-chip technology and its versatile and flexible use in biomedical research. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Role of Oxygen Free Radicals, Nitric Oxide and Mitochondria in Mediating Cardiac Alterations During Liver Cirrhosis Induced by Thioacetamide.

PubMed

Amirtharaj, G Jayakumar; Natarajan, Sathish Kumar; Pulimood, Anna; Balasubramanian, K A; Venkatraman, Aparna; Ramachandran, Anup

2017-04-01

Thioacetamide (TAA) administration is widely used for induction of liver cirrhosis in rats, where reactive oxygen radicals (ROS) and nitric oxide (NO) participate in development of liver damage. Cardiac dysfunction is an important complication of liver cirrhosis, but the role of ROS or NO in cardiac abnormalities during liver cirrhosis is not well understood. This was investigated in animals after TAA-induced liver cirrhosis and temporal changes in oxidative stress, NO and mitochondrial function in the heart evaluated. TAA induced elevation in cardiac levels of nitrate before development of frank liver cirrhosis, without gross histological alterations. This was accompanied by an early induction of P38 MAP kinase, which is influenced by ROS and plays an important signaling role for induction of iNOS. Increased nitrotyrosine, protein oxidation and lipid peroxidation in the heart and cardiac mitochondria, suggestive of oxidative stress, also preceded frank liver cirrhosis. However, compromised cardiac mitochondrial function with a decrease in respiratory control ratio and increased mitochondrial swelling was seen later, when cirrhosis was evident. In conclusion, TAA induces elevations in ROS and NO in the heart in parallel to early liver damage. This leads to later development of functional deficits in cardiac mitochondria after development of liver cirrhosis.

Postoperative Decrease in Platelet Counts Is Associated with Delayed Liver Function Recovery and Complications after Partial Hepatectomy.

PubMed

Takahashi, Kazuhiro; Kurokawa, Tomohiro; Oshiro, Yukio; Fukunaga, Kiyoshi; Sakashita, Shingo; Ohkohchi, Nobuhiro

2016-05-01

Peripheral platelet counts decrease after partial hepatectomy; however, the implications of this phenomenon are unclear. We assessed if the observed decrease in platelet counts was associated with postoperative liver function and morbidity (complications grade ≤ II according to the Clavien-Dindo classification). We enrolled 216 consecutive patients who underwent partial hepatectomy for primary liver cancers, metastatic liver cancers, benign tumors, and donor hepatectomy. We classified patients as either low or high platelet percentage (postoperative platelet count/preoperative platelet count) using the optimal cutoff value calculated by a receiver operating characteristic (ROC) curve analysis, and analyzed risk factors for delayed liver functional recovery and morbidity after hepatectomy. Delayed liver function recovery and morbidity were significantly correlated with the lowest value of platelet percentage based on ROC analysis. Using a cutoff value of 60% acquired by ROC analysis, univariate and multivariate analysis determined that postoperative lowest platelet percentage ≤ 60% was identified as an independent risk factor of delayed liver function recovery (odds ratio (OR) 6.85; P < 0.01) and morbidity (OR, 4.90; P < 0.01). Furthermore, patients with the lowest platelet percentage ≤ 60% had decreased postoperative prothrombin time ratio and serum albumin level and increased serum bilirubin level when compared with patients with platelet percentage ≥ 61%. A greater than 40% decrease in platelet count after partial hepatectomy was an independent risk factor for delayed liver function recovery and postoperative morbidity. In conclusion, the decrease in platelet counts is an early marker to predict the liver function recovery and complications after hepatectomy.

Physiological Ranges of Matrix Rigidity Modulate Primary Mouse Hepatocyte Function In Part Through Hepatocyte Nuclear Factor 4 Alpha

PubMed Central

Desai, Seema S.; Tung, Jason C.; Zhou, Vivian X.; Grenert, James P.; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M.; Chang, Tammy T.

2016-01-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of hepatic-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150Pa and increased to 1–6kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α) whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase (FAK). In addition, blockade of the Rho/Rho-associated protein kinase (ROCK) pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Conclusion Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/ROCK pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. PMID:26755329

Molecular regulation of urea cycle function by the liver glucocorticoid receptor.

PubMed

Okun, Jürgen G; Conway, Sean; Schmidt, Kathrin V; Schumacher, Jonas; Wang, Xiaoyue; de Guia, Roldan; Zota, Annika; Klement, Johanna; Seibert, Oksana; Peters, Achim; Maida, Adriano; Herzig, Stephan; Rose, Adam J

2015-10-01

One of the major side effects of glucocorticoid (GC) treatment is lean tissue wasting, indicating a prominent role in systemic amino acid metabolism. In order to uncover a novel aspect of GCs and their intracellular-receptor, the glucocorticoid receptor (GR), on metabolic control, we conducted amino acid and acylcarnitine profiling in human and mouse models of GC/GR gain- and loss-of-function. Blood serum and tissue metabolite levels were determined in Human Addison's disease (AD) patients as well as in mouse models of systemic and liver-specific GR loss-of-function (AAV-miR-GR) with or without dexamethasone (DEX) treatments. Body composition and neuromuscular and metabolic function tests were conducted in vivo and ex vivo, the latter using precision cut liver slices. A serum metabolite signature of impaired urea cycle function (i.e. higher [ARG]:[ORN + CIT]) was observed in human (CTRL: 0.45 ± 0.03, AD: 1.29 ± 0.04; p < 0.001) and mouse (AAV-miR-NC: 0.97 ± 0.13, AAV-miR-GR: 2.20 ± 0.19; p < 0.001) GC/GR loss-of-function, with similar patterns also observed in liver. Serum urea levels were consistently affected by GC/GR gain- (∼+32%) and loss (∼-30%) -of-function. Combined liver-specific GR loss-of-function with DEX treatment revealed a tissue-autonomous role for the GR to coordinate an upregulation of liver urea production rate in vivo and ex vivo, and prevent hyperammonaemia and associated neuromuscular dysfunction in vivo. Liver mRNA expression profiling and GR-cistrome mining identified Arginase I (ARG1) a urea cycle gene targeted by the liver GR. The liver GR controls systemic and liver urea cycle function by transcriptional regulation of ARG1 expression.

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

[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.

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

PubMed

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

2007-11-01

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

Effect of Liver Disease on Hepatic Transporter Expression and Function.

PubMed

Thakkar, Nilay; Slizgi, Jason R; Brouwer, Kim L R

2017-09-01

Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration and the European Medicines Evaluation Agency recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. Although extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma, human immunodeficiency virus infection, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and primary biliary cirrhosis are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Measurement of hepatic functional mass by means of 13C-methacetin and 13C-phenylalanine breath tests in chronic liver disease: Comparison with Child-Pugh score and serum bile acid levels

PubMed Central

Festi, D.; Capodicasa, S.; Sandri, L.; Colaiocco-Ferrante, L.; Staniscia, T.; Vitacolonna, E.; Vestito, A.; Simoni, P.; Mazzella, G.; Portincasa, P.; Roda, E.; Colecchia, A.

2005-01-01

AIM: To evaluate and compare the clinical usefulness of 13C-phenylalanine and 13C-methacetin breath tests in quantitating functional hepatic mass in patients with chronic liver disease and to further compare these results with those of conventional tests, Child-Pugh score and serum bile acid levels. METHODS: One hundred and forty patients (50 HCV- related chronic hepatitis, 90 liver cirrhosis patients) and 40 matched healthy controls were studied. Both breath test and routine liver test, serum levels of cholic and chenodeoxycholic acid conjugates were evaluated. RESULTS: Methacetin breath test, expressed as 60 min cumulative percent of oxidation, discriminated the hepatic functional capacity not only between controls and liver disease patients, but also between different categories of chronic liver disease patients. Methacetin breath test was correlated with liver function tests and serum bile acids. Furthermore, methacetin breath test, as well as serum bile acids, were highly predictive of Child-Pugh scores. The diagnostic power of phenylalanine breath test was always less than that of methacetin breath test. CONCLUSION: Methacetin breath test represents a safe and accurate diagnostic tool in the evaluation of hepatic functional mass in chronic liver disease patients. PMID:15609414

Lovastatin decreases mortality and improves liver functions in fulminant hepatic failure from 90% partial hepatectomy in rats.

PubMed

Cai, S R; Motoyama, K; Shen, K J; Kennedy, S C; Flye, M W; Ponder, K P

2000-01-01

Liver insufficiency occurs when the liver cannot perform critical functions such as ammonia metabolism, gluconeogenesis, or production of coagulation factors The hypothesis of this study was that decreased function of existing hepatocytes may contribute to hepatic failure, and that the function of these cells might be increased pharmacologically. Lovastatin is a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor that inhibits cholesterol biosynthesis and affects the activity of some signal transduction pathways and liver transcription factors. Changes in hepatic transcription factors during liver regeneration might result in decreased liver functions, and lovastatin might prevent these changes Rats received 90% partial hepatectomy (90% PH), and either lovastatin or vehicle alone daily. Survival and liver functions were assessed. Lovastatin increased survival to 58% (vs. 6% in controls that received 90% PH without drug), decreased the peak ammonia level to 427 microM (vs. 846 microM in controls), increased the nadir of glucose to 88 mg/dl (vs. 57 mg/dl in controls), decreased the peak prothrombin time to 23 s (vs 29 s in controls), and decreased the peak activated partial thromboplastin time to 29 s (vs. 39 s in controls). The full survival and metabolic benefits were observed when lovastatin was started at 30 min after 90% PH, but lovastatin was less efficacious when started at later times. Lovastatin increases the function of existing hepatocytes and might be used to improve liver function after extensive hepatic resection.

Chronic liver injury in mice promotes impairment of skin barrier function via tumor necrosis factor-alpha.

PubMed

Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

2016-09-01

Alcohol is frequently used to induce chronic liver injury in laboratory animals. Alcohol causes oxidative stress in the liver and increases the expression of inflammatory mediators that cause hepatocellular damage. However, during chronic liver injury, it is unclear if/how these liver-derived factors affect distal tissues, such as the skin. The purpose of this study was to evaluate skin barrier function during chronic liver injury. Hairless mice were administered 5% or 10% ethanol for 8 weeks, and damages to the liver and skin were assessed using histological and protein-analysis methods, as well as by detecting inflammatory mediators in the plasma. After alcohol administration, the plasma concentration of the aspartate and alanine aminotransferases increased, while albumin levels decreased. In mice with alcohol-induced liver injury, transepidermal water loss was significantly increased, and skin hydration decreased concurrent with ceramide and type I collagen degradation. The plasma concentrations of [Formula: see text]/[Formula: see text] and tumor necrosis factor-alpha (TNF-α) were significantly increased in mice with induced liver injury. TNF receptor (TNFR) 2 expression was upregulated in the skin of alcohol-administered mice, while TNFR1 levels remained constant. Interestingly, the impairment of skin barrier function in mice administered with 10% ethanol was ameliorated by administering an anti-TNF-α antibody. We propose a novel mechanism whereby plasma TNF-α, via TNFR2 alone or with TNFR1, plays an important role in skin barrier function during chronic liver disease in these mouse models.

Adipokines in Liver Cirrhosis.

PubMed

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

2017-06-29

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

Adipokines in Liver Cirrhosis

PubMed Central

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

2017-01-01

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

The Hepatic Response to Thermal Injury: Is the Liver Important for Postburn Outcomes?

PubMed Central

Jeschke, Marc G

2009-01-01

Thermal injury produces a profound hypermetabolic and hypercatabolic stress response characterized by increased endogenous glucose production via gluconeogenesis and glycogenolysis, lipolysis, and proteolysis. The liver is the central body organ involved in these metabolic responses. It is suggested that the liver, with its metabolic, inflammatory, immune, and acute phase functions, plays a pivotal role in patient survival and recovery by modulating multiple pathways following thermal injury. Studies have evaluated the role and function of the liver during the postburn response and showed that liver integrity and function are essential for survival, and that hepatic acute phase proteins are strong predictors for postburn survival. This review discusses these studies and delineates the pivotal role of the liver in patients following severe thermal injury. PMID:19603107

Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of nonalcoholic fatty liver disease

USDA-ARS?s Scientific Manuscript database

Obesity is often associated with a cluster of increased health risks collectively known as "Metabolic Syndrome" (MS). MS is often accompanied by development of fatty liver. Sometimes fatty liver results in damage leading to reduced liver function, and need for a transplant. This condition is known...

Approach to the patient with abnormal liver tests.

PubMed

Mahl, T C

1998-01-01

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

Iron homeostasis in the liver

PubMed Central

Anderson, Erik R; Shah, Yatrik M

2014-01-01

Iron is an essential nutrient that is tightly regulated. A principal function of the liver is the regulation of iron homeostasis. The liver senses changes in systemic iron requirements and can regulate iron concentrations in a robust and rapid manner. The last 10 years have led to the discovery of several regulatory mechanisms in the liver which control the production of iron regulatory genes, storage capacity, and iron mobilization. Dysregulation of these functions leads to an imbalance of iron, which is the primary causes of iron-related disorders. Anemia and iron overload are two of the most prevalent disorders worldwide and affect over a billion people. Several mutations in liver-derived genes have been identified, demonstrating the central role of the liver in iron homeostasis. During conditions of excess iron, the liver increases iron storage and protects other tissues, namely the heart and pancreas from iron-induced cellular damage. However, a chronic increase in liver iron stores results in excess reactive oxygen species production and liver injury. Excess liver iron is one of the major mechanisms leading to increased steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. PMID:23720289

Living Donor Liver Transplantation Using a Liver Graft With Congenital Intrahepatic Portosystemic Shunt

PubMed Central

Kamei, Hideya; Imai, Hisashi; Onishi, Yasuharu; Sugimoto, Hiroyuki; Suzuki, Kojiro; Ogura, Yasuhiro

2016-01-01

Background Despite of recent development of imaging modalities, congenital intrahepatic portosystemic shunt (IPSS) is rarely diagnosed. Therefore, living donor liver transplantation using a liver graft with IPSS has not been previously published. Materials and Methods We report a 28-year-old male patient with end-stage liver disease secondary to Wilson disease. His 26-year-old brother was a potential living donor, who had an IPSS of 25 mm in diameter at segment 6 as shown by computed tomography. Liver function tests were normal, and blood ammonia concentration was in the upper limit of normal. Results Living donor liver transplantation was uneventfully performed. After surgery, a recipient liver function tests showed a quick recovery, and serum ammonia levels were consistently normal. Although thrombosis inside the IPSS was confirmed by computed tomography on postoperative day 21, this thrombosis disappeared at 3 months posttransplant with anticoagulants. Currently (12 months posttransplant), the patient has fully recovered, and the IPSS is still the same size. Conclusions Based on our experience, liver allografts with IPSS can be accepted as potential liver allografts. PMID:27500240

Regional metabolic liver function measured in patients with cirrhosis by 2-[¹⁸F]fluoro-2-deoxy-D-galactose PET/CT.

PubMed

Sørensen, Michael; Mikkelsen, Kasper S; Frisch, Kim; Villadsen, Gerda E; Keiding, Susanne

2013-06-01

There is a clinical need for methods that can quantify regional hepatic function non-invasively in patients with cirrhosis. Here we validate the use of 2-[(18)F]fluoro-2-deoxy-d-galactose (FDGal) PET/CT for measuring regional metabolic function to this purpose, and apply the method to test the hypothesis of increased intrahepatic metabolic heterogeneity in cirrhosis. Nine cirrhotic patients underwent dynamic liver FDGal PET/CT with blood samples from a radial artery and a liver vein. Hepatic blood flow was measured by indocyanine green infusion/Fick's principle. From blood measurements, hepatic systemic clearance (Ksyst, Lblood/min) and hepatic intrinsic clearance (Vmax/Km, Lblood/min) of FDGal were calculated. From PET data, hepatic systemic clearance of FDGal in liver parenchyma (Kmet, mL blood/mL liver tissue/min) was calculated. Intrahepatic metabolic heterogeneity was evaluated in terms of coefficient-of-variation (CoV, %) using parametric images of Kmet. Mean approximation of Ksyst to Vmax/Km was 86% which validates the use of FDGal as PET tracer of hepatic metabolic function. Mean Kmet was 0.157 mL blood/mL liver tissue/min, which was lower than 0.274 mL blood/mL liver tissue/min, previously found in healthy subjects (p<0.001), in accordance with decreased metabolic function in cirrhotic livers. Mean CoV for Kmet in liver tissue was 24.4% in patients and 14.4% in healthy subjects (p<0.0001). The degree of intrahepatic metabolic heterogeneity correlated positively with HVPG (p<0.05). A 20-min dynamic FDGal PET/CT with arterial sampling provides an accurate measure of regional hepatic metabolic function in patients with cirrhosis. This is likely to have clinical implications for the assessment of patients with liver disease as well as treatment planning and monitoring. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Study of Abnormal Liver Function Test during Pregnancy in a Tertiary Care Hospital in Chhattisgarh.

PubMed

Mishra, Nalini; Mishra, V N; Thakur, Parineeta

2016-10-01

Abnormal liver function tests (LFTs) in pregnancy require proper interpretation in order to avoid pitfalls in the diagnosis. The underlying disorder can have a significant effect on the outcome of both mother and foetus. The present study was done with the objective to study the clinical profile, incidence and possible causes of derangements of liver function tests. Eighty pregnant women with abnormal liver dysfunction were studied prospectively. Women with chronic liver disease and drug-induced abnormal liver function test were excluded. All available LFTs including LDH were studied along with some more definitive tests to aid identification of underlying cause. Foetomaternal outcome was noted in all. The incidence of abnormal LFT was 0.9 %. 13/80 (16.75 %) women had liver disorder not specific to pregnancy, whereas 67/80 (83.25 %) women had pregnancy-specific liver dysfunction. Of these, 65(81.25 %) women with liver dysfunction had pre-eclampsia including 11 (13.75 %) with HELLP and six women with eclampsia. 48/65 (60 %) women had pre-eclampsia in the absence of HELLP syndrome or eclampsia. The mean value for bilirubin (mg %) in hypertensive disorders of pregnancy ranged from 1.64 to 3.8, between 5 and 10 for ICP and AFLP and >10 in infective hepatitis. Transaminases were highest in infective hepatitis, whereas alkaline phosphate was highest in ICP. Total 27 (33.75 %) women suffered from adverse outcome with four (5 %) maternal deaths and 23 (28.75 %) major maternal morbidities. 33/80 (41.25 %) women had intrauterine death. 26.25 % babies were small for date. Pregnancy-specific disorders are the leading cause of abnormal liver function test during pregnant state particularly in the third trimester. Pre-eclampsia-related disorder is the commonest. Gestational age of pregnancy and relative values of various liver function tests in different pregnancy-specific and pregnancy nonspecific disorders appear to be the best guide to clinch the diagnosis.

Prevalence and factors associated with the presence of abnormal function liver tests in patients with ulcerative colitis.

PubMed

Yamamoto-Furusho, Jesús K; Sánchez-Osorio, Magdalena; Uribe, Misael

2010-01-01

To investigate the prevalence of abnormal function liver tests and risk factors associated with their development in Mexican patients with UC. A total of 200 patients with confirmed diagnosis of UC were evaluated prospectively during a one year period from January 1, 2007 to December 31, 2008. A total of 94 females and 106 males patients with UC were analyzed. The age at diagnosis was 31.4 ± 13.2 years and the mean of disease duration was 6.7 ± 5.2 years. We found a high prevalence of abnormal function livers tests in 40% of UC patients. The pattern of abnormal function liver test was hepatitis in 70%, cholestatic (20%) and mixed (10%). The most common cause of abnormal function liver test was transient elevation in 50 patients (63%) followed by fatty liver disease (11.2%), primary sclerosing cholangitis (6.3%), drug-toxicity (6%) and others (13.5%) including chronic hepatitis C, total parenteral nutrition, granulomatous and ischemic hepatitis. In the multivariate logistic regression model, active disease, colectomy and abdominal sepsis were factors that persisted associated with the development of abnormal liver tests in UC patients. A high prevalence of abnormal function liver tests (40%) was found in Mexican UC patients is likely to be related to active disease, colectomy and the presence of sepsis.

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.

Functional hepatocyte clusters on bioactive blend silk matrices towards generating bioartificial liver constructs.

PubMed

Janani, G; Nandi, Samit K; Mandal, Biman B

2018-02-01

The creation of in vitro functional hepatic tissue simulating micro-environmental niche of native liver is a keen area of research due to its demand in bioartificial liver (BAL) and cell-based tissue engineering. Here, we investigated the potential of novel blend (BA) silk scaffold fabricated by blending mulberry (Bombyx mori, BM) silk fibroin with cell adhesion motif (RGD) rich non-mulberry (Antheraea assamensis, AA) silk fibroin, in generating a functional liver construct. Three-dimensional (3D) porous silk scaffolds (BM, AA and BA) were physico-chemically characterized and functionally evaluated using human hepatocarcinoma cells (HepG2) and primary neonatal rat hepatocytes. The growth and distribution of hepatocytes within the scaffolds were tracked by FESEM, alamar blue proliferation assay and live/dead staining. Hemocompatible BA scaffolds supported the formation of high density hepatocyte clusters, facilitating cell-matrix and cell-cell interactions. Blend scaffolds evinced enhanced liver-specific functions of cultured hepatocytes in terms of albumin synthesis, urea synthesis and cytochrome P450 enzyme activity over 21 days. Subcutaneous implantation of scaffolds demonstrated minimal macrophage infiltration in blend scaffolds. These findings substantiate that the integral property of blend (BA) scaffold offers a befitting environment by influencing spheroidal growth of hepatocytes with enhanced biological activity. Collectively, the present study provides a new 3D bio-matrix niche for growing functional liver cells that would have future prospects in BAL as well as regenerative medicine. An end stage liver disease called cirrhosis perturbs the self-healing ability and physiological functions of liver. Due to the scarcity of healthy donors, a functional in vitro hepatic construct retaining the liver-specific functions is in great demand for its prospects in bioartificial liver (BAL) and cell-based tissue engineering. Physicochemical attributes of a matrix influence the behavior of cultured hepatocytes in terms of attachment, morphology and functionality. Mulberry and non-mulberry silk fibroin presents unique amino acid sequence with difference in hydrophobicity and crystallinity. Considering this, the present study focuses on the development of a suitable three-dimensional (3D) bioactive matrix incorporating both mulberry silk fibroin and cell adhesion motif (RGD) rich non-mulberry silk fibroin. Porous silk blend scaffolds facilitated the formation of hepatocyte clusters with enhanced liver-specific functions emphasizing both cell-cell and cell-matrix interactions. Hemocompatibility and integral property of blend scaffolds offers a biological niche for seeding functional liver cells that would have future prospects in biohybrid devices. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

TU-F-12A-04: Differential Radiation Avoidance of Functional Liver Regions Defined by 99mTc-Sulfur Colloid SPECT/CT with Proton Therapy

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

Bowen, S; Miyaoka, R; Kinahan, P

2014-06-15

Purpose: Radiotherapy for hepatocellular carcinoma patients is conventionally planned without consideration of spatial heterogeneity in hepatic function, which may increase risk of radiation-induced liver disease. Pencil beam scanning (PBS) proton radiotherapy (pRT) plans were generated to differentially decrease dose to functional liver volumes (FLV) defined on [{sup 99m}Tc]sulfur colloid (SC) SPECT/CT images (functional avoidance plans) and compared against conventional pRT plans. Methods: Three HCC patients underwent SC SPECT/CT scans for pRT planning acquired 15 min post injection over 24 min. Images were reconstructed with OSEM following scatter, collimator, and exhale CT attenuation correction. Functional liver volumes (FLV) were defined bymore » liver:spleen uptake ratio thresholds (43% to 90% maximum). Planning objectives to FLV were based on mean SC SPECT uptake ratio relative to GTV-subtracted liver and inversely scaled to mean liver dose of 20 Gy. PTV target coverage (V{sub 95}) was matched between conventional and functional avoidance plans. PBS pRT plans were optimized in RayStation for single field uniform dose (SFUD) and systematically perturbed to verify robustness to uncertainty in range, setup, and motion. Relative differences in FLV DVH and target dose heterogeneity (D{sub 2}-D{sub 98})/D50 were assessed. Results: For similar liver dose between functional avoidance and conventional PBS pRT plans (D{sub mean}≤5% difference, V{sub 18Gy}≤1% difference), dose to functional liver volumes were lower in avoidance plans but varied in magnitude across patients (FLV{sub 70%max} D{sub mean}≤26% difference, V{sub 18Gy}≤8% difference). Higher PTV dose heterogeneity in avoidance plans was associated with lower functional liver dose, particularly for the largest lesion [(D{sub 2}-D{sub 98})/D{sub 50}=13%, FLV{sub 90%max}=50% difference]. Conclusion: Differential avoidance of functional liver regions defined on sulfur colloid SPECT/CT is feasible with proton therapy. The magnitude of benefit appears to be patient specific and dependent on tumor location, size, and proximity to functional volumes. Further investigation in a larger cohort of patients may validate the clinical utility of functional avoidance planning of HCC radiotherapy.« less

Prolonged Ischemia Triggers Necrotic Depletion of Tissue Resident Macrophages to Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury

PubMed Central

Yue, Shi; Zhou, Haoming; Wang, Xuehao; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.; Zhai, Yuan

2017-01-01

Although mechanisms of immune activation against liver ischemia reperfusion injury (IRI) have been studied extensively, questions regarding liver resident macrophages, i.e., Kupffer cells, remain controversial. Recent progress in the biology of tissue resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver resident vs. infiltrating macrophages by fluorescence-activated cell sorting (FACS) and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages (iMØ), but also necrotic depletion of KCs. Inhibition of Receptor Interacting Protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induce depletion, resulting in the reduction of iMØ infiltration, suppression of pro-inflammatory immune activation and protection of livers from IRI. The depletion of KCs by clodronate-liposomes abrogated these effects of Nec-1s. Additionally, liver reconstitutions with KCs post-ischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, i.e., RIP-1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI. PMID:28289160

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.

LncMAPK6 drives MAPK6 expression and liver TIC self-renewal.

PubMed

Huang, Guanqun; Jiang, Hui; He, Yueming; Lin, Ye; Xia, Wuzheng; Luo, Yuanwei; Liang, Min; Shi, Boyun; Zhou, Xinke; Jian, Zhixiang

2018-05-15

Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn't been explored. Online-available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH. Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression. MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation.

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

PubMed

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

2018-06-01

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

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

PubMed

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

2017-01-01

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

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

PubMed

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

2018-01-01

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

Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease.

PubMed

Bell, Catherine C; Hendriks, Delilah F G; Moro, Sabrina M L; Ellis, Ewa; Walsh, Joanne; Renblom, Anna; Fredriksson Puigvert, Lisa; Dankers, Anita C A; Jacobs, Frank; Snoeys, Jan; Sison-Young, Rowena L; Jenkins, Rosalind E; Nordling, Åsa; Mkrtchian, Souren; Park, B Kevin; Kitteringham, Neil R; Goldring, Christopher E P; Lauschke, Volker M; Ingelman-Sundberg, Magnus

2016-05-04

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI.

Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

PubMed Central

Bell, Catherine C.; Hendriks, Delilah F. G.; Moro, Sabrina M. L.; Ellis, Ewa; Walsh, Joanne; Renblom, Anna; Fredriksson Puigvert, Lisa; Dankers, Anita C. A.; Jacobs, Frank; Snoeys, Jan; Sison-Young, Rowena L.; Jenkins, Rosalind E.; Nordling, Åsa; Mkrtchian, Souren; Park, B. Kevin; Kitteringham, Neil R.; Goldring, Christopher E. P.; Lauschke, Volker M.; Ingelman-Sundberg, Magnus

2016-01-01

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI. PMID:27143246

Weight loss and severe jaundice in a patient with hyperthyroidism.

PubMed

Breidert, M; Offensperger, S; Blum, H E; Fischer, R

2011-09-01

Thyrotoxicosis may significantly alter hepatic function and is associated with autoimmune disorders of the liver. We report the case of a thyrotoxic patient with Graves' disease and histologically established cholestatic hepatitis. Medical treatment of hyperthyroidism normalized liver function tests. In patients with elevated liver function parameters and jaundice of unknown origin, thyroid function should generally be tested. Moreover, medical treatment of hyperthyroidism with thyrostatics may cause severe hepatitis whereas untreated hyperthyroid patients are at risk of developing chronic liver failure. © Georg Thieme Verlag KG Stuttgart · New York.

HEPATIC FUNCTION AFTER GENETICALLY-ENGINEERED PIG LIVER TRANSPLANTATION IN BABOONS

PubMed Central

Ekser, Burcin; Echeverri, Gabriel J.; Hassett, Andrea Cortese; Yazer, Mark H.; Long, Cassandra; Meyer, Michael; Ezzelarab, Mohamed; Lin, Chih Che; Hara, Hidetaka; van der Windt, Dirk J.; Dons, Eefje M.; Phelps, Carol; Ayares, David; Cooper, David K.C.; Gridelli, Bruno

2010-01-01

Background If ‘bridging’ to allotransplantation is to be achieved by a pig liver xenograft, adequate hepatic function needs to be assured. Methods We have studied hepatic function in baboons after transplantation of livers from α1,3-galactosyltransferase gene-knockout (GTKO,n=1) or GTKO pigs transgenic for CD46 (GTKO/CD46,n=5). Monitoring was by liver function tests and coagulation parameters. Pig-specific proteins in the baboon serum/plasma were identified by Western blot. In 4 baboons, coagulation factors were measured. The results were compared with values from healthy humans, baboons, and pigs. Results Recipient baboons died or were euthanized after 4-7 days following internal bleeding associated with profound thrombocytopenia. However, parameters of liver function, including coagulation, remained in the near-normal range, except for some cholestasis. Western blot demonstrated that pig proteins (albumin, fibrinogen, haptoglobin, plasminogen) were produced by the liver from day 1. Production of several pig coagulation factors was confirmed. Conclusions After the transplantation of genetically-engineered pig livers into baboons (1) many parameters of hepatic function, including coagulation, were normal or near-normal; (2) there was evidence for production of pig proteins, including coagulation factors, and (3) these appeared to function adequately in baboons, though inter-species compatibility of such proteins remains to be confirmed. PMID:20606605

Cell Patterning for Liver Tissue Engineering via Dielectrophoretic Mechanisms

PubMed Central

Yahya, Wan Nurlina Wan; Kadri, Nahrizul Adib; Ibrahim, Fatimah

2014-01-01

Liver transplantation is the most common treatment for patients with end-stage liver failure. However, liver transplantation is greatly limited by a shortage of donors. Liver tissue engineering may offer an alternative by providing an implantable engineered liver. Currently, diverse types of engineering approaches for in vitro liver cell culture are available, including scaffold-based methods, microfluidic platforms, and micropatterning techniques. Active cell patterning via dielectrophoretic (DEP) force showed some advantages over other methods, including high speed, ease of handling, high precision and being label-free. This article summarizes liver function and regenerative mechanisms for better understanding in developing engineered liver. We then review recent advances in liver tissue engineering techniques and focus on DEP-based cell patterning, including microelectrode design and patterning configuration. PMID:24991941

Mitochondrial DNA Unwinding Enzyme Required for Liver Regeneration | Center for Cancer Research

Cancer.gov

The liver has an exceptional capacity to proliferate. This ability allows the liver to regenerate its mass after partial surgical removal or injury and is the key to successful partial liver transplants. Liver cells, called hepatocytes, are packed with mitochondria, and regulating mitochondrial DNA (mtDNA) copy number is crucial to mitochondrial function, including energy

Chemical Selection Via In Vitro-In Vivo Correlation of ToxCast and ToxRefDB Data to Evaluate the Virtual Liver

EPA Science Inventory

The Virtual Liver Project (v-LiverTM) is a US EPA effort to simulate the function of the human liver with sufficient accuracy to predict how environmental exposure to xenobiotic compounds will perturb homeostasis. The better we understand the liver, the better we will understand...

Liv and Lucky in Liverland. . . Color Us Healthy! A Workbook about Your Liver = Un Cuaderno de trabajo sobre tu higado.

ERIC Educational Resources Information Center

1995

This workbook/coloring book, on the liver and good health is designed for primary school students. The 21 line drawings illustrate different aspects of liver function, maintaining a healthy liver, and preventing liver disease. Each page is captioned in both English and Spanish. (ND)

Efficient and Controlled Generation of 2D and 3D Bile Duct Tissue from Human Pluripotent Stem Cell-Derived Spheroids.

PubMed

Tian, Lipeng; Deshmukh, Abhijeet; Ye, Zhaohui; Jang, Yoon-Young

2016-08-01

While in vitro liver tissue engineering has been increasingly studied during the last several years, presently engineered liver tissues lack the bile duct system. The lack of bile drainage not only hinders essential digestive functions of the liver, but also leads to accumulation of bile that is toxic to hepatocytes and known to cause liver cirrhosis. Clearly, generation of bile duct tissue is essential for engineering functional and healthy liver. Differentiation of human induced pluripotent stem cells (iPSCs) to bile duct tissue requires long and/or complex culture conditions, and has been inefficient so far. Towards generating a fully functional liver containing biliary system, we have developed defined and controlled conditions for efficient 2D and 3D bile duct epithelial tissue generation. A marker for multipotent liver progenitor in both adult human liver and ductal plate in human fetal liver, EpCAM, is highly expressed in hepatic spheroids generated from human iPSCs. The EpCAM high hepatic spheroids can, not only efficiently generate a monolayer of biliary epithelial cells (cholangiocytes), in a 2D differentiation condition, but also form functional ductal structures in a 3D condition. Importantly, this EpCAM high spheroid based biliary tissue generation is significantly faster than other existing methods and does not require cell sorting. In addition, we show that a knock-in CK7 reporter human iPSC line generated by CRISPR/Cas9 genome editing technology greatly facilitates the analysis of biliary differentiation. This new ductal differentiation method will provide a more efficient method of obtaining bile duct cells and tissues, which may facilitate engineering of complete and functional liver tissue in the future.

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.

Mitochondrial DNA Unwinding Enzyme Required for Liver Regeneration | Center for Cancer Research

Cancer.gov

The liver has an exceptional capacity to proliferate. This ability allows the liver to regenerate its mass after partial surgical removal or injury and is the key to successful partial liver transplants. Liver cells, called hepatocytes, are packed with mitochondria, and regulating mitochondrial DNA (mtDNA) copy number is crucial to mitochondrial function, including energy production, during proliferation. Yves Pommier, M.D., Ph.D., of CCR’s Developmental Therapeutics Branch, and his colleagues recently showed that the vertebrate mitochondrial topoisomerase, Top1mt, was critical in maintaining mitochondrial function in the heart after doxorubicin-induced damage. The group wondered whether Top1mt might play a similar role in liver regeneration.

Drug Metabolism, Drug Interactions, and Drug-Induced Liver Injury in Living Donor Liver Transplant Patients.

PubMed

Ganesh, Swaytha; Almazroo, Omar Abdulhameed; Tevar, Amit; Humar, Abhinav; Venkataramanan, Raman

2017-02-01

Living donor liver transplant (LDLT) fills a critically needed gap in the number of livers available for transplant. However, little is known about the functional recovery of the liver in the donor and in the recipient after surgery. Given that both donor and recipients are treated with several drugs, it is important to characterize the time course of recovery of hepatic synthetic, metabolic, and excretory function in these patients. In the absence of data from LDLT, information on the effect of liver disease on the pharmacokinetics of medications can be used as guidance for drug dosing in LDLT patients. Copyright © 2016 Elsevier Inc. All rights reserved.

CD11c identifies a subset of murine liver natural killer cells that responds to adenoviral hepatitis

PubMed Central

Burt, Bryan M.; Plitas, George; Stableford, Jennifer A.; Nguyen, Hoang M.; Bamboat, Zubin M.; Pillarisetty, Venu G.; DeMatteo, Ronald P.

2008-01-01

The liver contains a unique repertoire of immune cells and a particular abundance of NK cells. We have found that CD11c defines a distinct subset of NK cells (NK1.1+CD3−) in the murine liver whose function was currently unknown. In naïve animals, CD11c+ liver NK cells displayed an activated phenotype and possessed enhanced effector functions when compared with CD11c− liver NK cells. During the innate response to adenovirus infection, CD11c+ NK cells were the more common IFN-γ-producing NK cells in the liver, demonstrated enhanced lytic capability, and gained a modest degree of APC function. The mechanism of IFN-γ production in vivo depended on TLR9 ligation as well as IL-12 and -18. Taken together, our findings demonstrate that CD11c+ NK cells are a unique subset of NK cells in the murine liver that contribute to the defense against adenoviral hepatitis. PMID:18664530

Sexual dysfunction after liver transplantation.

PubMed

Burra, Patrizia

2009-11-01

1. The goal of liver transplantation is not only to ensure the survival of patients but also to offer patients the opportunity to achieve a good balance between the functional efficacy of the graft and their psychological and physical integrity. The quality of life after transplantation may be affected by unsatisfactory sexual activity and reproductive performance. 2. Sexual dysfunction and sex hormone disturbances are widely reported in men and women with chronic liver disease before liver transplantation. 3. Successful liver transplantation should lead to improvements in sexual function and sex hormone disturbances in both men and women, therefore improving reproductive performance, but immunosuppressive drugs may interfere with hormone metabolism. 4. Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy, but fetal and maternal outcomes should be regularly assessed. 5. More detailed and comprehensive data are needed in the field of sexual function after transplantation, and new strategies are needed to support and inform patients on the waiting list and after liver transplantation. (c) 2009 AASLD.

Starring role of toll-like receptor-4 activation in the gut-liver axis

PubMed Central

Carotti, Simone; Guarino, Michele Pier Luca; Vespasiani-Gentilucci, Umberto; Morini, Sergio

2015-01-01

Since the introduction of the term “gut-liver axis”, many studies have focused on the functional links of intestinal microbiota, barrier function and immune responses to liver physiology. Intestinal and extra-intestinal diseases alter microbiota composition and lead to dysbiosis, which aggravates impaired intestinal barrier function via increased lipopolysaccharide translocation. The subsequent increased passage of gut-derived product from the intestinal lumen to the organ wall and bloodstream affects gut motility and liver biology. The activation of the toll-like receptor 4 (TLR-4) likely plays a key role in both cases. This review analyzed the most recent literature on the gut-liver axis, with a particular focus on the role of TLR-4 activation. Findings that linked liver disease with dysbiosis are evaluated, and links between dysbiosis and alterations of intestinal permeability and motility are discussed. We also examine the mechanisms of translocated gut bacteria and/or the bacterial product activation of liver inflammation and fibrogenesis via activity on different hepatic cell types. PMID:26600967

Modeling liver physiology: combining fractals, imaging and animation.

PubMed

Lin, Debbie W; Johnson, Scott; Hunt, C Anthony

2004-01-01

Physiological modeling of vascular and microvascular networks in several key human organ systems is critical for a deeper understanding of pharmacology and the effect of pharmacotherapies on disease. Like the lung and the kidney, the morphology of its vascular and microvascular system plays a major role in its functional capability. To understand liver function in absorption and metabolism of food and drugs, one must examine the morphology and physiology at both higher and lower level liver function. We have developed validated virtualized dynamic three dimensional (3D) models of liver secondary units and primary units by combining a number of different methods: three-dimensional rendering, fractals, and animation. We have simulated particle dynamics in the liver secondary unit. The resulting models are suitable for use in helping researchers easily visualize and gain intuition on results of in silico liver experiments.

[Kidney function and liver transplantation].

PubMed

Gámán, György; Gelley, Fanni; Gerlei, Zsuzsa; Dabasi, Eszter; Görög, Dénes; Fehérvári, Imre; Kóbori, László; Lengyel, Gabriella; Zádori, Gergely; Fazakas, János; Doros, Attila; Sárváry, Enikő; Nemes, Balázs

2013-06-30

In liver cirrhosis renal function decreases as well. Hepatorenal syndrome is the most frequent cause of the decrease, but primary kidney failure, diabetes mellitus and some diseases underlying endstage liver failure (such as hepatitis C virus infection) can also play an important role. In liver transplantation several further factors (total cross-clamping of vena cava inferior, polytransfusion, immunosuppression) impair the renal function, too. The aim of this study was to analyse the changes in kidney function during the first postoperative year after liver transplantation. Retrospective data analysis was performed after primary liver transplantations (n = 319). impaired preoperative renal function increased the devepolment of postoperative complications and the first year cumulative patient survival was significantly worse (91,7% vs 69,9%; p<0,001) in this group. If renal function of the patients increased above 60 ml/min/1,73 m2 after the first year, patient survival was better. Independently of the preoperative kidney function, 76% of the patients had impaired kidney function at the first postoperative year. In this group, de novo diabetes mellitus was more frequently diagnosed (22,5% vs 9,5%; p = 0,023). Selection of personalized immunosuppressive medication has a positive effect on renal function.

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.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein evaluates liver function and predicts prognosis in liver cirrhosis.

PubMed

Xu, Wen Ping; Wang, Ze Rui; Zou, Xia; Zhao, Chen; Wang, Rui; Shi, Pei Mei; Yuan, Zong Li; Yang, Fang; Zeng, Xin; Wang, Pei Qin; Sultan, Sakhawat; Zhang, Yan; Xie, Wei Fen

2018-04-01

Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA + -M2BP) is a novel glycobiomarker for evaluating liver fibrosis, but less is known about its role in liver cirrhosis (LC). This study aimed to investigate the utility of WFA + -M2BP in evaluating liver function and predicting prognosis of cirrhotic patients. We retrospectively included 197 patients with LC between 2013 and 2016. Serum WFA + -M2BP and various biochemical parameters were measured in all patients. With a median follow-up of 23 months, liver-related complications and deaths of 160 patients were recorded. The accuracy of WFA + -M2BP in evaluating liver function, predicting decompensation and mortality were measured by the receiver operating characteristic (ROC) curve, logistic and Cox's regression analyses, respectively. WFA + -M2BP levels increased with elevated Child-Pugh classification, especially in patients with hepatitis B virus (HBV) infection. ROC analysis confirmed the high reliability of WFA + -M2BP for the assessment of liver function using Child-Pugh classification. WFA + -M2BP was also significantly positively correlated with the model for end-stage liver disease (MELD) score. Multivariate logistic regression analysis indicated WFA + -M2BP as an independent predictor of clinical decompensation for compensated patients (odds ratio 11.958, 95% confidence interval [CI] 1.876-76.226, P = 0.009), and multivariate Cox's regression analysis verified WFA + -M2BP as an independent risk factor for liver-related death in patients with HBV infection (hazards ratio 10.596, 95% CI 1.356-82.820, P = 0.024). Serum WFA + -M2BP is a reliable predictor of liver function and prognosis in LC and could be incorporated into clinical surveillance strategies for LC patients, especially those with HBV infection. © 2018 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells

PubMed Central

Werner, Melanie; Driftmann, Sabrina; Kleinehr, Kathrin; Kaiser, Gernot M.; Mathé, Zotlan; Treckmann, Juergen-Walter; Paul, Andreas; Skibbe, Kathrin; Timm, Joerg; Canbay, Ali; Gerken, Guido; Schlaak, Joerg F.; Broering, Ruth

2015-01-01

Background & Aims Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen. Methods Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity. Results Cell preparation yielded the following cell counts per gram of liver tissue: 2.0±0.4×107 hepatocytes, 1.8±0.5×106 Kupffer cells, 4.3±1.9×105 liver sinusoidal endothelial cells, and 3.2±0.5×105 stellate cells. Hepatocytes were identified by albumin (95.5±1.7%) and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5±1.2%) and exhibited phagocytic activity, as determined with 1μm latex beads. Endothelial cells were CD146+ (97.8±1.1%) and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1±1.5%). These cells further exhibited retinol (vitamin A)-mediated autofluorescence. Conclusions Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease. PMID:26407160

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.

Growth hormone and drug metabolism. Acute effects on microsomal mixed-function oxidase activities in rat liver.

PubMed Central

Wilson, J T; Spelsberg, T C

1976-01-01

Adult male rats were subjected either to sham operation or to hypophysectomy and adrenalectomy and maintained for a total of 10 days before treatment with growth hormone. Results of the early effects of growth hormone on the activities of the mixed-function oxidases in rat liver over a 96h period after growth-hormone treatment are presented. 2. Hypophysectomy and adrenalectomy result in decreased body and liver weight and decreased drug metabolism (mixed-function oxidases). Concentrations of electron-transport-system components are also decreased. 3. In the hypophysectomized/adrenalectomized rats, growth hormone decreases the activities of the liver mixed-function oxidases and the cytochrome P-450 and cytochrome c reductases, as well as decreasing the concentration of cytochrome P-450 compared with that of control rats. Similar but less dramatic results are obtained with sham-operated rats. 4. It is concluded that whereas growth hormone enhances liver growth, including induction of many enzyme activities, it results in a decrease in mixed-function oxidase activity. Apparently, mixed-function oxidase activity decreases in liver when growth (mitogenesis) increases. PMID:938458

Liver metabolomics analysis associated with feed efficiency on steers

USDA-ARS?s Scientific Manuscript database

The liver represents a metabolic crossroad regulating and modulating nutrients available from digestive tract absorption to the peripheral tissues. To identify potential differences in liver function that lead to differences in feed efficiency, liver metabolomic analysis was conducted using ultra-pe...

Fibroblast growth factor (Fgf) signaling pathway regulates liver homeostasis in zebrafish.

PubMed

Tsai, Su-Mei; Liu, Da-Wei; Wang, Wen-Pin

2013-04-01

In mammals, fibroblast growth factor (FGF) signaling controls liver specification and regulates the metabolism of lipids, cholesterol, and bile acids. FGF signaling also promotes hepatocyte proliferation, and helps detoxify hepatotoxin during liver regeneration after partial hepatectomy. However, the function of Fgf in zebrafish liver is not yet well understood, specifically for postnatal homeostasis. The current study analyzed the expression of fgf receptors (fgfrs) in the liver of zebrafish. We then investigated the function of Fgf signaling in the zebrafish liver by expressing a dominant-negative Fgf receptor in hepatocytes (lfabp:dnfgfr1-egfp, lf:dnfr). Histological analysis showed that our genetic intervention resulted in a small liver size with defected medial expansion of developing livers in transgenic (Tg) larvae. Morphologically, the liver lobe of lf:dnfr adult fish was shorter than that of control. Ballooning degeneration of hepatocytes was observed in fish as young as 3 months. Further examination revealed the development of hepatic steatosis and cholestasis. In adult Tg fish, we unexpectedly observed increased liver-to-body-weight ratios, with higher percentages of proliferating hepatocytes. Considering all these findings, we concluded that as in mammals, in adult zebrafish the metabolism of lipid and bile acids in the liver are regulated by Fgf signaling. Disruption of the Fgf signal-mediated metabolism might indirectly affect hepatocyte proliferation.

Simulation and experimental research on micro-channel for detecting cell status in bio-artificial liver.

PubMed

Wu, Changzhe; Cao, Yue; Huo, Xiaolin; Li, Ming

2015-01-01

Bioartificial liver support system (BALSS) based on culturing hepatocytes is an important research field for the treatment of acute liver failure. It is necessary to monitor the state of liver cell functions during the treatment of BALSS in order to guide clinical treatment. To design a micro-channel chip to achieve flash mixing for timely detection of liver cell status in bioreactors and improving liver cells growth environment to ensure the efficacy of the bio-artificial liver support system. Alanine aminotransferase (ALT) and Urea are chosen as detection indicators to reflect the degree of liver cell injury and the detoxification function. A diamond tandem structure micro-channel is designed and optimized to achieve the efficient mixing of serum and ALT or Urea reagent. The simulation and experimental results show that the diamond tandem structure micro-channel can significantly improve the mixing efficiency and meet the online detecting requirements. The easily controllable diamond tandem structure micro-channel combines the advantages of active and passive mixer and can effectively mix the serum and ALT or Urea reagent. It lays the foundation for online monitoring of liver cells and will help to improve the viability of liver cell in the bioreactor.

Cognitive and Adaptive Functioning after Liver Transplantation for Maple Syrup Urine Disease: A Case Series

PubMed Central

Shellmer, D. A.; Dabbs, A. DeVito; Dew, M. A.; Noll, R. B.; Feldman, H.; Strauss, K.; Morton, D. H.; Vockley, G.; Mazariegos, G. V.

2011-01-01

MSUD is a complex metabolic disorder that has been associated with central nervous system damage, developmental delays, and neurocognitive deficits. Although liver transplantation provides a metabolic cure for MSUD, changes in cognitive and adaptive functioning following transplantation have not been investigated. In this report we present data from 14 patients who completed cognitive and adaptive functioning testing pre- and one year and/or three years post-liver transplantation. Findings show either no significant change or improvement in IQ scores pre- to post-liver transplantation. Greater variability was observed in adaptive functioning scores, but the majority of patients evidenced either no significant change or improvement in adaptive scores. In general, findings may indicate that liver transplantation curtails additional central nervous system damage and neurocognitive decline providing an opportunity for stabilization or improvement in functioning. PMID:20946191

Artificial and bioartificial liver support: A review of perfusion treatment for hepatic failure patients

PubMed Central

Naruse, Katsutoshi; Tang, Wei; Makuuchi, Masatoshi

2007-01-01

Liver transplantation and blood purification therapy, including plasmapheresis, hemodiafiltration, and bioartificial liver support, are the available treatments for patients with severe hepatic failure. Bioartificial liver support, in which living liver tissue is used to support hepatic function, has been anticipated as an effective treatment for hepatic failure. The two mainstream systems developed for bioartificial liver support are extracorporeal whole liver perfusion (ECLP) and bioreactor systems. Comparing various types of bioartificial liver in view of function, safety, and operability, we concluded that the best efficacy can be provided by the ECLP system. Moreover, in our subsequent experiments comparing ECLP and apheresis therapy, ECLP offers more ammonia metabolism than HD and HF. In addition, ECLP can compensate amino acid imbalance and can secret bile. A controversial point with ECLP is the procedure is labor intensive, resulting in high costs. However, ECLP has the potential to reduce elevated serum ammonia levels of hepatic coma patients in a short duration. When these problems are solved, bioartificial liver support, especially ECLP, can be adopted as an option in ordinary clinical therapy to treat patients with hepatic failure. PMID:17461442

Brain death and marginal grafts in liver transplantation.

PubMed

Jiménez-Castro, M B; Gracia-Sancho, J; Peralta, C

2015-06-04

It is well known that most organs for transplantation are currently procured from brain-dead donors; however, the presence of brain death is an important risk factor in liver transplantation. In addition, one of the mechanisms to avoid the shortage of liver grafts for transplant is the use of marginal livers, which may show higher risk of primary non-function or initial poor function. To our knowledge, very few reviews have focused in the field of liver transplantation using brain-dead donors; moreover, reviews that focused on both brain death and marginal grafts in liver transplantation, both being key risk factors in clinical practice, have not been published elsewhere. The present review aims to describe the recent findings and the state-of-the-art knowledge regarding the pathophysiological changes occurring during brain death, their effects on marginal liver grafts and summarize the more controversial topics of this pathology. We also review the therapeutic strategies designed to date to reduce the detrimental effects of brain death in both marginal and optimal livers, attempting to explain why such strategies have not solved the clinical problem of liver transplantation.

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.

Assessment of Liver Function in Patients With Hepatocellular Carcinoma: A New Evidence-Based Approach—The ALBI Grade

PubMed Central

Johnson, Philip J.; Berhane, Sarah; Kagebayashi, Chiaki; Satomura, Shinji; Teng, Mabel; Reeves, Helen L.; O'Beirne, James; Fox, Richard; Skowronska, Anna; Palmer, Daniel; Yeo, Winnie; Mo, Frankie; Lai, Paul; Iñarrairaegui, Mercedes; Chan, Stephen L.; Sangro, Bruno; Miksad, Rebecca; Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori

2015-01-01

Purpose Most patients with hepatocellular carcinoma (HCC) have associated chronic liver disease, the severity of which is currently assessed by the Child-Pugh (C-P) grade. In this international collaboration, we identify objective measures of liver function/dysfunction that independently influence survival in patients with HCC and then combine these into a model that could be compared with the conventional C-P grade. Patients and Methods We developed a simple model to assess liver function, based on 1,313 patients with HCC of all stages from Japan, that involved only serum bilirubin and albumin levels. We then tested the model using similar cohorts from other geographical regions (n = 5,097) and other clinical situations (patients undergoing resection [n = 525] or sorafenib treatment for advanced HCC [n = 1,132]). The specificity of the model for liver (dys)function was tested in patients with chronic liver disease but without HCC (n = 501). Results The model, the Albumin-Bilirubin (ALBI) grade, performed at least as well as the C-P grade in all geographic regions. The majority of patients with HCC had C-P grade A disease at presentation, and within this C-P grade, ALBI revealed two classes with clearly different prognoses. Its utility in patients with chronic liver disease alone supported the contention that the ALBI grade was indeed an index of liver (dys)function. Conclusion The ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C-P grade. PMID:25512453

Functional gadoxetate disodium-enhanced MRI in patients with primary sclerosing cholangitis (PSC).

PubMed

Hinrichs, Heiko; Hinrichs, Jan B; Gutberlet, Marcel; Lenzen, Henrike; Raatschen, Hans-Juergen; Wacker, Frank; Ringe, Kristina I

2016-04-01

To assess the value of variable flip angle-based T1 liver mapping on gadoxetate disodium-enhanced MRI in patients with primary sclerosing cholangitis (PSC) for evaluation of global and segmental liver function, and determine a possible correlation with disease severity. Sixty-one patients (19 female, 42 male; mean age 41 years) with PSC were included in this prospective study. T1 mapping was performed using a 3D-spoiled GRE sequence (flip angles 5°, 15°, 20°, 30°) before, 16 (HP1) and 132 min (HP2) after contrast injection. T1 values were measured and compared (Wilcoxon-Test) by placing ROIs in each liver segment. The mean reduction of T1 relaxation time at HP1 and HP2 was calculated and correlated with liver function tests (LFTs), MELD, Mayo Risk and Amsterdam Scores (Spearman correlation). Significant changes of T1 relaxation times between non-enhanced and gadoxetate disodium-enhanced MRI at HP1 and HP2 could be observed in all liver segments (p < 0.0001). A significant correlation of T1 reduction could be observed with LFTs, MELD and Mayo Risk Score (p < 0.05). T1 mapping of the liver using a variable flip angle-based sequence is a feasible technique to evaluate liver function on a global level, and may be extrapolated on a segmental level in patients with PSC. • T1 mapping enables evaluation of global liver function in PSC. • T1 relaxation time reduction correlates with the MELD and MayoRisk Score. • Extrapolated, T1 mapping may allow for segmental evaluation of liver function.

Liver function assessment using 99mTc-GSA single-photon emission computed tomography (SPECT)/CT fusion imaging in hilar bile duct cancer: A retrospective study.

PubMed

Sumiyoshi, Tatsuaki; Shima, Yasuo; Okabayashi, Takehiro; Kozuki, Akihito; Hata, Yasuhiro; Noda, Yoshihiro; Kouno, Michihiko; Miyagawa, Kazuyuki; Tokorodani, Ryotaro; Saisaka, Yuichi; Tokumaru, Teppei; Nakamura, Toshio; Morita, Sojiro

2016-07-01

The objective of this study was to determine the utility of Tc-99m-diethylenetriamine-penta-acetic acid-galactosyl human serum albumin ((99m)Tc-GSA) single-photon emission computed tomography (SPECT)/CT fusion imaging for posthepatectomy remnant liver function assessment in hilar bile duct cancer patients. Thirty hilar bile duct cancer patients who underwent major hepatectomy with extrahepatic bile duct resection were retrospectively analyzed. Indocyanine green plasma clearance rate (KICG) value and estimated KICG by (99m)Tc-GSA scintigraphy (KGSA) and volumetric and functional rates of future remnant liver by (99m)Tc-GSA SPECT/CT fusion imaging were used to evaluate preoperative whole liver function and posthepatectomy remnant liver function, respectively. Remnant (rem) KICG (= KICG × volumetric rate) and remKGSA (= KGSA × functional rate) were used to predict future remnant liver function; major hepatectomy was considered unsafe for values <0.05. The correlation of remKICG and remKGSA with posthepatectomy mortality and morbidity was determined. Although remKICG and remKGSA were not significantly different (median value: 0.071 vs 0.075), functional rates of future remnant liver were significantly higher than volumetric rates (median: 0.54 vs 0.46; P < .001). Hepatectomy was considered unsafe in 17% and 0% of patients using remKICG and remKGSA, respectively. Postoperative liver failure and mortality did not occur in the patients for whom hepatectomy was considered unsafe based on remKICG. remKGSA showed a stronger correlation with postoperative prothrombin time activity than remKICG. (99m)Tc-GSA SPECT/CT fusion imaging enables accurate assessment of future remnant liver function and suitability for hepatectomy in hilar bile duct cancer patients. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Choline Metabolism Provides Novel Insights into Non-alcoholic Fatty Liver Disease and its Progression

PubMed Central

Corbin, Karen D.; Zeisel, Steven H.

2013-01-01

Purpose of review Choline is an essential nutrient and the liver is a central organ responsible for choline metabolism. Hepatosteatosis and liver cell death occur when humans are deprived of choline. In the last few years there have been significant advances in our understanding of the mechanisms that influence choline requirements in humans and in our understanding of choline’s effects on liver function. These advances are useful in elucidating why non-alcoholic fatty liver disease (NAFLD) occurs and progresses sometimes to hepatocarcinogenesis. Recent findings Humans eating low choline diets develop fatty liver and liver damage,. This dietary requirement for choline is modulated by estrogen and by single nucleotide polymorphisms (SNPs) in specific genes of choline and folate metabolism. The spectrum of choline’s effects on liver range from steatosis to development of hepatocarcinomas, and several mechanisms for these effects have been identified. They include abnormal phospholipid synthesis, defects in lipoprotein secretion, oxidative damage caused by mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Furthermore, the hepatic steatosis phenotype and can be characterized more fully via metabolomic signatures and is influenced by the gut microbiome. Importantly, the intricate connection between liver function, one carbon metabolism, and energy metabolism is just beginning to be elucidated. Summary Choline influences liver function, and the dietary requirement for this nutrient varies depending on an individual’s genotype and estrogen status. Understanding these individual differences is important for gastroenterologists seeking to understand why some individuals develop NAFLD and others do not, and why some patients tolerate total parenteral nutrition and others develop liver dysfunction. PMID:22134222

Delayed gastric emptying of both the liquid and solid components of a meal in chronic liver disease.

PubMed

Galati, J S; Holdeman, K P; Dalrymple, G V; Harrison, K A; Quigley, E M

1994-05-01

To evaluate gastric emptying in patients with chronic liver disease and portal hypertension. We measured gastric emptying of both the liquid and solid components of a meal in 10 consecutive patients with chronic liver disease and portal hypertension, but free of ascites, and 14 age- and sex-matched healthy controls. In the patients with liver disease, relationships between emptying and liver function were examined. To measure gastric emptying, subjects consumed a test meal that consisted of scrambled eggs labeled with 99mTc-sulfur colloid and 4 oz of water labeled with 111In-diethylene triamine pentacetic acid (DTPA). Patients with liver disease and portal hypertension demonstrated delayed emptying of both the liquid (t1/2, min, mean +/- SE, patients vs. 69.4 +/- 19.4 vs. 31.4 +/- 1.8, p < 0.01) and solid (post-lag phase solid emptying: 141 +/- 32.9 vs. 69.8 +/- 4.6, p < 0.006) components of the meal. We could not identify any correlation between gastric emptying and tests of liver function. Gastric emptying is delayed in patients with liver disease and portal hypertension; this abnormal gastric motor function may contribute to the pathophysiology of foregut complaints in this patient population.

Intraoperative factors associated with delayed recovery of liver function after hepatectomy: analysis of 1969 living donors.

PubMed

Choi, S-S; Cho, S-S; Ha, T-Y; Hwang, S; Lee, S-G; Kim, Y-K

2016-02-01

The safety of healthy living donors who are undergoing hepatic resection is a primary concern. We aimed to identify intraoperative anaesthetic and surgical factors associated with delayed recovery of liver function after hepatectomy in living donors. We retrospectively analysed 1969 living donors who underwent hepatectomy for living donor liver transplantation. Delayed recovery of hepatic function was defined by increases in international normalised ratio of prothrombin time and concomitant hyperbilirubinaemia on or after post-operative day 5. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with delayed recovery of hepatic function after living donor hepatectomy. Delayed recovery of liver function after donor hepatectomy was observed in 213 (10.8%) donors. Univariate logistic regression analysis showed that sevoflurane anaesthesia, synthetic colloid, donor age, body mass index, fatty change and remnant liver volume were significant factors for prediction of delayed recovery of hepatic function. Multivariate logistic regression analysis showed that independent factors significantly associated with delayed recovery of liver function after donor hepatectomy were sevoflurane anaesthesia (odds ratio = 3.514, P < 0.001), synthetic colloid (odds ratio = 1.045, P = 0.033), donor age (odds ratio = 0.970, P = 0.003), female gender (odds ratio = 1.512, P = 0.014) and remnant liver volume (odds ratio = 0.963, P < 0.001). Anaesthesia with sevoflurane was an independent factor in predicting delayed recovery of hepatic function after donor hepatectomy. Although synthetic colloid may be associated with delayed recovery of hepatic function after donor hepatectomy, further study is required. These results can provide useful information on perioperative management of living liver donors. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration

PubMed Central

Pu, Wenjuan; Zhang, Hui; Huang, Xiuzhen; Tian, Xueying; He, Lingjuan; Wang, Yue; Zhang, Libo; Liu, Qiaozhen; Li, Yan; Li, Yi; Zhao, Huan; Liu, Kuo; Lu, Jie; Zhou, Yingqun; Huang, Pengyu; Nie, Yu; Yan, Yan; Hui, Lijian; Lui, Kathy O.; Zhou, Bin

2016-01-01

Hepatocytes are functionally heterogeneous and are divided into two distinct populations based on their metabolic zonation: the periportal and pericentral hepatocytes. During liver injury and regeneration, the cellular dynamics of these two distinct populations remain largely elusive. Here we show that major facilitator super family domain containing 2a (Mfsd2a), previously known to maintain blood–brain barrier function, is a periportal zonation marker. By genetic lineage tracing of Mfsd2a+ periportal hepatocytes, we show that Mfsd2a+ population decreases during liver homeostasis. Nevertheless, liver regeneration induced by partial hepatectomy significantly stimulates expansion of the Mfsd2a+ periportal hepatocytes. Similarly, during chronic liver injury, the Mfsd2a+ hepatocyte population expands and completely replaces the pericentral hepatocyte population throughout the whole liver. After injury recovery, the adult liver re-establishes the metabolic zonation by reprogramming the Mfsd2a+-derived hepatocytes into pericentral hepatocytes. The evidence of entire zonation replacement during injury increases our understanding of liver biology and disease. PMID:27857132

Technical aspects of virtual liver resection planning.

PubMed

Glombitza, G; Lamadé, W; Demiris, A M; Göpfert, M R; Mayer, A; Bahner, M L; Meinzer, H P; Richter, G; Lehnert, T; Herfarth, C

1998-01-01

Operability of a liver tumor is depending on its three dimensional relation to the intrahepatic vascular trees which define autonomously functioning liver (sub-)segments. Precise operation planning is complicated by anatomic variability, distortion of the vascular trees by the tumor or preceding liver resections. Because of the missing possibility to track the deformation of the liver during the operation an integration of the resection planning system into an intra-operative navigation system is not feasible. So the main task of an operation planning system in this domain is a quantifiable patient selection by exact prediction of post-operative liver function and a quantifiable resection proposal. The system quantifies the organ structures and resection volumes by means of absolute and relative values. It defines resection planes depending on security margins and the vascular trees and presents the data in visualized form as a 3D movie. The new 3D operation planning system offers quantifiable liver resection proposals based on individualized liver anatomy. The results are visualized in digital movies as well as in quantitative reports.

Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice.

PubMed

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

2015-07-01

Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. Livers explanted from wild-type, inducible nitric oxide synthase knockout (iNOS(-/-)), JNK1(-/-) or JNK2(-/-) mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS deficiency. JNK inhibition and JNK2 deficiency, but not JNK1 deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS deficiency, JNK inhibition and JNK2 deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization, and is an attractive target to improve liver function and survival in CDD liver transplantation recipients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure

PubMed Central

Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

2015-01-01

Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called “second pathway of liver regeneration.” The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin. PMID:26136687

Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure.

PubMed

Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

2015-01-01

Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called "second pathway of liver regeneration." The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin.

Non-Invasive Assessment of Liver Function

PubMed Central

Helmke, Steve; Colmenero, Jordi; Everson, Gregory T.

2015-01-01

Purpose of review It is our opinion that there is an unmet need in Hepatology for a minimally- or noninvasive test of liver function and physiology. Quantitative liver function tests (QLFTs) define the severity and prognosis of liver disease by measuring the clearance of substrates whose uptake or metabolism is dependent upon liver perfusion or hepatocyte function. Substrates with high affinity hepatic transporters exhibit high “first-pass” hepatic extraction and their clearance measures hepatic perfusion. In contrast, substrates metabolized by the liver have low first-pass extraction and their clearance measures specific drug metabolizing pathways. Recent Findings We highlight one QLFT, the dual cholate test, and introduce the concept of a disease severity index (DSI) linked to clinical outcome that quantifies the simultaneous processes of hepatocyte uptake, clearance from the systemic circulation, clearance from the portal circulation, and portal-systemic shunting. Summary It is our opinion that dual cholate is a relevant test for defining disease severity, monitoring the natural course of disease progression, and quantifying the response to therapy. PMID:25714706

The use of a projection method to simplify portal and hepatic vein segmentation in liver anatomy.

PubMed

Huang, Shaohui; Wang, Boliang; Cheng, Ming; Huang, Xiaoyang; Ju, Ying

2008-12-01

In living donor liver transplantation, the volume of the potential graft must be measured to ensure sufficient liver function after surgery. Couinaud divided the liver into 8 functionally independent segments. However, this method is not simple to perform in 3D space directly. Thus, we propose a rapid method to segment the liver based on the hepatic vessel tree. The most important step of this method is vascular projection. By carefully selecting a projection plane, a 3D point can be fixed in the projection plane. This greatly helps in rapid classification. This method was validated by applying it to a 3D liver depicted on CT images, and the result was in good agreement with Couinaud's classification.

The liver in regulation of iron homeostasis.

PubMed

Rishi, Gautam; Subramaniam, V Nathan

2017-09-01

The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body's metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism. Copyright © 2017 the American Physiological Society.

Differential Location and Distribution of Hepatic Immune Cells

PubMed Central

Freitas-Lopes, Maria Alice; Mafra, Kassiana; David, Bruna A.; Carvalho-Gontijo, Raquel; Menezes, Gustavo B.

2017-01-01

The liver is one of the main organs in the body, performing several metabolic and immunological functions that are indispensable to the organism. The liver is strategically positioned in the abdominal cavity between the intestine and the systemic circulation. Due to its location, the liver is continually exposed to nutritional insults, microbiota products from the intestinal tract, and to toxic substances. Hepatocytes are the major functional constituents of the hepatic lobes, and perform most of the liver’s secretory and synthesizing functions, although another important cell population sustains the vitality of the organ: the hepatic immune cells. Liver immune cells play a fundamental role in host immune responses and exquisite mechanisms are necessary to govern the density and the location of the different hepatic leukocytes. Here we discuss the location of these pivotal cells within the different liver compartments, and how their frequency and tissular location can dictate the fate of liver immune responses. PMID:29215603

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

PubMed

Mercado, M A; Orozco, H

1992-01-01

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

Metabonomics Research Progress on Liver Diseases.

PubMed

Yu, Mengqian; Zhu, Ying; Cong, Qingwei; Wu, Chunyan

2017-01-01

Metabolomics as the new omics technique develops after genomics, transcriptomics, and proteomics and has rapid development at present. Liver diseases are worldwide public health problems. In China, chronic hepatitis B and its secondary diseases are the common liver diseases. They can be diagnosed by the combination of history, virology, liver function, and medical imaging. However, some patients seldom have relevant physical examination, so the diagnosis may be delayed. Many other liver diseases, such as drug-induced liver injury (DILI), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases, still do not have definite diagnostic markers; the diagnosis consists of history, medical imaging, and the relevant score. As a result, the clinical work becomes very complex. So it has broad prospects to explore the specific and sensitive biomarkers of liver diseases with metabolomics. In this paper, there are several summaries which are related to the current research progress and application of metabolomics on biomarkers of liver diseases.

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

PubMed Central

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

2016-01-01

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

Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation

PubMed Central

Mazza, Giuseppe; Rombouts, Krista; Rennie Hall, Andrew; Urbani, Luca; Vinh Luong, Tu; Al-Akkad, Walid; Longato, Lisa; Brown, David; Maghsoudlou, Panagiotis; Dhillon, Amar P.; Fuller, Barry; Davidson, Brian; Moore, Kevin; Dhar, Dipok; De Coppi, Paolo; Malago, Massimo; Pinzani, Massimo

2015-01-01

Liver synthetic and metabolic function can only be optimised by the growth of cells within a supportive liver matrix. This can be achieved by the utilisation of decellularised human liver tissue. Here we demonstrate complete decellularization of whole human liver and lobes to form an extracellular matrix scaffold with a preserved architecture. Decellularized human liver cubic scaffolds were repopulated for up to 21 days using human cell lines hepatic stellate cells (LX2), hepatocellular carcinoma (Sk-Hep-1) and hepatoblastoma (HepG2), with excellent viability, motility and proliferation and remodelling of the extracellular matrix. Biocompatibility was demonstrated by either omental or subcutaneous xenotransplantation of liver scaffold cubes (5 × 5 × 5 mm) into immune competent mice resulting in absent foreign body responses. We demonstrate decellularization of human liver and repopulation with derived human liver cells. This is a key advance in bioartificial liver development. PMID:26248878

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

PubMed

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

2016-01-01

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

Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut

PubMed Central

Seki, Ekihiro; Schnabl, Bernd

2012-01-01

Liver fibrosis occurs as a wound-healing scar response following chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, viral hepatitis, cholestatic liver disease and autoimmune liver diseases. The liver has a unique vascular system within the gastrointestinal tract, as the majority of the liver's blood supply comes from the intestine through the portal vein. When the intestinal barrier function is disrupted, an increase in intestinal permeability leads to the translocation of intestine-derived bacterial products such as lipopolysaccharide (LPS) and unmethylated CpG containing DNA to the liver via the portal vein. These gut-derived bacterial products stimulate innate immune receptors, namely Toll-like receptors (TLRs), in the liver. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes. TLRs activate these cells to contribute to acute and chronic liver diseases. This review summarizes recent studies investigating the role of TLRs, intestinal microbiota and bacterial translocation in liver fibrosis, alcoholic liver disease and non-alcoholic steatohepatitis. PMID:22124143

Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia.

PubMed

Ohno, Yukako; Hanawa, Haruo; Jiao, Shuang; Hayashi, Yuka; Yoshida, Kaori; Suzuki, Tomoyasu; Kashimura, Takeshi; Obata, Hiroaki; Tanaka, Komei; Watanabe, Tohru; Minamino, Tohru

2015-01-01

Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.

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.

Ectopic fat depots and left ventricular function in nondiabetic men with nonalcoholic fatty liver disease.

PubMed

Granér, Marit; Nyman, Kristofer; Siren, Reijo; Pentikäinen, Markku O; Lundbom, Jesper; Hakkarainen, Antti; Lauerma, Kirsi; Lundbom, Nina; Nieminen, Markku S; Taskinen, Marja-Riitta

2015-01-01

Nonalcoholic fatty liver disease has emerged as a novel cardiovascular risk factor. The aim of the study was to assess the effect of different ectopic fat depots on left ventricular (LV) function in subjects with nonalcoholic fatty liver disease. Myocardial and hepatic triglyceride contents were measured with 1.5 T magnetic resonance spectroscopy and LV function, visceral adipose tissue (VAT) and subcutaneous adipose tissue, epicardial and pericardial fat by MRI in 75 nondiabetic men. Subjects were stratified by hepatic triglyceride content into low, moderate, and high liver fat groups. Myocardial triglyceride, epicardial and pericardial fat, VAT, and subcutaneous adipose tissue increased stepwise from low to high liver fat group. Parameters of LV diastolic function showed a stepwise decrease over tertiles of liver fat and VAT, and they were inversely correlated with hepatic triglyceride, VAT, and VAT/subcutaneous adipose tissue ratio. In multivariable analyses, hepatic triglyceride and VAT were independent predictors of LV diastolic function, whereas myocardial triglyceride was not associated with measures of diastolic function. Myocardial triglyceride, epicardial and pericardial fat increased with increasing amount of liver fat and VAT. Hepatic steatosis and VAT associated with significant changes in LV structure and function. The association of LV diastolic function with hepatic triglyceride and VAT may be because of toxic systemic effects. The effects of myocardial triglyceride on LV structure and function seem to be more complex than previously thought and merit further study. © 2014 American Heart Association, Inc.

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.

Stopping Liver Cancer's Rogue COP | Center for Cancer Research

Cancer.gov

Liver cancer is the fourth most common cancer type and the third leading cause of cancer death worldwide. Many liver tumors are actually metastases, tumors seeded in the liver by cancer cells from another organ, but hepatocellular carcinomas (HCCs), the most common liver tumors, are a heterogeneous family of cancers that arise in hepatocytes, the functional cells of the liver. HCCs are often associated with cirrhosis or liver scarring. Because of the variation in tumor phenotypes, the poor understanding of the molecular origins of these tumors, and the increasing number of diagnoses especially in the US, HCC is a major clinical challenge.

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

PubMed

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

2012-07-01

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

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

Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE).

PubMed

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

2007-04-16

Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs. A population-based retrospective cohort study will follow up all those who have had an incident liver function test (LFT) in primary care to subsequent liver disease or mortality over a period of 15 years (approx. 2.3 million tests in 99,000 people). The study is set in Primary Care in the region of Tayside, Scotland (pop approx. 429,000) between 1989 and 2003. The target population consists of patients with no recorded clinical signs or symptoms of liver disease and registered with a GP. The health technologies being assessed are LFTs, viral and auto-antibody tests, ultrasound, CT, MRI and liver biopsy. The study will utilise the Epidemiology of Liver Disease In Tayside (ELDIT) database to determine the outcomes of liver disease. These are based on hospital admission data (Scottish Morbidity Record 1), dispensed medication records, death certificates, and examination of medical records from Tayside hospitals. A sample of patients (n = 150) with recent initial ALF tests or invitation to biopsy will complete questionnaires to obtain quality of life data and anxiety measures. Cost-effectiveness and cost utility Markov model analyses will be performed from health service and patient perspectives using standard NHS costs. The findings will also be used to develop a computerised clinical decision support tool. The results of this study will be widely disseminated to primary care, as well as G.I. hospital specialists through publications and presentations at local and national meetings and the project website. This will facilitate optimal decision-making both for the benefit of the patient and the National Health Service.

The functional interrelationship between gap junctions and fenestrae in endothelial cells of the liver organoid.

PubMed

Saito, Masaya; Matsuura, Tomokazu; Nagatsuma, Keisuke; Tanaka, Ken; Maehashi, Haruka; Shimizu, Keiko; Hataba, Yoshiaki; Kato, Fumitaka; Kashimori, Isao; Tajiri, Hisao; Braet, Filip

2007-06-01

Functional intact liver organoid can be reconstructed in a radial-flow bioreactor when human hepatocellular carcinoma (FLC-5), mouse immortalized sinusoidal endothelial M1 (SEC) and A7 (HSC) hepatic stellate cell lines are cocultured. The structural and functional characteristics of the reconstructed organoid closely resemble the in vivo liver situation. Previous liver organoid studies indicated that cell-to-cell communications might be an important factor for the functional and structural integrity of the reconstructed organoid, including the expression of fenestrae. Therefore, we examined the possible relationship between functional intact gap junctional intercellular communication (GJIC) and fenestrae dynamics in M1-SEC cells. The fine morphology of liver organoid was studied in the presence of (1) irsogladine maleate (IM), (2) oleamide and (3) oleamide followed by IM treatment. Fine ultrastructural changes were studied by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and compared with control liver organoid data. TEM revealed that oleamide affected the integrity of cell-to-cell contacts predominantly in FLC-5 hepatocytes. SEM observation showed the presence of fenestrae on M1-SEC cells; however, oleamide inhibited fenestrae expression on the surface of endothelial cells. Interestingly, fenestrae reappeared when IM was added after initial oleamide exposure. GJIC mediates the number of fenestrae in endothelial cells of the liver organoid.

Long-term culture of human liver tissue with advanced hepatic functions.

PubMed

Ng, Soon Seng; Xiong, Anming; Nguyen, Khanh; Masek, Marilyn; No, Da Yoon; Elazar, Menashe; Shteyer, Eyal; Winters, Mark A; Voedisch, Amy; Shaw, Kate; Rashid, Sheikh Tamir; Frank, Curtis W; Cho, Nam Joon; Glenn, Jeffrey S

2017-06-02

A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver's natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450-mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus. The tissues permit the assessment of antiviral agents and maintain their advanced functions for over 5 months in culture. This extended functionality enabled the prediction of a fatal human-specific hepatotoxicity caused by fialuridine (FIAU), which had escaped detection by preclinical models and short-term clinical studies. The results obtained with the engineered human liver tissue in this study provide proof-of-concept determination of human-specific drug metabolism, demonstrate the ability to support infection with human hepatitis virus derived from an infected patient and subsequent antiviral drug testing against said infection, and facilitate detection of human-specific drug hepatotoxicity associated with late-onset liver failure. Looking forward, the scalability and biocompatibility of the scaffold are also ideal for future cell replacement therapeutic strategies.

Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome

PubMed Central

Oshida, Keiyu; Waxman, David J.; Corton, J. Christopher

2016-01-01

The growth hormone (GH)-activated transcription factor signal transducer and activator of transcription 5b (STAT5b) is a key regulator of sexually dimorphic gene expression in the liver. Suppression of hepatic STAT5b signaling is associated with lipid metabolic dysfunction leading to steatosis and liver cancer. In the companion publication, a STAT5b biomarker gene set was identified and used in a rank-based test to predict both increases and decreases in liver STAT5b activation status/function with high (≥ 97%) accuracy. Here, this computational approach was used to identify chemicals and hormones that activate (masculinize) or suppress (feminize) STAT5b function in a large, annotated mouse liver and primary hepatocyte gene expression compendium. Exposure to dihydrotestosterone and thyroid hormone caused liver masculinization, whereas glucocorticoids, fibroblast growth factor 15, and angiotensin II caused liver feminization. In mouse models of diabetes and obesity, liver feminization was consistently observed and was at least partially reversed by leptin or resveratrol exposure. Chemical-induced feminization of male mouse liver gene expression profiles was a relatively frequent phenomenon: of 156 gene expression biosets from chemically-treated male mice, 29% showed feminization of liver STAT5b function, while <1% showed masculinization. Most (93%) of the biosets that exhibited feminization of male liver were also associated with activation of one or more xenobiotic-responsive receptors, most commonly constitutive activated receptor (CAR) or peroxisome proliferator-activated receptor alpha (PPARα). Feminization was consistently associated with increased expression of peroxisome proliferator-activated receptor gamma (Pparg) but not other lipogenic transcription factors linked to steatosis. GH-activated STAT5b signaling in mouse liver is thus commonly altered by diverse chemicals, and provides a linkage between chemical exposure and dysregulated gene expression associated with adverse effects on the liver. PMID:26959237

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

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.

Characterization of a Liver Organoid Tissue Composed of Hepatocytes and Fibroblasts in Dense Collagen Fibrils

PubMed Central

Tamai, Miho; Adachi, Eijiro

2013-01-01

The adult liver is wrapped in a connective tissue sheet called the liver capsule, which consists of collagen fibrils and fibroblasts. In this study, we set out to construct a liver organoid tissue that would be comparable to the endogenous liver, using a bioreactor. In vitro liver organoid tissue was generated by combining collagen fibrils, fibroblasts, and primary murine hepatocytes or Hep G2 on a mesh of poly-lactic acid fabric using a bioreactor. Then, the suitability of this liver organoid tissue for transplantation was tested by implanting the constructs into partially hepatectomized BALB/cA-nu/nu mice. As determined by using scanning and transmission electron microscopes, the liver organoid tissues were composed of densely packed collagen fibrils with fibroblasts and aggregates of oval or spherical hepatocytes. Angiogenesis was induced after the transplantation, and blood vessels connected the liver organoid tissue with the surrounding tissue. Thus, a novel approach was applied to generate transplantable liver organoid tissue within a condensed collagen fibril matrix. These results suggested that a dense collagen network populated with fibroblasts can hold a layer of concentrated hepatocytes, providing a three-dimensional microenvrionment suitable for the reestablishment of cell–cell and cell–extracellular matrix (ECM) interactions, and resulting in the maintenance of their liver-specific functions. This liver organoid tissue may be useful for the study of intrahepatic functions of various cells, cytokines, and ECMs, and may fulfill the fundamental requirements of a donor tissue. PMID:23815236

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

PubMed Central

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

2017-01-01

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

[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.

Entrapment of hepatocyte spheroids in a hollow fiber bioreactor as a potential bioartificial liver.

PubMed

Wu, F J; Peshwa, M V; Cerra, F B; Hu, W S

1995-01-01

A bioartificial liver (BAL) employing xenogeneic hepatocytes has been developed as a potential interim support for patients in hepatic failure. For application in human therapy, the BAL requires a substantial increase in liver-specific functions. Cultivation of hepatocytes as spheroids leads to enhanced liver specific functions. We explored the possibility of entrapping spheroids into the BAL in order to improve device performance. Rat hepatocyte spheroids were entrapped in collagen gel within the lumen fibers of the BAL. The morphology and ultrastructure of collagen-entrapped spheroids resembled those of suspended spheroids formed on petri dishes. Albumin synthesis and P-450 enzyme activity were measured as markers of liver specific functions of spheroids entrapped in the BAL. At least a 4-fold improvement in these functions was observed compared to BAL devices entrapped with dispersed hepatocytes in collagen gels.

Real time monitoring of rat liver energy state during ischemia.

PubMed

Barbiro, E; Zurovsky, Y; Mayevsky, A

1998-11-01

Hepatic failure is one of the major problems developed during the posttransplantation period. A possible cause of hepatic failure is the prolonged ischemia induced during the implantation procedure. Hepatic ischemia leads to a reduction in oxygen supply, ATP level decline, liver metabolism impairment, and finally organ failure. The purpose of this study was to estimate the functional state of the liver by monitoring liver blood flow and the mitochondrial NADH redox state simultaneously and continuously during in situ liver ischemia followed by reperfusion. Measurements were performed using the multiprobe developed in our laboratory consisting of fibers for the measurement of relative liver blood flow (laser Doppler flowmetry) and mitochondrial redox state (NADH fluorescence). The experimental procedure included the temporary interruption of blood flow to the liver using three types of ischemia, hepatic artery occlusion, portal vein occlusion, and simultaneous occlusion of hepatic artery and portal vein, followed by a reperfusion period. These preliminary experiments showed a significant decrease in liver blood flow, following the three types of liver ischemia, and a significant increase in NADH levels. The probe used in this study incorporates the advantage of monitoring NADH and liver blood flow simultaneously and continuously from the same area on the surface of the liver. Since each of these two parameters is not calibrated in absolute units, the simultaneous monitoring decreases possible artifacts. Also, it will allow us to determine of the coupling between tissue blood flow and oxidative phosphorylation. It is believed that the measurements of respiratory chain dysfunction might predict organ viability in clinical organ transplantation situations. Using this probe may also help to decrease the variability in liver blood flow monitoring since liver blood flow monitoring is supported simultaneously with the mitochondrial redox state, which supplies the information on liver metabolic and functional state. Copyright 1998 Academic Press.

Radiation-Induced Liver Damage: Correlation of Histopathology with Hepatobiliary Magnetic Resonance Imaging, a Feasibility Study

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

Seidensticker, Max, E-mail: max.seidensticker@med.ovgu.de; Burak, Miroslaw; Kalinski, Thomas

PurposeRadiotherapy of liver malignancies shows promising results (radioembolization, stereotactic irradiation, interstitial brachytherapy). Regardless of the route of application, a certain amount of nontumorous liver parenchyma will be collaterally damaged by radiation. The functional reserve may be significantly reduced with an impact on further treatment planning. Monitoring of radiation-induced liver damage by imaging is neither established nor validated. We performed an analysis to correlate the histopathological presence of radiation-induced liver damage with functional magnetic resonance imaging (MRI) utilizing hepatobiliary contrast media (Gd-BOPTA).MethodsPatients undergoing local high-dose-rate brachytherapy for whom a follow-up hepatobiliary MRI within 120 days after radiotherapy as well as an evaluablemore » liver biopsy from radiation-exposed liver tissue within 7 days before MRI were retrospectively identified. Planning computed tomography (CT)/dosimetry was merged to the CT-documentation of the liver biopsy and to the MRI. Presence/absence of radiation-induced liver damage (histopathology) and Gd-BOPTA uptake (MRI) as well as the dose applied during brachytherapy at the site of tissue sampling was determined.ResultsFourteen biopsies from eight patients were evaluated. In all cases with histopathological evidence of radiation-induced liver damage (n = 11), no uptake of Gd-BOPTA was seen. In the remaining three, cases no radiation-induced liver damage but Gd-BOPTA uptake was seen. Presence of radiation-induced liver damage and absence of Gd-BOPTA uptake was correlated with a former high-dose exposition.ConclusionsAbsence of hepatobiliary MRI contrast media uptake in radiation-exposed liver parenchyma may indicate radiation-induced liver damage. Confirmatory studies are warranted.« less

The 24-hour normothermic machine perfusion of discarded human liver grafts.

PubMed

Vogel, Thomas; Brockmann, Jens G; Quaglia, Alberto; Morovat, Alireza; Jassem, Wayel; Heaton, Nigel D; Coussios, Constantin C; Friend, Peter J

2017-02-01

Donor organ shortage necessitates use of less than optimal donor allografts for transplantation. The current cold storage preservation technique fails to preserve marginal donor grafts sufficiently. Evidence from large animal experiments suggests superiority of normothermic machine preservation (NMP) of liver allografts. In this study, we analyze discarded human liver grafts that underwent NMP for the extended period of 24 hours. Thirteen human liver grafts which had been discarded for transplantation were entered into this study. Perfusion was performed with an automated device using an oxygenated, sanguineous perfusion solution at normothermia. Automated control was incorporated for temperature-, flow-, and pressure-regulation as well as oxygenation. All livers were perfused for 24 hours; parameters of biochemical and synthetic liver function as well as histological parameters of liver damage were analyzed. Livers were stratified for expected viability according to the donor's medical history, procurement data, and their macroscopic appearance. Normothermic perfusion preservation of human livers for 24 hours was shown to be technically feasible. Human liver grafts, all of which had been discarded for transplantation, showed levels suggesting organ viability with respect to metabolic and synthetic liver function (to varying degrees). There was positive correlation between instantly available perfusion parameters and generally accepted predictors of posttransplant graft survival. In conclusion, NMP is feasible reliably for periods of at least 24 hours, even in highly suboptimal donor organs. Potential benefits include not only viability testing (as suggested in recent clinical implementations), but also removal of the time constraints associated with the utilization of high-risk livers, and recovery of ischemic and other preretrieval injuries (possibly by enabling therapeutic strategies during NMP). Liver Transplantation 23 207-220 2017 AASLD. © 2016 by the American Association for the Study of Liver Diseases.

Effect of probiotics and synbiotics consumption on serum concentrations of liver function test enzymes: a systematic review and meta-analysis.

PubMed

Khalesi, Saman; Johnson, David Wayne; Campbell, Katrin; Williams, Susan; Fenning, Andrew; Saluja, Sonia; Irwin, Christopher

2017-11-08

The gut-liver interaction suggests that modification of gut bacterial flora using probiotics and synbiotics may improve liver function. This systematic review and meta-analysis aimed to clarify the effect of probiotics and synbiotics consumption on the serum concentration of liver function enzymes. PubMed (MEDLINE), Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library (Central) were searched from 1980 to August 2017 for studies where adults consumed probiotics and/or synbiotics in controlled trials and changes in liver function enzymes were examined. A total of 17 studies (19 trials) were included in the meta-analysis. Random effects meta-analyses were applied. Probiotics and synbiotics significantly reduced serum alanine aminotransferase [- 8.05 IU/L, 95% confidence interval (CI) - 13.07 to - 3.04; p = 0.002]; aspartate aminotransferase (- 7.79 IU/L, 95% CI: - 13.93 to - 1.65; p = 0.02) and gamma-glutamyl transpeptidase (- 8.40 IU/L, 95% CI - 12.61 to - 4.20; p < 0.001). Changes in the serum concentration of alkaline phosphatase and albumin did not reach a statistically significant level. Changes to bilirubin levels were in favour of the control group (0.95 μmol/L, 95% CI 0.48-1.42; p < 0.001). Subgroup analysis suggested the existence of liver disease at baseline, synbiotics supplementation and duration of supplementation ≥ 8 weeks resulted in more pronounced improvement in liver function enzymes than their counterparts. Probiotics and synbiotics may be suggested as supplements to improve serum concentration of liver enzymes, especially when synbiotics administered for a period ≥ 8 weeks and in individuals with liver disease.

Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance

PubMed Central

Dietrich, Christoph G; Götze, Oliver; Geier, Andreas

2016-01-01

Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests. PMID:26755861

Livers from fasted rats acquire resistance to warm and cold ischemia injury.

PubMed

Sumimoto, R; Southard, J H; Belzer, F O

1993-04-01

Successful liver transplantation is dependent upon many factors, one of which is the quality of the donor organ. Previous studies have suggested that the donor nutritional status may affect the outcome of liver transplantation and starvation, due to prolonged stay in the intensive care unit, may adversely affect the liver. In this study we have used the orthotopic rat liver transplant model to measure how fasting the donor affects the outcome of liver transplantation. Rat livers were preserved with UW solution either at 37 degrees C (warm ischemia for 45-60 min) or at 4 degrees C (cold ischemia for 30 or 44 hr). After preservation the livers were orthotopically transplanted and survival (for 7 days) was measured, as well as liver functions 6 hr after transplantation. After 45 min of warm ischemia 50% (3 of 6) animals survived when the liver was obtained from a fed donor about 80% (4 of 5) survived when the liver was obtained from a three-day-fasted donor. After 60 min warm ischemia no animal survived (0 of 8, fed group). However, if the donor was fasted for 3 days 89% (8 of 9) of the animals survived for 7 days. Livers cold-stored for 30 hr were 50% viable (3 of 6) and fasting for 1-3 days did not affect this outcome. However, if the donor was fasted for 4 days 100% (9 of 9) survival was obtained. After 44-hr preservation only 29% (2/7) of the recipients survived for 7 days. If the donor was fasted for 4 days, survival increased to 83% (5/6). Liver functions, bile production, and serum enzymes were better in livers from the fasted rats than from the fed rats. Fasting caused a 95% decrease in liver glycogen content. Even with this low concentration of glycogen, liver viability (animal survival) after warm or cold ischemia was not affected, and livers with a low glycogen content were fully viable. Thus liver glycogen does not appear to be important in liver preservation. This study shows that fasting the donor does not cause injury to the liver after warm or cold ischemia. In fact, the livers appeared to be better able to tolerate ischemia when obtained from fasted rats. Thus donor nutritional status may be an important factor for outcome of liver transplantation. Livers from fasted donors may be capable of tolerating long-term preservation better than livers from fed donors.

Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats

NASA Astrophysics Data System (ADS)

Thorling, Camilla A.; Liu, Xin; Burczynski, Frank J.; Fletcher, Linda M.; Gobe, Glenda C.; Roberts, Michael S.

2011-11-01

Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery. In orthotopic transplantation, the donor liver is exposed to periods of ischemia and when oxygenated blood is reintroduced to the liver, oxidative stress may develop and lead to graft failure. The aim of this project was to investigate whether noninvasive multiphoton and fluorescence lifetime imaging microscopy, without external markers, were useful in detecting early liver damage caused by I/R injury. Localized hepatic ischemia was induced in rats for 1 h followed by 4 h reperfusion. Multiphoton and fluorescence lifetime imaging microscopy was conducted prior to ischemia and up to 4 h of reperfusion and compared to morphological and biochemical assessment of liver damage. Liver function was significantly impaired at 2 and 4 h of reperfusion. Multiphoton microscopy detected liver damage at 1 h of reperfusion, manifested by vacuolated cells and heterogeneous spread of damage over the liver. The damage was mainly localized in the midzonal region of the liver acinus. In addition, fluorescence lifetime imaging showed a decrease in cellular metabolic activity. Multiphoton and fluorescence lifetime imaging microscopy detected evidence of early I/R injury both structurally and functionally. This provides a simple noninvasive technique useful for following progressive liver injury without external markers.

Various stress stimuli rewire the profile of liver secretome in a p53-dependent manner.

PubMed

Charni-Natan, Meital; Solomon, Hilla; Molchadsky, Alina; Jacob-Berger, Adi; Goldfinger, Naomi; Rotter, Varda

2018-05-29

Liver is an important secretory organ that consistently manages various insults in order to retain whole-body homeostasis. Importantly, it was suggested that the tumor-suppressor p53 plays a role in a variety of liver physiological processes and thus it is being regarded as a systemic homeostasis regulator. Using high-throughput mass spectrometric analysis, we identified various p53-dependent liver secretome profiles. This allowed a global view on the role of p53 in maintaining the harmony of liver and whole-body homeostasis. We found that p53 altered the liver secretome differently under various conditions. Under physiological conditions, p53 controls factors that are related mainly to lipid metabolism and injury response. Upon exposure to various types of cancer therapy agents, the hepatic p53 is activated and induces the secretion of proteins related to additional pathways, such as hemostasis, immune response, and cell adhesion. Interestingly, we identified a possible relationship between p53-dependent liver functions and lung tumors. The latter modify differently liver secretome profile toward the secretion of proteins mainly related to cell migration and immune response. The notion that p53 may rewire the liver secretome profile suggests a new non-cell autonomous role of p53 that affect different liver functions and whole organism homeostasis.

FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration

PubMed Central

Takase, Hinako M.; Itoh, Tohru; Ino, Seitaro; Wang, Ting; Koji, Takehiko; Akira, Shizuo; Takikawa, Yasuhiro; Miyajima, Atsushi

2013-01-01

The liver is a unique organ with a remarkably high potential to regenerate upon injuries. In severely damaged livers where hepatocyte proliferation is impaired, facultative liver progenitor cells (LPCs) proliferate and are assumed to contribute to regeneration. An expansion of LPCs is often observed in patients with various types of liver diseases. However, the underlying mechanism of LPC activation still remains largely unknown. Here we show that a member of the fibroblast growth factor (FGF) family, FGF7, is a critical regulator of LPCs. Its expression was induced concomitantly with LPC response in the liver of mouse models as well as in the serum of patients with acute liver failure. Fgf7-deficient mice exhibited markedly depressed LPC expansion and higher mortality upon toxin-induced hepatic injury. Transgenic expression of FGF7 in vivo led to the induction of cells with characteristics of LPCs and ameliorated hepatic dysfunction. We revealed that Thy1+ mesenchymal cells produced FGF7 and appeared in close proximity to LPCs, implicating a role for those cells as the functional LPC niche in the regenerating liver. These findings provide new insights into the cellular and molecular basis for LPC regulation and identify FGF7 as a potential therapeutic target for liver diseases. PMID:23322300

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.

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.

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

PubMed Central

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

2017-01-01

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

Association between liver function and metabolic syndrome in Chinese men and women

PubMed Central

Wang, Sen; Zhang, Jie; Zhu, Li; Song, Linlin; Meng, Zhaowei; Jia, Qiang; Li, Xue; Liu, Na; Hu, Tianpeng; Zhou, Pingping; Zhang, Qing; Liu, Li; Song, Kun; Jia, Qiyu

2017-01-01

Metabolic syndrome (MS) could be associated with liver function. Our study aimed to investigate the association between liver function and MS in a large cohort of Chinese men and women. We enrolled 32,768 ostensibly healthy participants. The associations between liver function and MS of both genders were analyzed separately after dividing total bilirubin (TBIL), gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) into quartiles. Young males had significantly higher MS prevalence than females, yet after menopause, females had higher MS prevalence. We used TBIL, GGT and ALT quartiles as categorical variables in binary logistic regression models. Significantly decreased MS risks were demonstrated in TBIL quartiles 2 to 4 for males, and quartiles 3 to 4 for females. As to GGT and ALT, significantly increased MS risks were shown in high quartiles for both genders. Aging also resulted in significantly higher MS risks in both genders except for young females. This study displayed close associations between liver function and MS, which were influenced by gender and age. A high TBIL level had protective effect against MS, while high GGT and ALT levels were risk factors for MS. It is meaningful that liver function is used as clinical risk predictors for MS. PMID:28317840

Risk factors for deterioration of long-term liver function after radiofrequency ablation therapy

PubMed Central

Honda, Koichi; Seike, Masataka; Oribe, Junya; Endo, Mizuki; Arakawa, Mie; Syo, Hiroki; Iwao, Masao; Tokoro, Masanori; Nishimura, Junko; Mori, Tetsu; Yamashita, Tsutomu; Fukuchi, Satoshi; Muro, Toyokichi; Murakami, Kazunari

2016-01-01

AIM: To identify factors that influence long-term liver function following radiofrequency ablation (RFA) in patients with viral hepatitis-related hepatocellular carcinoma. METHODS: A total of 123 patients with hepatitis B virus- or hepatitis C virus-related hepatocellular car-cinoma (HCC) (n = 12 and n = 111, respectively) were enrolled. Cumulative rates of worsening Child-Pugh (CP) scores (defined as a 2-point increase) were examined. RESULTS: CP score worsening was confirmed in 22 patients over a mean follow-up period of 43.8 ± 26.3 mo. Multivariate analysis identified CP class, platelet count, and aspartate aminotransferase levels as signi-ficant predictors of a worsening CP score (P = 0.000, P = 0.011 and P = 0.024, respectively). In contrast, repeated RFA was not identified as a risk factor for liver function deterioration. CONCLUSION: Long-term liver function following RFA was dependent on liver functional reserve, the degree of fibrosis present, and the activity of the hepatitis condition for this cohort. Therefore, in order to maintain liver function for an extended period following RFA, suppression of viral hepatitis activity is important even after the treatment of HCC. PMID:27168872

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-07-14

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

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

In vitro differentiated hepatic oval-like cells enhance hepatic regeneration in CCl4 -induced hepatic injury.

PubMed

Awan, Sana Javaid; Baig, Maria Tayyab; Yaqub, Faiza; Tayyeb, Asima; Ali, Gibran

2017-01-01

Hepatic oval cells are likely to be activated during advanced stage of liver fibrosis to reconstruct damaged hepatic tissue. However, their scarcity, difficulties in isolation, and in vitro expansion hampered their transplantation in fibrotic liver. This study was aimed to investigate the repair potential of in vitro differentiated hepatic oval-like cells in CCl 4 -induced liver fibrosis. BMSCs and oval cells were isolated and characterized from C57BL/6 GFP + mice. BMSCs were differentiated into oval cells by preconditioning with HGF, EGF, SCF, and LIF and analyzed for the oval cells-specific genes. Efficiency of oval cells to reduce hepatocyte injury was studied by determining cell viability, release of LDH, and biochemical tests in a co-culture system. Further, in vivo repair potential of differentiated oval cells was determined in CCl 4 -induced fibrotic model by gene expression analysis, biochemical tests, mason trichrome, and Sirius red staining. Differentiated oval cells expressed hepatic oval cells-specific markers AFP, ALB, CK8, CK18, CK19. These differentiated cells when co-cultured with injured hepatocytes showed significant hepato-protection as measured by reduction in apoptosis, LDH release, and improvement in liver functions. Transplantation of differentiated oval cells like cells in fibrotic livers exhibited enhanced homing, reduced liver fibrosis, and improved liver functions by augmenting hepatic microenvironment by improved liver functions. This preconditioning strategy to differentiate BMSCs into oval cell leads to improved survival and homing of transplanted cells. In addition, reduction in fibrosis and functional improvement in mice with CCl 4 -induced liver fibrosis was achieved. © 2016 International Federation for Cell Biology.

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

PubMed

Ding, Yi-Tao; Shi, Xiao-Lei

2011-03-01

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

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.

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

PubMed Central

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

2011-01-01

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

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

PubMed

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

2011-04-01

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

Moderate doses of commercial preparations of Ginkgo biloba do not alter markers of liver function but moderate alcohol intake does: A new approach to identify and quantify biomarkers of 'adverse effects' of dietary supplements.

PubMed

Lieberman, Harris R; Kellogg, Mark D; Fulgoni, Victor L; Agarwal, Sanjiv

2017-03-01

It is difficult to determine if certain dietary supplements are safe for human consumption. Extracts of leaves of Ginkgo biloba trees are dietary supplements used for various purported therapeutic benefits. However, recent studies reported they increased risk of liver cancer in rodents. Therefore, this study assessed the association between ginkgo consumption and liver function using NHANES 2001-2012 data (N = 29,684). Since alcohol is known to adversely affect liver function, association of its consumption with liver function was also assessed. Alcohol and ginkgo extract intake of adult consumers and clinical markers of liver function (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, bilirubin) were examined. Moderate consumers of alcohol (0.80 ± 0.02 drinks/day) had higher levels of aspartate aminotransferase and gamma glutamyl transferase than non-consumers (P < 0.001). There was no difference (P > 0.01) in levels of markers of liver function in 616 ginkgo consumers (65.1 ± 4.4 mg/day intake) compared to non-consumers. While moderate alcohol consumption was associated with changes in markers of liver function, ginkgo intake as typically consumed by U.S. adults was not associated with these markers. Biomarkers measured by NHANES may be useful to examine potential adverse effects of dietary supplements for which insufficient human adverse event and toxicity data are available. Not applicable, as this is secondary analysis of publicly released observational data (NHANES 2001-2012). Published by Elsevier Inc.

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.

13C Methacetin Breath Test for Assessment of Microsomal Liver Function: Methodology and Clinical Application.

PubMed

Gorowska-Kowolik, Katarzyna; Chobot, Agata; Kwiecien, Jaroslaw

2017-01-01

Assessment of the liver function, and the need of constant monitoring of the organ's capacity, concerns not only patients with primary liver diseases, but also those at risk of hepatopathies secondary to other chronic diseases. Most commonly, the diagnostics is based on measurements of static biochemical parameters, which allow us to draw conclusions only indirectly about the function and the degree of damage of the organ. On the other hand, liver biopsy is an invasive procedure and therefore it is associated with a considerable risk of complications. Dynamic tests enable us to assess quantitatively the organ's functional reserve by analyzing the kinetics of the metabolization of the substrate by the liver. In practice applied are breath tests using substances such as aminopyrine, caffeine, methacetin, erythromycin (for assessment of the microsomal function); phenylalanine, galactose (for assessment of the cytosolic function); methionine, octanoate, ketoisocaproic acid (for assessment of the mitochondrial function). The test with 13 C methacetin belongs to the best described and most widely applied methods in noninvasive liver function assessment. Due to the rising availability of this method, knowledge concerning its limitations and controversies regarding the methodology, as well as its usefulness in chosen groups of patients, seems to be vital.

Prediction of liver disease in patients whose liver function tests have been checked in primary care: model development and validation using population-based observational cohorts.

PubMed

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

2014-06-02

To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care. Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2 years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model. Primary care, Tayside, Scotland. Derivation cohort: LFT results from 310 511 patients. After exclusions (including: patients under 16 years, patients having initial LFTs measured in secondary care, bilirubin >35 μmol/L, liver complications within 6 weeks and history of a liver condition), the derivation cohort contained 95 977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11 653 patients. Diagnosis of a liver condition within 2 years. From the derivation cohort (n=95 977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20-30% for high-risk patients. This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk. 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.

[Liver and sport].

PubMed

Watelet, J

2008-11-01

The liver is a vital organ and plays a central role in energy exchange, protein synthesis as well as the elimination of waste products from the body. Acute and chronic injury may disturb a variety of liver functions to different degrees. Over the last three decades, the effects of physical activity and competitive sport on the liver have been described by various investigators. These include viral hepatitis and drug-induced liver disorders. Herein, we review acute and chronic liver diseases potentially caused by sport. Team physicians, trainers and others, responsible for the health of athletes, should be familiar with the risk factors, clinical features, and consequences of liver diseases that occur in sports.

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.

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

PubMed

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

2008-01-01

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

[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.

Role of scavenger receptors in the pathophysiology of chronic liver diseases.

PubMed

Armengol, Carolina; Bartolí, Ramon; Sanjurjo, Lucía; Serra, Isabel; Amézaga, Núria; Sala, Margarita; Sarrias, Maria-Rosa

2013-01-01

Scavenger receptors comprise a large family of structurally diverse proteins that are involved in many homeostatic functions. They recognize a wide range of ligands, from pathogen-associated molecular patterns (PAMPs) to endogenous, as well as modified host-derived molecules (DAMPs). The liver deals with blood micro-organisms and DAMPs released from injured organs, thus performing vital metabolic and clearance functions that require the uptake of nutrients and toxins. Many liver cell types, including hepatocytes and Kupffer cells, express scavenger receptors that play key roles in hepatitis C virus entry, lipid uptake, and macrophage activation, among others. Chronic liver disease causes high morbidity and mortality worldwide. Hepatitis virus infection, alcohol abuse, and non-alcoholic fatty liver are the main etiologies associated with this disease. In this context, continuous inflammation as a result of liver damage leads to hepatic fibrosis, which frequently brings about cirrhosis and ultimately hepatocellular carcinoma. In this review, we will summarize the role of scavenger receptors in the pathophysiology of chronic liver diseases. We will also emphasize their potential as biomarkers of advanced liver disease, including cirrhosis and cancer.

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.

Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology

PubMed Central

Russell, Jacquelyn O.; Monga, Satdarshan P.

2018-01-01

The liver is an organ that performs a multitude of functions, and its health is pertinent and indispensable to survival. Thus, the cellular and molecular machinery driving hepatic functions is of utmost relevance. The Wnt signaling pathway is one such signaling cascade that enables hepatic homeostasis and contributes to unique hepatic attributes such as metabolic zonation and regeneration. The Wnt/β-catenin pathway plays a role in almost every facet of liver biology. Furthermore, its aberrant activation is also a hallmark of various hepatic pathologies. In addition to its signaling function, β-catenin also plays a role at adherens junctions. Wnt/β-catenin signaling also influences the function of many different cell types. Due to this myriad of functions, Wnt/β-catenin signaling is complex, context-dependent, and highly regulated. In this review, we discuss the Wnt/β-catenin signaling pathway, its role in cell-cell adhesion and liver function, and the cell type–specific roles of Wnt/β-catenin signaling as it relates to liver physiology and pathobiology. PMID:29125798

Human liver infiltrating γδ T cells are composed of clonally expanded circulating and tissue-resident populations.

PubMed

Hunter, Stuart; Willcox, Carrie R; Davey, Martin S; Kasatskaya, Sofya A; Jeffery, Hannah C; Chudakov, Dmitriy M; Oo, Ye H; Willcox, Benjamin E

2018-05-18

γδ T-cells comprise a substantial proportion of tissue-associated lymphocytes. However, our current understanding of human γδ T-cells is primarily based on peripheral blood subsets, while the immunobiology of tissue-associated subsets remains largely unclear. To address this, we characterised the TCR diversity, immunophenotype and function of human liver infiltrating γδ T-cells, focussing on the predominant tissue-associated Vδ2 neg γδ subset, which is implicated in liver immunopathology. Intrahepatic Vδ2 neg γδ T-cells were highly clonally focussed, with single expanded clonotypes featuring complex, private TCR rearrangements frequently dominating the compartment. Such T-cells were predominantly CD27 lo/neg effector lymphocytes, whereas naïve CD27 hi , TCR diverse populations present in matched blood were generally absent in the liver. Furthermore, while a CD45RA hi Vδ2 neg γδ effector subset present in both liver and peripheral blood contained overlapping TCR clonotypes, the liver Vδ2 neg γδ T-cell pool also included a phenotypically distinct CD45RA lo effector compartment that was enriched for expression of the tissue tropism marker CD69, the hepatic homing chemokine receptors CXCR3 and CXCR6, and liver-restricted TCR clonotypes, suggestive of intrahepatic tissue residency. Liver infiltrating Vδ2 neg γδ cells were capable of polyfunctional cytokine secretion, and unlike peripheral blood subsets, were responsive to both TCR and innate stimuli. These findings suggest the ability of Vδ2 neg γδ T-cells to undergo clonotypic expansion and differentiation is crucial in permitting access to solid tissues such as the liver, and can result in functionally distinct peripheral and liver-resident memory γδ T-cell subsets. They highlight the inherent functional plasticity within the Vδ2 neg γδ T-cell compartment, and may inform design of cellular therapies involving intrahepatic trafficking of γδ T-cells to suppress liver inflammation or combat liver cancer. γδ T cells are frequently enriched in many solid tissues, however the immunobiology of such tissue-associated subsets in humans has remained unclear. We show that intrahepatic γδ T cells are enriched for clonally expanded effector T cells, whereas naïve γδ T cells are largely excluded; moreover, whereas a distinct proportion of circulating T cell clonotypes was present in both the liver tissue and peripheral blood, a functionally and clonotypically distinct population of liver-resident γδ T cells was also evident. Our findings suggest that factors triggering γδ T cell clonal selection and differentiation, such as infection, can drive enrichment of γδ T cells into liver tissue, allowing the development of functionally distinct tissue-restricted memory populations specialised in local hepatic immunosurveillance. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Functional image-guided stereotactic body radiation therapy planning for patients with hepatocellular carcinoma

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

Tsegmed, Uranchimeg; Kimura, Tomoki, E-mail: tkkimura@hiroshima-u.ac.jp; Nakashima, Takeo

The aim of the current planning study is to evaluate the ability of gadoxetate disodium-enhanced magnetic resonance imaging (EOB-MRI)–guided stereotactic body radiation therapy (SBRT) planning by using intensity-modulated radiation therapy (IMRT) techniques in sparing the functional liver tissues during SBRT for hepatocellular carcinoma. In this study, 20 patients with hepatocellular carcinoma were enrolled. Functional liver tissues were defined according to quantitative liver-spleen contrast ratios ≥ 1.5 on a hepatobiliary phase scan. Functional images were fused with the planning computed tomography (CT) images; the following 2 SBRT plans were designed using a “step-and-shoot” static IMRT technique for each patient: (1) an anatomicalmore » SBRT plan optimization based on the total liver; and (2) a functional SBRT plan based on the functional liver. The total prescribed dose was 48 gray (Gy) in 4 fractions. Dosimetric parameters, including dose to 95% of the planning target volume (PTV D{sub 95%}), percentages of total and functional liver volumes, which received doses from 5 to 30 Gy (V5 to V30 and fV5 to fV30), and mean doses to total and functional liver (MLD and fMLD, respectively) of the 2 plans were compared. Compared with anatomical plans, functional image-guided SBRT plans reduced MLD (mean: plan A, 5.5 Gy; and plan F, 5.1 Gy; p < 0.0001) and fMLD (mean: plan A, 5.4 Gy; and plan F, 4.9 Gy; p < 0.0001), as well as V5 to V30 and fV5 to fV30. No differences were noted in PTV coverage and nonhepatic organs at risk (OARs) doses. In conclusion, EOB-MRI–guided SBRT planning using the IMRT technique may preserve functional liver tissues in patients with hepatocellular carcinoma (HCC).« less

Albumin in chronic liver disease: structure, functions and therapeutic implications.

PubMed

Spinella, Rosaria; Sawhney, Rohit; Jalan, Rajiv

2016-01-01

Human serum albumin is a critical plasma protein produced by the liver with a number of accepted clinical indications in chronic liver disease including management of circulatory and renal dysfunction in patients with ascites. Advanced cirrhosis is characterised by reduced albumin concentration as well as impaired albumin function as a result of specific structural changes and oxidative damage. Traditionally, the biologic and therapeutic role of albumin in liver disease was attributed to its oncotic effects but it is now understood that albumin has a wide range of other important physiologic functions such as immunomodulation, endothelial stabilisation, antioxidant effects and binding multiple drugs, toxins and other molecules. This review discusses the multifunctional properties of albumin and, in particular, the biologic and clinical implications of structural and functional changes of albumin that are associated with cirrhosis. Based on these insights, we explore the current and potential future therapeutic uses of albumin in liver disease.

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

PubMed

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

2016-01-01

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

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

PubMed

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

2008-06-01

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

The SHH/Gli axis regulates CD90-mediated liver cancer stem cell function by activating the IL6/JAK2 pathway.

PubMed

Zhang, Ketao; Che, Siyao; Pan, Chuzhi; Su, Zheng; Zheng, Shangyou; Yang, Shanglin; Zhang, Huayao; Li, Wenda; Wang, Weidong; Liu, Jianping

2018-05-02

The cell surface antigen CD90 has recently been established as a promising marker for liver cancer stem cells. This study aimed to investigate potential implications of SHH/Gli signalling in CD90+ liver cancer stem cells. Correlation of the expression of SHH signalling components and CD90 in liver cancer cells and clinical tissues, as well as in enriched CD90+ liver cancer stem cells and the TCGA database, were analysed by quantitative RT-PCR, Western blotting and flow cytometry. Functional analysis was conducted by siRNA-mediated CD90, Gli1 and Gli3 gene knockdown, SHH treatment and application of the JAK2 inhibitor AZD1480 and IL6 neutralizing antibody in CD90+ liver cancer stem cells, followed by cell proliferation, migration, sphere formation and tumorigenicity assays. CD90 expression exhibited a high positive correlation with Gli1 and Gli3 in multiple liver cancer cell lines and human cancerous liver tissues, both of which showed a significant increase in liver cancer. Analysis of TCGA data revealed an association of CD90, Gli1 and Gli3 with a short overall survival and positive correlation between CD90 expression and Gli3 expression level. The stem cell potentials of CD90+ 97L liver cancer cells were greatly impaired by Gli1/3 knockdown with siRNA but enhanced by SHH treatment. Application of the JAK2 inhibitor AZD1480 and IL6 neutralizing antibody showed the CD90 and SHH/Gli-regulated liver cancer stem cell functions were mediated by the IL6/JAK2/STAT3 pathway. The stem cell properties of CD90+ liver cancer cells are regulated by the downstream SHH/Gli and IL6/JAK2/STAT3 signalling pathways. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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

PubMed Central

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

2009-01-01

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

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.

Simplified technique for auxiliary orthotopic liver transplantation using a whole graft

PubMed Central

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

2015-01-01

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

Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration

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

Obayashi, Yoko, E-mail: youko_oobayashi@ajinomoto.com; Campbell, Jean S.; Fausto, Nelson

Highlights: •Tuberin phosphorylation correlated with mTOR activation in early liver regeneration. •Liver regeneration in the Tsc2+/− mice was not enhanced. •The Tsc2+/− livers failed to accumulate lipid bodies during liver regeneration. •Mortality rate increased in Tsc2+/− mice after partial hepatectomy. •Tuberin plays a critical role in hepatic lipid accumulation to support regeneration. -- Abstract: Tuberin is a negative regulator of mTOR pathway. To investigate the function of tuberin during liver regeneration, we performed 70% hepatectomy on wild-type and Tsc2+/− mice. We found the tuberin phosphorylation correlated with mTOR activation during early liver regeneration in wild-type mice. However, liver regeneration inmore » the Tsc2+/− mice was not enhanced. Instead, the Tsc2+/− livers failed to accumulate lipid bodies, and this was accompanied by increased mortality. These findings suggest that tuberin plays a critical role in liver energy balance by regulating hepatocellular lipid accumulation during early liver regeneration. These effects may influence the role of mTORC1 on cell growth and proliferation.« less

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.

Long-term pathological and immunohistochemical features in the liver after intraoperative whole-liver irradiation in rats.

PubMed

Imaeda, Masumi; Ishikawa, Hitoshi; Yoshida, Yukari; Takahashi, Takeo; Ohkubo, Yu; Musha, Atsushi; Komachi, Mayumi; Nakazato, Yoichi; Nakano, Takashi

2014-07-01

Radiation therapy (RT) has become particularly important recently for treatment of liver tumors, but there are few experimental investigations pertaining to radiation-induced liver injuries over long-term follow-up periods. Thus, the present study examined pathological liver features over a 10-month period using an intraoperative whole-liver irradiation model. Liver function tests were performed in blood samples, whereas cell death, cell proliferation, and fibrotic changes were evaluated pathologically in liver tissues, which were collected from irradiated rats 24 h, 1, 2, 4 and 40 weeks following administration of single irradiation doses of 0 (control), 15 or 30 Gy. The impaired liver function, increased hepatocyte number, and decreased apoptotic cell proportion observed in the 15 Gy group, but not the 30 Gy group, returned to control group levels after 40 weeks; however, the Ki-67 indexes in the 15 Gy group were still higher than those in the control group after 40 weeks. Azan staining showed a fibrotic pattern in the irradiated liver in the 30 Gy group only, but the expression levels of alpha smooth muscle actin (α-SMA) and transforming growth factor-beta 1 (TGF-β1) in both the 15 and 30 Gy groups were significantly higher than those in the control group (P < 0.05). There were differences in the pathological features of the irradiated livers between the 15 Gy and 30 Gy groups, but TGF-β1 and α-SMA expression patterns supported the gradual progression of radiation-induced liver fibrosis in both groups. These findings will be useful in the future development of protective drugs for radiation-induced liver injury. © The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Platelets in liver disease, cancer and regeneration.

PubMed

Kurokawa, Tomohiro; Ohkohchi, Nobuhiro

2017-05-14

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

MicroRNA Expression Profiling in CCl4-Induced Liver Fibrosis of Mus musculus

PubMed Central

Hyun, Jeongeun; Park, Jungwook; Wang, Sihyung; Kim, Jieun; Lee, Hyun-Hee; Seo, Young-Su; Jung, Youngmi

2016-01-01

Liver fibrosis is a major pathological feature of chronic liver diseases, including liver cancer. MicroRNAs (miRNAs), small noncoding RNAs, regulate gene expression posttranscriptionally and play important roles in various kinds of diseases; however, miRNA-associated hepatic fibrogenesis and its acting mechanisms are poorly investigated. Therefore, we performed an miRNA microarray in the fibrotic livers of Mus musculus treated with carbon-tetrachloride (CCl4) and analyzed the biological functions engaged by the target genes of differentially-expressed miRNAs through gene ontology (GO) and in-depth pathway enrichment analysis. Herein, we found that four miRNAs were upregulated and four miRNAs were downregulated more than two-fold in CCl4-treated livers compared to a control liver. Eight miRNAs were predicted to target a total of 4079 genes. GO analysis revealed that those target genes were located in various cellular compartments, including cytoplasm, nucleolus and cell surface, and they were involved in protein-protein or protein-DNA bindings, which influence the signal transductions and gene transcription. Furthermore, pathway enrichment analysis demonstrated that the 72 subspecialized signaling pathways were associated with CCl4-induced liver fibrosis and were mostly classified into metabolic function-related pathways. These results suggest that CCl4 induces liver fibrosis by disrupting the metabolic pathways. In conclusion, we presented several miRNAs and their biological processes that might be important in the progression of liver fibrosis; these findings help increase the understanding of liver fibrogenesis and provide novel ideas for further studies of the role of miRNAs in liver fibrosis. PMID:27322257

[Establishment of a D-galactosamine/lipopolysaccharide induced acute-on-chronic liver failure model in rats].

PubMed

Liu, Xu-hua; Chen, Yu; Wang, Tai-ling; Lu, Jun; Zhang, Li-jie; Song, Chen-zhao; Zhang, Jing; Duan, Zhong-ping

2007-10-01

To establish a practical and reproducible animal model of human acute-on-chronic liver failure for further study of the pathophysiological mechanism of acute-on-chronic liver failure and for drug screening and evaluation in its treatment. Immunological hepatic fibrosis was induced by human serum albumin in Wistar rats. In rats with early-stage cirrhosis (fibrosis stage IV), D-galactosamine and lipopolysaccharide were administered. Mortality and survival time were recorded in 20 rats. Ten rats were sacrificed at 4, 8, and 12 hours. Liver function tests and plasma cytokine levels were measured after D-galactosamine/lipopolysaccharide administration and liver pathology was studied. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Most of the rats treated with human albumin developed cirrhosis and fibrosis, and 90% of them died from acute liver failure after administration of D-galactosamine/lipopolysaccharide, with a mean survival time of (16.1+/-3.7) hours. Liver histopathology showed massive or submassive necrosis of the regenerated nodules, while fibrosis septa were intact. Liver function tests were compatible with massive necrosis of hepatocytes. Plasma level of TNFalpha increased significantly, parallel with the degree of the hepatocytes apoptosis. Plasma IL-10 levels increased similarly as seen in patients with acute-on-chronic liver failure. We established an animal model of acute-on-chronic liver failure by treating rats with human serum albumin and later with D-galactosamine and lipopolysaccharide. TNFalpha-mediated liver cell apoptoses plays a very important role in the pathogenesis of acute liver failure.

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.

p300 Regulates Liver Functions by Controlling p53 and C/EBP Family Proteins through Multiple Signaling Pathways.

PubMed

Breaux, Meghan; Lewis, Kyle; Valanejad, Leila; Iakova, Polina; Chen, Fengju; Mo, Qianxing; Medrano, Estela; Timchenko, Lubov; Timchenko, Nikolai

2015-09-01

The histone acetyltransferase p300 has been implicated in the regulation of liver biology; however, molecular mechanisms of this regulation are not known. In this paper, we examined these mechanisms using transgenic mice expressing a dominant negative p300 molecule (dnp300). While dnp300 mice did not show abnormal growth within 1 year, these mice have many alterations in liver biology and liver functions. We found that the inhibition of p300 leads to the accumulation of heterochromatin foci in the liver of 2-month-old mice. Transcriptome sequencing (RNA-Seq) analysis showed that this inhibition of p300 also causes alterations of gene expression in many signaling pathways, including chromatin remodeling, apoptosis, DNA damage, translation, and activation of the cell cycle. Livers of dnp300 mice have a high rate of proliferation and a much higher rate of proliferation after partial hepatectomy. We found that livers of dnp300 mice are resistant to CCl4-mediated injury and have reduced apoptosis but have increased proliferation after injury. Underlying mechanisms of resistance to liver injury and increased proliferation in dnp300 mice include ubiquitin-proteasome-mediated degradation of C/EBPα and translational repression of the p53 protein by the CUGBP1-eukaryotic initiation factor 2 (eIF2) repressor complex. Our data demonstrate that p300 regulates a number of critical signaling pathways that control liver functions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Cell sources for in vitro human liver cell culture models.

PubMed

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

2016-09-01

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

Cell sources for in vitro human liver cell culture models

PubMed Central

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

2016-01-01

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

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

A Liver Index and its Relationship to Indices of HCC Aggressiveness

PubMed Central

Carr, Brian I; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Ciccarese, Francesca; Rapaccini, Gian Ludovico; Di Marco, Maria; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Masotto, Alberto; Trevisani, Franco

2017-01-01

A Hepatocellular (HCC) Aggressiveness Index was recently constructed, consisting of the sum of the scores for the 4 clinical parameters of maximum tumor size, multifocality, presence of portal vein thrombus and blood alphafetoprotein levels. It was observed that there was an association with several liver function tests. We have now formed a Liver Index from the 4 liver parameters with the highest hazard ratios with respect to HCC aggressiveness, namely: blood total bilirubin, gamma glutamyl transpeptidase (GGTP), albumin and platelet levels (cirrhosis surrogate). We found that the scores for the Liver Index related significantly to survival, but also to the Aggressiveness Index and to its individual HCC components as well as showing significant trends with the components. These results support the hypothesis that liver function is not only an important prognostic factor in HCC patients, but may also be involved in HCC biology and aggressiveness. Blood albumin, GGTP, albumin and platelet levels were used to create a Liver Index that related significantly to parameters of HCC aggressiveness. PMID:28580457

Management of Liver Cancer Argon-helium Knife Therapy with Functional Computer Tomography Perfusion Imaging.

PubMed

Wang, Hongbo; Shu, Shengjie; Li, Jinping; Jiang, Huijie

2016-02-01

The objective of this study was to observe the change in blood perfusion of liver cancer following argon-helium knife treatment with functional computer tomography perfusion imaging. Twenty-seven patients with primary liver cancer treated with argon-helium knife and were included in this study. Plain computer tomography (CT) and computer tomography perfusion (CTP) imaging were conducted in all patients before and after treatment. Perfusion parameters including blood flows, blood volume, hepatic artery perfusion fraction, hepatic artery perfusion, and hepatic portal venous perfusion were used for evaluating therapeutic effect. All parameters in liver cancer were significantly decreased after argon-helium knife treatment (p < 0.05 to all). Significant decrease in hepatic artery perfusion was also observed in pericancerous liver tissue, but other parameters kept constant. CT perfusion imaging is able to detect decrease in blood perfusion of liver cancer post-argon-helium knife therapy. Therefore, CTP imaging would play an important role for liver cancer management followed argon-helium knife therapy. © The Author(s) 2014.

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

PubMed

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

2017-10-01

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

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2017-10-01

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

Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma

PubMed Central

Lacotte, Stéphanie; Slits, Florence; Orci, Lorenzo A.; Meyer, Jeremy; Oldani, Graziano; Gonelle-Gispert, Carmen; Morel, Philippe; Toso, Christian

2016-01-01

ABSTRACT Kupffer cells represent the first line of defense against tumor cells in the liver. Myeloid-derived suppressor cells (MDSC) have recently been observed in the liver parenchyma of tumor-bearing animals. The present study investigates the function of the MDSC subsets, and their impact on Kupffer cell phenotype and function. RIL-175 mouse hepatocellular carcinoma (HCC) cells were injected into the median liver lobe of C57BL/6 mice. Three weeks later, the median lobe hosting the tumor nodule was removed, and Kupffer cells and MDSCs were sorted from the remaining liver. Mouse livers devoid of HCC served as control. Kupffer cells expressed less co-stimulatory CD86 and MHCII and more co-inhibitory CD274 molecules in HCC-bearing livers than in control livers. Corresponding to this phenotype, Kupffer cells from HCC-bearing mice were less efficient in their function as antigen-presenting cells. Three CD11b+ cell populations were identified and sorted from HCC-bearing mice. These cells had various phenotypes with different levels of MDSC-specific surface markers (Ly6Ghigh cells, Gr1high cells, and Ly6Clow cells), and may be considered as bonafide MDSCs given their suppression of antigen-specific T cell proliferation. Primary isolated Kupffer cells in co-culture with the three MDSC subsets showed a decrease in CCL2 and IL-18 secretion, and an increase in IL-10 and IL-1β secretion, and an increased expression of CD86, CD274, and MHCII. In conclusion, these data demonstrated the existence of three MDSC subsets in HCC-bearing animals. These cells altered Kupffer cell function and may decrease the migration and activation of anticancer effector cells in the liver. PMID:27999748

Advances in hepatic stem/progenitor cell biology

PubMed Central

Verhulst, Stefaan; Best, Jan; van Grunsven, Leo A.; Dollé, Laurent

2015-01-01

The liver is famous for its strong regenerative capacity, employing different modes of regeneration according to type and extent of injury. Mature liver cells are able to proliferate in order to replace the damaged tissue allowing the recovery of the parenchymal function. In more severe scenarios hepatocytes are believed to arise also from a facultative liver progenitor cell compartment. In human, severe acute liver failure and liver cirrhosis are also both important clinical targets in which regeneration is impaired, where the role of this stem cell compartment seems more convincing. In animal models, the current state of ambiguity regarding the identity and role of liver progenitor cells in liver physiology dampens the enthusiasm for the potential use of these cells in regenerative medicine. The aim of this review is to give the basics of liver progenitor cell biology and discuss recent results vis-à-vis their identity and contribution to liver regeneration. PMID:26600740

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

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.

Anthocyanins Delay Ageing-Related Degenerative Changes in the Liver.

PubMed

Wei, Jie; Zhang, Guokun; Zhang, Xiao; Xu, Dexin; Gao, Jun; Fan, Jungang

2017-12-01

Liver ageing is a significant risk factor for chronic liver diseases. Anthocyanin is a food additive that has previously shown efficacy in increasing longevity. Here, we tested whether anthocyanins could protect young mice from accelerated ageing of the liver. Kunming mice were injected with D-galactose to accelerate ageing and were given 20 or 40 mg/kg anthocyanins as an intervention. After eight weeks, whole liver function and structure were evaluated, and the expression levels of genes involved in the DNA damage signalling pathway were assessed by Western blot analysis. Anthocyanins delayed the reduction of the liver index (p < 0.05), hepatic tissue injury and fibrosis. Anthocyanins also maintained the stability of the redox system (GSH-PX, T-SOD and MDA) in plasma and liver structures (p < 0.001) and reduced the levels of inflammatory factors (IL-1, IL-6 and TNF-α) in the liver (p < 0.05). Moreover, the expression levels of sensors (ATM and ATR), mediators (H2AX and γ-H2AX) and effectors (Chk1, Chk2, p53 and p-p53) in the DNA damage signalling pathway were all reduced. Anthocyanins could be widely used in the field of health products to slow ageing-related deterioration of liver function and structure by inhibiting DNA damage.

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

Wang, Hesheng, E-mail: hesheng@umich.edu; Feng, Mary; Jackson, Andrew

Purpose: To develop a local and global function model in the liver based on regional and organ function measurements to support individualized adaptive radiation therapy (RT). Methods and Materials: A local and global model for liver function was developed to include both functional volume and the effect of functional variation of subunits. Adopting the assumption of parallel architecture in the liver, the global function was composed of a sum of local function probabilities of subunits, varying between 0 and 1. The model was fit to 59 datasets of liver regional and organ function measures from 23 patients obtained before, during, andmore » 1 month after RT. The local function probabilities of subunits were modeled by a sigmoid function in relating to MRI-derived portal venous perfusion values. The global function was fitted to a logarithm of an indocyanine green retention rate at 15 minutes (an overall liver function measure). Cross-validation was performed by leave-m-out tests. The model was further evaluated by fitting to the data divided according to whether the patients had hepatocellular carcinoma (HCC) or not. Results: The liver function model showed that (1) a perfusion value of 68.6 mL/(100 g · min) yielded a local function probability of 0.5; (2) the probability reached 0.9 at a perfusion value of 98 mL/(100 g · min); and (3) at a probability of 0.03 [corresponding perfusion of 38 mL/(100 g · min)] or lower, the contribution to global function was lost. Cross-validations showed that the model parameters were stable. The model fitted to the data from the patients with HCC indicated that the same amount of portal venous perfusion was translated into less local function probability than in the patients with non-HCC tumors. Conclusions: The developed liver function model could provide a means to better assess individual and regional dose-responses of hepatic functions, and provide guidance for individualized treatment planning of RT.« less

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

PubMed Central

Li, R; Barton, HA; Maurer, TS

2015-01-01

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

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.

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.

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

PubMed

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

2018-05-01

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

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

PubMed

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

2018-06-20

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

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

PubMed

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

2011-10-01

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

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.

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

PubMed Central

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

2012-01-01

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

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.

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.

CT liver volumetry using geodesic active contour segmentation with a level-set algorithm

NASA Astrophysics Data System (ADS)

Suzuki, Kenji; Epstein, Mark L.; Kohlbrenner, Ryan; Obajuluwa, Ademola; Xu, Jianwu; Hori, Masatoshi; Baron, Richard

2010-03-01

Automatic liver segmentation on CT images is challenging because the liver often abuts other organs of a similar density. Our purpose was to develop an accurate automated liver segmentation scheme for measuring liver volumes. We developed an automated volumetry scheme for the liver in CT based on a 5 step schema. First, an anisotropic smoothing filter was applied to portal-venous phase CT images to remove noise while preserving the liver structure, followed by an edge enhancer to enhance the liver boundary. By using the boundary-enhanced image as a speed function, a fastmarching algorithm generated an initial surface that roughly estimated the liver shape. A geodesic-active-contour segmentation algorithm coupled with level-set contour-evolution refined the initial surface so as to more precisely fit the liver boundary. The liver volume was calculated based on the refined liver surface. Hepatic CT scans of eighteen prospective liver donors were obtained under a liver transplant protocol with a multi-detector CT system. Automated liver volumes obtained were compared with those manually traced by a radiologist, used as "gold standard." The mean liver volume obtained with our scheme was 1,520 cc, whereas the mean manual volume was 1,486 cc, with the mean absolute difference of 104 cc (7.0%). CT liver volumetrics based on an automated scheme agreed excellently with "goldstandard" manual volumetrics (intra-class correlation coefficient was 0.95) with no statistically significant difference (p(F<=f)=0.32), and required substantially less completion time. Our automated scheme provides an efficient and accurate way of measuring liver volumes.

Cholangiocarcinoma

MedlinePlus

... microscope Blood tests that may be done include: Liver function tests (especially alkaline phosphatase or bilirubin levels) Complete blood count (CBC) Treatment ... and may result in a cure. If the tumor is large, the entire liver may need to be removed and a liver ...

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

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

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

2014-07-15

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

Short and long-term soy diet vs. casein protects liver steatosis independent of the arginine content

USDA-ARS?s Scientific Manuscript database

Non-alcoholic fatty liver disease (NAFLD), the major cause of abnormal liver function, is often associated with obesity. Arginine (ARG) plays a role in modulating body weight/fat, but there are limited data as to the role that ARG may play in soy protein’s ability to protect from liver steatosis. Th...

Practice-Based Recommendations from the American Society of Transplantation Liver and Intestine Community of Practice

PubMed Central

Levitsky, J.; O’Leary, J.G.; Asrani, S.; Sharma, P.; Fung, J.; Wiseman, A.; Niemann, C.U.

2016-01-01

Acute and chronic kidney disease after liver transplantation is common and results in significant morbidity and mortality. The introduction of MELD has directly correlated with an increased prevalence of perioperative renal dysfunction and the number of simultaneous liver-kidney transplants performed. Thus, kidney dysfunction in this population is typically multifactorial and related to pre-existing conditions, pre-transplant renal injury, peri-operative events, and post-transplant nephrotoxic immunosuppressive therapies. The management of kidney disease following liver transplantation is challenging, as by the time the serum creatinine is significantly elevated, few interventions impact the course of progression. Also, immunological factors such as antibody-mediated rejection have become of greater interest given the rising liver-kidney transplant population. Therefore this review, assembled by experts in the field and endorsed by the American Society of Transplantation Liver and Intestinal Community of Practice, provides a critical assessment of measures of renal function and interventions aimed at preserving renal function early and late after liver and simultaneous liver-kidney transplantation. Key points and practice-based recommendations for the prevention and management of kidney injury in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations. PMID:26932352

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

PubMed

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

2018-06-01

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

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

PubMed

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

2016-06-01

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

Accurate Prediction of Drug-Induced Liver Injury Using Stem Cell-Derived Populations

PubMed Central

Szkolnicka, Dagmara; Farnworth, Sarah L.; Lucendo-Villarin, Baltasar; Storck, Christopher; Zhou, Wenli; Iredale, John P.; Flint, Oliver

2014-01-01

Despite major progress in the knowledge and management of human liver injury, there are millions of people suffering from chronic liver disease. Currently, the only cure for end-stage liver disease is orthotopic liver transplantation; however, this approach is severely limited by organ donation. Alternative approaches to restoring liver function have therefore been pursued, including the use of somatic and stem cell populations. Although such approaches are essential in developing scalable treatments, there is also an imperative to develop predictive human systems that more effectively study and/or prevent the onset of liver disease and decompensated organ function. We used a renewable human stem cell resource, from defined genetic backgrounds, and drove them through developmental intermediates to yield highly active, drug-inducible, and predictive human hepatocyte populations. Most importantly, stem cell-derived hepatocytes displayed equivalence to primary adult hepatocytes, following incubation with known hepatotoxins. In summary, we have developed a serum-free, scalable, and shippable cell-based model that faithfully predicts the potential for human liver injury. Such a resource has direct application in human modeling and, in the future, could play an important role in developing renewable cell-based therapies. PMID:24375539

Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

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

Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori

Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxicmore » compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression via ERα.« less

Surgical anatomy of the liver, hepatic vasculature and bile ducts in the rat.

PubMed

Martins, Paulo Ney Aguiar; Neuhaus, Peter

2007-04-01

The rat is the most used experimental model in surgical research. Virtually all procedures in clinical liver surgery can be performed in the rat. However, the use of the rat model in liver surgery is limited by its small size and limited knowledge of the liver anatomy. As in humans, the rat liver vasculature and biliary system have many anatomical variations. The development of surgical techniques, and the study of liver function and diseases require detailed knowledge of the regional anatomy. The objective of this study was to describe and illustrate systematically the surgical anatomy of the rat liver to facilitate the planning and performance of studies in this animal. Knowledge of the diameter and length of liver vessels is also important for the selection of catheters and perivascular devices. Twelve Wistar rat livers were dissected using a surgical microscope. Hepatic and extrahepatic anatomical structures were measured under magnification with a millimeter scale. In this study, we describe the rat liver topographical anatomy, compare it with the human liver and review the literature. Increased knowledge of the rat liver anatomy and microsurgical skills permit individualized dissection, parenchymal section, embolization and ligature of vascular and biliary branches.

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

Blood mercury concentrations are associated with decline in liver function in an elderly population: a panel study.

PubMed

Lee, Mee-Ri; Lim, Youn-Hee; Lee, Bo-Eun; Hong, Yun-Chul

2017-03-04

Mercury is a toxic heavy metal and is known to affect many diseases. However, few studies have examined the effects of mercury exposure on liver function in the general population. We examined the association between blood mercury concentrations and liver enzyme levels in the elderly. We included 560 elderly participants (60 years or older) who were recruited from 2008 to 2010 and followed up to 2014. Subjects visited a community welfare center and underwent a medical examination and measurement of mercury levels up to five times. Analyses using generalized estimating equations model were performed after adjusting for age, sex, education, overweight, alcohol consumption, smoking, regular exercise, high-density lipoproteins cholesterol, and total calorie intake. Additionally, we estimated interaction effects of alcohol consumption with mercury and mediation effect of oxidative stress in the relationship between mercury levels and liver function. The geometric mean (95% confidence interval (CI)) of blood mercury concentrations was 2.81 μg/L (2.73, 2.89). Significant relationships were observed between blood mercury concentrations and the level of liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT), after adjusting for potential confounders (P < 0.05). The odds ratios of having abnormal ALT levels were statistically significant in the highest mercury quartile compared to those with the lowest quartile. Particularly, regular alcohol drinkers showed greater effect estimates of mercury on the liver function than non-drinkers groups. There was no mediation effect of oxidative stress in the relationship between blood mercury concentrations and liver function. Our results suggest that blood mercury levels are associated with elevated liver enzymes and interact with alcohol consumption for the association in the elderly.

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.

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

PubMed

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

2016-08-05

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

Hepatic steatosis and non-alcoholic fatty liver disease are not associated with decline in renal function in people with Type 2 diabetes.

PubMed

Jenks, S J; Conway, B R; Hor, T J; Williamson, R M; McLachlan, S; Robertson, C; Morling, J R; Strachan, M W J; Price, J F

2014-09-01

We aimed to determine whether the presence of hepatic steatosis and/or non-alcoholic fatty liver disease was associated with decline in renal function or onset of microalbuminuria in a cohort of people with Type 2 diabetes, including those managed in both primary and secondary care. Nine hundred and thirty-three patients from the Edinburgh Type 2 Diabetes Study, a cohort of Scottish men and women aged 60-74 years with Type 2 diabetes, underwent assessment for hepatic steatosis by liver ultrasonography 1 year after recruitment. Non-alcoholic fatty liver disease was defined as the presence of steatosis following exclusion of secondary causes of liver disease. Patients were followed for 4 years and decline in renal function was assessed by the change in estimated glomerular filtration rate over time. Of the 933 subjects, 530 had hepatic steatosis and, of those with hepatic steatosis, 388 had non-alcoholic fatty liver disease. Neither hepatic steatosis nor non-alcoholic fatty liver disease were significantly associated with rate of decline in renal function, with the mean rate of decline in estimated glomerular filtration rate being -1.55 ml min(-1) 1.73 m(-2) per year for participants with hepatic steatosis compared with -1.84 ml min(-1) 1.73 m(-2) for those without steatosis (P = 0.19). Similar results were obtained when the analysis was restricted to participants with and without non-alcoholic fatty liver disease (-1.44 vs. -1.64 ml min(-1) 1.73 m(-2) per year, respectively; P = 0.44). Additionally, neither hepatic steatosis nor non-alcoholic fatty liver disease were associated with the onset or regression of albuminuria during follow-up (all P ≥ 0.05). The presence of hepatic steatosis/non-alcoholic fatty liver disease was not associated with decline in renal function during a 4-year follow-up in our cohort of older people with Type 2 diabetes. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice

PubMed Central

Williams, Jessica A.; Ni, Hong-Min; Ding, Yifeng

2015-01-01

Alcoholic liver disease claims two million lives per year. We previously reported that autophagy protected against alcohol-induced liver injury and steatosis by removing damaged mitochondria. However, the mechanisms for removal of these mitochondria are unknown. Parkin is an evolutionarily conserved E3 ligase that is recruited to damaged mitochondria to initiate ubiquitination of mitochondrial outer membrane proteins and subsequent mitochondrial degradation by mitophagy. In addition to its role in mitophagy, Parkin has been shown to have other roles in maintaining mitochondrial function. We investigated whether Parkin protected against alcohol-induced liver injury and steatosis using wild-type (WT) and Parkin knockout (KO) mice treated with alcohol by the acute-binge and Gao-binge (chronic plus acute-binge) models. We found that Parkin protected against liver injury in both alcohol models, likely because of Parkin's role in maintaining a population of healthy mitochondria. Alcohol caused greater mitochondrial damage and oxidative stress in Parkin KO livers compared with WT livers. After alcohol treatment, Parkin KO mice had severely swollen and damaged mitochondria that lacked cristae, which were not seen in WT mice. Furthermore, Parkin KO mice had decreased mitophagy, β-oxidation, mitochondrial respiration, and cytochrome c oxidase activity after acute alcohol treatment compared with WT mice. Interestingly, liver mitochondria seemed able to adapt to alcohol treatment, but Parkin KO mouse liver mitochondria had less capacity to adapt to Gao-binge treatment compared with WT mouse liver mitochondria. Overall, our findings indicate that Parkin is an important mediator of protection against alcohol-induced mitochondrial damage, steatosis, and liver injury. PMID:26159696

Caspase-3/7-mediated Cleavage of β2-spectrin is Required for Acetaminophen-induced Liver Damage

PubMed Central

Baek, Hye Jung; Lee, Yong Min; Kim, Tae Hyun; Kim, Joo-Young; Park, Eun Jung; Iwabuchi, Kuniyoshi; Mishra, Lopa; Kim, Sang Soo

2016-01-01

The ubiquitously expressed β2-spectrin (β2SP, SPTBN1) is the most common non-erythrocytic member of the β-spectrin gene family. Loss of β2-spectrin leads to defects in liver development, and its haploinsufficiency spontaneously leads to chronic liver disease and the eventual development of hepatocellular cancer. However, the specific role of β2-spectrin in liver homeostasis remains to be elucidated. Here, we reported that β2-spectrin was cleaved by caspase-3/7 upon treatment with acetaminophen which is the main cause of acute liver injury. Blockage of β2-spectrin cleavage robustly attenuated β2-spectrin-specific functions, including regulation of the cell cycle, apoptosis, and transcription. Cleaved fragments of β2-spectrin were physiologically active, and the N- and C-terminal fragments retained discrete interaction partners and activity in transcriptional regulation and apoptosis, respectively. Cleavage of β2-spectrin facilitated the redistribution of the resulting fragments under conditions of liver damage induced by acetaminophen. In contrast, downregulation of β2-spectrin led to resistance to acetaminophen-induced cytotoxicity, and its insufficiency in the liver promoted suppression of acetaminophen-induced liver damage and enhancement of liver regeneration. Conclusions: β2-Spectrin, a TGF-β mediator and signaling molecule, is cleaved and activated by caspase-3/7, consequently enhancing apoptosis and transcriptional control to determine cell fate upon liver damage. These findings have extended our knowledge on the spectrum of β2-spectrin functions from a scaffolding protein to a target and transmitter of TGF-β in liver damage. PMID:26884715

Abate Cytochrome C induced apoptosome to protect donor liver against ischemia reperfusion injury on rat liver transplantation model.

PubMed

Zhuang, Zhuonan; Lian, Peilong; Wu, Xiaojuan; Shi, Baoxu; Zhuang, Maoyou; Zhou, Ruiling; Zhao, Rui; Zhao, Zhen; Guo, Sen; Ji, Zhipeng; Xu, Kesen

2016-01-01

Aim of this study is to protect donor liver against ischemia-reperfusion injury by abating Cytochrome C induced apoptosome on rat model. A total of 25 clean SD inbred male rats were used in this research. The rats in ischemia-reperfusion injury group (I/R group, n=5) were under liver transplantation operation; rats in dichloroacetate diisopropylamine group (DADA group, n=5) were treated DADA before liver transplantation; control group (Ctrl group, n=5); other 10 rats were used to offer donor livers. In DADA therapy group, Cytochrome C expression in donor hepatocellular cytoplasm was detected lower than that in I/R group. And the Cytochrome C induced apoptosome was also decreased in according to the lower expressions of Apaf-1 and Caspase3. Low level of cleaved PARP expression revealed less apoptosis in liver tissue. The morphology of donor liver mitochondria in DADA group was observed to be slightly edema but less than I/R group after operation 12 h. The liver function indexes of ALT and AST in serum were tested, and the results in DADA group showed it is significantly lower than I/R group after operation 12 h. The inflammation indexes of IL-6 and TNF-α expressions in DADA group were significantly lower than that in I/R group after operation 24 h. The dichloroacetate diisopropylamine treatment could protect the hepatocellular mitochondria in case of the spillage of Cytochrome C induced apoptosome, and protect the liver against ischemia-reperfusion injury. Thus, it may be a method to promote the recovery of donor liver function after transplantation.

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

PubMed

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

2016-11-01

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

Transient postpartum diabetes insipidus associated with HELLP syndrome.

PubMed

Ellidokuz, Ender; Uslan, Ihsan; Demir, Serap; Cevrioglu, Serhan; Tufan, Gulnihal

2006-12-01

Diabetes insipidus in pregnancy has different causes. The association of diabetes insipidus with disturbances of liver function has been reported, however, diabetes insipidus has rarely been reported in HELLP syndrome. We present a 23-year-old primigravida with a singleton gestation complicated by HELLP syndrome who developed postpartum diabetes insipidus. Labor was induced promptly to terminate pregnancy because of intrauterine fetal death and liver dysfunction. 1-deamino-8-D-arginine-vasopressin was administered. Diabetes insipidus and liver dysfunction resolved within 2 weeks. Development of diabetes insipidus may result from increased vasopressinase activity mainly caused by deterioration of liver functions caused by HELLP syndrome. In pregnant women with liver disease as a result of any cause, the development of diabetes insipidus should be assessed with particular attention.

Liver ERα regulates AgRP neuronal activity in the arcuate nucleus of female mice.

PubMed

Benedusi, Valeria; Della Torre, Sara; Mitro, Nico; Caruso, Donatella; Oberto, Alessandra; Tronel, Claire; Meda, Clara; Maggi, Adriana

2017-04-26

Recent work revealed the major role played by liver Estrogen Receptor α (ERα) in the regulation of metabolic and reproductive functions. By using mutant mice with liver-specific ablation of Erα, we here demonstrate that the hepatic ERα is essential for the modulation of the activity of Agouti Related Protein (AgRP) neurons in relation to the reproductive cycle and diet. Our results suggest that the alterations of hepatic lipid metabolism due to the lack of liver ERα activity are responsible for a neuroinflammatory status that induces refractoriness of AgRP neurons to reproductive and dietary stimuli. The study therefore points to the liver ERα as a necessary sensor for the coordination of systemic energy metabolism and reproductive functions.

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

PubMed

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

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

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

PubMed

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

2018-03-24

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

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.

Presentation of an acquired urea cycle disorder post liver transplantation.

PubMed

Ghabril, Marwan; Nguyen, Justin; Kramer, David; Genco, Trina; Mai, Martin; Rosser, Barry G

2007-12-01

The liver's role as the largest organ of metabolism and the unique and often critical function of liver-specific enzyme pathways imply a greater risk to the recipient of acquiring a donor metabolic disease with liver transplants versus other solid organ transplants. With clinical consequences rarely reported, the frequency of solid organ transplant transfer of metabolic disease is not known. Ornithine transcarbamylase deficiency (OTCD), although rare, is the most common of the urea cycle disorders (UCDs). Because of phenotypic heterogeneity, OTCD may go undiagnosed into adulthood. With over 5000 liver transplant procedures annually in the United States, the likelihood of unknowingly transmitting OTCD through liver transplantation is very low. We describe the clinical course of a liver transplant recipient presenting with acute hyperammonemia and encephalopathy after receiving a liver graft form a donor with unrecognized OTCD. Copyright (c) 2007 AASLD.

A comparison of liver function after hepatectomy with inflow occlusion between sevoflurane and propofol anesthesia.

PubMed

Song, J C; Sun, Y M; Yang, L Q; Zhang, M Z; Lu, Z J; Yu, W F

2010-10-01

In this study, we compared liver function tests after hepatectomy with inflow occlusion as a function of propofol versus sevoflurane anesthesia. One hundred patients undergoing elective liver resection with inflow occlusion were randomized into a sevoflurane group or a propofol group. General anesthesia was induced with 3 μg/kg fentanyl, 0.2 mg/kg cisatracurium, and target-controlled infusion of propofol, set at a plasma target concentration of 4 to 6 μg/mL, or sevoflurane initially started at 8%. Anesthesia was maintained with target-controlled infusion of propofol (2-4 μg/mL) or sevoflurane (1.5%-2.5%). The primary end point was postoperative liver injury assessed by peak values of liver transaminases. Transaminase levels peaked between the first and the third postoperative day. Peak alanine aminotransferase was 504 and 571 U/L in the sevoflurane group and the propofol group, respectively. Peak aspartate aminotransferase was 435 U/L after sevoflurane and 581 U/L in the propofol group. There were no significant differences in peak alanine aminotransferase or peak aspartate aminotransferase between groups. Other liver function tests including bilirubin and alkaline phosphatase, and peak values of white blood cell counts and creatinine, were also not different between groups. Sevoflurane and propofol anesthetics resulted in similar patterns of liver function tests after hepatectomy with inflow occlusion. These data suggest that the 2 anesthetics are equivalent in this clinical context.

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

PubMed

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

2016-09-01

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

[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.

In Vitro Generation of Functional Liver Organoid-Like Structures Using Adult Human Cells.

PubMed

Ramachandran, Sarada Devi; Schirmer, Katharina; Münst, Bernhard; Heinz, Stefan; Ghafoory, Shahrouz; Wölfl, Stefan; Simon-Keller, Katja; Marx, Alexander; Øie, Cristina Ionica; Ebert, Matthias P; Walles, Heike; Braspenning, Joris; Breitkopf-Heinlein, Katja

2015-01-01

In this study we used differentiated adult human upcyte® cells for the in vitro generation of liver organoids. Upcyte® cells are genetically engineered cell strains derived from primary human cells by lenti-viral transduction of genes or gene combinations inducing transient proliferation capacity (upcyte® process). Proliferating upcyte® cells undergo a finite number of cell divisions, i.e., 20 to 40 population doublings, but upon withdrawal of proliferation stimulating factors, they regain most of the cell specific characteristics of primary cells. When a defined mixture of differentiated human upcyte® cells (hepatocytes, liver sinusoidal endothelial cells (LSECs) and mesenchymal stem cells (MSCs)) was cultured in vitro on a thick layer of Matrigel™, they self-organized to form liver organoid-like structures within 24 hours. When further cultured for 10 days in a bioreactor, these liver organoids show typical functional characteristics of liver parenchyma including activity of cytochromes P450, CYP3A4, CYP2B6 and CYP2C9 as well as mRNA expression of several marker genes and other enzymes. In summary, we hereby describe that 3D functional hepatic structures composed of primary human cell strains can be generated in vitro. They can be cultured for a prolonged period of time and are potentially useful ex vivo models to study liver functions.

Early outcomes of liver transplants in patients receiving organs from hypernatremic donors.

PubMed

Khosravi, Mohammad Bagher; Firoozifar, Mohammad; Ghaffaripour, Sina; Sahmeddini, Mohammad Ali; Eghbal, Mohammad Hossien

2013-12-01

Uncorrected hypernatremia in organ donors has been associated with poor graft or patient survival during liver transplants. However, recent studies have found no association between the donor serum sodium and transplant outcome. This study sought to show the negative effect donor hypernatremia has on initial liver allograft function. This is the first study to investigate international normalized ratio and renal factors of patients with normal and those with hypernatremic donor livers. This study was conducted at the Shiraz Transplant Research Center in Shiraz, Iran, between May 2009, and July 2011. Four hundred seven consecutive adult orthotopic liver transplants were performed at the University of Shiraz Medical Center. There were 93 donors in the group with hypernatremia with terminal serum sodium of 155 mEq/L or greater (group 1), and 314 with terminal serum sodium less than 155 mEq/L (group 2). Posttransplant data after 5 days showed that aspartate aminotransferase, alanine aminotransferase, international normalized ratio, and kidney function did not differ between the groups. Hypernatremia is the most important complication after brain death. Previous studies have suggested donor hypernatremia results in a greater incidence of early postoperative graft dysfunction in liver transplant and is considered one of the extended criteria donor. However, in recent years, this hypothesis has been questioned. Our study shows no difference between patients' initial results of liver and kidney functioning with normal and hypernatremic donor livers. This is the first study to investigate international normalized ratio as a fundamental factor in defining early allograft dysfunction and renal factors between patients with normal and hypernatremic donor's livers.

Recellularization via the bile duct supports functional allogenic and xenogenic cell growth on a decellularized rat liver scaffold.

PubMed

Hassanein, Wessam; Uluer, Mehmet C; Langford, John; Woodall, Jhade D; Cimeno, Arielle; Dhru, Urmil; Werdesheim, Avraham; Harrison, Joshua; Rivera-Pratt, Carlos; Klepfer, Stephen; Khalifeh, Ali; Buckingham, Bryan; Brazio, Philip S; Parsell, Dawn; Klassen, Charlie; Drachenberg, Cinthia; Barth, Rolf N; LaMattina, John C

2017-01-02

Recent years have seen a proliferation of methods leading to successful organ decellularization. In this experiment we examine the feasibility of a decellularized liver construct to support growth of functional multilineage cells. Bio-chamber systems were used to perfuse adult rat livers with 0.1% SDS for 24 hours yielding decellularized liver scaffolds. Initially, we recellularized liver scaffolds using a human tumor cell line (HepG2, introduced via the bile duct). Subsequent studies were performed using either human tumor cells co-cultured with human umbilical vein endothelial cells (HUVECs, introduced via the portal vein) or rat neonatal cell slurry (introduced via the bile duct). Bio-chambers were used to circulate oxygenated growth medium via the portal vein at 37C for 5-7 days. Human HepG2 cells grew readily on the scaffold (n = 20). HepG2 cells co-cultured with HUVECs demonstrated viable human endothelial lining with concurrent hepatocyte growth (n = 10). In the series of neonatal cell slurry infusion (n = 10), distinct foci of neonatal hepatocytes were observed to repopulate the parenchyma of the scaffold. The presence of cholangiocytes was verified by CK-7 positivity. Quantitative albumin measurement from the grafts showed increasing albumin levels after seven days of perfusion. Graft albumin production was higher than that observed in traditional cell culture. This data shows that rat liver scaffolds support human cell ingrowth. The scaffold likewise supported the engraftment and survival of neonatal rat liver cell slurry. Recellularization of liver scaffolds thus presents a promising model for functional liver engineering.

Iron overload and HFE gene mutations in Polish patients with liver cirrhosis.

PubMed

Sikorska, Katarzyna; Romanowski, Tomasz; Stalke, Piotr; Iżycka-Świeszewska, Ewa; Bielawski, Krzysztof Piotr

2011-06-01

Increased liver iron stores may contribute to the progression of liver injury and fibrosis, and are associated with a higher risk of hepatocellular carcinoma development. Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients. HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins. This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis. Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases. Liver function tests and serum iron markers were assessed in both groups. All patients were screened for HFE mutations (C282Y, H63D, S65C). Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes. The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis. There were no differences in the prevalence of all HFE mutations in both groups. In patients with a diagnosis of hepatocellular carcinoma, no significant associations with iron disorders and HFE gene mutations were found. Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations. Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis. As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease, there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis.

Tocotrienols Reverse Cardiovascular, Metabolic and Liver Changes in High Carbohydrate, High Fat Diet-Fed Rats

PubMed Central

Wong, Weng-Yew; Poudyal, Hemant; Ward, Leigh C.; Brown, Lindsay

2012-01-01

Tocotrienols have been reported to improve lipid profiles, reduce atherosclerotic lesions, decrease blood glucose and glycated haemoglobin concentrations, normalise blood pressure in vivo and inhibit adipogenesis in vitro, yet their role in the metabolic syndrome has not been investigated. In this study, we investigated the effects of palm tocotrienol-rich fraction (TRF) on high carbohydrate, high fat diet-induced metabolic, cardiovascular and liver dysfunction in rats. Rats fed a high carbohydrate, high fat diet for 16 weeks developed abdominal obesity, hypertension, impaired glucose and insulin tolerance with increased ventricular stiffness, lower systolic function and reduced liver function. TRF treatment improved ventricular function, attenuated cardiac stiffness and hypertension, and improved glucose and insulin tolerance, with reduced left ventricular collagen deposition and inflammatory cell infiltration. TRF improved liver structure and function with reduced plasma liver enzymes, inflammatory cell infiltration, fat vacuoles and balloon hepatocytes. TRF reduced plasma free fatty acid and triglyceride concentrations but only omental fat deposition was decreased in the abdomen. These results suggest that tocotrienols protect the heart and liver, and improve plasma glucose and lipid profiles with minimal changes in abdominal obesity in this model of human metabolic syndrome. PMID:23201770

Increase in left liver lobe function after preoperative right portal vein embolisation assessed with gadolinium-EOB-DTPA MRI.

PubMed

Geisel, Dominik; Lüdemann, Lutz; Keuchel, Thomas; Malinowski, Maciej; Seehofer, Daniel; Stockmann, Martin; Hamm, Bernd; Gebauer, Bernhard; Denecke, Timm

2013-09-01

To prospectively evaluate the early development of regional liver function after right portal vein embolisation (PVE) with Gd-EOB-DTPA-enhanced MRI in patients scheduled for extended right hemihepatectomy. Ten patients who received a PVE before an extended hemihepatectomy were examined before and 14 days after PVE using Gd-EOB-DTPA-enhanced MRI of the liver. In these sequences representative region of interest measurements were performed in the embolised right (RLL) and the non-embolised left liver lobe (LLL). The volume as well as hepatic uptake index (HUI) was calculated independently for each lobe. Relative enhancement 14 days after PVE decreased in the RLL and increased significantly in the LLL (P < 0.05). Average hepatic uptake index (HUI) for RLL was significantly lower 14 days after PVE than before PVE (P < 0.05) and significantly higher for LLL (P < 0.05). A significant shift of contrast uptake from the right to the left liver lobe can be depicted as early as 14 days after right PVE by using Gd-EOB-DTPA-enhanced MRI, which could reflect the redirected portal venous blood flow and the rapid utilisation of a hepatic functional reserve. • Preoperative portal vein embolisation (PVE) is widely performed before right-sided hepatic resection. • PVE increases intravenous contrast medium uptake in the left lobe of liver. • The hepatic uptake index for the left liver lobe increases rapidly after PVE. • Left liver lobe function increase may be visualised by Gd-EOB-DTPA-enhanced MRI.

Metabolism of 7-ethyoxycoumarin by Isolated Perfused Rainbow Trout Livers

EPA Science Inventory

Isolated trout livers were perfused using methods designed to preserve tissue viability and function. Liver performance was evaluated by measuring O2 consumption, vascular resistance, K+ leakage, glucose flux, lactate flux, alanine aminotransferase leakage, and metabolic clearanc...

Ascites: A Common Problem in People with Cirrhosis

MedlinePlus

... liver (portal hypertension) and a decrease in liver function caused by scarring of the liver, i.e., cirrhosis. Symptoms Most patients who develop ascites notice abdominal distension and rapid weight gain. Some people also develop swelling of ankles and ...

Shear wave elastography results correlate with liver fibrosis histology and liver function reserve.

PubMed

Feng, Yan-Hong; Hu, Xiang-Dong; Zhai, Lin; Liu, Ji-Bin; Qiu, Lan-Yan; Zu, Yuan; Liang, Si; Gui, Yu; Qian, Lin-Xue

2016-05-07

To evaluate the correlation of shear wave elastography (SWE) results with liver fibrosis histology and quantitative function reserve. Weekly subcutaneous injection of 60% carbon tetrachloride (1.5 mL/kg) was given to 12 canines for 24 wk to induce experimental liver fibrosis, with olive oil given to 2 control canines. At 24 wk, liver condition was evaluated using clinical biochemistry assays, SWE imaging, lidocaine metabolite monoethylglycine-xylidide (MEGX) test, and histologic fibrosis grading. Clinical biochemistry assays were performed at the institutional central laboratory for routine liver function evaluation. Liver stiffness was measured in triplicate from three different intercostal spaces and expressed as mean liver stiffness modulus (LSM). Plasma concentrations of lidocaine and its metabolite MEGX were determined using high-performance liquid chromatography repeated in duplicate. Liver biopsy samples were fixed in 10% formaldehyde, and liver fibrosis was graded using the modified histological activity index Knodell score (F0-F4). Correlations among histologic grading, LSM, and MEGX measures were analyzed with the Pearson linear correlation coefficient. At 24 wk liver fibrosis histologic grading was as follows: F0, n = 2 (control); F1, n = 0; F2, n = 3; F3, n = 7; and F4, n = 2. SWE LSM was positively correlated with histologic grading (r = 0.835, P < 0.001). Specifically, the F4 group had a significantly higher elastic modulus than the F3, F2, and F0 groups (P = 0.002, P = 0.003, and P = 0.006, respectively), and the F3 group also had a significantly higher modulus than the control F0 group (P = 0.039). LSM was negatively associated with plasma MEGX concentrations at 30 min (r = -0.642; P = 0.013) and 60 min (r = -0.651; P = 0.012), time to ½ of the maximum concentration (r = -0.538; P = 0.047), and the area under the curve (r = -0.636; P = 0.014). Multiple comparisons showed identical differences in these three measures: significantly lower with F4 (P = 0.037) and F3 (P = 0.032) as compared to F0 and significantly lower with F4 as compared to F2 (P = 0.032). SWE LSM shows a good correlation with histologic fibrosis grading and pharmacologic quantitative liver function reserve in experimental severe fibrosis and cirrhosis.

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

Respiratory analysis of coupled mitochondria in cryopreserved liver biopsies.

PubMed

García-Roche, Mercedes; Casal, Alberto; Carriquiry, Mariana; Radi, Rafael; Quijano, Celia; Cassina, Adriana

2018-07-01

The aim of this work was to develop a cryopreservation method of small liver biopsies for in situ mitochondrial function assessment. Herein we describe a detailed protocol for tissue collection, cryopreservation, high-resolution respirometry using complex I and II substrates, calculation and interpretation of respiratory parameters. Liver biopsies from cow and rat were sequentially frozen in a medium containing dimethylsulfoxide as cryoprotectant and stored for up to 3 months at -80 °C. Oxygen consumption rate studies of fresh and cryopreserved samples revealed that most respiratory parameters remained unchanged. Additionally, outer mitochondrial membrane integrity was assessed adding cytochrome c, proving that our cryopreservation method does not harm mitochondrial structure. In sum, we present a reliable way to cryopreserve small liver biopsies without affecting mitochondrial function. Our protocol will enable the transport and storage of samples, extending and facilitating mitochondrial function analysis of liver biopsies. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Meta-Analysis of Structured Triglyceride versus Physical Mixture Medium- and Long-Chain Triglycerides for PN in Liver Resection Patients.

PubMed

Zhao, Yajie; Wang, Chengfeng

2017-01-01

The use of total parenteral nutrition can affect liver function, causing a series of problems such as cholestasis. The aim of this meta-analysis was to compare structured triglyceride- (STG-) based lipid emulsions with physical medium-chain triglyceride (MCT)/long-chain triglyceride (LCT) mixtures in patients who had undergone liver surgery to identify any differences between these two types of parenteral nutrition. We searched the databases of PubMed, the Cochrane Library, Web of Science, EMBASE, and Chinese Biomedicine Database from January 2007 to March 2017 and included studies that compared STG-based lipid emulsions with physical MCT/LCT mixtures for surgical patients with liver disease. The STG was more beneficial than physical MCT/LCT on recovery of liver function and immune function. Therefore, STGs may represent a promising alternative to other types of lipid emulsions for hepatic surgery patients.

Changes in nutritional status after liver transplantation.

PubMed

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

2014-08-21

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

Gene Expression Profile Change and Associated Physiological and Pathological Effects in Mouse Liver Induced by Fasting and Refeeding

PubMed Central

Zhang, Fang; Xu, Xiang; Zhou, Ben; He, Zhishui; Zhai, Qiwei

2011-01-01

Food availability regulates basal metabolism and progression of many diseases, and liver plays an important role in these processes. The effects of food availability on digital gene expression profile, physiological and pathological functions in liver are yet to be further elucidated. In this study, we applied high-throughput sequencing technology to detect digital gene expression profile of mouse liver in fed, fasted and refed states. Totally 12162 genes were detected, and 2305 genes were significantly regulated by food availability. Biological process and pathway analysis showed that fasting mainly affected lipid and carboxylic acid metabolic processes in liver. Moreover, the genes regulated by fasting and refeeding in liver were mainly enriched in lipid metabolic process or fatty acid metabolism. Network analysis demonstrated that fasting mainly regulated Drug Metabolism, Small Molecule Biochemistry and Endocrine System Development and Function, and the networks including Lipid Metabolism, Small Molecule Biochemistry and Gene Expression were affected by refeeding. In addition, FunDo analysis showed that liver cancer and diabetes mellitus were most likely to be affected by food availability. This study provides the digital gene expression profile of mouse liver regulated by food availability, and demonstrates the main biological processes, pathways, gene networks and potential hepatic diseases regulated by fasting and refeeding. These results show that food availability mainly regulates hepatic lipid metabolism and is highly correlated with liver-related diseases including liver cancer and diabetes. PMID:22096593

Enhanced in vivo targeting of murine nonparenchymal liver cells with monophosphoryl lipid A functionalized microcapsules.

PubMed

Pietrzak-Nguyen, Anette; Fichter, Michael; Dedters, Marvin; Pretsch, Leah; Gregory, Stephen H; Meyer, Claudius; Doganci, Aysefa; Diken, Mustafa; Landfester, Katharina; Baier, Grit; Gehring, Stephan

2014-07-14

A broad spectrum of infectious liver diseases emphasizes the need of microparticles for targeted delivery of immunomodulatory substances to the liver. Microcapsules (MCs) are particularly attractive for innovative drug and vaccine formulations, enabling the combination of antigen, drugs, and adjuvants. The present study aimed to develop microcapsules characterized by an enhanced liver deposition and accelerated uptake by nonparenchymal liver cells (NPCs). Initially, two formulations of biodegradable microcapsules were synthesized from either hydroxyethyl starch (HES) or mannose. Notably, HES-MCs accumulated primarily in the liver, while mannose particles displayed a lung preference. Functionalization of HES-MCs with anti-CD40, anti-DEC205, and/or monophosphoryl lipid A (MPLA) enhanced uptake of MCs by nonparenchymal liver cells in vitro. In contrast, only MPLA-coated HES-MCs promoted significantly the in vivo uptake by NPCs. Finally, HES-MCs equipped with MPLA, anti-CD40, and anti-DEC205 induced the secretion of TNF-α, IL-6 by Kupffer cells (KCs), and IFN-γ and IL-12p70 by liver dendritic cells (DCs). The enhanced uptake and activation of KCs by MPLA-HES-MCs is a promising approach to prevent or treat infection, since KCs are exploited as an entry gate in various infectious diseases, such as malaria. In parallel, loading and activating liver DCs, usually prone to tolerance, bears the potential to induce antigen specific, intrahepatic immune responses necessary to prevent and treat infections affecting the liver.

Gene expression profile change and associated physiological and pathological effects in mouse liver induced by fasting and refeeding.

PubMed

Zhang, Fang; Xu, Xiang; Zhou, Ben; He, Zhishui; Zhai, Qiwei

2011-01-01

Food availability regulates basal metabolism and progression of many diseases, and liver plays an important role in these processes. The effects of food availability on digital gene expression profile, physiological and pathological functions in liver are yet to be further elucidated. In this study, we applied high-throughput sequencing technology to detect digital gene expression profile of mouse liver in fed, fasted and refed states. Totally 12162 genes were detected, and 2305 genes were significantly regulated by food availability. Biological process and pathway analysis showed that fasting mainly affected lipid and carboxylic acid metabolic processes in liver. Moreover, the genes regulated by fasting and refeeding in liver were mainly enriched in lipid metabolic process or fatty acid metabolism. Network analysis demonstrated that fasting mainly regulated Drug Metabolism, Small Molecule Biochemistry and Endocrine System Development and Function, and the networks including Lipid Metabolism, Small Molecule Biochemistry and Gene Expression were affected by refeeding. In addition, FunDo analysis showed that liver cancer and diabetes mellitus were most likely to be affected by food availability. This study provides the digital gene expression profile of mouse liver regulated by food availability, and demonstrates the main biological processes, pathways, gene networks and potential hepatic diseases regulated by fasting and refeeding. These results show that food availability mainly regulates hepatic lipid metabolism and is highly correlated with liver-related diseases including liver cancer and diabetes.

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

PubMed

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

2017-12-05

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

Effect of commonly used vehicles on gastrointestinal, renal, and liver function in rats.

PubMed

Pestel, Sabine; Martin, Hans-Juergen; Maier, Gerd-Michael; Guth, Brian

2006-01-01

Solubility is often a limiting factor when testing new compounds in animal experiments. Various solubilizing agents may be used, but each have their own pharmacological effects. We investigated the effects of selected vehicles having different chemical characteristics on gastrointestinal, renal, and liver function. Rats were treated orally, intravenously or intraperitoneally and gastric emptying, intestinal transit, renal, and liver function were investigated. Gastrointestinal motility was influenced by hydroxyethylcellulose, hydroxypropyl-beta-cyclodextrin (HPbetaCD), HPgammaCD, DMSO, polyethylene glycol 400 (PEG 400), fat emulsion, and the corresponding emulsifier. Liver function was affected by HPbetaCD, HPgammaCD, DMSO, PEG 400, Polysorbate 80, Cremophor RH 40, and fat emulsion. An increase in liver enzymes was observed after PEG 400 and Polysorbate 80. DMSO interfered with clinical chemistry measurements in serum. Urinary function was modified by HPgammaCD, DMSO, PEG 400, and Polysorbate 80, while enhanced urine enzyme excretion was observed after HPbetaCD, HPgammaCD, DMSO, PEG 400, and Polysorbate 80. Most of the investigated vehicles changed gastrointestinal, renal, and/or liver parameters after application of a certain threshold dose for each assay. No "best" vehicle could be identified that may be used in each test system. Thus, vehicles must be selected not only on their chemical characteristics but also on their potential pharmacological activity in a given test system.

Influence of Prescribed Herbal and Western Medicine on Patients with Abnormal Liver Function Tests: A Retrospective Quasi-Experimental Study

PubMed Central

Lee, Ah-Ram; Yim, Je-Min; Kim, Won-Il

2012-01-01

Objectives: The aim of this study was to investigate the safety and the efficacy of Korean herbal, western and combination medicine use in patients with abnormal liver function tests. Methods: We investigated nerve disease patients with abnormal liver function tests who were treated with Korean herbal, western and combination medicine at Dong-Eui University Oriental Hospital from January 2011 to August 2011. We compared aspartic aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (T-bil) levels before and after taking medicine and excluded patients who had liver-related disease when admitted. Results: AST and ALT were decreased significantly in patients who had taken herbal, western medicine. AST, ALT and ALP were decreased significantly in patients who had taken combination medicine. Compare to herbal medicine, AST, ALT and ALP were decreased significantly in patients who had taken western medicine, and ALT and ALP were decreased significantly in patients who had taken combination medicine. There were no significant differences between western and combination medicine. Conclusions: This study suggests that prescribed Korean herbal medicine, at least, does not injure liver function for patients’, moreover, it was shown to be effective in patients with abnormal liver function tests. PMID:25780634

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

Human Umbilical Cord MSC-Derived Exosomes Suppress the Development of CCl4-Induced Liver Injury through Antioxidant Effect.

PubMed

Jiang, Wenqian; Tan, Youwen; Cai, Mengjie; Zhao, Ting; Mao, Fei; Zhang, Xu; Xu, Wenrong; Yan, Zhixin; Qian, Hui; Yan, Yongmin

2018-01-01

Mesenchymal stem cells (MSCs) have been increasingly applied into clinical therapy. Exosomes are small (30-100 nm in diameter) membrane vesicles released by different cell types and possess the similar functions with their derived cells. Human umbilical cord MSC-derived exosomes (hucMSC-Ex) play important roles in liver repair. However, the effects and mechanisms of hucMSC-Ex on liver injury development remain elusive. Mouse models of acute and chronic liver injury and liver tumor were induced by carbon tetrachloride (CCl 4 ) injection, followed by administration of hucMSC-Ex via the tail vein. Alleviation of liver injury by hucMSC-Ex was determined. We further explored the production of oxidative stress and apoptosis in the development of liver injury and compared the antioxidant effects of hucMSC-Ex with frequently used hepatic protectant, bifendate (DDB) in liver injury. hucMSC-Ex alleviated CCl 4 -induced acute liver injury and liver fibrosis and restrained the growth of liver tumors. Decreased oxidative stress and apoptosis were found in hucMSC-Ex-treated mouse models and liver cells. Compared to bifendate (DDB) treatment, hucMSC-Ex presented more distinct antioxidant and hepatoprotective effects. hucMSC-Ex may suppress CCl 4 -induced liver injury development via antioxidant potentials and could be a more effective antioxidant than DDB in CCl 4 -induced liver tumor development.

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

PubMed

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

2006-05-01

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

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

Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions with Hepatocytes

PubMed Central

Tabariès, Sébastien; Dupuy, Fanny; Dong, Zhifeng; Monast, Anie; Annis, Matthew G.; Spicer, Jonathan; Ferri, Lorenzo E.; Omeroglu, Atilla; Basik, Mark; Amir, Eitan; Clemons, Mark

2012-01-01

We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes. PMID:22645303

Crosstalk between the gut and the liver via susceptibility loci: Novel advances in inflammatory bowel disease and autoimmune liver disease.

PubMed

Li, Xinyang; Shen, Jun; Ran, Zhihua

2017-02-01

Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by chronic, relapsing intestinal inflammation. Autoimmune liver disease (AILD) may be involved in IBD as an extra-intestinal manifestation (EIM). Epidemiologic and anatomic evidence have demonstrated an intimate crosstalk between the gut and the liver. In this review, we briefly introduced nine groups of susceptibility loci shared by inflammatory bowel and autoimmune liver disease for the first time. The genome-wide association studies (GWAS) evidence of pathways involving crosstalk between the gut and the liver is clarified and explained. It has been found that HNF4-α, GPR35, MST1R, CARD9, IL2/IL21/IL2R, BACH2, TNFRSF14, MAdCAM-1, and FUT2 are the genes involved in tight junction formation, macrophage function, T helper cell or T reg cell cycle and function, TNF secretion, lymphocyte homing or intestinal dysbiosis, respectively. The intimate crosstalk between the gut and liver in immunity is also highlighted and discussed in this review. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

Graham, Jay A; Guarrera, James V

2014-08-01

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

Hepatitis A, B, C, D, E, G: an update.

PubMed

Hall, Gairy F

2007-01-01

Acute and chronic liver diseases are an assortment of disorders brought to the clinician's attention by abnormal liver function tests or specific signs and symptoms. The differential diagnosis includes disorders that have primary or secondary liver involvement. This paper will be limited to the epidemiology, clinical manifestations, diagnosis, treatment, and prevention of the different viral liver diseases: A, B, C, D, E and G.

The Effects of Space Flight and Microgravity on the Growth and Differentiation of PICM-19 Pig Liver Stem Cells.

USDA-ARS?s Scientific Manuscript database

In order to answer the question, what effects would microgravity have on the growth, differentiation, and function on liver stem cells, the ARS-PICM-19 pig liver stem cell line was cultured in space aboard space shuttle Endeavor for the 16 days of mission STS-126. The liver is among the few organs ...

Dietary fat source alters hepatic gene expression profile and determines the type of live pathology in rats overfed via total eteral nutrtion

USDA-ARS?s Scientific Manuscript database

Non-alcoholic fatty liver disease (NAFLD) is considered a part of the 'metabolic syndrome' associated with obesity and can progress in some patients to chirrosis, loss of liver function and liver cancer. NAFLD is now the most common form of liver injury, and rates are rising dramatically as a result...

[Liver stiffness measured by acoustic radiation force impulse imaging in assessing hepatic functional reserve in patients with space-occupying lesions in the liver].

PubMed

Yan, Hui-tong; Luo, Yu-kun; Tang, Wen-bo; Jiao, Zi-yu; Yao, Chun-xiao; Lv, Fa-qin; Tang, Jie

2013-04-01

To investigate the value of liver stiffness measured by acoustic radiation force impulse imaging(ARFI) in assessing hepatic functional reserve in patients with space-occupying lesions in the liver. Sixty-three patients with space-occupying lesions in the liver were enrolled. Liver stiffness (LS) measurements with ARFI and indocyanine green(ICG) retention test were performed in the same day, and plasma clearance rate of indocyanine green(ICG-K), ICG retention at 15 minutes(ICGR15) as well as 10 effective values of LS were recorded. The correlation between Child-Pugh score, ICGR15, ICG-K, and LS were evaluated. The LS measurements with ARFI failed in one patient. A strong correlation between LS and ICGR15(r=0.789, P<0.01) and an inverse correlation between LS and ICG-K(r=-0.738, P<0.01) were observed. Besides, there was a significant correlation between LS measurements and Child-Pugh score(r=0.929, P<0.01) . The LS significantly differed among patients with Child-Pugh class A, B, and C(P<0.01) . ARFI is a simple, feasible and non-invasive method for assessing hepatic functional reserve in patients with space-occupying lesions in the liver.

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

PubMed

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

2017-12-14

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

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

PubMed Central

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

2017-01-01

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

Scaling down of a clinical three-dimensional perfusion multicompartment hollow fiber liver bioreactor developed for extracorporeal liver support to an analytical scale device useful for hepatic pharmacological in vitro studies.

PubMed

Zeilinger, Katrin; Schreiter, Thomas; Darnell, Malin; Söderdahl, Therese; Lübberstedt, Marc; Dillner, Birgitta; Knobeloch, Daniel; Nüssler, Andreas K; Gerlach, Jörg C; Andersson, Tommy B

2011-05-01

Within the scope of developing an in vitro culture model for pharmacological research on human liver functions, a three-dimensional multicompartment hollow fiber bioreactor proven to function as a clinical extracorporeal liver support system was scaled down in two steps from 800 mL to 8 mL and 2 mL bioreactors. Primary human liver cells cultured over 14 days in 800, 8, or 2 mL bioreactors exhibited comparable time-course profiles for most of the metabolic parameters in the different bioreactor size variants. Major drug-metabolizing cytochrome P450 activities analyzed in the 2 mL bioreactor were preserved over up to 23 days. Immunohistochemical studies revealed tissue-like structures of parenchymal and nonparenchymal cells in the miniaturized bioreactor, indicating physiological reorganization of the cells. Moreover, the canalicular transporters multidrug-resistance-associated protein 2, multidrug-resistance protein 1 (P-glycoprotein), and breast cancer resistance protein showed a similar distribution pattern to that found in human liver tissue. In conclusion, the down-scaled multicompartment hollow fiber technology allows stable maintenance of primary human liver cells and provides an innovative tool for pharmacological and kinetic studies of hepatic functions with small cell numbers.

Hepatocyte transplantation for liver-based metabolic disorders.

PubMed

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

2006-01-01

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

[Portal hypertension. Evidence-based guide].

PubMed

Mercado, Miguel Angel; Orozco Zepeda, Héctor; Plata-Muñoz, Juan José

2004-01-01

Treatment of portal hypertension has evolved widely during the last decades. Advances in physiopathology have allowed better application of therapeutic options and also have permitted to know the natural history of varices and variceal bleeding, predicting which patients have a higher risk of bleeding. It also permits probability of designing patient treatment. According to liver function and subadjacent liver disease, it is possible to offer different alternatives within the three possible scenarios (primary prophylaxis, acute bleeding episode, and secondary prophylaxis). For primary prophylaxis, pharmacotherapy offers the best choice. Endoscopic banding is also growing in these scenarios and probably will be accepted in the near future. For the acute bleeding episode, endoscopic therapy (sclerosis and/or bands) and/or pharmacologic therapy (octreotide, terlipresin) represent best choice, considering TIPS as a rescue option. Surgery is not used routinely in this scenario in most centers. For secondary prophylaxis, pharmaco- and endoscopic therapy are first-line treatments, while TIPS and surgery as second-line treatments. TIPS is mainly used in patients on a waiting list for liver transplantation. Surgery offers good results for low-risk patients, with good liver function and with portal blood-flow preserving procedures (selective shunts, extensive devascularizations). Liver transplantation is recommended for patients with poor liver function because together with portal hypertension, it treats subadjacent liver disease.

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

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

Kostadinova, Radina; Boess, Franziska; Applegate, Dawn

2013-04-01

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

Gut microbiome can control antitumor immune function in liver

Cancer.gov

An NCI study in mice that found a connection between gut bacteria and antitumor immune responses in the liver has implications for understanding mechanisms that lead to liver cancer and for potential treatments. The study was published in Science.

Outcomes of 5-year survivors of pediatric liver transplantation: report on 461 children from a north american multicenter registry.

PubMed

Ng, Vicky Lee; Fecteau, Annie; Shepherd, Ross; Magee, John; Bucuvalas, John; Alonso, Estella; McDiarmid, Suzanne; Cohen, Geoff; Anand, Ravinder

2008-12-01

Although liver transplantation has been the standard of care therapy for life-threatening liver diseases for >20 years, data on the long-term impact of liver transplantation in children have been primarily limited to single-center experiences. The objective of this study was to characterize and evaluate the clinical course of children who have survived >or=5 years after pediatric liver transplantation in multiple centers across North America. Patients enrolled in the Studies of Pediatric Liver Transplantation database registry who had undergone liver transplantation at 1 of 45 pediatric centers between 1996 and 2001 and survived >5 years from liver transplantation were identified and their clinical courses retrospectively reviewed. The first graft survival for 461 five-year survivors was 88%, with 55 (12%) and 10 (2%) children undergoing a second and third liver transplantation. At the 5-year anniversary clinic visit, liver function was preserved in the majority with daily use of immunosuppression therapy, including a calcineurin inhibitor and oral prednisone, reported by 97% and 25% of children, respectively. The probability of an episode of acute cellular rejection occurring within 5 years after liver transplantation was 60%. Chronic rejection occurred in 5% patients. Posttransplant lymphoproliferative disease was diagnosed in 6% children. Calculated glomerular filtration rate was <90 mL/minute per 1.73 m2 in 13% of 5-year survivors. Age- and gender-adjusted BMI>95th percentile was noted in 12%, with height below the 10th percentile in 29%. Children who are 5-year survivors of liver transplantation have good graft function, but chronic medical conditions and posttransplantation complications affect extrahepatic organs. A comprehensive approach to the management of these patients' multiple unique needs requires the expertise and commitment of health care providers both beyond and within transplant centers to further optimize long-term outcomes for pediatric liver transplant recipients.

Diagnostic value of fibronectin discriminant score for predicting liver fibrosis stages in chronic hepatitis C virus patients.

PubMed

Attallah, Abdelfattah M; Abdallah, Sanaa O; Attallah, Ahmed A; Omran, Mohamed M; Farid, Khaled; Nasif, Wesam A; Shiha, Gamal E; Abdel-Aziz, Abdel-Aziz F; Rasafy, Nancy; Shaker, Yehia M

2013-01-01

Several noninvasive predictive models were developed to substitute liver biopsy for fibrosis assessment. To evaluate the diagnostic value of fibronectin which reflect extracellular matrix metabolism and standard liver functions tests which reflect alterations in hepatic functions. Chronic hepatitis C (CHC) patients (n = 145) were evaluated using ROC curves and stepwise multivariate discriminant analysis (MDA) and was validated in 180 additional patients. Liver biochemical profile including transaminases, bilirubin, alkaline phosphatase, albumin, complete blood count were estimated. Fibronectin concentration was determined using monoclonal antibody and ELISA. A novel index named fibronectin discriminant score (FDS) based on fibronectin, APRI and albumin was developed. FDS produced areas under ROC curves (AUC) of 0.91 for significant fibrosis and 0.81 for advanced fibrosis. The FDS correctly classified 79% of the significant liver fibrosis patients (F2-F4) with 87% sensitivity and 75% specificity. The relative risk [odds ratio (OR)] of having significant liver fibrosis using the cut-off values determined by ROC curve analyses were 6.1 for fibronectin, 4.9 for APRI, and 4.2 for albumin. FDS predicted liver fibrosis with an OR of 16.8 for significant fibrosis and 8.6 for advanced fibrosis. The FDS had similar AUC and OR in the validation group to the estimation group without statistically significant difference. FDS predicted liver fibrosis with high degree of accuracy, potentially decreasing the number of liver biopsy required.

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

Liver Function Indicators Performed Better to Eliminate Cardioembolic Stroke than to Identify It from Stroke Subtypes.

PubMed

Tan, Ge; Yuan, Ruozhen; Hao, Zilong; Lei, Chunyan; Xiong, Yao; Xu, Mangmang; Liu, Ming

2017-01-01

Identifying the etiology of ischemic stroke is essential to acute management and secondary prevention. The value of liver function indicators in differentiating stroke subtypes remains to be evaluated. A total of 1333 acute ischemic stroke patients were included. Liver function indicators collected within 24 hours from stroke onset, including alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and bilirubin (BILI), were collapsed into quartiles (Q) and also dichotomized by Q1. Multivariate regression analysis was conducted to identify the independent association between liver function indicators and cardioembolic stroke (SCE). Area under the curve (AUC) of receiver operating characteristic analysis was conducted, and sensitivity (Sen), specificity (Spe), positive prospective value (PPV), and negative prospective value (NPV) were determined to evaluate the predictive value of liver function indicators for SCE. AST, GGT, and BILI were associated with SCE. After adjustment, only AST was related to SCE independently. The incidence of SCE in the Q1 of AST, GGT, and BILI, particularly in the Q1 of AST, was quite low. The ability of AST, GGT, and BILI to identify SCE was poor, with low AUC, Sen, and PPV. The value of AST, GGT, and BILI in eliminating SCE from stroke subtypes was good, with high Spe and moderate NPV, and was enhanced after combining each liver function indicator. Results of present study demonstrated that AST, GGT, and BILI, particularly AST, had a potential to eliminate SCE from stroke subtypes, and the ability of eliminating SCE would be strengthened after combining each liver function indicator together. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Hepatopathy in an adult, secondary to congenital untreated panhypopituitarism and ectopic posterior pituitary gland.

PubMed

Valle-Murillo, Miguel A; Perez-Diaz, Ivan

2012-09-01

We report a rare case of an adult with advanced liver failure in the setting of an untreated congenital panhypopituitarism. A 32-years-old man presented with a newly onset seizure episode secondary to hypoglycemia. In the initial exploration, we found eunuchoid habitus, absence of secondary sexual characteristics, ascites, and hepatic encephalopathy. Hormonal evaluation confirmed the absence of anterior hypophyseal hormones and the liver function tests showed derangement of liver function. Magnetic Resonance Imaging (MRI) showed hypoplastic adenohypophysis and ectopic posterior pituitary gland. In the approach to liver disease, no cause was identified, besides the untreated panhypopituitarism.

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.

Mesenchymal Stem Cell/Red Blood Cell-Inspired Nanoparticle Therapy in Mice with Carbon Tetrachloride-Induced Acute Liver Failure.

PubMed

Liang, Hongxia; Huang, Ke; Su, Teng; Li, Zhenhua; Hu, Shiqi; Dinh, Phuong-Uyen; Wrona, Emily A; Shao, Chen; Qiao, Li; Vandergriff, Adam C; Hensley, M Taylor; Cores, Jhon; Allen, Tyler; Zhang, Hongyu; Zeng, Qinglei; Xing, Jiyuan; Freytes, Donald O; Shen, Deliang; Yu, Zujiang; Cheng, Ke

2018-06-26

Acute liver failure is a critical condition characterized by global hepatocyte death and often time needs a liver transplantation. Such treatment is largely limited by donor organ shortage. Stem cell therapy offers a promising option to patients with acute liver failure. Yet, therapeutic efficacy and feasibility are hindered by delivery route and storage instability of live cell products. We fabricated a nanoparticle that carries the beneficial regenerative factors from mesenchymal stem cells and further coated it with the membranes of red blood cells to increase blood stability. Unlike uncoated nanoparticles, these particles promote liver cell proliferation in vitro and have lower internalization by macrophage cells. After intravenous delivery, these artificial stem cell analogs are able to remain in the liver and mitigate carbon tetrachloride-induced liver failure in a mouse model, as gauged by histology and liver function test. Our technology provides an innovative and off-the-shelf strategy to treat liver failure.

Implications of microbiota and bile acid in liver injury and regeneration

PubMed Central

Liu, Hui-Xin; Keane, Ryan; Sheng, Lili; Wan, Yu-Jui Yvonne

2015-01-01

Summary Studies examining the mechanisms by which the liver injures and regenerates usually focus on factors and pathways within the liver, neglecting the signaling derived from the gut-liver axis. The intestinal content is rich in microorganisms as well as metabolites generated from both the host and colonizing bacteria. Via the gut-liver axis, this complex “soup” exerts an immense impact on liver integrity and function. This review article summarizes data published in the past 30 years that have demonstrated the signaling derived from the gut-liver axis in relation to liver injury and regeneration. Despite many correlative findings, the intricate networks of pathways involved along with a scarcity of mechanistic data urgently require nutrigenomic, metabolomics, and microbiota profiling approaches to provide a deep understanding of the interplay between nutrition, bacteria, and host response. Such knowledge would better elucidate the molecular mechanisms that link microbiota alteration to host physiological response and vice-versa. PMID:26256437

High-Content Functional Screening of AEG-1 and AKR1C2 for the Promotion of Metastasis in Liver Cancer.

PubMed

Li, Cong; Wu, Xia; Zhang, Wei; Li, Jia; Liu, Huawei; Hao, Ming; Wang, Junsong; Zhang, Honghai; Yang, Gengxia; Hao, Meijun; Sheng, Shoupeng; Sun, Yu; Long, Jiang; Li, Juan; Zhuang, Fengfeng; Hu, Caixia; Li, Li; Zheng, Jiasheng

2016-01-01

Liver cancer is one of the most lethal cancer types in humans, but our understanding of the molecular mechanisms underlying this process remains insufficient. Here, we conducted high-content screening of the potential genes involved in liver cancer metastasis, which we selected from the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, based on the SAMcell method and RNA interference technology. We identified two powerful genes in the liver cancer metastasis process, AEG-1 and AKR1C2, both of which proved to be positive regulators in promoting metastasis in liver cancer. Further clinical results verified their roles in liver cancer. In summary, these findings could provide new insight into the liver cancer mechanism and potentially therapeutic novel targets for liver cancer therapies in the future. © 2015 Society for Laboratory Automation and Screening.

Hepatic progenitor cells in canine and feline medicine: potential for regenerative strategies

PubMed Central

2014-01-01

New curative therapies for severe liver disease are urgently needed in both the human and veterinary clinic. It is important to find new treatment modalities which aim to compensate for the loss of parenchymal tissue and to repopulate the liver with healthy hepatocytes. A prime focus in regenerative medicine of the liver is the use of adult liver stem cells, or hepatic progenitor cells (HPCs), for functional recovery of liver disease. This review describes recent developments in HPC research in dog and cat and compares these findings to experimental rodent studies and human pathology. Specifically, the role of HPCs in liver regeneration, key components of the HPC niche, and HPC activation in specific types of canine and feline liver disease will be reviewed. Finally, the potential applications of HPCs in regenerative medicine of the liver are discussed and a potential role is suggested for dogs as first target species for HPC-based trials. PMID:24946932

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

Digital liver biopsy: Bio-imaging of fatty liver for translational and clinical research.

PubMed

Mancini, Marcello; Summers, Paul; Faita, Francesco; Brunetto, Maurizia R; Callea, Francesco; De Nicola, Andrea; Di Lascio, Nicole; Farinati, Fabio; Gastaldelli, Amalia; Gridelli, Bruno; Mirabelli, Peppino; Neri, Emanuele; Salvadori, Piero A; Rebelos, Eleni; Tiribelli, Claudio; Valenti, Luca; Salvatore, Marco; Bonino, Ferruccio

2018-02-27

The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a "digital biopsy" for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines (Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver.

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

PubMed

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

2018-05-01

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

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.

[Effects of an oxacephem antibiotic on liver function in orthopedic surgery].

PubMed

Kuroyama, M; Otori, K; Yokota, S; Aoto, H; Sawada, M; Yago, K; Fujita, T; Kumagai, Y

1999-07-01

The subjects were 531 patients who underwent orthopedic surgery. Flomoxef was administered, and liver function was examined before and after administration. Abnormal liver function after administration of flomoxef was found in 14.3% of patients. In male patients, a high rate of 18.8% was observed. A particularly high rate of 37.0% was obtained among patients who showed GOT values of more than 40 U/L before treatment with flomoxef. The prevalence of abnormal GOT and GPT values after administration of flomoxef was 3.6% and 13.2%, respectively. These values were significantly higher than those obtained with other cephem antibiotics. These rates of occurrence of abnormally high GOT and GPT are obviously higher than those submitted at the time of approval and reported in the drug use investigation. The prevalence of abnormal liver function values was high in patients receiving flomoxef, and particularly high in male patients and patients whose GOT was high before administration of flomoxef. Therefore, sufficient check of liver function appears important when administration of flomoxef to these types of patients is intended.

Sleep apnea hypopnea syndrome and liver injury.

PubMed

Tian, Jian-li; Zhang, Yun; Chen, Bao-yuan

2010-01-05

A general review was made of studies involving: (1) the relationship between sleep apnea hypopnea syndrome/sleep apnea style intermittent hypoxia and liver injury and (2) the mechanism that causes the liver injury. The data used in this review were mainly from Medline and PubMed published in English from 1993 to February 2009. The search term was "sleep apnea hypopnea syndrome". (1) Clinical and laboratory evidence that sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia leads to liver injury; (2) the mechanism that causes the liver injury. The effect of sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia on the liver function is characterized by serum aminotransferase elevation. The liver histological injury includes hepatic steatosis, hepatocyte ballooning, lobular inflammation, lobular necrosis, and liver fibrosis. Sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia can cause insulin resistance and oxidative stress. Sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia can lead to chronic liver injury, which, in most cases, is shown as nonalcoholic fatty liver disease. Insulin resistance and oxidative stress caused by sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia play an important role in the mechanism of chronic liver disease development.

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

PubMed Central

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

2012-01-01

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

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

Optimized Mouse Models for Liver Fibrosis.

PubMed

Kim, Yong Ook; Popov, Yury; Schuppan, Detlef

2017-01-01

Fibrosis is the excessive accumulation of extracellular matrix components due to chronic injury, with collagens as predominant structural components. Liver fibrosis can progress to cirrhosis, which is characterized by a severe distortion of the delicate hepatic vascular architecture, the shunting of the blood supply away from hepatocytes and the resultant functional liver failure. Cirrhosis is associated with a highly increased morbidity and mortality and represents the major hard endpoint in clinical studies of chronic liver diseases. Moreover, cirrhosis is a strong cofactor of primary liver cancer. In vivo models are indispensable tools to study the cellular and molecular mechanisms of liver fibrosis and to develop specific antifibrotic therapies towards clinical translation. Here, we provide a detailed description of select optimized mouse models of liver fibrosis and state-of-the-art fibrosis readouts.

The CD8 T-cell response during tolerance induction in liver transplantation

PubMed Central

Wong, Yik Chun; McCaughan, Geoffrey W; Bowen, David G; Bertolino, Patrick

2016-01-01

Both experimental and clinical studies have shown that the liver possesses unique tolerogenic properties. Liver allografts can be spontaneously accepted across complete major histocompatibility mismatch in some animal models. In addition, some liver transplant patients can be successfully withdrawn from immunosuppressive medications, developing ‘operational tolerance'. Multiple mechanisms have been shown to be involved in inducing and maintaining alloimmune tolerance associated with liver transplantation. Here, we focus on CD8 T-cell tolerance in this setting. We first discuss how alloreactive cytotoxic T-cell responses are generated against allografts, before reviewing how the liver parenchyma, donor passenger leucocytes and the host immune system function together to attenuate alloreactive CD8 T-cell responses to promote the long-term survival of liver transplants. PMID:27867515

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.

[Clinical and experimental study of treating aplastic anemia with fetal liver cell suspension and fetal liver cell-free suspension].

PubMed

Han, J R; Yuan, S W; Ren, Q F

1990-06-01

Fresh fetal liver obtained from 3- to 6-month fetus was prepared. Fetal liver cell suspension (FLC) or fetal liver cell-free suspension (FLCF) were then transfused into two groups of patient of aplastic anemia. 15 of 21 patients of aplastic anemia treated with FLC showed reconstitution of haemopoietic function or improvement of peripheral blood pictures, while 27 of 30 patients treated with FLCF showed reconstitution or improvement. It is verified that there is a stimulating factor for CFU-CM, BFU-E, and CFU-E and also a immunologic stimulant for improving the nonspecific immunologic function of the organism as shown by clinical analysis and experimental study. It is obvious that the therapeutic effect of FLCF is much better than that of the FLC.

Indocyanine green kinetics to assess liver function: Ready for a clinical dynamic assessment in major liver surgery?

PubMed Central

De Gasperi, Andrea; Mazza, Ernestina; Prosperi, Manlio

2016-01-01

Indocyanine green (ICG) kinetics (PDR/R15) used to quantitatively assess hepatic function in the perioperative period of major resective surgery and liver transplantation have been the object of an extensive, updated and critical review. New, non invasive bedside monitors (pulse dye densitometry technology) make this opportunity widely available in clinical practice. After having reviewed basic concepts of hepatic clearance, we analysed the most common indications ICG kinetic parameters have nowadays in clinical practice, focusing in particular on the diagnostic and prognostic role of PDR and R15 in the perioperative period of major liver surgery and liver transplantation. As recently pointed out, even if of extreme interest, ICG clearance parameters have still some limitations, to be considered when using these tests. PMID:26981173

Alpha-Fetoprotein and Hepatocellular Carcinoma Immunity

PubMed Central

Wang, Qiaoxia

2018-01-01

Hepatocarcinoma is one of the most prevalent gastroenterological cancers in the world with less effective therapy. As an oncofetal antigen and diagnostic marker for liver cancer, alpha-fetoprotein (AFP) possesses a variety of biological functions. Except for its diagnosis in liver cancer, AFP has become a target for liver cancer immunotherapy. Although the immunogenicity of AFP is weak and it could induce the immune escapes through inhibiting the function of dendritic cells, natural killer cells, and T lymphocytes, AFP has attracted more attention in liver cancer immunotherapy. By in vitro modification, the immunogenicity and immune response of AFP could be enhanced. AFP-modified immune cell vaccine or peptide vaccine has displayed the specific antitumor immunity against AFP-positive tumor cells and laid a better foundation for the immunotherapy of liver cancer.

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

PubMed

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

2011-05-01

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

Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study.

PubMed

Lee, Karla C L; Baker, Luisa A; Stanzani, Giacomo; Alibhai, Hatim; Chang, Yu Mei; Jimenez Palacios, Carolina; Leckie, Pamela J; Giordano, Paola; Priestnall, Simon L; Antoine, Daniel J; Jenkins, Rosalind E; Goldring, Christopher E; Park, B Kevin; Andreola, Fausto; Agarwal, Banwari; Mookerjee, Rajeshwar P; Davies, Nathan A; Jalan, Rajiv

2015-09-01

In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure. The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

MiR-525-3p Enhances the Migration and Invasion of Liver Cancer Cells by Downregulating ZNF395

PubMed Central

Pang, Fei; Zha, Ruopeng; Zhao, Yingjun; Wang, Qifeng; Chen, Di; Zhang, Zhenfeng; Chen, Taoyang; Yao, Ming; Gu, Jianren; He, Xianghuo

2014-01-01

Liver cancer is one of leading causes of cancer-related deaths. A deeper mechanistic understanding of liver cancer could lead to the development of more effective therapeutic strategies. In our previous work, we screened 646 miRNAs and identified 11 that regulate liver cancer cell migration. The current study shows that miR-525-3p is frequently up-regulated in liver cancer tissues, and enhanced expression of miR-525-3p can promote liver cancer cell migration and invasion. Zinc finger protein 395 (ZNF395) is the direct functional target gene for miR-525-3p, and it is frequently down-regulated in liver cancer tissues. High expression of ZNF395 can significantly inhibit while knockdown of ZNF395 expression can markedly enhance the migration and invasion of liver cancer cells, suggesting that ZNF395 suppresses metastasis in liver cancer. Down-regulation of ZNF395 can mediate miR-525-3p induced liver cancer cell migration and invasion. In conclusion, miR-525-3p promotes liver cancer cell migration and invasion by directly targeting ZNF395, and the fact that miR-525-3p and ZNF395 both play important roles in liver cancer progression makes them potential therapeutic targets. PMID:24599008

[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.

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

PubMed

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

2012-12-01

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

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

PubMed Central

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

2016-01-01

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

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

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.

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

PubMed

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

2016-03-01

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

Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice.

PubMed

Williams, Jessica A; Ni, Hong-Min; Ding, Yifeng; Ding, Wen-Xing

2015-09-01

Alcoholic liver disease claims two million lives per year. We previously reported that autophagy protected against alcohol-induced liver injury and steatosis by removing damaged mitochondria. However, the mechanisms for removal of these mitochondria are unknown. Parkin is an evolutionarily conserved E3 ligase that is recruited to damaged mitochondria to initiate ubiquitination of mitochondrial outer membrane proteins and subsequent mitochondrial degradation by mitophagy. In addition to its role in mitophagy, Parkin has been shown to have other roles in maintaining mitochondrial function. We investigated whether Parkin protected against alcohol-induced liver injury and steatosis using wild-type (WT) and Parkin knockout (KO) mice treated with alcohol by the acute-binge and Gao-binge (chronic plus acute-binge) models. We found that Parkin protected against liver injury in both alcohol models, likely because of Parkin's role in maintaining a population of healthy mitochondria. Alcohol caused greater mitochondrial damage and oxidative stress in Parkin KO livers compared with WT livers. After alcohol treatment, Parkin KO mice had severely swollen and damaged mitochondria that lacked cristae, which were not seen in WT mice. Furthermore, Parkin KO mice had decreased mitophagy, β-oxidation, mitochondrial respiration, and cytochrome c oxidase activity after acute alcohol treatment compared with WT mice. Interestingly, liver mitochondria seemed able to adapt to alcohol treatment, but Parkin KO mouse liver mitochondria had less capacity to adapt to Gao-binge treatment compared with WT mouse liver mitochondria. Overall, our findings indicate that Parkin is an important mediator of protection against alcohol-induced mitochondrial damage, steatosis, and liver injury. Copyright © 2015 the American Physiological Society.

Associations of insulin resistance, inflammation and liver synthetic function with very low-density lipoprotein: The Cardiovascular Health Study.

PubMed

Jiang, Z Gordon; de Boer, Ian H; Mackey, Rachel H; Jensen, Majken K; Lai, Michelle; Robson, Simon C; Tracy, Russell; Kuller, Lewis H; Mukamal, Kenneth J

2016-03-01

Production of very low-density lipoprotein (VLDL) is increased in states of metabolic syndrome, leading to hypertriglyceridemia. However, metabolic syndrome is often associated with non-alcoholic fatty liver disease, which leads to liver fibrosis and inflammation that may decrease VLDL production. In this study, we aim to determine the interactive impact on VLDL profiles from insulin resistance, impairment in liver synthetic function and inflammation. We examined cross-sectional associations of insulin sensitivity, inflammation, and liver synthetic function with VLDL particle (VLDL-P) concentration and size among 1,850 older adults in the Cardiovascular Health Study. Indices for high insulin sensitivity and low liver synthetic function were associated with lower concentrations of VLDL-P. In addition, insulin resistance preferentially increased concentration of large VLDL and was associated with mean VLDL size. Indices for inflammation however demonstrated a nonlinear relationship with both VLDL-P concentration and VLDL size. When mutually adjusted, one standard deviation (SD) increment in Matsuda index and C-reactive protein (CRP) were associated with 4.9 nmol/L (-8.2 to -1.5, p=0.005) and 6.3 nmol/L (-11.0 to -1.6, p=0.009) lower VLDL-P concentration respectively. In contrast, one-SD increment in factor VII, a marker for liver synthetic function, was associated with 16.9 nmol/L (12.6-21.2, p<0.001) higher VLDL-P concentration. Furthermore, a one-SD increment in the Matsuda index was associated with 1.1 nm (-2.0 to -0.3, p=0.006) smaller mean VLDL size, whereas CRP and factor VII were not associated with VLDL size. Insulin sensitivity, inflammation and markers for liver synthetic function differentially impact VLDL-P concentration and VLDL size. These results underscore the complex effects of insulin resistance and its complications on VLDL production. Copyright © 2015 Elsevier Inc. All rights reserved.

Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism.

PubMed

Ayyar, Vivaswath S; Almon, Richard R; DuBois, Debra C; Sukumaran, Siddharth; Qu, Jun; Jusko, William J

2017-05-08

Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS. Clinical use of corticosteroid (CS) therapy is frequent and chronic. However, current knowledge on the proteome-level effects of CS in liver and other tissues is sparse. While transcriptomic regulation following methylprednisolone (MPL) dosing has been temporally examined in rat liver, proteomic assessments are needed to better characterize the tissue-specific functional aspects of MPL actions. This study describes a functional pharmacoproteomic analysis of dynamic changes in MPL-regulated proteins in liver and provides biological insight into how steroid-induced perturbations on a molecular level may relate to both adverse and therapeutic responses presented clinically. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed

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

2006-11-01

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

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.

Interstage Assessment of Remnant Liver Function in ALPPS Using Hepatobiliary Scintigraphy: Prediction of Posthepatectomy Liver Failure and Introduction of the HIBA Index.

PubMed

Serenari, Matteo; Collaud, Carlos; Alvarez, Fernando A; de Santibañes, Martin; Giunta, Diego; Pekolj, Juan; Ardiles, Victoria; de Santibañes, Eduardo

2018-06-01

The aim of this study was to evaluate interstage liver function in associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS) using hepatobiliary scintigraphy (HBS) and whether this may help to predict posthepatectomy liver failure (PHLF). ALPPS remains controversial given the high rate of liver-related mortality after stage 2. HBS combined with single photon emission computed tomography (SPECT) accurately estimates future liver remnant function and may be useful to predict PHLF. Between 2011 and 2016, 20 of 39 patients (51.3%) underwent SPECT-HBS before ALPPS stage 2 for primary (n = 3) or secondary liver tumors (n = 17) at the Hospital Italiano de Buenos Aires (HIBA). PHLF was defined by the International Study Group of Liver Surgery criteria, 50-50 criteria, or peak bilirubin >7 mg/dL. Grade A PHLF was excluded, as it requires no change in clinical management. Receiver-operating characteristic curves were used to determine cutoff for HBS parameters. Interstagely, 3 HBS parameters differed significantly between patients with (n = 4) and without PHLF (n = 16) after stage 2. Among these, the HIBA-index best predicted PHLF, with a cutoff value of 15%. The risk of PHLF in patients with cutoff <15% was 80%, whereas no patient with cutoff ≥15% developed PHLF. Interstage HBS could help to predict clinically significant PHLF after ALPPS stage 2. An HIBA-index cutoff of 15% seemed to give the best diagnostic performance. Although further studies are needed to confirm our findings, the routine application of this noninvasive low-cost examination could facilitate decision-making in institutions performing ALPPS.

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

Rahman, Shaikh M., E-mail: rmizanoor@hotmail.com; Choudhury, Mahua; Janssen, Rachel C.

Highlights: Black-Right-Pointing-Pointer LXR agonist activation increases liver TG accumulation by increasing lipogenesis. Black-Right-Pointing-Pointer C/EBP{beta}{sup -/-} mouse prevents LXR activation-mediated induction of hepatic lipogenesis. Black-Right-Pointing-Pointer C/EBP{beta} deletion increases mitochondrial transport chain function. Black-Right-Pointing-Pointer Beneficial effects of LXR activation on liver cholesterol metabolism did not change. Black-Right-Pointing-Pointer C/EBP{beta} inhibition might have important therapeutic potential. -- Abstract: Drugs designed specifically to activate liver X receptors (LXRs) have beneficial effects on lowering cholesterol metabolism and inflammation but unfortunately lead to severe hepatic steatosis. The transcription factor CCAAT/enhancer binding protein beta (C/EBP{beta}) is an important regulator of liver gene expression but little is known aboutmore » its involvement in LXR-based steatosis and cholesterol metabolism. The present study investigated the role of C/EBP{beta} expression in LXR agonist (T0901317)-mediated alteration of hepatic triglyceride (TG) and lipogenesis in mice. C/EBP{beta} deletion in mice prevented LXR agonist-mediated induction of lipogenic gene expression in liver in conjunction with significant reduction of liver TG accumulation. Surprisingly, C/EBP{beta}{sup -/-} mice showed a major increase in liver mitochondrial electron chain function compared to WT mice. Furthermore, LXR activation in C/EBP{beta}{sup -/-} mice increased the expression of liver ATP-binding cassette transporter ABCG1, a gene implicated in cholesterol efflux and reducing blood levels of total and LDL-cholesterol. Together, these findings establish a central role for C/EBP{beta} in the LXR-mediated steatosis and mitochondrial function, without impairing the influence of LXR activation on lowering LDL and increasing HDL-cholesterol. Inactivation of C/EBP{beta} might therefore be an important therapeutic strategy to prevent LXR activation-mediated adverse effects on liver TG metabolism without disrupting its beneficial effects on cholesterol metabolism.« less

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.

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.

Identification and differentiation of hepatic stem cells during liver development.

PubMed

Kamiya, Akihide; Gonzalez, Frank J; Nakauchi, Hiromitsu

2006-05-01

Stem cells responsible for maintenance and repair of tissues are found in a number of organs. The liver's remarkable capacity to regenerate after hepatectomy or chemical-induced injury does not involve proliferation of stem cells. However, recent studies suggest that liver stem cells exist in both embryonic and adult livers. Using fluorescence-activated cell sorting and a culture system in which primitive hepatic progenitor cells form colonies, a novel class of cells with the marker profile c-Met(+)CD49f(+/low)c-Kit(-)CD45(-)TER119(-) was found in the developing liver. This class apparently represents the population of cells that form colonies containing distinct hepatocytes and cholangiocytes. When cells in this class are transplanted into the spleen or liver of mice subjected to liver injury, the cells migrate and differentiate into liver parenchymal cells and cholangiocytes that are morphologically and functionally indistinguishable from their native counterparts. During mid-gestation, hematopoietic cells migrate into the liver from a region bounded by aorta, gonad, and mesonephros and produce oncostatin M (OSM). In combination with glucocorticoid hormones, OSM induces maturation of liver stem and progenitor cells, including those of the c-Met(+)CD49f(+/low)c-Kit(-)CD45(-)TER119(-) class. The ability to manipulate the proliferation and differentiation of liver stem cells in vitro will greatly aid in analyzing mechanisms of liver development and offers promise in stem cell therapy of liver diseases.

Fibronectin Extra Domain A Promotes Liver Sinusoid Repair following Hepatectomy.

PubMed

Sackey-Aboagye, Bridget; Olsen, Abby L; Mukherjee, Sarmistha M; Ventriglia, Alexander; Yokosaki, Yasuyuki; Greenbaum, Linda E; Lee, Gi Yun; Naga, Hani; Wells, Rebecca G

2016-01-01

Liver sinusoidal endothelial cells (LSECs) are the main endothelial cells in the liver and are important for maintaining liver homeostasis as well as responding to injury. LSECs express cellular fibronectin containing the alternatively spliced extra domain A (EIIIA-cFN) and increase expression of this isoform after liver injury, although its function is not well understood. Here, we examined the role of EIIIA-cFN in liver regeneration following partial hepatectomy. We carried out two-thirds partial hepatectomies in mice lacking EIIIA-cFN and in their wild type littermates, studied liver endothelial cell adhesion on decellularized, EIIIA-cFN-containing matrices and investigated the role of cellular fibronectins in liver endothelial cell tubulogenesis. We found that liver weight recovery following hepatectomy was significantly delayed and that sinusoidal repair was impaired in EIIIA-cFN null mice, especially females, as was the lipid accumulation typical of the post-hepatectomy liver. In vitro, we found that liver endothelial cells were more adhesive to cell-deposited matrices containing the EIIIA domain and that cellular fibronectin enhanced tubulogenesis and vascular cord formation. The integrin α9β1, which specifically binds EIIIA-cFN, promoted tubulogenesis and adhesion of liver endothelial cells to EIIIA-cFN. Our findings identify a role for EIIIA-cFN in liver regeneration and tubulogenesis. We suggest that sinusoidal repair is enhanced by increased LSEC adhesion, which is mediated by EIIIA-cFN.

Fibronectin Extra Domain A Promotes Liver Sinusoid Repair following Hepatectomy

PubMed Central

Sackey-Aboagye, Bridget; Olsen, Abby L.; Mukherjee, Sarmistha M.; Ventriglia, Alexander; Yokosaki, Yasuyuki; Greenbaum, Linda E.; Lee, Gi Yun; Naga, Hani

2016-01-01

Liver sinusoidal endothelial cells (LSECs) are the main endothelial cells in the liver and are important for maintaining liver homeostasis as well as responding to injury. LSECs express cellular fibronectin containing the alternatively spliced extra domain A (EIIIA-cFN) and increase expression of this isoform after liver injury, although its function is not well understood. Here, we examined the role of EIIIA-cFN in liver regeneration following partial hepatectomy. We carried out two-thirds partial hepatectomies in mice lacking EIIIA-cFN and in their wild type littermates, studied liver endothelial cell adhesion on decellularized, EIIIA-cFN-containing matrices and investigated the role of cellular fibronectins in liver endothelial cell tubulogenesis. We found that liver weight recovery following hepatectomy was significantly delayed and that sinusoidal repair was impaired in EIIIA-cFN null mice, especially females, as was the lipid accumulation typical of the post-hepatectomy liver. In vitro, we found that liver endothelial cells were more adhesive to cell-deposited matrices containing the EIIIA domain and that cellular fibronectin enhanced tubulogenesis and vascular cord formation. The integrin α9β1, which specifically binds EIIIA-cFN, promoted tubulogenesis and adhesion of liver endothelial cells to EIIIA-cFN. Our findings identify a role for EIIIA-cFN in liver regeneration and tubulogenesis. We suggest that sinusoidal repair is enhanced by increased LSEC adhesion, which is mediated by EIIIA-cFN. PMID:27741254

Stem Cells Transplantation in the Treatment of Patients with Liver Failure.

PubMed

Tao, Ya-Chao; Wang, Meng-Lan; Chen, En-Qiang; Tang, Hong

2018-02-23

Liver failure is a life-threatening liver disease encompassing severe acute deterioration of liver function. Emergency liver transplantation is the only curative treatment for liver failure, but is restricted by the severe shortage of organ donors. Stem cell, including embroyonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, hematopoietic stem cells and hepatic progenitor cells, have capacity to proliferate and differentiate and could be used in a variety of liver diseases including hereditary liver diseases, cirrhosis and liver failure. We summarized the basic experimental and clinical advances of stem cell transplantation in liver failure treatment, and also discussed the advantages and disadvantage of different stem cells subtype in this field, aiming to provide a perspective on the stem cell-based therapy for liver failure. Stem cells, especially mesenchymal stem cells (mainly low immunogenicity and paracrine characteristics) and induced pluripotent stem cells (generation of desired cell type from somatic cell), are feasible candidates for cell therapy in the treatment of liver failure, but there are some drawbacks remaining to be resolved, such as low engraftment, cryotpreservation methods and tumorigenesis. Stem cell transplantation is a promising but challenging strategy and paves a new way for curing liver failure. But more efforts need to be made to overcome problems before this new strategy could be safely and effectively applied to humans. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

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.

Intrinsic and Extrinsic Modifiers of the Regulative Capacity of the Developing Liver

PubMed Central

Shin, Donghun; Weidinger, Gilbert; Moon, Randall T.; Stainier, Didier Y.R.

2012-01-01

Zebrafish wnt2bb mutants initially fail to form a liver, but surprisingly the liver eventually forms in a majority of these embryos which then develop into fertile adults. This unexpected result raised the possibility that identifying the mechanisms of liver formation in wnt2bb mutants could provide insights into the poorly understood yet general principle of regulative development, a process by which some cells can change fate in order to compensate for a deficiency. Here, we identify two factors that underlie the regulative capacity of endodermal tissues: an intrinsic factor, Sox32, a transcription factor of the SoxF subfamily, and an extrinsic factor, Fgf10a. sox32 is expressed in the extrahepatic duct primordium which is not affected in wnt2bb mutants. Blocking Sox32 function prevented liver formation in most wnt2bb mutants. fgf10a, which is expressed in the mesenchyme surrounding non-hepatic endodermal cells, negatively impacts the regulative capacity of endodermal tissues. In Wnt/β-catenin signaling deficient embryos, in which the liver completely fails to form, the repression of Fgf10a function allowed liver formation. Altogether, these studies reveal that there is more than one way to form a liver, and provide molecular insights into the phenomenon of tissue plasticity. PMID:22313811

A microfluidically perfused three dimensional human liver model.

PubMed

Rennert, Knut; Steinborn, Sandra; Gröger, Marko; Ungerböck, Birgit; Jank, Anne-Marie; Ehgartner, Josef; Nietzsche, Sandor; Dinger, Julia; Kiehntopf, Michael; Funke, Harald; Peters, Frank T; Lupp, Amelie; Gärtner, Claudia; Mayr, Torsten; Bauer, Michael; Huber, Otmar; Mosig, Alexander S

2015-12-01

Within the liver, non-parenchymal cells (NPCs) are critically involved in the regulation of hepatocyte polarization and maintenance of metabolic function. We here report the establishment of a liver organoid that integrates NPCs in a vascular layer composed of endothelial cells and tissue macrophages and a hepatic layer comprising stellate cells co-cultured with hepatocytes. The three-dimensional liver organoid is embedded in a microfluidically perfused biochip that enables sufficient nutrition supply and resembles morphological aspects of the human liver sinusoid. It utilizes a suspended membrane as a cell substrate mimicking the space of Disse. Luminescence-based sensor spots were integrated into the chip to allow online measurement of cellular oxygen consumption. Application of microfluidic flow induces defined expression of ZO-1, transferrin, ASGPR-1 along with an increased expression of MRP-2 transporter protein within the liver organoids. Moreover, perfusion was accompanied by an increased hepatobiliary secretion of 5(6)-carboxy-2',7'-dichlorofluorescein and an enhanced formation of hepatocyte microvilli. From this we conclude that the perfused liver organoid shares relevant morphological and functional characteristics with the human liver and represents a new in vitro research tool to study human hepatocellular physiology at the cellular level under conditions close to the physiological situation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hepatic growth hormone and glucocorticoid receptor signaling in body growth, steatosis and metabolic liver cancer development

PubMed Central

Mueller, Kristina M.; Themanns, Madeleine; Friedbichler, Katrin; Kornfeld, Jan-Wilhelm; Esterbauer, Harald; Tuckermann, Jan P.; Moriggl, Richard

2012-01-01

Growth hormone (GH) and glucocorticoids (GCs) are involved in the control of processes that are essential for the maintenance of vital body functions including energy supply and growth control. GH and GCs have been well characterized to regulate systemic energy homeostasis, particular during certain conditions of physical stress. However, dysfunctional signaling in both pathways is linked to various metabolic disorders associated with aberrant carbohydrate and lipid metabolism. In liver, GH-dependent activation of the transcription factor signal transducer and activator of transcription (STAT) 5 controls a variety of physiologic functions within hepatocytes. Similarly, GCs, through activation of the glucocorticoid receptor (GR), influence many important liver functions such as gluconeogenesis. Studies in hepatic Stat5 or GR knockout mice have revealed that they similarly control liver function on their target gene level and indeed, the GR functions often as a cofactor of STAT5 for GH-induced genes. Gene sets, which require physical STAT5–GR interaction, include those controlling body growth and maturation. More recently, it has become evident that impairment of GH-STAT5 signaling in different experimental models correlates with metabolic liver disease, ranging from hepatic steatosis to hepatocellular carcinoma (HCC). While GH-activated STAT5 has a protective role in chronic liver disease, experimental disruption of GC-GR signaling rather seems to ameliorate metabolic disorders under metabolic challenge. In this review, we focus on the current knowledge about hepatic GH-STAT5 and GC-GR signaling in body growth, metabolism, and protection from fatty liver disease and HCC development. PMID:22564914

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

PubMed

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

2016-02-01

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

The role of sex differences in the effect of anabolics on the liver.

PubMed

Kulcsár-Gergely, J; Kulcsár, A; Kiss, A

1975-03-01

The effect of two anabolic steroids, norandrostenolone-phenylpropionate (Nerobolil) and norandrostenolone-decanoate (Retabolil) on the liver was studied in rats. Body weight, wet liver weight and the protein content of the liver homogenisates were found to increase under the effect of anabolic treatment, the most explicitely in females treated with Nerobolil. The function of the liver to metabolize hexobarbital, measured in vivo, is increased by a single dose of anabolic. The prolongation of treatment keeps on shortening hexobarbital anaesthesia only in females. Even 8 weeks after the end of treatment the effect is invariably lasting in females, in males it is not. Studies of the vaginal cycle cannot prove a decline of ovarial function. In females the hepatotropic effect of anabolic treatment, performed simultaneously with the chronic carbon tetrachloride lesion can be demonstrated. The liver weight and protein content are maintained on the control level. Under the effect of anabolic treatment the function to metabolize the effect of anabolic treatment the function to metabolize hexobarbital, which has been impaired by the lesion, remains near the level of the untreated animals. Our experiments support the observations of the inductive property of the steroids being parallel to their anabolic characteristics. Their catatoxic effect is pronounced in females. Nerobolil was found to be more advantageous from the point of view of both anabolic and hepatotropic effect. Our experiments do not suggest the possibility of liver damage during the administration of these two anabolics. The effect of the anabolics on the enzymatic induction may be of therapeutic value when adequate preparations are selected and sex differences as well as the character of the liver damage are taken into consideration.

GGPPS deficiency aggravates CCl4-induced liver injury by inducing hepatocyte apoptosis.

PubMed

Chen, Wei-Bo; Lai, Shan-Shan; Yu, De-Cai; Liu, Jia; Jiang, Shan; Zhao, Dan-Dan; Ding, Yi-Tao; Li, Chao-Jun; Xue, Bin

2015-04-28

GGPPS catalyses the expression of GGPP, a key protein in the mevalonate metabolic pathway. HMG-CoA reductase inhibitor statins can induce liver injury by inhibiting GGPP. However, the function of GGPPS in liver injury has not yet been revealed. In this study, we found that GGPPS increased in liver injury and that GGPPS deletion augmented liver injury and fibrosis. GGPPS inhibition induced hepatocyte apoptosis, inflammation and TGF-β1 secretion, which activated hepatic stellate cells. Our findings imply that GGPPS deletion induces hepatocyte apoptosis, which makes the liver vulnerable to hepatotoxicity. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Diagnosis of liver involvement in early syphilis. A critical review.

PubMed

Veeravahu, M

1985-01-01

The diagnosis of liver involvement in early syphilis has always posed problems because of its rarity and the difficulty of excluding coincidental liver disease caused by a multitude of pathogens. Case reports deal predominantly with jaundiced homosexual men in whom syphilis is discovered later, and the prospective studies of patients with early syphilis disclose only mild biochemical abnormalities in liver function test results. There is no single characteristic feature attributable to early syphilitic hepatitis. Even liver histologic findings are variable. At least in those patients who have jaundice, there is a likelihood of coincidental viral hepatitis. Therefore, the evidence to implicate Treponema pallidum as a liver pathogen in early syphilis is not convincing.

IL-27 Production and STAT3-Dependent Upregulation of B7-H1 Mediate Immune Regulatory Functions of Liver Plasmacytoid DC1

PubMed Central

Matta, Benjamin M.; Raimondi, Giorgio; Rosborough, Brian R.; Sumpter, Tina L.; Thomson, Angus W.

2012-01-01

Plasmacytoid (p) dendritic cells (DC) are highly-specialized APC that, in addition to their well-recognized role in anti-viral immunity, also regulate immune responses. Liver-resident pDC are considerably less immunostimulatory than those from secondary lymphoid tissues and are equipped to promote immune tolerance/regulation through various mechanisms. IL-27 is an IL-12-family cytokine that regulates the function of both APC and T cells, although little is known about its role in pDC immunobiology. In this study, we show that mouse liver pDC express higher levels of IL-27p28 and EBV-induced protein (Ebi)3 compared to splenic pDC. Both populations of pDC express the IL-27Rα/WSX-1; however, only liver pDC significantly upregulate expression of the co-regulatory molecule B7 homolog-1 (B7-H1) in response to IL-27. Inhibition of STAT3 activation completely abrogates IL-27-induced upregulation of B7-H1 expression on liver pDC. Liver pDC treated with IL-27 increase the percentage of CD4+Foxp3+ T cells in MLR, which is dependent upon expression of B7-H1. pDC from Ebi3-deficient mice lacking functional IL-27, show increased capacity to stimulate allogeneic T cell proliferation and IFN-γ production in MLR. Liver but not spleen pDC suppress delayed-type hypersensitivity responses to OVA, an effect that is lost with Ebi3−/− and B7-H1−/− liver pDC compared to wild-type (WT) liver pDC. These data suggest that IL-27 signaling in pDC promotes their immunoregulatory function and that IL-27 produced by pDC contributes to their capacity to regulate immuneresponses in vitro and in vivo. PMID:22508931

Cystinyl and pyroglutamyl-beta-naphthylamide hydrolyzing activities are modified coordinately between hypothalamus, liver and plasma depending on the thyroid status of adult male rats.

PubMed

Segarra, A B; Prieto, I; Martinez-Canamero, M; Vargas, F; De Gasparo, M; Vanderheyden, P; Zorad, S; Ramirez-Sanchez, M

2018-04-01

The hypothalamus determinates metabolic processes in liver through endocrine and autonomic control. Hypothalamic neuropeptides, such as thyrotropin releasing hormone or vasopressin, have been involved in liver metabolism. The thyroid status influences metabolic processes including liver metabolism in modulating those hypothalamic peptides whose functional status is regulated in part by aminopeptidase activities. In order to obtain data for a possible coordinated interaction between hypothalamus, plasma and liver, of some aminopeptidase activities that may partially reflect the hydrolysis of those peptides, pyroglutamyl- (pGluAP) and cystinyl- (CysAP) beta-naphthylamide hydrolyzing activities were determined fluorimetrically, both in their soluble and membrane-bound forms, in eu- hypo- and hyperthyroid adult male rats. Hyperthyroidism and hypothyroidism were induced with daily subcutaneous injections of tetraiodothyronine (300 μg/kg/day) or with 0.03% methimazole in drinking water for 6 weeks. Results demonstrated significant changes depending on the type of enzyme and the thyroid status. The most striking changes were observed for CysAP in liver where it was reduced in hypothyroidism and increased in hyperthyroidism. Significant intra- and inter-tissue correlations were observed. While there were positive inter-tissue correlations between liver, plasma and hypothalamus in eu-and hypothyroid rats, a negative correlation between hypothalamus and liver was observed in hyperthyroidism. These results suggest the influence of thyroid hormones and an interactive role for these activities in the control of liver metabolism. The present data also suggest a role for CysAP and pGluAP activities in liver function linked to their activities in hypothalamus.

Optimization of an Isolated Perfused Rainbow Trout Liver Model: Clearance Studies with 7-Ethoxycoumarin

EPA Science Inventory

Isolated trout livers were perfused using methods designed to preserve tissue viability and function. Liver performance was evaluated by measuring O2 consumption (VO2), vascular resistance, K+ leakage, glucose flux, lactate flux, alanine aminotransferase (ALT) leakage, and meta...

[Simultaneous Hepatorenal Transplantation from a Brain-Dead Donor for Graft Dysfunction and Renal Insufficiency in a Liver Transplant Recipient : A Case Report].

PubMed

Takada, Hideaki; Kobayashi, Takashi; Ogawa, Kohei; Miyata, Hitomi; Sawada, Atsuro; Akamatsu, Shusuke; Negoro, Hiromitsu; Saito, Ryoichi; Terada, Naoki; Yamasaki, Toshinari; Inoue, Takahiro; Teramoto, Yuki; Shibuya, Shinsuke; Haga, Hironori; Kaido, Toshimi; Uemoto, Shinji; Ogawa, Osamu

2017-08-01

We report a case of lethal hepatorenal insufficiency in a 52-year-old man who received successful simultaneous hepatorenal transplantation from a deceased donor. The patient had undergone live-donor liver transplantation for type-C hepatitis and liver cirrhosis 11 years before he developed graft liver dysfunction due to recurrent viral hepatitis and cirrhosis. At that instance, he also developed end-stage renal dysfunction due to calcineurin inhibitor nephropathy and hepatorenal syndrome. Although he needed three open hemostases and abundant blood transfusion, he was withdrawn from continuous hemodiafiltration on the 55th day and discharged from the hospital on the 272nd day postoperatively. Simultaneous hepatorenal transplantation was reported to be associated with more favorable outcomes of graft function, lower rejection rates, but higher perioperative complication rates compared with liver transplantation alone in patients on hemodialysis. Particularly, close attention should be paid for hemostasis since patients have a hemorrhagic tendency until the recovery of graft liver function.

Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies

PubMed Central

Ju, Cynthia; Tacke, Frank

2016-01-01

Macrophages represent a major cell type of innate immunity and have emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Hepatic macrophages consist of Kupffer cells, which are originated from the fetal yolk-sack, and infiltrated bone marrow-derived monocytes/macrophages. Hepatic macrophages play a central role in maintaining homeostasis of the liver and in the pathogenesis of liver injury, making them an attractive therapeutic target for liver diseases. However, the various populations of hepatic macrophages display different phenotypes and exert distinct functions. Thus, more research is required to better understand these cells to guide the development of macrophage-based therapeutic interventions. This review article will summarize the current knowledge on the origins and composition of hepatic macrophages, their functions in maintaining hepatic homeostasis, and their involvement in both promoting and resolving liver inflammation, injury, and fibrosis. Finally, the current strategies being developed to target hepatic macrophages for the treatment of liver diseases will be reviewed. PMID:26908374

Novel Index (Hepatic Receptor: IHR) to Evaluate Hepatic Functional Reserve Using (99m)Tc-GSA Scintigraphy.

PubMed

Hasegawa, Daisuke; Onishi, Hideo; Matsutomo, Norikazu

2016-02-01

This study aimed to evaluate the novel index of hepatic receptor (IHR) on the regression analysis derived from time activity curve of the liver for hepatic functional reserve. Sixty patients had undergone (99m)Tc-galactosyl serum albumin ((99m)Tc-GSA) scintigraphy in the retrospective clinical study. Time activity curves for liver were obtained by region of interest (ROI) on the whole liver. A novel hepatic functional predictor was calculated with multiple regression analysis of time activity curves. In the multiple regression function, the objective variables were the indocyanine green (ICG) retention rate at 15 min, and the explanatory variables were the liver counts in 3-min intervals until end from beginning. Then, this result was defined by IHR, and we analyzed the correlation between IHR and ICG, uptake ratio of the heart at 15 minutes to that at 3 minutes (HH15), uptake ratio of the liver to the liver plus heart at 15 minutes (LHL15), and index of convexity (IOC). Regression function of IHR was derived as follows: IHR=0.025×L(6)-0.052×L(12)+0.027×L(27). The multiple regression analysis indicated that liver counts at 6 min, 12 min, and 27 min were significantly related to objective variables. The correlation coefficient between IHR and ICG was 0.774, and the correlation coefficient between ICG and conventional indices (HH15, LHL15, and IOC) were 0.837, 0.773, and 0.793, respectively. IHR had good correlation with HH15, LHL15, and IOC. The finding results suggested that IHR would provide clinical benefit for hepatic functional assessment in the (99m)Tc-GSA scintigraphy.

Changes in markers of liver function in relation to changes in perfluoroalkyl substances - A longitudinal study.

PubMed

Salihovic, Samira; Stubleski, Jordan; Kärrman, Anna; Larsson, Anders; Fall, Tove; Lind, Lars; Lind, P Monica

2018-08-01

While it is known that perfluoroalkyl substances (PFASs) induce liver toxicity in experimental studies, the evidence of an association in humans is inconsistent. The main aim of the present study was to examine the association of PFAS concentrations and markers of liver function using panel data. We investigated 1002 individuals from Sweden (50% women) at ages 70, 75 and 80 in 2001-2014. Eight PFASs were measured in plasma using isotope dilution ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). Bilirubin and hepatic enzymes alanine aminotransferase (ALT), alkaline phosphatase (ALP), and γ-glutamyltransferase (GGT) were determined in serum using an immunoassay methodology. Mixed-effects linear regression models were used to examine the relationship between the changes in markers of liver function and changes in PFAS levels. The changes in majority of PFAS concentrations were positively associated with the changes in activity of ALT, ALP, and GGT and inversely associated with the changes in circulating bilirubin after adjustment for gender and the time-updated covariates LDL- and HDL-cholesterol, serum triglycerides, BMI, statin use, smoking, fasting glucose levels and correction for multiple testing. For example, changes in perfluorononanoic acid (PFNA) were associated with the changes liver function markers β BILIRUBIN  = -1.56, 95% confidence interval (CI) -1.93 to -1.19, β ALT  = 0.04, 95% CI 0.03-0.06, and β ALP  = 0.11, 95% CI 0.06-0.15. Our longitudinal assessment established associations between changes in markers of liver function and changes in plasma PFAS concentrations. These findings suggest a relationship between low-dose background PFAS exposure and altered liver function in the general population. Copyright © 2018 Elsevier Ltd. All rights reserved.

Measuring hepatic functional reserve using low temporal resolution Gd-EOB-DTPA dynamic contrast-enhanced MRI: a preliminary study comparing galactosyl human serum albumin scintigraphy with indocyanine green retention.

PubMed

Saito, Kazuhiro; Ledsam, Joseph; Sourbron, Steven; Hashimoto, Tsuyoshi; Araki, Yoichi; Akata, Soichi; Tokuuye, Koichi

2014-01-01

To investigate if tracer kinetic modelling of low temporal resolution dynamic contrast-enhanced (DCE) MRI with Gd-EOB-DTPA could replace technetium-99 m galactosyl human serum albumin (GSA) single positron emission computed tomography (SPECT) and indocyanine green (ICG) retention for the measurement of liver functional reserve. Twenty eight patients awaiting liver resection for various cancers were included in this retrospective study that was approved by the institutional review board. The Gd-EOB-DTPA MRI sequence acquired five images: unenhanced, double arterial phase, portal phase, and 4 min after injection. Intracellular contrast uptake rate (UR) and extracellular volume (Ve) were calculated from DCE-MRI, along with the ratio of GSA radioactivity of liver to heart-plus-liver and per cent of cumulative uptake from 15-16 min (LHL15 and LU15, respectively) from GSA-scintigraphy. ICG retention at 15 min, Child-Pugh cirrhosis score (CPS) and postoperative Inuyama fibrosis criteria were also recorded. Statistical analysis was with Spearman rank correlation analysis. Comparing MRI parameters with the reference methods, significant correlations were obtained for UR and LHL15, LU15, ICG15 (all 0.4-0.6, P < 0.05); UR and CPS (-0.64, P < 0.001); Ve and Inuyama (0.44, P < 0.05). Measures of liver function obtained by routine Gd-EOB-DTPA DCE-MRI with tracer kinetic modelling may provide a suitable method for the evaluation of liver functional reserve. • Magnetic resonance imaging (MRI) provides new methods of measuring hepatic functional reserve. • DCE-MRI with Gd-EOB-DTPA offers the possibility of replacing scintigraphy. • The analysis method can be used for preoperative liver function evaluation.

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.

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.

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

PubMed Central

Di Martino, Julie; Ruiz, Mathias; Garin, Roman; Restier, Lioara; Belmalih, Abdelouahed; Marchal, Christelle; Cullin, Christophe; Arveiler, Benoit; Fergelot, Patricia; Gitler, Aaron D.; Lachaux, Alain; Couthouis, Julien

2017-01-01

Background The most common and severe disease causing allele of Alpha 1-Antitrypsin Deficiency (1ATD) is Z-1AT. This protein aggregates in the endoplasmic reticulum, which is the main cause of liver disease in childhood. Based on recent evidences and on the frequency of liver disease occurrence in Z-1AT patients, it seems that liver disease progression is linked to still unknown genetic factors. Methods We used an innovative approach combining yeast genetic screens with next generation exome sequencing to identify and functionally characterize the genes involved in 1ATD associated liver disease. Results Using yeast genetic screens, we identified HRD1, an Endoplasmic Reticulum Associated Degradation (ERAD) associated protein, as an inducer of Z-mediated toxicity. Whole exome sequencing of 1ATD patients resulted in the identification of two variants associated with liver damages in Z-1AT homozygous cases: HFE H63D and HERPUD1 R50H. Functional characterization in Z-1AT model cell lines demonstrated that impairment of the ERAD machinery combined with the HFE H63D variant expression decreased both cell proliferation and cell viability, while Unfolded Protein Response (UPR)-mediated cell death was hyperstimulated. Conclusion This powerful experimental pipeline allowed us to identify and functionally validate two genes involved in Z-1AT-mediated severe liver toxicity. This pilot study moves forward our understanding on genetic modifiers involved in 1ATD and highlights the UPR pathway as a target for the treatment of liver diseases associated with 1ATD. Finally, these findings support a larger scale screening for HERPUD1 R50H and HFE H63D variants in the sub-group of 1ATD patients developing significant chronic hepatic injuries (hepatomegaly, chronic cholestasis, elevated liver enzymes) and at risk developing liver cirrhosis. PMID:28617828

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

PubMed

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

2018-05-30

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

Liver Function in Areas of Hepatic Venous Congestion After Hepatectomy for Liver Cancer: 99mTc-GSA SPECT/CT Fused Imaging Study.

PubMed

Yoshida, Morikatsu; Beppu, Toru; Shiraishi, Shinya; Tsuda, Noriko; Sakamoto, Fumi; Kuramoto, Kunitaka; Okabe, Hirohisa; Nitta, Hidetoshi; Imai, Katsunori; Tomiguchi, Seiji; Baba, Hideo; Yamashita, Yasuyuki

2018-05-01

Background/Aim: The sacrifice of a major hepatic vein can cause hepatic venous congestion (HVC). We evaluated the effects of HVC on regional liver function using the liver uptake value (LUV), that was calculated from 99m Tc-labeled-galactosyl-human-serum-albumin ( 99m Tc-GSA) single-photon emission computed tomography (SPECT) /contrast-enhanced computed tomography (CE-CT) fused images. Patients and Methods: Sixty-two patients underwent 99m Tc-GSA SPECT/CE-CT prior to hepatectomy for liver cancer and at 7 days after surgery were divided into groups with (n=8) and without HVC (n=54). In the HVC group, CT volume (CTv) and LUV were separately calculated in both congested and non-congested areas. Results: The remnant LUV/CTv of the HVC group was significantly smaller than that of the non-HVC group (p<0.01). The mean functional ratio was 0.47±0.05, and all ratios were ≥0.39. Conclusion: After hepatectomy with sacrifice of major hepatic vein, liver function per unit volume in the congested areas was approximately 40% of that in the non-congested areas. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

The effect of nanofibrous galactosylated chitosan scaffolds on the formation of rat primary hepatocyte aggregates and the maintenance of liver function.

PubMed

Feng, Zhang-Qi; Chu, Xuehui; Huang, Ning-Ping; Wang, Tao; Wang, Yichun; Shi, Xiaolei; Ding, Yitao; Gu, Zhong-Ze

2009-05-01

Liver tissue engineering requires a perfect extracellular matrix (ECM) for primary hepatocytes culture to maintain high level of liver-specific functions and desirable mechanical stability. The aim of this study was to develop a novel natural nanofibrous scaffold with surface-galactose ligands to enhance the bioactivity and mechanical stability of primary hepatocytes in culture. The nanofibrous scaffold was fabricated by electrospinning a natural material, galactosylated chitosan (GC), into nanofibers with an average diameter of approximately 160 nm. The GC nanofibrous scaffolds displayed slow degradation and suitable mechanical properties as an ECM for hepatocytes according to the evaluation of disintegration and Young's modulus testing. The results of morphology characterization, double-staining fluorescence assay and function detection showed that hepatocytes cultured on GC nanofibrous scaffold formed stably immobilized 3D flat aggregates and exhibited superior cell bioactivity with higher levels of liver-specific function maintenance in terms of albumin secretion, urea synthesis and cytochrome P-450 enzyme than 3D spheroid aggregates formed on GC films. These spheroid aggregates could be detached easily during culture period from the flat GC films. We suggest such GC-based nanofibrous scaffolds could be useful for various applications such as bioartificial liver-assist devices and tissue engineering for liver regeneration as primary hepatocytes culture substrates.

Mesenchymal stem cells support hepatocyte function in engineered liver grafts.

PubMed

Kadota, Yoshie; Yagi, Hiroshi; Inomata, Kenta; Matsubara, Kentaro; Hibi, Taizo; Abe, Yuta; Kitago, Minoru; Shinoda, Masahiro; Obara, Hideaki; Itano, Osamu; Kitagawa, Yuko

2014-01-01

Recent studies suggest that organ decellularization is a promising approach to facilitate the clinical application of regenerative therapy by providing a platform for organ engineering. This unique strategy uses native matrices to act as a reservoir for the functional cells which may show therapeutic potential when implanted into the body. Appropriate cell sources for artificial livers have been debated for some time. The desired cell type in artificial livers is primary hepatocytes, but in addition, other supportive cells may facilitate this stem cell technology. In this context, the use of mesenchymal stem cells (MSC) is an option meeting the criteria for therapeutic organ engineering. Ideally, supportive cells are required to (1) reduce the hepatic cell mass needed in an engineered liver by enhancing hepatocyte function, (2) modulate hepatic regeneration in a paracrine fashion or by direct contact, and (3) enhance the preservability of parenchymal cells during storage. Here, we describe enhanced hepatic function achieved using a strategy of sequential infusion of cells and illustrate the advantages of co-cultivating bone marrow-derived MSCs with primary hepatocytes in the engineered whole-liver scaffold. These co-recellularized liver scaffolds colonized by MSCs and hepatocytes were transplanted into live animals. After blood flow was established, we show that expression of adhesion molecules and proangiogenic factors was upregulated in the graft.

Liver function and DNA integrity in hepatocytes of rats evaluated after treatments with strawberry tree (Arbutus unedo L.) water leaf extract and arbutin.

PubMed

Jurica, Karlo; Benković, Vesna; Sikirić, Sunčana; Kopjar, Nevenka; Brčić Karačonji, Irena

2018-06-07

Due to their beneficial health effects, strawberry tree (Arbutus unedo L.) leaves have for decades been used as herbal remedy in countries of the Mediterranean region. This pilot study is the first to investigate the liver function and DNA integrity in rat hepatocytes evaluated after 14 and 28 day treatments with strawberry tree water leaf extract and arbutin, administered per os to Lewis rats of both genders at a daily dose 200 mg/kg b.w. We focused on two types of biomarkers: enzyme serum markers of liver function (AST, ALT, and LDH), and primary DNA damage in the liver cells, which was estimated using the alkaline comet assay. At the tested dose, strawberry tree water leaf extract showed acceptable biocompatibility with liver tissue both in male and female rats, especially after shorter exposure. Our results also suggest that oral administration of single arbutin to rats was not associated with significant impairments either in the liver function or DNA integrity in hepatocytes. Considering that prolonged exposure to the tested compounds revealed minor changes in the studied biomarkers, future in vivo studies have to further clarify the biological and physiological relevance of these findings.

Predictive Models for Regional Hepatic Function Based on 99mTc-IDA SPECT and Local Radiation Dose for Physiologic Adaptive Radiation Therapy

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

Wang, Hesheng, E-mail: hesheng@umich.edu; Feng, Mary; Frey, Kirk A.

2013-08-01

Purpose: High-dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed before and during the course of RT using 99mTc-labeled iminodiacetic acid (IDA) single photon emission computed tomography (SPECT) could predict regional liver function reserve after RT. Methods and Materials: Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans before RT, during, and 1 month after completion of RT. Indocyanine green (ICG) tests, a measure of overall liver function, were performed within 1 day of each scan. Three-dimensional volumetric hepatic extraction fraction (HEF)more » images of the liver were estimated by deconvolution analysis. After coregistration of the CT/SPECT and the treatment planning CT, HEF dose–response functions during and after RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, dose, priori, and adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function after RT. Results: The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r=−0.80, P<.0001), for all time points. Linear correlations between local doses and regional HEFs 1 month after RT were significant in 12 patients. In the priori model, regional HEF after RT was predicted by the planned dose and regional HEF assessed before RT (R=0.71, P<.0001). In the adaptive model, regional HEF after RT was predicted by regional HEF reassessed during RT and the remaining planned local dose (R=0.83, P<.0001). Conclusions: 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of liver damage.« less

Predictive models for regional hepatic function based on 99mTc-IDA SPECT and local radiation dose for physiologic adaptive radiation therapy.

PubMed

Wang, Hesheng; Feng, Mary; Frey, Kirk A; Ten Haken, Randall K; Lawrence, Theodore S; Cao, Yue

2013-08-01

High-dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed before and during the course of RT using 99mTc-labeled iminodiacetic acid (IDA) single photon emission computed tomography (SPECT) could predict regional liver function reserve after RT. Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans before RT, during, and 1 month after completion of RT. Indocyanine green (ICG) tests, a measure of overall liver function, were performed within 1 day of each scan. Three-dimensional volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After coregistration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and after RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, dose, priori, and adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function after RT. The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r=-0.80, P<.0001), for all time points. Linear correlations between local doses and regional HEFs 1 month after RT were significant in 12 patients. In the priori model, regional HEF after RT was predicted by the planned dose and regional HEF assessed before RT (R=0.71, P<.0001). In the adaptive model, regional HEF after RT was predicted by regional HEF reassessed during RT and the remaining planned local dose (R=0.83, P<.0001). 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of liver damage. Published by Elsevier Inc.

Branched-chain amino acids to tyrosine ratio value as a potential prognostic factor for hepatocellular carcinoma.

PubMed

Ishikawa, Toru

2012-05-07

The prognosis of hepatocellular carcinoma (HCC) depends on tumor extension as well as hepatic function. Hepatic functional reserve is recognized as a factor affecting survival in the treatment of HCC; the Child-Pugh classification system is the most extensively used method for assessing hepatic functional reserve in patients with chronic liver disease, using serum albumin level to achieve accurate assessment of the status of protein metabolism. However, insufficient attention has been given to the status of amino acid (AA) metabolism in chronic liver disease and HCC. Fischer's ratio is the molar ratio of branched-chain AAs (BCAAs: leucine, valine, isoleucine) to aromatic AAs (phenylalanine, tyrosine) and is important for assessing liver metabolism, hepatic functional reserve and the severity of liver dysfunction. Although this ratio is difficult to determine in clinical situations, BCAAs/tyrosine molar concentration ratio (BTR) has been proposed as a simpler substitute. BTR correlates with various liver function examinations, including markers of hepatic fibrosis, hepatic blood flow and hepatocyte function, and can thus be considered as reflecting the degree of hepatic impairment. This manuscript examines the literature to clarify whether BTR can serve as a prognostic factor for treatment of HCC.

Identification and characterization of long noncoding RNAs and mRNAs expression profiles related to postnatal liver maturation of breeder roosters using Ribo-zero RNA sequencing.

PubMed

Wu, Shengru; Liu, Yanli; Guo, Wei; Cheng, Xi; Ren, Xiaochun; Chen, Si; Li, Xueyuan; Duan, Yongle; Sun, Qingzhu; Yang, Xiaojun

2018-06-27

The liver is mainly hematopoietic in the embryo, and converts into a major metabolic organ in the adult. Therefore, it is intensively remodeled after birth to adapt and perform adult functions. Long non-coding RNAs (lncRNAs) are involved in organ development and cell differentiation, likely they have potential roles in regulating postnatal liver development. Herein, in order to understand the roles of lncRNAs in postnatal liver maturation, we analyzed the lncRNAs and mRNAs expression profiles in immature and mature livers from one-day-old and adult (40 weeks of age) breeder roosters by Ribo-Zero RNA-Sequencing. Around 21,939 protein-coding genes and 2220 predicted lncRNAs were expressed in livers of breeder roosters. Compared to protein-coding genes, the identified chicken lncRNAs shared fewer exons, shorter transcript length, and significantly lower expression levels. Notably, in comparison between the livers of newborn and adult breeder roosters, a total of 1570 mRNAs and 214 lncRNAs were differentially expressed with the criteria of log 2 fold change > 1 or < - 1 and P values < 0.05, which were validated by qPCR using randomly selected five mRNAs and five lncRNAs. Further GO and KEGG analyses have revealed that the differentially expressed mRNAs were involved in the hepatic metabolic and immune functional changes, as well as some biological processes and pathways including cell proliferation, apoptotic and cell cycle that are implicated in the development of liver. We also investigated the cis- and trans- regulatory effects of differentially expressed lncRNAs on its target genes. GO and KEGG analyses indicated that these lncRNAs had their neighbor protein coding genes and trans-regulated genes associated with adapting of adult hepatic functions, as well as some pathways involved in liver development, such as cell cycle pathway, Notch signaling pathway, Hedgehog signaling pathway, and Wnt signaling pathway. This study provides a catalog of mRNAs and lncRNAs related to postnatal liver maturation of chicken, and will contribute to a fuller understanding of biological processes or signaling pathways involved in significant functional transition during postnatal liver development that differentially expressed genes and lncRNAs could take part in.

Effect of airplane transport of donor livers on post-liver transplantation survival.

PubMed

Huang, Yi; MacQuillan, Gerry; Adams, Leon A; Garas, George; Collins, Megan; Nwaba, Albert; Mou, Linjun; Bulsara, Max K; Delriviere, Luc; Jeffrey, Gary P

2016-11-07

To evaluate the effect of long haul airplane transport of donor livers on post-transplant outcomes. A retrospective cohort study of patients who received a liver transplantation was performed in Perth, Australia from 1992 to 2012. Donor and recipient characteristics information were extracted from Western Australian liver transplantation service database. Patients were followed up for a mean of six years. Patient and graft survival were evaluated and compared between patients who received a local donor liver and those who received an airplane transported donor liver. Predictors of survival were determined by univariate and multivariate analysis using cox regression. One hundred and ninety-three patients received a local donor liver and 93 patients received an airplane transported donor liver. Airplane transported livers had a significantly lower alanine transaminase (mean: 45 U/L vs 84 U/L, P = 0.035), higher donor risk index (mean: 1.88 vs 1.42, P < 0.001) and longer cold ischemic time (CIT) (mean: 10.1 h vs 6.4 h, P < 0.001). There was a weak correlation between CIT and transport distance ( r 2 = 0.29, P < 0.001). Mean follow up was six years and 93 patients had graft failure. Multivariate analysis found only airplane transport retained significance for graft loss (HR = 1.92, 95%CI: 1.16-3.17). One year graft survival was 0.88 for those with a local liver and was 0.71 for those with an airplane transported liver. One year graft loss was due to primary graft non-function or associated with preservation injury in 20.8% of recipients of an airplane transported liver compared with 4.6% in those with a local liver ( P = 0.027). Airplane transport of donor livers was independently associated with reduced graft survival following liver transplantation.

High regenerative capacity of the liver and irreversible injury of male reproductive system in carbon tetrachloride-induced liver fibrosis rat model.

PubMed

Bubnov, Rostyslav V; Drahulian, Maria V; Buchek, Polina V; Gulko, Tamara P

2018-03-01

Liver fibrosis (LF) is a chronic disease, associated with many collateral diseases including reproductive dysfunction. Although the normal liver has a large regenerative capacity the complications of LF could be severe and irreversible. Hormone and sex-related issues of LF development and interactions with male reproductive have not been finally studied. The aim was to study the reproductive function of male rats in experimental CCl 4 -induced liver fibrosis rat model, and the capability for restoration of both the liver and male reproduction system. Studies were conducted on 20 3-month old Wistar male rats. The experimental animals were injected with freshly prepared 50% olive oil solution of carbohydrate tetrachloride (CCl 4 ). On the 8th week after injection we noted the manifestations of liver fibrosis. The rats were left to self-healing of the liver for 8 weeks. All male rats underwent ultrasound and biopsy of the liver and testes on the 8th and 16th weeks. The male rats were mated with healthy females before CCl 4 injection, after modeling LF on the 8th week, and after self-healing of the liver. Pregnancy was monitored on ultrasound. On the 8th week of experiment we observed ultrasound manifestation of advanced liver fibrosis, including hepatosplenomegaly, portal hypertension. Ultrasound exam of the rat testes showed testicular degeneration, hydrocele, fibrosis, scarring, petrifications, size reduction, and restriction of testicular descent; testes size decreased from 1.24 ± 0.62 ml to 0.61 ± 0.13, p  < 0.01. Liver histology showed granular dystrophy of hepatocytes, necrotic areas, lipid inclusions in parenchyma. Rats with liver fibrosis demonstrated severe injury of the reproductive system and altering of fertility: the offspring of male rats with advanced LF was 4.71 ± 0.53 born alive vs 9.55 ± 0.47 born from mating with healthy males, p  < 0.001. Eight weeks after last CCl 4 injection, we revealed signs of liver regeneration, significant recovery of its structure. The ALT and AST levels significantly decreased and reached background measurements. As a result of the second interbreeding after liver self-healing no significant difference was found vs previous mating. Carbohydrate tetrachloride induces injury of liver parenchyma evoking fast and severe liver fibrosis, and is associated with irreversible structural and functional changes in testes, reducing fertility, decreasing potential pregnancy rate, and affecting its development. Liver showed high potential to regenerate, however the self-restoring after liver fibrosis was not accompanied with recovery of the reproductive system.

Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers.

PubMed

Anavi, Sarit; Madar, Zecharia; Tirosh, Oren

2017-10-01

Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Acute-on-chronic liver failure due to thiamazole in a patient with hyperthyroidism and trilogy of Fallot: case report

PubMed Central

2010-01-01

Background Thiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases. Case Presentation We described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation. Conclusions This case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important. PMID:20707932

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

ClinicalTrials.gov

2018-06-06

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

Inflammatory pseudotumor of the liver: ferumoxide-enhanced MR imaging as a tiebreaker.

PubMed

Kato, Hiroki; Kanematsu, Masayuki; Kondo, Hiroshi; Osada, Shinji; Goshima, Satoshi; Yamada, Tetsuya; Yamada, Yasuhiro; Yokoyama, Ryujiro; Hoshi, Hiroaki; Moriyama, Noriyuki

2004-09-01

We examined a 70-year-old male patient with an inflammatory pseudotumor of the liver mimicking a peripheral-type cholangiocellular carcinoma. Ferumoxide-enhanced magnetic resonance (MR) imaging revealed residual Kupffer cell function in liver parenchyma in and surrounding the inflammatory pseudotumor involvement, which suggested the diagnosis of inflammatory pseudotumor of the liver. We correlate the MR imaging and pathologic findings in this report. Copyright 2004 Wiley-Liss, Inc.

Cell and Tissue Engineering for Liver Disease

PubMed Central

Bhatia, Sangeeta N.; Underhill, Gregory H.; Zaret, Kenneth S.; Fox, Ira J.

2015-01-01

Despite the tremendous hurdles presented by the complexity of the liver’s structure and function, advances in liver physiology, stem cell biology and reprogramming, and the engineering of tissues and devices are accelerating the development of cell-based therapies for treating liver disease and liver failure. This State of the Art Review discusses both the near and long-term prospects for such cell-based therapies and the unique challenges for clinical translation. PMID:25031271

Encephalopathy and liver transplantation.

PubMed

Chavarria, Laia; Cordoba, Juan

2013-06-01

Liver transplantation (LT) candidates experience frequently episodic or persistent hepatic encephalopathy. In addition, these patients can exhibit neurological comorbidities that contribute to cognitive impairment in the pre-transplant period. Assessment of the respective contribution of hepatic encephalopathy or comorbidities in the cognitive manifestations is critical to estimate the neurological benefits of restoring liver function. Magnetic resonance imaging and spectroscopy are useful to assess the impact of liver failure or comorbidities. This assessment is critical to decide liver transplant in difficult cases. In the early postoperative period, LT is commonly complicated by a confusional syndrome. The possible role of persisting hepatic encephalopathy in its development has not been clearly established. The origin is usually considered multifactorial and relates to complications following LT, such as infections, rejection, primary liver dysfunction, immunosuppressors, etc.… The diagnosis and treatment is based in the recognition of comorbidities and optimal care of metabolic disturbances. Several studies have demonstrated recovery of cognitive function after LT in patients that have exhibited hepatic encephalopathy. However, some deficits may persist specifically among patients with persistent HE. Other factors present before LT that contribute to a worse neuropsychological outcome after LT are diabetes mellitus and alcohol consumption. Long-term after LT, cognitive function may worsen in relation to vascular risk factors.

Effects of liver function on ionized hypocalcaemia following rapid blood transfusion.

PubMed

Chung, H S; Cho, S J; Park, C S

2012-01-01

Hypocalcaemia detrimentally affects the cardiovascular system and massive transfusion-related hypocalcaemia is particularly severe in end-stage liver disease patients undergoing liver transplantation (LT). This study, therefore, compared the severity and duration of ionized hypocalcaemia between patients with normal and impaired liver function. Patients (n = 26 per group) were transfused at a rate of 10 ml/kg within 10 min with packed red blood cells (PRBCs) during LT (group LP) or spinal surgery (group SP), or were infused with 0.9% normal saline during spinal surgery (group SN). Serum levels of ionized calcium were assessed before (T(0)), just after (T(1)), and at 20 (T(2)) and 60 min (T(3)) after transfusion. Transfusion with PRBCs caused more severe ionized hypocalcaemia than 0.9% normal saline at T(1). In contrast to the faster (20 min) normalization in group SP, ionized hypocalcaemia in group LP persisted at T(3). Serum ionized calcium levels at T(3) showed correlations with vital signs, blood glucose, serum potassium, base deficit and lactate. Rapid blood transfusion caused more severe and prolonged ionized hypo calcaemia in patients with liver dysfunction than in those with normal liver function.

Sex, metabolism and health.

PubMed

Maggi, Adriana; Della Torre, Sara

2018-02-27

Epidemiological and clinical studies have largely demonstrated major differences in the prevalence of metabolic disorders in males and females, but the biological cause of these dissimilarities remain to be elucidated. Mammals are characterized by a major change in reproductive strategies and it is conceivable that these changes subjected females to a significant evolutionary pressure that perfected the coupling between energy metabolism and reproduction. This review will address the plausibility that female liver functions diverged significantly from males given the role of liver in the control of metabolism. Indeed, it is well known that the liver is sexually dimorphic, and this might be relevant to explain the lower susceptibility to hepatic diseases and liver-derived metabolic disturbances (such as the cardiovascular diseases) characteristic of females during their fertile period. Furthermore, estrogens and the hepatic ERα play a significant role in liver sexual-specific functions and in the control of metabolic functions. A better grasp of the role of male and female sex steroids in the liver of the two sexes may therefore represent an important element to conceive novel treatments aimed at preventing metabolic diseases particularly in ageing women or limiting undesired side effect in the treatment of gender dysphoria. Copyright © 2018. Published by Elsevier GmbH.

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.

Stepwise approach to curative surgery using percutaneous transhepatic cholangiodrainage and portal vein embolization for severe bile duct injury during laparoscopic cholecystectomy: a case report.

PubMed

Honmyo, Naruhiko; Kuroda, Shintaro; Kobayashi, Tsuyoshi; Ishiyama, Kohei; Ide, Kentaro; Tahara, Hiroyuki; Ohira, Masahiro; Ohdan, Hideki

2016-12-01

Laparoscopic cholecystectomy (LC) has been recently adapted to acute cholecystitis. Major bile duct injury during LC, especially Strasberg-Bismuth classification type E, can be a critical problem sometimes requiring hepatectomy. Safety and definitive treatment without further morbidities, such as posthepatectomy liver failure, is required. Here, we report a case of severe bile duct injury treated with a stepwise approach using (99m)Tc-galactosyl human serum albumin ((99m)Tc-GSA) single-photon emission computed tomography (SPECT)/CT fusion imaging to accurately estimate liver function.A 52-year-old woman diagnosed with acute cholecystitis underwent LC at another hospital and was transferred to our university hospital for persistent bile leakage on postoperative day 20. She had no jaundice or infection, although an intraperitoneal drainage tube discharged approximately 500 ml of bile per day. Recorded operation procedure showed removal of the gallbladder with a part of the common bile duct due to its misidentification, and each of the hepatic ducts and right hepatic artery was injured. Abdominal enhanced CT revealed obstructive jaundice of the left liver and arterial shunt through the hilar plate to the right liver. Magnetic resonance cholangiopancreatography revealed type E4 or more advanced bile duct injury according to the Bismuth-Strasberg classification. We planned a stepwise approach using percutaneous transhepatic cholangiodrainage (PTCD) and portal vein embolization (PVE) for secure right hemihepatectomy and biliary-jejunum reconstruction and employed (99m)Tc-GSA SPECT/CT fusion imaging to estimate future remnant liver function. The left liver function rate had changed from 26.2 % on admission to 26.3 % after PTCD and 54.5 % after PVE, while the left liver volume rate was 33.8, 33.3, and 49.6 %, respectively. The increase of liver function was higher than that of volume (28.3 vs. 15.8 %). On postoperative day 63, the curative operation, right hemihepatectomy and biliary-jejunum reconstruction, was performed, and posthepatectomy liver failure could be avoided.Careful consideration of treatment strategy for each case is necessary for severe bile duct injury with arterial injury requiring hepatectomy. The stepwise approach using PTCD and PVE could enable hemihepatectomy, and (99m)Tc-GSA SPECT/CT fusion imaging was useful to estimate heterogeneous liver function.

Liver mitochondrial dysfunction and electron transport chain defect induced by high dietary copper in broilers.

PubMed

Yang, Fan; Cao, Huabin; Su, Rongsheng; Guo, Jianying; Li, Chengmei; Pan, Jiaqiang; Tang, Zhaoxin

2017-09-01

Copper is an important trace mineral in the diet of poultry due to its biological activity. However, limited information is available concerning the effects of high copper on mitochondrial dysfunction. In this study, 72 broilers were used to investigate the effects of high dietary copper on liver mitochondrial dysfunction and electron transport chain defect. Birds were fed with different concentrations [11, 110, 220, and 330 mg of copper/kg dry matter (DM)] of copper from tribasic copper chloride (TBCC). The experiment lasted for 60 d. Liver tissues on d 60 were subjected to histopathological observation. Additionally, liver mitochondrial function was recorded on d 12, 36, and 60. Moreover, a site-specific defect in the electron transport chain in liver mitochondria was also identified by using various chemical inhibitors of mitochondrial respiration. The results showed different degrees of degeneration, mitochondrial swelling, and high-density electrons in hepatocytes. In addition, the respiratory control ratio (RCR) and oxidative phosphorylation rate (OPR) in liver mitochondria increased at first and then decreased in high-dose groups. Moreover, hydrogen peroxide (H2O2) generation velocity in treated groups was higher than that in control group, which were magnified by inhibiting electron transport at Complex IV. The results indicated that high dietary copper could decline liver mitochondrial function in broilers. The presence of a site-specific defect at Complex IV in liver mitochondria may be responsible for liver mitochondrial dysfunction caused by high dietary copper. © 2017 Poultry Science Association Inc.

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.

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

PubMed

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

2014-12-01

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

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.

Effect of cryopreservation on the appearance and liver function of hepatocyte-like cells in cultures of cirrhotic liver of biliary atresia.

PubMed

Yamazaki, Taisuke; Enosawa, Shin; Tokiwa, Takayoshi

2018-06-01

Previously, we reported that non-parenchymal cell (NPC) fractions from cirrhotic liver of biliary atresia (BA) may contain stem/progenitor cells, and clusters of hepatocyte-like cells appear via hepatocyte growth factor/c-Met signaling in primary cultures of NPCs. BA is a rare and serious liver disease, and procurement of BA cells is difficult. Therefore, cryopreservation of BA liver cells is an unavoidable challenge. In this study, we examined the appearance and liver function of hepatocyte-like cells in cultures of BA liver-derived NPC fractions after cryopreservation for 1 or 6 mo using a chemically defined cryopreservation solution, STEM-CELLBANKER. Although a decrease in cell viability was observed in recovered cells after 1 mo of cryopreservation, clusters of hepatocyte-like cells appeared in the culture of cells that had been cryopreserved for 1 or 6 mo, similar to non-cryopreserved cells. In addition, these hepatocyte-like cells expressed hepatocyte-related mRNAs and demonstrated albumin production and glycogen storage. The present results suggest that hepatic stem/progenitor cells in NPC fractions may be efficiently cryopreserved, as demonstrated by the appearance of hepatocyte-like cells that show various hepatic functions even after cryopreservation. This study may lead to future BA cell therapy using the patient's own cells.

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

PubMed

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

2017-07-01

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

Evaluation of liver functional reserve by combining D-sorbitol clearance rate and CT measured liver volume

PubMed Central

Li, Yi-Ming; Lv, Fan; Xu, Xin; Ji, Hong; Gao, Wen-Tao; Lei, Tuan-Jie; Ren, Gui-Bing; Bai, Zhi-Lan; Li, Qiang

2003-01-01

AIM: Our research attempted to evaluate the overall functional reserve of cirrhotic liver by combination of hepatic functional blood flow, liver volume, and Child-Pugh’s classification, and to discuss its value of clinical application. METHODS: Ninety two patients with portal hypertension due to hepatic cirrhosis were investigated. All had a history of haematemesis and hematochezia, esophageal and gastric fundus varices, splenomegaly and hypersplenia. A 2-year follow-up was routinely performed and no one was lost. Twenty two healthy volunteers were used as control group. Blood and urine samples were collected 4 times before and after intravenous D-sorbitol infusion. The hepatic clearance (CLH) of D-sorbitol was then calculated according to enzymatic spectrophotometric method while the total blood flow (QTOTAL) and intrahepatic shunt (RINS) were detected by multicolor Doppler ultrasound, and the liver volume was measured by spiral CT. Data were estimated by t-test, variance calculation and chi-squared test. The relationships between all these parameters and different groups were investigated according to Child-Pugh classification and postoperative complications respectively. RESULTS: Steady blood concentration was achieved 120 mins after D-sorbitol intravenous infusion, which was (0.358 ± 0.064) mmol·L-1 in cirrhotic group and (0.189 ± 0.05) mmol·L-1 in control group (P < 0.01). CLH = (812.7 ± 112.4) mL·min-1, QTOTAL = (1280.6 ± 131.4) mL·min-1, and RINS = (36.54 ± 10.65)% in cirrhotic group and CLH = (1248.3 ± 210.5) mL·min-1, QTOTAL = (1362.4 ± 126.9) mL·min-1, and RINS = (8.37 ± 3.32)% in control group (P < 0.01). The liver volume of cirrhotic group was 1057 ± 249 cm3, 851 ± 148 cm3 and 663 ± 77 cm3 in Child A, B and C group respectively with significant difference (P < 0.001). The average volume of cirrhotic liver in Child B, C group was significantly reduced in comparison with that in control group (P < 0.001). The patient, whose liver volume decreased by 40% with the CLH below 600 mL·min-1, would have a higher incidence of postoperative complications. There was no strict correspondent relationship between CLH, liver volume and Child-Pugh’s classification. CONCLUSION: The hepatic clearance of D-sorbitol, CT measured liver volume can be reliably used for the evaluation of hepatic functional blood flow and liver metabolic volume. Combined with the Child-Pugh’s classification, it could be very useful for further understanding the liver functional reserve, therefore help determine reasonable therapeutic plan, choose surgical procedures and operating time. PMID:12970913

Effect of high-dose stereotactic body radiation therapy on liver function in the treatment of primary and metastatic liver malignancies using the Child-Pugh score classification system.

PubMed

Dyk, Pawel; Weiner, Ashley; Badiyan, Shahed; Myerson, Robert; Parikh, Parag; Olsen, Jeffrey

2015-01-01

The purpose of this study was to evaluate liver function after high-dose liver stereotactic body radiation therapy (SBRT) in the treatment of metastatic and primary malignancies of the liver using the Child-Pugh score classification system. This was a retrospective analysis of 46 patients treated with SBRT for metastatic and primary malignancies of the liver. Patient, disease, prior treatment, and SBRT dosimetric factors were analyzed to correlate with decline in Child-Pugh class after liver SBRT. Median follow-up was 11.0 months for patients alive at last follow-up. Twenty-three patients (50%) had primary liver malignancies. Median delivered dose was 55 Gy in 5 fractions (range, 36-60 Gy in 3-6 fractions) to 1 lesion (range, 1-4 lesions) measuring 4.0 cm (range, 1.3-12.4 cm). Forty-one patients (89%) received ≥50 Gy in 3 to 6 fractions. Child-Pugh score classification was A in 42 patients (91%). Seven patients (15%) received adjuvant chemotherapy or targeted therapy. Twenty-nine patients (63%) experienced an intrahepatic recurrence after treatment. Ten patients (22%) experienced a decline in Child-Pugh class at a median of 1.6 months (range, 0.2-6 months). Eighty percent experienced a one-category decline. Only the V20, V25, V30, and V50 were correlated with decline in Child-Pugh class on univariate analysis, with V25 being most significant (P = .027). A V25 >32% was associated with a 42% incidence of Child-Pugh class decline compared with 9% for V25 ≤32 (P = .029). For primary liver malignancies, a V25 >36% was associated with a 4-fold increase in the incidence of Child-Pugh class decline (60% vs 15%, P = .021). Approximately one-quarter of patients experience a decline in Child-Pugh class after high-dose liver SBRT. The V25 may be an important dosimetric parameter predicting decline in liver function after treatment. Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Accuracy of indocyanine green pulse spectrophotometry clearance test for liver function prediction in transplanted patients

PubMed Central

Hsieh, Chung-Bao; Chen, Chung-Jueng; Chen, Teng-Wei; Yu, Jyh-Cherng; Shen, Kuo-Liang; Chang, Tzu-Ming; Liu, Yao-Chi

2004-01-01

AIM: To investigate whether the non-invasive real-time Indocynine green (ICG) clearance is a sensitive index of liver viability in patients before, during, and after liver transplantation. METHODS: Thirteen patients were studied, two before, three during, and eight following liver transplantation, with two patients suffering acute rejection. The conventional invasive ICG clearance test and ICG pulse spectrophotometry non-invasive real-time ICG clearance test were performed simultaneously. Using linear regression analysis we tested the correlation between these two methods. The transplantation condition of these patients and serum total bilirubin (T. Bil), alanine aminotransferase (ALT), and platelet count were also evaluated. RESULTS: The correlation between these two methods was excellent (r2 = 0.977). CONCLUSION: ICG pulse spectrophotometry clearance is a quick, non-invasive, and reliable liver function test in transplantation patients. PMID:15285026

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

PubMed

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

2016-06-01

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

Characteristics of hepatic stem/progenitor cells in the fetal and adult liver.

PubMed

Koike, Hiroyuki; Taniguchi, Hideki

2012-11-01

The liver is an essential organ that maintains vital activity through its numerous important functions. It has a unique capability of fully regenerating after injury. Regulating a balance between self-renewal and differentiation of hepatic stem cells that are resources for functional mature liver cells is required for maintenance of tissue homeostasis. This review describes the characteristics of hepatic stem/progenitor cells and the regulatory mechanism of their self-renewal and differentiation capacity. In liver organogenesis, undifferentiated hepatic stem/progenitor cells expand their pool by repeated self-renewal in the early stage of liver development and then differentiate into two different types of cell lineage, namely hepatocytes and cholangiocytes. Liver development is regulated by expression of stem cell transcription factors in a complex multistep process. Recent studies suggest that stem cells are maintained by integrative regulation of gene expression patterns related to self-renewal and differentiation by epigenetic mechanisms such as histone modification and DNA methylation. Analysis of the proper regulatory mechanism of hepatic stem/progenitor cells is important for regenerative medicine that utilizes hepatic stem cells and for preventing liver cancer through clarification of the carcinogenetic mechanism involved in stem cell system failure.

Activation of farnesoid X receptor induces RECK expression in mouse liver

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

Peng, Xiaomin; Wu, Weibin; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032

2014-01-03

Highlights: •RECK is a novel transcriptional target gene of FXR in mouse liver. •The FXR response element is located within the intron 1 of RECK gene. •FXR agonist reverses the down-regulation of RECK in the liver in mouse NASH model. -- Abstract: Farnesoid X receptor (FXR) belongs to the ligand-activated nuclear receptor superfamily, and functions as a transcription factor regulating the transcription of numerous genes involved in bile acid homeostasis, lipoprotein and glucose metabolism. In the present study, we identified RECK, a membrane-anchored inhibitor of matrix metalloproteinases, as a novel target gene of FXR in mouse liver. We found thatmore » FXR agonist substantially augmented hepatic RECK mRNA and protein expression in vivo and in vitro. FXR regulated the transcription of RECK through directly binding to FXR response element located within intron 1 of the mouse RECK gene. Moreover, FXR agonist reversed the down-regulation of RECK in the livers from mice fed a methionine and choline deficient diet. In summary, our data suggest that RECK is a novel transcriptional target of FXR in mouse liver, and provide clues to better understanding the function of FXR in liver.« less

In Vitro Hepatic Trans-Differentiation of Human Mesenchymal Stem Cells Using Sera from Congestive/Ischemic Liver during Cardiac Failure

PubMed Central

Bishi, Dillip Kumar; Mathapati, Santosh; Cherian, Kotturathu Mammen; Guhathakurta, Soma; Verma, Rama Shanker

2014-01-01

Cellular therapy for end-stage liver failures using human mesenchymal stem cells (hMSCs)-derived hepatocytes is a potential alternative to liver transplantation. Hepatic trans-differentiation of hMSCs is routinely accomplished by induction with commercially available recombinant growth factors, which is of limited clinical applications. In the present study, we have evaluated the potential of sera from cardiac-failure-associated congestive/ischemic liver patients for hepatic trans-differentiation of hMSCs. Results from such experiments were confirmed through morphological changes and expression of hepatocyte-specific markers at molecular and cellular level. Furthermore, the process of mesenchymal-to-epithelial transition during hepatic trans-differentiation of hMSCs was confirmed by elevated expression of E-Cadherin and down-regulation of Snail. The functionality of hMSCs-derived hepatocytes was validated by various liver function tests such as albumin synthesis, urea release, glycogen accumulation and presence of a drug inducible cytochrome P450 system. Based on these findings, we conclude that sera from congestive/ischemic liver during cardiac failure support a liver specific microenvironment for effective hepatic trans-differentiation of hMSCs in vitro. PMID:24642599

Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

PubMed Central

Huch, Meritxell; Gehart, Helmuth; van Boxtel, Ruben; Hamer, Karien; Blokzijl, Francis; Verstegen, Monique M.A.; Ellis, Ewa; van Wenum, Martien; Fuchs, Sabine A.; de Ligt, Joep; van de Wetering, Marc; Sasaki, Nobuo; Boers, Susanne J.; Kemperman, Hans; de Jonge, Jeroen; Ijzermans, Jan N.M.; Nieuwenhuis, Edward E.S.; Hoekstra, Ruurdtje; Strom, Stephen; Vries, Robert R.G.; van der Laan, Luc J.W.; Cuppen, Edwin; Clevers, Hans

2015-01-01

Summary Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from α1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy. PMID:25533785

Biomaterials and Culture Technologies for Regenerative Therapy of Liver Tissue.

PubMed

Perez, Roman A; Jung, Cho-Rok; Kim, Hae-Won

2017-01-01

Regenerative approach has emerged to substitute the current extracorporeal technologies for the treatment of diseased and damaged liver tissue. This is based on the use of biomaterials that modulate the responses of hepatic cells through the unique matrix properties tuned to recapitulate regenerative functions. Cells in liver preserve their phenotype or differentiate through the interactions with extracellular matrix molecules. Therefore, the intrinsic properties of the engineered biomaterials, such as stiffness and surface topography, need to be tailored to induce appropriate cellular functions. The matrix physical stimuli can be combined with biochemical cues, such as immobilized functional groups or the delivered actions of signaling molecules. Furthermore, the external modulation of cells, through cocultures with nonparenchymal cells (e.g., endothelial cells) that can signal bioactive molecules, is another promising avenue to regenerate liver tissue. This review disseminates the recent approaches of regenerating liver tissue, with a focus on the development of biomaterials and the related culture technologies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of gadolinium-EOB-DTPA uptake after portal vein embolization: value of an increased flip angle.

PubMed

Geisel, Dominik; Lüdemann, Lutz; Wagner, Clemens; Stelter, Lars; Grieser, Christian; Malinowski, Maciej; Stockmann, Martin; Seehofer, Daniel; Hamm, Bernd; Gebauer, Bernhard; Denecke, Timm

2014-03-01

The optimal sequence for Gd-EOB-DTPA uptake measurement in the liver with the purpose of liver function measurement is still not defined. To prospectively evaluate the effect of an increased flip angle (FA) of a T1-weighted fat-saturated 3D sequence for the measurement of hepatocyte uptake of Gd-EOB-DTPA magnetic resonance imaging (MRI) after right portal vein embolization (PVE). Ten patients who received a PVE prior to an extended hemihepatectomy were examined 14 days after PVE using Gd-EOB-DTPA enhanced MRI of the liver using the standard FA of 10° and the increased FA of 30°. Relative enhancement of the right liver lobe (RLL) was 0.52 ± 0.12 for 10° and 1.41 ± 0.39 for 30°. Relative enhancement of the left liver lobe (LLL) was 0.58 ± 0.11 for 10° and 2.05 ± 0.61 for 30°. Relative enhancement of the RLL was significantly higher for 30° than for 10° (P = 0.009) and significantly higher in the 30° than in the 10° sequences (P = 0.005) for the LLL. A flip angle of 30° increases the contrast between liver partitions with and without portal venous embolization. Thereby, the sensitivity for differences in uptake intensity is increased. This could be of value for a more exact determination of differences in regional liver function and, consequently, the estimation of the future remnant liver function.

Impaired TFEB-mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-induced Liver Injury and Steatosis in Mice.

PubMed

Chao, Xiaojuan; Wang, Shaogui; Zhao, Katrina; Li, Yuan; Williams, Jessica A; Li, Tiangang; Chavan, Hemantkumar; Krishnamurthy, Partha; He, Xi C; Li, Linheng; Ballabio, Andrea; Ni, Hong-Min; Ding, Wen-Xing

2018-05-18

Defects in lysosome function and autophagy contribute to pathogenesis of alcoholic liver disease. We investigated the mechanisms by which alcohol consumption affects these processes, evaluating the functions transcription factor EB (TFEB), which regulates lysosomal biogenesis. We performed studies with GFP-LC3 mice, mice with liver-specific deletion of transcription factor EB (TFEB), mice with disruption of the transcription factor E3 gene (TFE3-knockout mice), mice with disruption of the Tefb and Tfe3 genes (TFEB, TFE3 double-knockout mice), and Tfeb flox/flox albumin cre-negative mice (controls). TFEB was overexpressed from adenoviral vectors or knocked down with small interfering RNAs in mouse livers. Mice were placed on diets of chronic ethanol feeding plus an acute binge to induce liver damage (ethanol diet); some mice were also given injections of torin1, an inhibitor of the kinase activity of the mechanistic target of rapamycin (mTOR). Liver tissues were collected and analyzed by immunohistochemistry, immunoblots, and quantitative real-time PCR to monitor lysosome biogenesis. We analyzed levels of TFEB in liver tissues from patients with alcoholic hepatitis and from healthy donors (controls) by immunohistochemistry. Liver tissues from mice on the ethanol diet had lower levels of total and nuclear TFEB, compared with control mice, and hepatocytes had reduced lysosome biogenesis and autophagy. Hepatocytes from mice on the ethanol diet had increased translocation of mTOR into lysosomes, resulting increased mTOR activation. Administration of torin1 increased liver levels of TFEB and reduced steatosis and liver injury induced by ethanol. Mice that overexpressed TFEB in liver developed less-severe ethanol-induced liver injury and had increased lysosomal biogenesis and mitochondrial bioenergetics compared to mice carrying a control vector. Mice with knockdown of TFEB, as well as TFEB, TFE3 double-knockout mice, developed more severe liver injury in response to the ethanol diet than control mice. Liver tissues from patients with alcohol-induced hepatitis had lower nuclear levels of TFEB than control tissues CONCLUSIONS: We found chronic ethanol feeding plus an acute binge to reduce hepatic expression of the transcription factor TFEB, which is required for lysosomal biogenesis and autophagy. Strategies to block mTOR activity or increase levels of TFEB might be developed to protect liver from ethanol-induced damage. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

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.

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.

Liver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature

PubMed Central

Tong, Hoi Y.; Díaz, Carmen; Collantes, Elena; Medrano, Nicolás; Borobia, Alberto M.; Jara, Paloma; Ramírez, Elena

2015-01-01

Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of “possible” relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the liver's function is highly recommended. PMID:25688317

Tauroursodeoxycholic acid attenuates endoplasmic reticulum stress and protects the liver from chronic intermittent hypoxia induced injury.

PubMed

Hou, Yanpeng; Yang, Huai'an; Cui, Zeshi; Tai, Xuhui; Chu, Yanling; Guo, Xing

2017-09-01

Obstructive sleep apnea that characterized by chronic intermittent hypoxia (CIH) has been reported to associate with chronic liver injury. Tauroursodeoxycholic acid (TUDCA) exerts liver-protective effects in various liver diseases. The purpose of this study was to test the hypothesis that TUDCA could protect liver against CIH injury. C57BL/6 mice were subjected to intermittent hypoxia for eight weeks and applied with TUDCA by intraperitoneal injection. The effect of TUDCA on liver histological changes, liver function, oxidative stress, inflammatory response, hepatocyte apoptosis and endoplasmic reticulum (ER) stress were investigated. The results showed that administration of TUDCA attenuated liver pathological changes, reduced serum alanine aminotransferase and aspartate aminotransferase level, suppressed reactive oxygen species activity, decreased tumor necrosis factor-α and interleukin-1β level and inhibited hepatocyte apoptosis induced by CIH. TUDCA also inhibited CIH-induced ER stress in liver as evidenced by decreased expression of ER chaperone 78 kDa glucose-related protein, unfolded protein response transducers and ER proapoptotic proteins. Altogether, the present study described a liver-protective effect of TUDCA in CIH mice model, and this effect seems at least partly through the inhibition of ER stress.

Digital liver biopsy: Bio-imaging of fatty liver for translational and clinical research

PubMed Central

Mancini, Marcello; Summers, Paul; Faita, Francesco; Brunetto, Maurizia R; Callea, Francesco; De Nicola, Andrea; Di Lascio, Nicole; Farinati, Fabio; Gastaldelli, Amalia; Gridelli, Bruno; Mirabelli, Peppino; Neri, Emanuele; Salvadori, Piero A; Rebelos, Eleni; Tiribelli, Claudio; Valenti, Luca; Salvatore, Marco; Bonino, Ferruccio

2018-01-01

The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a “digital biopsy” for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines (Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver. PMID:29527259

How important is donor age in liver transplantation?

PubMed

Lué, Alberto; Solanas, Estela; Baptista, Pedro; Lorente, Sara; Araiz, Juan J; Garcia-Gil, Agustin; Serrano, M Trinidad

2016-06-07

The age of liver donors has been increasing in the past several years because of a donor shortage. In the United States, 33% of donors are age 50 years or older, as are more than 50% in some European countries. The impact of donor age on liver transplantation (LT) has been analyzed in several studies with contradictory conclusions. Nevertheless, recent analyses of the largest databases demonstrate that having an older donor is a risk factor for graft failure. Donor age is included as a risk factor in the more relevant graft survival scores, such as the Donor Risk Index, donor age and Model for End-stage Liver Disease, Survival Outcomes Following Liver Transplantation, and the Balance of Risk. The use of old donors is related to an increased rate of biliary complications and hepatitis C virus-related graft failure. Although liver function does not seem to be significantly affected by age, the incidence of several liver diseases increases with age, and the capacity of the liver to manage or overcome liver diseases or external injuries decreases. In this paper, the importance of age in LT outcomes, the role of donor age as a risk factor, and the influence of aging on liver regeneration are reviewed.

How important is donor age in liver transplantation?

PubMed Central

Lué, Alberto; Solanas, Estela; Baptista, Pedro; Lorente, Sara; Araiz, Juan J; Garcia-Gil, Agustin; Serrano, M Trinidad

2016-01-01

The age of liver donors has been increasing in the past several years because of a donor shortage. In the United States, 33% of donors are age 50 years or older, as are more than 50% in some European countries. The impact of donor age on liver transplantation (LT) has been analyzed in several studies with contradictory conclusions. Nevertheless, recent analyses of the largest databases demonstrate that having an older donor is a risk factor for graft failure. Donor age is included as a risk factor in the more relevant graft survival scores, such as the Donor Risk Index, donor age and Model for End-stage Liver Disease, Survival Outcomes Following Liver Transplantation, and the Balance of Risk. The use of old donors is related to an increased rate of biliary complications and hepatitis C virus-related graft failure. Although liver function does not seem to be significantly affected by age, the incidence of several liver diseases increases with age, and the capacity of the liver to manage or overcome liver diseases or external injuries decreases. In this paper, the importance of age in LT outcomes, the role of donor age as a risk factor, and the influence of aging on liver regeneration are reviewed. PMID:27275089

Liver transplantation for metastatic liver malignancies.

PubMed

Foss, Aksel; Lerut, Jan P

2014-06-01

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

A bioartificial liver to treat severe acute liver failure.

PubMed Central

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

1994-01-01

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

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.

Anatomic Peculiarities of Pig and Human Liver.

PubMed

Nykonenko, Andriy; Vávra, Petr; Zonča, Pavel

2017-02-01

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

Molecular pathogenesis and clinical consequences of iron overload in liver cirrhosis.

PubMed

Sikorska, Katarzyna; Bernat, Agnieszka; Wroblewska, Anna

2016-10-01

The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.

Pathogenesis and Prevention of Hepatic Steatosis

PubMed Central

Nassir, Fatiha; Rector, R. Scott; Hammoud, Ghassan M.

2015-01-01

Hepatic steatosis is defined as intrahepatic fat of at least 5% of liver weight. Simple accumulation of triacylglycerols in the liver could be hepatoprotective; however, prolonged hepatic lipid storage may lead to liver metabolic dysfunction, inflammation, and advanced forms of nonalcoholic fatty liver disease. Nonalcoholic hepatic steatosis is associated with obesity, type 2 diabetes, and dyslipidemia. Several mechanisms are involved in the accumulation of intrahepatic fat, including increased flux of fatty acids to the liver, increased de novo lipogenesis, and/or reduced clearance through β-oxidation or very-low-density lipoprotein secretion. This article summarizes the mechanisms involved in the accumulation of triacylglycerols in the liver, the clinical implications, and the prevention of hepatic steatosis, with a focus on the role of mitochondrial function and lifestyle modifications. PMID:27099587

Biochemical effects of vinyl chloride monomer on the liver of occupationally exposed workers.

PubMed

Saad, A A; el-Sewedy, S M; Bader, G A; Mousa, S M; Mahdy, M M

2000-01-01

We investigated the effects of vinyl chloride monomer exposure on the liver of 86 workers by measuring beta-glucuronidase, arylsulfatase A, adenosine deaminase, 5'-nucleotidase and routine liver function enzymes in the sera of the workers. In 21 of them, three or more of these parameters were raised, with a significant decrease in the level of blood glutathione and a significant increase in the enzyme activity level of glutathione S-transferase. Of these 21 workers, 14 had fatty liver infiltration, 8 of whom were also suffering from liver enlargement. Also, 4 workers had liver enlargement without fatty infiltration and 3 had enlarged spleens. The study highlights the need for vigilance in environmental monitoring and medical surveillance of workers exposed to this chemical.

Hepatic stellate cells in liver development, regeneration, and cancer

PubMed Central

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

2013-01-01

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

Fulminant liver failure: clinical and experimental study.

PubMed Central

Slapak, M.

1975-01-01

Clinical experience of some newer methods of hepatic support is described. The results are unpredictable and far from satisfactory. The need for an animal model in which potential therapeutic methods can be studied is emphasized. Such a model based on carefully imposed ischaemic insult to the liver in the absence of portacaval shunting is described. It is suggested that bacterial presence in the bowel together with a depression of the liver reticuloendothelial function plays an important part in the early and rapid mortality of acute liver failure. Temporary auxiliary liver transplantation using an allograft or a closely related primate heterograft seem to be the 2 best available methods of hepatic support for potentially reversible acute liver failure. Images Fig. 8 PMID:812415

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.

ROLE OF COPPER,ZINC-SUPEROXIDE DISMUTASE IN CATALYZING NITROTYROSINE FORMATION IN MURINE LIVER

USDA-ARS?s Scientific Manuscript database

The solely known function of Cu,Zn-superoxide dismutase (SOD1) is to catalyze the dismutation of superoxide anion into hydrogen peroxide. Our objective was to determine if SOD1 catalyzed murine liver protein nitration induced by acetaminophen (APAP) and lipopolysaccharide (LPS). Liver and plasma ...

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...

Omics for Understanding the Gut-Liver-Microbiome Axis and Precision Medicine

USDA-ARS?s Scientific Manuscript database

Human metabolic disease opens a new view to understanding the contribution of the intestinal microbiome to drug metabolism and drug-induced toxicity in gut-liver function. Gut microbiota, a key determinant of intestinal inflammation, also plays a direct role in chronic inflammation and liver disease...

Deep residual networks for automatic segmentation of laparoscopic videos of the liver

NASA Astrophysics Data System (ADS)

Gibson, Eli; Robu, Maria R.; Thompson, Stephen; Edwards, P. Eddie; Schneider, Crispin; Gurusamy, Kurinchi; Davidson, Brian; Hawkes, David J.; Barratt, Dean C.; Clarkson, Matthew J.

2017-03-01

Motivation: For primary and metastatic liver cancer patients undergoing liver resection, a laparoscopic approach can reduce recovery times and morbidity while offering equivalent curative results; however, only about 10% of tumours reside in anatomical locations that are currently accessible for laparoscopic resection. Augmenting laparoscopic video with registered vascular anatomical models from pre-procedure imaging could support using laparoscopy in a wider population. Segmentation of liver tissue on laparoscopic video supports the robust registration of anatomical liver models by filtering out false anatomical correspondences between pre-procedure and intra-procedure images. In this paper, we present a convolutional neural network (CNN) approach to liver segmentation in laparoscopic liver procedure videos. Method: We defined a CNN architecture comprising fully-convolutional deep residual networks with multi-resolution loss functions. The CNN was trained in a leave-one-patient-out cross-validation on 2050 video frames from 6 liver resections and 7 laparoscopic staging procedures, and evaluated using the Dice score. Results: The CNN yielded segmentations with Dice scores >=0.95 for the majority of images; however, the inter-patient variability in median Dice score was substantial. Four failure modes were identified from low scoring segmentations: minimal visible liver tissue, inter-patient variability in liver appearance, automatic exposure correction, and pathological liver tissue that mimics non-liver tissue appearance. Conclusion: CNNs offer a feasible approach for accurately segmenting liver from other anatomy on laparoscopic video, but additional data or computational advances are necessary to address challenges due to the high inter-patient variability in liver appearance.

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.

The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2

NASA Astrophysics Data System (ADS)

Ma, Linglan; Zhao, Jinfang; Wang, Jue; Liu, Jie; Duan, Yanmei; Liu, Huiting; Li, Na; Yan, Jingying; Ruan, Jie; Wang, Han; Hong, Fashui

2009-11-01

Although it is known that nano-TiO2 or other nanoparticles can induce liver toxicities, the mechanisms and the molecular pathogenesis are still unclear. In this study, nano-anatase TiO2 (5 nm) was injected into the abdominal cavity of ICR mice for consecutive 14 days, and the inflammatory responses of liver of mice was investigated. The results showed the obvious titanium accumulation in liver DNA, histopathological changes and hepatocytes apoptosis of mice liver, and the liver function damaged by higher doses nano-anatase TiO2. The real-time quantitative RT-PCR and ELISA analyses showed that nano-anatase TiO2 can significantly alter the mRNA and protein expressions of several inflammatory cytokines, including nucleic factor-κB, macrophage migration inhibitory factor, tumor necrosis factor-α, interleukin-6, interleukin-1β, cross-reaction protein, interleukin-4, and interleukin-10. Our results also implied that the inflammatory responses and liver injury may be involved in nano-anatase TiO2-induced liver toxicity.

Evaluation of liver regeneration diet supplemented with omega-3 fatty acids: experimental study in rats.

PubMed

Silva, Rosilda Mendes da; Malafaia, Osvaldo; Torres, Orlando Jorge Martins; Czeczko, Nicolau Gregori; Marinho Junior, Carlos Hespanha; Kozlowski, Ronaldo Kiviatcoski

2015-01-01

to evaluate liver regeneration in rats after partial hepatectomy of 60% with and without action diet supplemented with fatty acids through the study of the regenerated liver weight, laboratory parameters of liver function and histological study. thirty-six Wistar rats, males, adults were used, weighing between 195 and 330 g assigned to control and groups. The supplementation group received the diet by gavage and were killed after 24h, 72h and seven days. Evaluation of regeneration occurred through analysis of weight gain liver, serum aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase, and mitosis of the liver stained with H&E. the diet supplemented group showed no statistical difference (p>0.05) on the evolution of weights. Administration of fatty acids post-hepatectomy had significant reduction in gamma glutamyltransferase levels and may reflect liver regeneration. Referring to mitotic index, it did not differ between period of times among the groups. supplementation with fatty acids in rats undergoing 60% hepatic resection showed no significant interference related to liver regeneration.

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

PubMed

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

2016-01-01

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

Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).

PubMed

Donnan, P T; McLernon, D; Dillon, J F; Ryder, S; Roderick, P; Sullivan, F; Rosenberg, W

2009-04-01

To determine the natural history of abnormalities in liver function tests (LFTs), derive predictive algorithms for liver disease and identify the most cost-effective strategies for further investigation. MEDLINE database from 1966 to September 2006, EMBASE, CINAHL and the Cochrane Library. Population-based retrospective cohort study set in primary care in Tayside, Scotland, between 1989 and 2003. Participants were patients with no obvious signs of liver disease and registered with a general practitioner (GP). The study followed up those with an incident batch of LFTs in primary care to subsequent liver disease or mortality over a maximum of 15 years. The health technologies being assessed were primary care LFTs, viral and autoantibody tests, ultrasound and liver biopsy. Measures used were the epidemiology of liver disease in Tayside (ELDIT) database, time-to-event modelling, predictive algorithms derived using the Weibull survival model, decision analyses from an NHS perspective, cost-utility analyses, and one-way and two-way sensitivity analyses. A total of 95,977 patients had 364,194 initial LFTs, with a median follow-up of 3.7 years. Of these, 21.7% had at least one abnormal liver function test (ALFT) and 1090 (1.14%) developed liver disease. Elevated transaminases were strongly associated with diagnosed liver disease, with hazard ratios (HRs) of 4.23 [95% CI (confidence interval) 3.55-5.04] for mild levels and 12.67 (95% CI 9.74-16.47) for severe levels versus normal. For gamma-glutamyltransferase (GGT), these HRs were 2.54 (95% CI 2.17-2.96) and 13.44 (10.71-16.87) respectively. Low albumin was strongly associated with all cause mortality, with ratios of 2.65 (95% CI 2.47-2.85) for mild levels and 4.99 (95% CI 4.26-5.84) for severe levels. Sensitivity for predicting events over 5 years was low and specificity was high. Follow-up time was split into baseline to 3 months, 3 months to 1 year and over 1 year. All LFTs were predictive of liver disease, and high probability of liver disease was associated with being female, methadone use, alcohol dependency and deprivation. The shorter-term models had overall c-statistics of 0.85 and 0.72 for outcome of liver disease at 3 months and 1 year respectively, and 0.88 and 0.82 for all cause mortality at 3 months and 1 year respectively. Calibration was good for models predicting liver disease. Discrimination was low for models predicting events at over 1 year. In cost-utility analyses, retesting dominated referral as an option. However, using the predictive algorithms to identify the top percentile at high risk of liver disease, retesting had an incremental cost-utility ratio of 7588 pounds relative to referral. GGT should be included in the batch of LFTs in primary care. If the patient in primary care has no obvious liver disease and a low or moderate risk of liver disease, retesting in primary care is the most cost-effective option. If the patient with ALFTs in primary care has a high risk of liver disease, retesting depends on the willingness to pay of the NHS. Cut-offs are arbitrary and in developing decision aids it is important to treat the LFT results as continuous variables.

Liver fibrosis markers in alcoholic liver disease.

PubMed

Chrostek, Lech; Panasiuk, Anatol

2014-07-07

Alcohol is one of the main factors of liver damage. The evaluation of the degree of liver fibrosis is of great value for therapeutic decision making in patients with alcoholic liver disease (ALD). Staging of liver fibrosis is essential to define prognosis and management of the disease. Liver biopsy is a gold standard as it has high sensitivity and specificity in fibrosis diagnostics. Taking into account the limitations of liver biopsy, there is an exigency to introduce non-invasive serum markers for fibrosis that would be able to replace liver biopsy. Ideal serum markers should be specific for the liver, easy to perform and independent to inflammation and fibrosis in other organs. Serum markers of hepatic fibrosis are divided into direct and indirect. Indirect markers reflect alterations in hepatic function, direct markers reflect extracellular matrix turnover. These markers should correlate with dynamic changes in fibrogenesis and fibrosis resolution. The assessment of the degree of liver fibrosis in alcoholic liver disease has diagnostic and prognostic implications, therefore noninvasive assessment of fibrosis remains important. There are only a few studies evaluating the diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with ALD. Several noninvasive laboratory tests have been used to assess liver fibrosis in patients with alcoholic liver disease, including the hyaluronic acid, FibroTest, FibrometerA, Hepascore, Forns and APRI indexes, FIB4, an algorithm combining Prothrombin index (PI), α-2 macroglobulin and hyaluronic acid. Among these tests, Fibrotest, FibrometerA and Hepascore demonstrated excellent diagnostic accuracy in identifying advanced fibrosis and cirrhosis, and additionally, Fibrotest was independently associated with survival. Therefore, the use of biomarkers may reduce the need for liver biopsy and permit an earlier treatment of alcoholic patients.

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.

Chronic liver disease and 90-day mortality in 21,359 patients following peptic ulcer bleeding--a Nationwide Cohort Study.

PubMed

Holland-Bill, L; Christiansen, C F; Gammelager, H; Mortensen, R N; Pedersen, L; Sørensen, H T

2015-03-01

Bleeding is a serious and frequent complication of peptic ulcer disease. Hepatic dysfunction can cause coagulopathy and increases the risk of peptic ulcer bleeding. However, whether chronic liver disease increases mortality after peptic ulcer bleeding remains unclear. To examine the prognostic impact of chronic liver disease on mortality after peptic ulcer bleeding. We used population-based medical registries to conduct a cohort study of all Danish residents hospitalised with incident peptic ulcer bleeding from 2004 through 2011. We identified patients diagnosed with liver cirrhosis or non-cirrhotic chronic liver disease before their admission for peptic ulcer bleeding. We then computed 90-day mortality after peptic ulcer bleeding based on the Kaplan-Meier method (1 - survival function) and used a Cox regression model to estimate mortality rate ratios (MRRs), controlling for potential confounders. We identified 21,359 patients hospitalised with peptic ulcer bleeding. Among these, 653 (3.1%) had a previous diagnosis of liver cirrhosis and 474 (2.2%) had a history of non-cirrhotic chronic liver disease. Patients with liver cirrhosis and non-cirrhotic chronic liver disease had a cumulative 90-day mortality of 25.3% and 20.7%, respectively, compared to 18.3% among patients without chronic liver disease. Liver cirrhosis was associated with an adjusted 90-day MRR of 2.38 (95% CI: 2.02-2.80), compared to 1.49 (95% CI: 1.22-1.83) among patients with non-cirrhotic chronic liver disease. Patients with chronic liver disease, particularly liver cirrhosis, are at increased risk of death within 90 days after hospitalisation for peptic ulcer bleeding compared to patients without chronic liver disease. © 2015 John Wiley & Sons Ltd.

Radiation-Induced Liver Injury in Three-Dimensional Conformal Radiation Therapy (3D-CRT) for Postoperative or Locoregional Recurrent Gastric Cancer: Risk Factors and Dose Limitations.

PubMed

Li, Guichao; Wang, Jiazhou; Hu, Weigang; Zhang, Zhen

2015-01-01

This study examined the status of radiation-induced liver injury in adjuvant or palliative gastric cancer radiation therapy (RT), identified risk factors of radiation-induced liver injury in gastric cancer RT, analysed the dose-volume effects of liver injury, and developed a liver dose limitation reference for gastric cancer RT. Data for 56 post-operative gastric cancer patients and 6 locoregional recurrent gastric cancer patients treated with three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) from Sep 2007 to Sep 2009 were analysed. Forty patients (65%) were administered concurrent chemotherapy. Pre- and post-radiation chemotherapy were given to 61 patients and 43 patients, respectively. The radiation dose was 45-50.4 Gy in 25-28 fractions. Clinical parameters, including gender, age, hepatic B virus status, concurrent chemotherapy, and the total number of chemotherapy cycles, were included in the analysis. Univariate analyses with a non-parametric rank test (Mann-Whitney test) and logistic regression test and a multivariate analysis using a logistic regression test were completed. We also analysed the correlation between RT and the changes in serum chemistry parameters [including total bilirubin, (TB), direct bilirubin (D-TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum albumin (ALB)] after RT. The Child-Pugh grade progressed from grade A to grade B after radiotherapy in 10 patients. A total of 16 cases of classic radiation-induced liver disease (RILD) were observed, and 2 patients had both Child-Pugh grade progression and classic RILD. No cases of non-classic radiation liver injury occurred in the study population. Among the tested clinical parameters, the total number of chemotherapy cycles correlated with liver function injury. V35 and ALP levels were significant predictive factors for radiation liver injury. In 3D-CRT for gastric cancer patients, radiation-induced liver injury may occur and affect the overall treatment plan. The total number of chemotherapy cycles correlated with liver function injury, and V35 and ALP are significant predictive factors for radiation-induced liver injury. Our dose limitation reference for liver protection is feasible.

Cultured Mycelium Cordyceps sinensis allevi¬ates CCl4-induced liver inflammation and fibrosis in mice by activating hepatic natural killer cells.

PubMed

Peng, Yuan; Huang, Kai; Shen, Li; Tao, Yan-yan; Liu, Cheng-hai

2016-02-01

Recent evidence shows that cultured mycelium Cordyceps sinensis (CMCS) effectively protects against liver fibrosis in mice. Here, we investigated whether the anti-fibrotic action of CMCS was related to its regulation of the activity of hepatic natural killer (NK) cells in CCl4-treated mice. C57BL/6 mice were injected with 10% CCl4 (2 mL/kg, ip) 3 times per week for 4 weeks, and received CMCS (120 mg·kg(-1)·d(-1), ig) during this period. In another part of experiments, the mice were also injected with an NK cell-deleting antibody ASGM-1 (20 μg, ip) 5 times in the first 3 weeks. After the mice were sacrificed, serum liver function, and liver inflammation, hydroxyproline content and collagen deposition were assessed. The numbers of hepatic NK cells and expression of NKG2D (activation receptor of NK cells) on isolated liver lymphocytes were analyzed using flow cytometry. Desmin expression and cell apoptosis in liver tissues were studied using desmin staining and TUNEL assay, respectively. The levels of α-SMA, TGF-β, RAE-1δ and RAE-1ε in liver tissues were determined by RT-qPCR. In CCl4-treated mice, CMCS administration significantly improved liver function, attenuated liver inflammation and fibrosis, and increased the numbers of hepatic NK cells and expression level of NKG2D on hepatic NK cells. Furthermore, CMCS administration significantly decreased desmin expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Injection with NK cell-deleting ASGM-1 not only diminished the numbers of hepatic NK cells, but also greatly accelerated liver inflammation and fibrosis in CCl4-treated mice. In CCl4-treated mice with NK cell depletion, CMCS administration decelerated the rate of liver fibrosis development, and mildly upregulated the numbers of hepatic NK cells but without changing NKG2D expression. CMCS alleviates CCl4-induced liver inflammation and fibrosis via promoting activation of hepatic NK cells. CMCS partially reverses ASGM-1-induced depletion of hepatic NK cells.

CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure

PubMed Central

Stutchfield, Benjamin M.; Antoine, Daniel J.; Mackinnon, Alison C.; Gow, Deborah J.; Bain, Calum C.; Hawley, Catherine A.; Hughes, Michael J.; Francis, Benjamin; Wojtacha, Davina; Man, Tak Y.; Dear, James W.; Devey, Luke R.; Mowat, Alan M.; Pollard, Jeffrey W.; Park, B. Kevin; Jenkins, Stephen J.; Simpson, Kenneth J.; Hume, David A.; Wigmore, Stephen J.; Forbes, Stuart J.

2015-01-01

Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions Serum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury. PMID:26344055

Elevated alanine aminotransferase (ALT) in the deceased donor: impact on early post-transplant liver allograft function.

PubMed

Mangus, Richard S; Fridell, Jonathan A; Kubal, Chandrashekhar A; Davis, Jason P; Tector, A Joseph

2015-02-01

Serum alanine aminotransferase (ALT) levels are frequently elevated with liver injury and such elevations are common in deceased organ donors. The impact of this injury on early liver allograft function has not been well described. This study analyses the immediate function and 1-year graft and patient survival for liver allografts stratified by peak serum ALT levels in the deceased donor. The on-site organ procurement records for 1348 consecutive deceased liver donors were reviewed (2001–2011). Serum ALT was categorized into three study groups: normal/mild elevation, 0–499 μ/L; moderate elevation, 500–999 μ/L (>10× upper limit of normal) and severe elevation, ≥1000 μ/L (>20× upper limit of normal). Outcomes included early graft function and graft loss, and 1-year graft and patient survival. Distribution of subjects included: normal/mild, 1259 (93%); moderate, 34 (3%) and severe, 55 (4%). Risk of 30-day graft loss for the three study groups was: 72 (6%), 3 (9%) and 3 (6%) (P = 0.74). Graft and patient survival at 1 year for the three groups was: normal/mild, 1031 (87%), 1048 (88%); moderate, 31 (91%), 31 (91%) and severe, 43 (88%), 44 (90%) (P = 0.71, 0.79). Cox proportional hazards modelling of survival while controlling for donor age and recipient model for end-stage liver disease score (MELD) demonstrates no statistically significant difference among the three study groups. This study demonstrates clinical equivalence in early graft function and 1-year graft and patient survival for donor livers with varying peak levels of serum ALT. These donor allografts may, therefore, be utilized successfully.

[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.

Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression

PubMed Central

Nantasanti, Sathidpak; Toussaint, Mathilda J. M.; Youssef, Sameh A.; Tooten, Peter C. J.; de Bruin, Alain

2016-01-01

The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC. PMID:26967735

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

PubMed

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

2014-03-27

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

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.

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

PubMed

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

2007-03-01

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

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.

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.

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.