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

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.

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 ...

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

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.

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

[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.

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.

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.

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

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

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.

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.

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.

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

PubMed Central

Chambers, John C; Zhang, Weihua; Sehmi, Joban; Li, Xinzhong; Wass, Mark N; Van der Harst, Pim; Holm, Hilma; Sanna, Serena; Kavousi, Maryam; Baumeister, Sebastian E; Coin, Lachlan J; Deng, Guohong; Gieger, Christian; Heard-Costa, Nancy L; Hottenga, Jouke-Jan; Kühnel, Brigitte; Kumar, Vinod; Lagou, Vasiliki; Liang, Liming; Luan, Jian’an; Vidal, Pedro Marques; Leach, Irene Mateo; O’Reilly, Paul F; Peden, John F; Rahmioglu, Nilufer; Soininen, Pasi; Speliotes, Elizabeth K; Yuan, Xin; Thorleifsson, Gudmar; Alizadeh, Behrooz Z; Atwood, Larry D; Borecki, Ingrid B; Brown, Morris J; Charoen, Pimphen; Cucca, Francesco; Das, Debashish; de Geus, Eco J C; Dixon, Anna L; Döring, Angela; Ehret, Georg; Eyjolfsson, Gudmundur I; Farrall, Martin; Forouhi, Nita G; Friedrich, Nele; Goessling, Wolfram; Gudbjartsson, Daniel F; Harris, Tamara B; Hartikainen, Anna-Liisa; Heath, Simon; Hirschfield, Gideon M; Hofman, Albert; Homuth, Georg; Hyppönen, Elina; Janssen, Harry L A; Johnson, Toby; Kangas, Antti J; Kema, Ido P; Kühn, Jens P; Lai, Sandra; Lathrop, Mark; Lerch, Markus M; Li, Yun; Liang, T Jake; Lin, Jing-Ping; Loos, Ruth J F; Martin, Nicholas G; Moffatt, Miriam F; Montgomery, Grant W; Munroe, Patricia B; Musunuru, Kiran; Nakamura, Yusuke; O’Donnell, Christopher J; Olafsson, Isleifur; Penninx, Brenda W; Pouta, Anneli; Prins, Bram P; Prokopenko, Inga; Puls, Ralf; Ruokonen, Aimo; Savolainen, Markku J; Schlessinger, David; Schouten, Jeoffrey N L; Seedorf, Udo; Sen-Chowdhry, Srijita; Siminovitch, Katherine A; Smit, Johannes H; Spector, Timothy D; Tan, Wenting; Teslovich, Tanya M; Tukiainen, Taru; Uitterlinden, Andre G; Van der Klauw, Melanie M; Vasan, Ramachandran S; Wallace, Chris; Wallaschofski, Henri; Wichmann, H-Erich; Willemsen, Gonneke; Würtz, Peter; Xu, Chun; Yerges-Armstrong, Laura M; Abecasis, Goncalo R; Ahmadi, Kourosh R; Boomsma, Dorret I; Caulfield, Mark; Cookson, William O; van Duijn, Cornelia M; Froguel, Philippe; Matsuda, Koichi; McCarthy, Mark I; Meisinger, Christa; Mooser, Vincent; Pietiläinen, Kirsi H; Schumann, Gunter; Snieder, Harold; Sternberg, Michael J E; Stolk, Ronald P; Thomas, Howard C; Thorsteinsdottir, Unnur; Uda, Manuela; Waeber, Gérard; Wareham, Nicholas J; Waterworth, Dawn M; Watkins, Hugh; Whitfield, John B; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Fox, Caroline S; Ala-Korpela, Mika; Stefansson, Kari; Vollenweider, Peter; Völzke, Henry; Schadt, Eric E; Scott, James; Järvelin, Marjo-Riitta; Elliott, Paul; Kooner, Jaspal S

2012-01-01

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10−8 to P = 10−190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. PMID:22001757

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

PubMed

Chambers, John C; Zhang, Weihua; Sehmi, Joban; Li, Xinzhong; Wass, Mark N; Van der Harst, Pim; Holm, Hilma; Sanna, Serena; Kavousi, Maryam; Baumeister, Sebastian E; Coin, Lachlan J; Deng, Guohong; Gieger, Christian; Heard-Costa, Nancy L; Hottenga, Jouke-Jan; Kühnel, Brigitte; Kumar, Vinod; Lagou, Vasiliki; Liang, Liming; Luan, Jian'an; Vidal, Pedro Marques; Mateo Leach, Irene; O'Reilly, Paul F; Peden, John F; Rahmioglu, Nilufer; Soininen, Pasi; Speliotes, Elizabeth K; Yuan, Xin; Thorleifsson, Gudmar; Alizadeh, Behrooz Z; Atwood, Larry D; Borecki, Ingrid B; Brown, Morris J; Charoen, Pimphen; Cucca, Francesco; Das, Debashish; de Geus, Eco J C; Dixon, Anna L; Döring, Angela; Ehret, Georg; Eyjolfsson, Gudmundur I; Farrall, Martin; Forouhi, Nita G; Friedrich, Nele; Goessling, Wolfram; Gudbjartsson, Daniel F; Harris, Tamara B; Hartikainen, Anna-Liisa; Heath, Simon; Hirschfield, Gideon M; Hofman, Albert; Homuth, Georg; Hyppönen, Elina; Janssen, Harry L A; Johnson, Toby; Kangas, Antti J; Kema, Ido P; Kühn, Jens P; Lai, Sandra; Lathrop, Mark; Lerch, Markus M; Li, Yun; Liang, T Jake; Lin, Jing-Ping; Loos, Ruth J F; Martin, Nicholas G; Moffatt, Miriam F; Montgomery, Grant W; Munroe, Patricia B; Musunuru, Kiran; Nakamura, Yusuke; O'Donnell, Christopher J; Olafsson, Isleifur; Penninx, Brenda W; Pouta, Anneli; Prins, Bram P; Prokopenko, Inga; Puls, Ralf; Ruokonen, Aimo; Savolainen, Markku J; Schlessinger, David; Schouten, Jeoffrey N L; Seedorf, Udo; Sen-Chowdhry, Srijita; Siminovitch, Katherine A; Smit, Johannes H; Spector, Timothy D; Tan, Wenting; Teslovich, Tanya M; Tukiainen, Taru; Uitterlinden, Andre G; Van der Klauw, Melanie M; Vasan, Ramachandran S; Wallace, Chris; Wallaschofski, Henri; Wichmann, H-Erich; Willemsen, Gonneke; Würtz, Peter; Xu, Chun; Yerges-Armstrong, Laura M; Abecasis, Goncalo R; Ahmadi, Kourosh R; Boomsma, Dorret I; Caulfield, Mark; Cookson, William O; van Duijn, Cornelia M; Froguel, Philippe; Matsuda, Koichi; McCarthy, Mark I; Meisinger, Christa; Mooser, Vincent; Pietiläinen, Kirsi H; Schumann, Gunter; Snieder, Harold; Sternberg, Michael J E; Stolk, Ronald P; Thomas, Howard C; Thorsteinsdottir, Unnur; Uda, Manuela; Waeber, Gérard; Wareham, Nicholas J; Waterworth, Dawn M; Watkins, Hugh; Whitfield, John B; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Fox, Caroline S; Ala-Korpela, Mika; Stefansson, Kari; Vollenweider, Peter; Völzke, Henry; Schadt, Eric E; Scott, James; Järvelin, Marjo-Riitta; Elliott, Paul; Kooner, Jaspal S

2011-10-16

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

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.

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.

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.

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.

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.

Systems biology in hepatology: approaches and applications.

PubMed

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

2018-06-01

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

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.

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

Monitoring of Total and Regional Liver Function after SIRT.

PubMed

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

2014-01-01

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

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

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

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.

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.

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

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.

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.

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

PubMed

Vootla, Vamshidhar R; Daniel, Myrta

2015-01-01

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

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

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.

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.

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

[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.

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

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.

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.

c-MYC—Making Liver Sick: Role of c-MYC in Hepatic Cell Function, Homeostasis and Disease

PubMed Central

Zheng, Kang; Cubero, Francisco Javier; Nevzorova, Yulia A.

2017-01-01

Over 35 years ago, c-MYC, a highly pleiotropic transcription factor that regulates hepatic cell function, was identified. In recent years, a considerable increment in the number of publications has significantly shifted the way that the c-MYC function is perceived. Overexpression of c-MYC alters a wide range of roles including cell proliferation, growth, metabolism, DNA replication, cell cycle progression, cell adhesion and differentiation. The purpose of this review is to broaden the understanding of the general functions of c-MYC, to focus on c-MYC-driven pathogenesis in the liver, explain its mode of action under basal conditions and during disease, and discuss efforts to target c-MYC as a plausible therapy for liver disease. PMID:28422055

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.

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.

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.

Nuclear receptors and nonalcoholic fatty liver disease1

PubMed Central

Cave, Matthew C.; Clair, Heather B.; Hardesty, Josiah E.; Falkner, K. Cameron; Feng, Wenke; Clark, Barbara J.; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A.; McClain, Craig J.; Prough, Russell A.

2016-01-01

Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. PMID:26962021

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.

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

PubMed Central

Vootla, Vamshidhar R.; Daniel, Myrta

2015-01-01

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

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

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.

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.

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.

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

PubMed

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

2015-11-01

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

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.

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.

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

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

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.

Utility of pre-procurement bedside liver biopsy in the deceased extended-criteria liver donor.

PubMed

Mangus, Richard S; Borup, Tim C; Popa, Sam; Saxena, Romil; Cummings, Oscar; Tector, A Joseph

2014-12-01

The Indiana Organ Procurement Organization (IOPO) utilizes preoperative bedside liver biopsies in certain extended-criteria donors (ECDs), obtained by the on-site coordinator, to determine the utility of pursuing donation. This study reports the clinical and financial outcomes for this management strategy. All bedside liver biopsies obtained in ECDs over a five-yr period were reviewed. Study variables included the following: indication for biopsy, biopsy results, taking the case to the operating room, transplantation of the donor liver, and graft survival. All biopsies were processed at a single university center. There were 110 donors biopsied. Primary indications included the following: old age (29%), extensive/current alcohol abuse (26%), hepatitis C-positive serology (21%), obesity (25%), and severely elevated liver function enzymes (18%). Biopsy results demonstrated a potentially transplantable liver in 73 cases (66%), all of whom were taken to the OR (while 37 ruled out for donation based upon liver biopsy [34%]). Of all biopsied livers, 49 ultimately were transplanted (45%). Intra-operative decisions included the following: transplant 51/73 (70%), surgeon decision to exclude 20/73 (27%), nonuse due to finding of malignancy two (3%). Bedside liver biopsy may be a valuable tool to determine the utility in pursuing donation in ECDs, particularly with liver-only donors. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Elevated red blood cell distribution width is associated with liver function tests in patients with primary hepatocellular carcinoma.

PubMed

Wei, Ting-Ting; Tang, Qing-Qin; Qin, Bao-Dong; Ma, Ning; Wang, Li-Li; Zhou, Lin; Zhong, Ren-Qian

2016-11-25

Red blood cell distribution width (RDW), a routinely tested parameter of the complete blood count (CBC), has been reported to be increased in various cancers and correlated with the patients' clinical characteristics. However, the significance of RDW in primary hepatocellular carcinoma (pHCC) is largely unknown. The aim of this study was to evaluate the associations between RDW and the clinical characteristics of pHCC patients. Medical records of 110 treatment-naive pHCC patients were retrospectively reviewed. Their clinical characteristics on admission, including RDW, liver function tests and tumor stage, were extracted, and their relationships were analyzed using Spearman correlation and Kruskal-Wallis test. Sixty-eight healthy individuals were set as controls. RDW was significantly increased in pHCC patients and correlated with the liver function tests. However, no correlation between RDW and tumor stage was found. RDW may be used to assess the liver function, but not the tumor stage in pHCC patients.

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

Hepatic (Liver) Function Panel

MedlinePlus

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

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

PubMed

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

2014-09-17

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

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

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.

Biotechnology Challenges to In Vitro Maturation of Hepatic Stem Cells.

PubMed

Chen, Chen; Soto-Gutierrez, Alejandro; Baptista, Pedro M; Spee, Bart

2018-04-01

The incidence of liver disease is increasing globally. The only curative therapy for severe end-stage liver disease, liver transplantation, is limited by the shortage of organ donors. In vitro models of liver physiology have been developed and new technologies and approaches are progressing rapidly. Stem cells might be used as a source of liver tissue for development of models, therapies, and tissue-engineering applications. However, we have been unable to generate and maintain stable and mature adult liver cells ex vivo. We review factors that promote hepatocyte differentiation and maturation, including growth factors, transcription factors, microRNAs, small molecules, and the microenvironment. We discuss how the hepatic circulation, microbiome, and nutrition affect liver function, and the criteria for considering cells derived from stem cells to be fully mature hepatocytes. We explain the challenges to cell transplantation and consider future technologies for use in hepatic stem cell maturation, including 3-dimensional biofabrication and genome modification. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Opportunities and challenges in the wider adoption of liver and interconnected microphysiological systems

PubMed Central

Kostrzewski, Tomasz; Sceats, Emma L

2017-01-01

Liver disease represents a growing global health burden. The development of in vitro liver models which allow the study of disease and the prediction of metabolism and drug-induced liver injury in humans remains a challenge. The maintenance of functional primary hepatocytes cultures, the parenchymal cell of the liver, has historically been difficult with dedifferentiation and the consequent loss of hepatic function limiting utility. The desire for longer term functional liver cultures sparked the development of numerous systems, including collagen sandwiches, spheroids, micropatterned co-cultures and liver microphysiological systems. This review will focus on liver microphysiological systems, often referred to as liver-on-a-chip, and broaden to include platforms with interconnected microphysiological systems or multi-organ-chips. The interconnection of microphysiological systems presents the opportunity to explore system level effects, investigate organ cross talk, and address questions which were previously the preserve of animal experimentation. As a field, microphysiological systems have reached a level of maturity suitable for commercialization and consequent evaluation by a wider community of users, in academia and the pharmaceutical industry. Here scientific, operational, and organizational considerations relevant to the wider adoption of microphysiological systems will be discussed. Applications in which microphysiological systems might offer unique scientific insights or enable studies currently feasible only with animal models are described, and challenges which might be addressed to enable wider adoption of the technologies are highlighted. A path forward which envisions the development of microphysiological systems in partnerships between academia, vendors and industry, is proposed. Impact statement Microphysiological systems are in vitro models of human tissues and organs. These systems have advanced rapidly in recent years and are now being commercialized. To achieve wide adoption in the biological and pharmaceutical research communities, microphysiological systems must provide unique insights which translate to humans. This will be achieved by identifying key applications and making microphysiological systems intuitive to use. PMID:28504617

Opportunities and challenges in the wider adoption of liver and interconnected microphysiological systems.

PubMed

Hughes, David J; Kostrzewski, Tomasz; Sceats, Emma L

2017-10-01

Liver disease represents a growing global health burden. The development of in vitro liver models which allow the study of disease and the prediction of metabolism and drug-induced liver injury in humans remains a challenge. The maintenance of functional primary hepatocytes cultures, the parenchymal cell of the liver, has historically been difficult with dedifferentiation and the consequent loss of hepatic function limiting utility. The desire for longer term functional liver cultures sparked the development of numerous systems, including collagen sandwiches, spheroids, micropatterned co-cultures and liver microphysiological systems. This review will focus on liver microphysiological systems, often referred to as liver-on-a-chip, and broaden to include platforms with interconnected microphysiological systems or multi-organ-chips. The interconnection of microphysiological systems presents the opportunity to explore system level effects, investigate organ cross talk, and address questions which were previously the preserve of animal experimentation. As a field, microphysiological systems have reached a level of maturity suitable for commercialization and consequent evaluation by a wider community of users, in academia and the pharmaceutical industry. Here scientific, operational, and organizational considerations relevant to the wider adoption of microphysiological systems will be discussed. Applications in which microphysiological systems might offer unique scientific insights or enable studies currently feasible only with animal models are described, and challenges which might be addressed to enable wider adoption of the technologies are highlighted. A path forward which envisions the development of microphysiological systems in partnerships between academia, vendors and industry, is proposed. Impact statement Microphysiological systems are in vitro models of human tissues and organs. These systems have advanced rapidly in recent years and are now being commercialized. To achieve wide adoption in the biological and pharmaceutical research communities, microphysiological systems must provide unique insights which translate to humans. This will be achieved by identifying key applications and making microphysiological systems intuitive to use.

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.

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.

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

PubMed

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

2016-12-01

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

The CCCH-type zinc finger transcription factor Zc3h8 represses NF-κB-mediated inflammation in digestive organs in zebrafish.

PubMed

Zou, Qingliang; Gang, Kai; Yang, Qifen; Liu, Xiaolin; Tang, Xuemei; Lu, Huiqiang; He, Jianbo; Luo, Lingfei

2018-06-05

Degenerative diseases of organs lead to their impaired function. The cellular and molecular mechanisms underlying organ degeneration are therefore of great research and clinical interest but are currently incompletely characterized. Here, using a forward-genetic screen for genes regulating liver development and function in zebrafish, we identified a cq5 mutant that exhibited a liver-degeneration phenotype at 5 days post-fertilization, the developmental stage at which a functional liver develops. Positional cloning revealed that the liver degeneration was caused by a single point mutation in the gene zinc finger CCCH-type containing 8 (zc3h8), changing a highly conserved histidine to glutamine at position 353 of the Zc3h8 protein. The zc3h8 mutation-induced liver degeneration in the mutant was accompanied by reduced proliferation, increased apoptosis, and macrophage phagocytosis of hepatocytes. Transcriptional profile analyses revealed up-regulation and activation of both pro-inflammatory cytokines and the NF-κB signaling pathway in the zc3h8 mutant. Suppression of NF-κB signaling activity efficiently rescued the pro-inflammatory cytokine response as well as the inflammation-mediated liver degeneration phenotype of the mutant. Of note, the zc3h8 mutation induced degeneration of several other organs, including the gut and exocrine pancreas, indicating that Zc3h8 is a general repressor of inflammation in zebrafish. Collectively, our findings demonstrate that Zc3h8 maintains organ homeostasis by inhibiting the NF-κB-mediated inflammatory response in zebrafish and that Zc3h8 dysfunction causes degeneration of multiple organs, including the liver, gut, and pancreas. Copyright © 2018, The American Society for Biochemistry and Molecular Biology.

Primary non-function is frequently associated with fatty liver allografts and high mortality after re-transplantation.

PubMed

Kulik, Ulf; Lehner, Frank; Klempnauer, Jürgen; Borlak, Jürgen

2017-08-01

The shortage of liver donations demands the use of suboptimal grafts with steatosis being a frequent finding. Although ≤30% macrovesicular steatosis is considered to be safe the risk for primary non-function (PNF) and outcome after re-transplantation (re-OLT) is unknown. Among 1205 orthotopic liver transplantations performed at our institution the frequency, survival and reason of re-OLT were evaluated. PNF (group A) cases and those with initial transplant function but subsequent need for re-OLT (group B) were analysed. Histopathology and clinical judgement determined the cause of PNF and included an assessment of hepatic steatosis. Additionally, survival of fatty liver allografts (group C) not requiring re-OLT was considered in Kaplan-Meier and multivariate regression analysis. A total of 77 high urgency re-OLTs were identified and included 39 PNF cases. Nearly 70% of PNF cases were due to primary fatty liver allografts. The 3-month in-hospital mortality for PNF cases after re-OLT was 46% and the mean survival after re-OLT was 0.5 years as compared to 5.2 and 5.1 years for group B, C, respectively, (P<.008). In multivariate Cox regression analysis only hepatic steatosis was associated with an inferior survival (HR 4.272, P=.002). The MELD score, donor BMI, age, cold ischaemic time, ICU stay, serum sodium and transaminases did not influence overall survival. Our study highlights fatty liver allografts to be a major cause for PNF with excessive mortality after re-transplantation. The findings demand the development of new methods to predict risk for PNF of fatty liver allografts. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease.

PubMed

Dubinkina, Veronika B; Tyakht, Alexander V; Odintsova, Vera Y; Yarygin, Konstantin S; Kovarsky, Boris A; Pavlenko, Alexander V; Ischenko, Dmitry S; Popenko, Anna S; Alexeev, Dmitry G; Taraskina, Anastasiya Y; Nasyrova, Regina F; Krupitsky, Evgeny M; Shalikiani, Nino V; Bakulin, Igor G; Shcherbakov, Petr L; Skorodumova, Lyubov O; Larin, Andrei K; Kostryukova, Elena S; Abdulkhakov, Rustam A; Abdulkhakov, Sayar R; Malanin, Sergey Y; Ismagilova, Ruzilya K; Grigoryeva, Tatiana V; Ilina, Elena N; Govorun, Vadim M

2017-10-17

Alcohol abuse has deleterious effects on human health by disrupting the functions of many organs and systems. Gut microbiota has been implicated in the pathogenesis of alcohol-related liver diseases, with its composition manifesting expressed dysbiosis in patients suffering from alcoholic dependence. Due to its inherent plasticity, gut microbiota is an important target for prevention and treatment of these diseases. Identification of the impact of alcohol abuse with associated psychiatric symptoms on the gut community structure is confounded by the liver dysfunction. In order to differentiate the effects of these two factors, we conducted a comparative "shotgun" metagenomic survey of 99 patients with the alcohol dependence syndrome represented by two cohorts-with and without liver cirrhosis. The taxonomic and functional composition of the gut microbiota was subjected to a multifactor analysis including comparison with the external control group. Alcoholic dependence and liver cirrhosis were associated with profound shifts in gut community structures and metabolic potential across the patients. The specific effects on species-level community composition were remarkably different between cohorts with and without liver cirrhosis. In both cases, the commensal microbiota was found to be depleted. Alcoholic dependence was inversely associated with the levels of butyrate-producing species from the Clostridiales order, while the cirrhosis-with multiple members of the Bacteroidales order. The opportunist pathogens linked to alcoholic dependence included pro-inflammatory Enterobacteriaceae, while the hallmarks of cirrhosis included an increase of oral microbes in the gut and more frequent occurrence of abnormal community structures. Interestingly, each of the two factors was associated with the expressed enrichment in many Bifidobacterium and Lactobacillus-but the exact set of the species was different between alcoholic dependence and liver cirrhosis. At the level of functional potential, the patients showed different patterns of increase in functions related to alcohol metabolism and virulence factors, as well as pathways related to inflammation. Multiple shifts in the community structure and metabolic potential suggest strong negative influence of alcohol dependence and associated liver dysfunction on gut microbiota. The identified differences in patterns of impact between these two factors are important for planning of personalized treatment and prevention of these pathologies via microbiota modulation. Particularly, the expansion of Bifidobacterium and Lactobacillus suggests that probiotic interventions for patients with alcohol-related disorders using representatives of the same taxa should be considered with caution. Taxonomic and functional analysis shows an increased propensity of the gut microbiota to synthesis of the toxic acetaldehyde, suggesting higher risk of colorectal cancer and other pathologies in alcoholics.

Abnormalities of Lipoprotein Levels in Liver Cirrhosis: Clinical Relevance.

PubMed

Privitera, Graziella; Spadaro, Luisa; Marchisello, Simona; Fede, Giuseppe; Purrello, Francesco

2018-01-01

Progressive lipoprotein impairment occurs in liver cirrhosis and is associated with increased morbidity and mortality. The present review aims to summarize the current evidence regarding the prognostic value of lipoprotein abnormalities in liver cirrhosis and to address the need of a better prognostic stratification of patients, including lipoprotein profile assessment. Low levels of lipoproteins are usual in cirrhosis. Much evidence supports the prognostic role of hypolipidemia in cirrhotic patients. In particular, hypocholesterolemia represents an independent predictor of survival in cirrhosis. In cirrhotic patients, lipoprotein impairment is associated with several complications: infections, malnutrition, adrenal function, and spur cell anemia. Alterations of liver function are associated with modifications of circulating lipids. Decreased levels of lipoproteins significantly impact the survival of cirrhotic patients and play an important role in the pathogenesis of some cirrhosis-related complications.

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.

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

Peritonitis - secondary

MedlinePlus

... blood pressure. Tests may include: Blood culture Blood chemistry, including pancreatic enzymes Complete blood count Liver and kidney function tests X-rays or CT scan Peritoneal fluid culture Urinalysis

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

PubMed

Jin, Tianru; Weng, Jianping

2016-09-01

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

Surgical Strategy Based on Indocyanine Green Test for Chemotherapy-Associated Liver Injury and Long-Term Outcome in Colorectal Liver Metastases.

PubMed

Takamoto, Takeshi; Hashimoto, Takuya; Ichida, Akihiko; Shimada, Kei; Maruyama, Yoshikazu; Makuuchi, Masatoshi

2018-06-01

It remains unclear whether the presence of chemotherapy-induced liver injury (CALI) or impaired liver functional reserve affects the long-term outcome. This study assessed the applicability and long-term effects of using criteria based on the indocyanine green (ICG) test results in selecting the operative procedure among patients with colorectal liver metastases (CRLM) who had a risk of CALI. CRLM patients who received preoperative chemotherapy including oxaliplatin and/or irinotecan prior to a curative hepatectomy between 2007 and 2017 were included. For each case, the minimum required future remnant liver volume and operative procedure were decided based on the ICG retention rate at 15 min (ICG R15). Patients with an ICG R15 > 10% and who had undergone a major hepatectomy were categorized in a marginal liver functional reserve (MHML) group. Overall, 161 patients were included; 77 of them had an ICG R15 > 10%, and 57 had pathological liver injury (PLI). After the median follow-up time of 30.9 months, the 5-year overall survival rate was 36.1%. The presence of an impaired ICG test result or CALI did not negatively impact the overall and recurrence-free survival outcomes. A multivariate analysis revealed that the presence of four or more nodules of liver metastases was the only independent predictor of a poor overall survival. A significantly larger proportion of patients in the MHML group (n = 37) had a 25% or larger increase in splenic volume (30 vs. 13%; P = 0.024). The presence of an impaired ICG test result or PLI did not affect the long-term outcome after individually selected operative procedure. However, patients undergoing MHML had a higher possibility of developing a > 25% splenic volume increase after hepatectomy.

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.

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.

Dendrobium huoshanense polysaccharide prevents ethanol-induced liver injury in mice by metabolomic analysis.

PubMed

Wang, Xiao-Yu; Luo, Jian-Ping; Chen, Rui; Zha, Xue-Qiang; Pan, Li-Hua

2015-01-01

The prevalence of alcohol consumption has increased in modern dietary life and alcoholic liver injury can follow. Dendrobium huoshanense polysaccharide (DHP) is a homogeneous polysaccharide isolated from Dendrobium huoshanense, which possesses hepatoprotection function. In this study, we investigated the metabolic profiles of serum and liver tissues extracts from control, ethanol-treated and DHP\\ethanol-treated mice using a UHPLC/LTQ Orbitrap XL MS-based metabolomics approach. Our results indicated that DHP alleviated early steatosis and inflammation in liver histology and the metabolomic analysis of serum and hepatic tissue revealed that first, ethanol treatment mainly altered phosphatidylcholines (PCs) including PC (13:0) and phosphocholine, arachidonic acid metabolites including 20-ethyl PGF2α and amino acids including L-Proline; Second, DHP supplementation ameliorated the altered metabolic levels particularly involved in phosphocholine and L-Proline. These data suggested that DHP might restore the perturbed metabolism pathways by ethanol exposure to prevent the progression of alcoholic liver injury. Copyright © 2015 Elsevier B.V. All rights reserved.

Metabolic effects of the iodothyronine functional analogue TRC150094 on the liver and skeletal muscle of high-fat diet fed overweight rats: an integrated proteomic study.

PubMed

Silvestri, Elena; Glinni, Daniela; Cioffi, Federica; Moreno, Maria; Lombardi, Assunta; de Lange, Pieter; Senese, Rosalba; Ceccarelli, Michele; Salzano, Anna Maria; Scaloni, Andrea; Lanni, Antonia; Goglia, Fernando

2012-07-06

A novel functional iodothyronine analogue, TRC150094, which has a much lower potency toward thyroid hormone receptor (α1/β1) activation than triiodothyronine, has been shown to be effective at reducing adiposity in rats simultaneously receiving a high-fat diet (HFD). Here, by combining metabolic, functional and proteomic analysis, we studied how the hepatic and skeletal muscle phenotypes might respond to TRC150094 treatment in HFD-fed overweight rats. Drug treatment increased both the liver and skeletal muscle mitochondrial oxidative capacities without altering mitochondrial efficiency. Coherently, in terms of individual respiratory in-gel activity, blue-native analysis revealed an increased activity of complex V in the liver and of complexes II and V in tibialis muscle in TCR150094-treated animals. Subsequently, the identification of differentially expressed proteins and the analysis of their interrelations gave an integrated view of the phenotypic/metabolic adaptations occurring in the liver and muscle proteomes during drug treatment. TRC150094 significantly altered the expression of several proteins involved in key liver metabolic pathways, including amino acid and nitrogen metabolism, and fructose and mannose metabolism. The canonical pathways most strongly influenced by TRC150094 in tibialis muscle included glycolysis and gluconeogenesis, amino acid, fructose and mannose metabolism, and cell signaling. The phenotypic/metabolic influence of TRC150094 on the liver and skeletal muscle of HFD-fed overweight rats suggests the potential clinical application of this iodothyronine analogue in ameliorating metabolic risk parameters altered by diet regimens.

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.

Ambiguous roles of innate lymphoid cells in chronic development of liver diseases.

PubMed

Shen, Yue; Li, Jing; Wang, Si-Qi; Jiang, Wei

2018-05-14

Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets.

Ambiguous roles of innate lymphoid cells in chronic development of liver diseases

PubMed Central

Shen, Yue; Li, Jing; Wang, Si-Qi; Jiang, Wei

2018-01-01

Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets. PMID:29760540

Coding and non-coding gene regulatory networks underlie the immune response in liver cirrhosis.

PubMed

Gao, Bo; Zhang, Xueming; Huang, Yongming; Yang, Zhengpeng; Zhang, Yuguo; Zhang, Weihui; Gao, Zu-Hua; Xue, Dongbo

2017-01-01

Liver cirrhosis is recognized as being the consequence of immune-mediated hepatocyte damage and repair processes. However, the regulation of these immune responses underlying liver cirrhosis has not been elucidated. In this study, we used GEO datasets and bioinformatics methods to established coding and non-coding gene regulatory networks including transcription factor-/lncRNA-microRNA-mRNA, and competing endogenous RNA interaction networks. Our results identified 2224 mRNAs, 70 lncRNAs and 46 microRNAs were differentially expressed in liver cirrhosis. The transcription factor -/lncRNA- microRNA-mRNA network we uncovered that results in immune-mediated liver cirrhosis is comprised of 5 core microRNAs (e.g., miR-203; miR-219-5p), 3 transcription factors (i.e., FOXP3, ETS1 and FOS) and 7 lncRNAs (e.g., ENTS00000671336, ENST00000575137). The competing endogenous RNA interaction network we identified includes a complex immune response regulatory subnetwork that controls the entire liver cirrhosis network. Additionally, we found 10 overlapping GO terms shared by both liver cirrhosis and hepatocellular carcinoma including "immune response" as well. Interestingly, the overlapping differentially expressed genes in liver cirrhosis and hepatocellular carcinoma were enriched in immune response-related functional terms. In summary, a complex gene regulatory network underlying immune response processes may play an important role in the development and progression of liver cirrhosis, and its development into hepatocellular carcinoma.

Significance of Portal Venous Velocity in Short-term Graft Function in Living Donor Liver Transplantation.

PubMed

Wakiyama, S; Takano, Y; Shiba, H; Gocho, T; Sakamoto, T; Ishida, Y; Yanaga, K

2017-06-01

Graft regeneration and functional recovery after reperfusion of transplanted graft are very important for successful living donor liver transplantation (LDLT). The aim of this study was to evaluate the significance of postoperative portal venous velocity (PVV) in short-term recovery of graft function in LDLT. From February 2007 through December 2015, we performed 17 primary LDLTs, which were included in the present study. The patients ranged in age from 12 to 65 years (mean: 50 years), and 11 were female patients. Postoperatively, Doppler ultrasonography was performed daily to measure PVV (cm/s), and liver function parameters were measured daily. The change in PVV (ΔPVV) was defined as follows: ΔPVV = PVV on postoperative day (POD) 1 - PVV on POD 7. Maximal value of serum aspartate aminotransferase (ASTmax) and maximal value of serum alanine transaminase (ALTmax) at 24 hours after graft reperfusion were used as parameters of reperfusion injury. Correlation analyses were performed as follows: (1) correlation of ΔPVV and PVV on POD 1 (PVV-POD 1) with the values such as ASTmax, ALTmax, other liver function parameters on POD 7 and graft regeneration rate; (2) correlation of ASTmax and ALTmax with other liver function parameters on POD 7. ΔPVV significantly correlated with the values of serum total bilirubin (P < .01), prothrombin time (P < .01), and platelet count (P < .05), and PVV-POD 1 significantly correlated with the values of serum total bilirubin (P < .05) and prothrombin time (P < .05). ΔPVV and PVV-POD 1 may be useful parameters of short-term functional recovery of the transplant liver in LDLT. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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

2012-05-01

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

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

PubMed

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

2016-06-01

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

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.

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

PubMed

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

2013-01-01

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

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

Liver Function in Patients With Nonalcoholic Fatty Liver Disease Randomized to Roux-en-Y Gastric Bypass Versus Sleeve Gastrectomy: A Secondary Analysis of a Randomized Clinical Trial.

PubMed

Kalinowski, Piotr; Paluszkiewicz, Rafał; Ziarkiewicz-Wróblewska, Bogna; Wróblewski, Tadeusz; Remiszewski, Piotr; Grodzicki, Mariusz; Krawczyk, Marek

2017-11-01

The aim of the study was to compare the influence of sleeve gastrectomy (SG) versus Roux-en-Y gastric bypass (RYGB) on liver function in bariatric patients with non-alcoholic fatty liver disease (NAFLD) in a randomized clinical trial (NCT01806506). Rapid weight loss and malabsorption after bariatric surgery in patients with NAFLD or steatohepatitis (NASH) may impair liver function. Sixty-six morbidly obese patients randomized to SG or RYGB were included in a secondary outcome analysis. Intraoperative liver biopsies were categorized with NAFLD Activity Score (NAS) and liver function tests were done before surgery and after 1, 6 and 12 months. NASH was present in 54.5% RYGB and 51.5% SG patients (P > 0.05). At 12 months excess weight loss was 68.7 ± 19.7% after SG and 62.8 ± 18.5% after RYGB (P > 0.05). At 1 month international normalized ratio (INR) increased after RYGB (0.98 ± 0.05 vs 1.14 ± 0.11; P < 0.05) and SG (0.99 ± 0.06 vs 1.04 ± 0.06; P < 0.05), RYGB induced significantly greater increase in INR in the whole group and NASH patients than SG. After RYGB albumin decreased at 1 month (41.2 ± 2.7 vs 39.0 ± 3.2 g/L; P < 0.05). At 12 months, INR and albumin returned to baseline. At 12 months in NASH group, SG induced significant improvement in aspartate aminotransferase (32.4 ± 17.4 vs 21.5 ± 6.9U/L), alanine aminotransferase (39.9 ± 28.6U/L vs 23.8 ± 14.1U/L), gamma-glutamyl transpeptidase (34.3 ± 16.6 vs 24.5 ± 16.8U/L), and lactate dehydrogenase (510.8 ± 33 vs 292.4 ± 29). Variables predictive of INR change after 1 month included operation type, NAS ≥ 5, bilirubin, body mass index, hemoglobin A1C, and dyslipidemia. Patients with NASH undergoing RYGB are more susceptible to early transient deterioration of liver function than after SG.

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

PubMed

Hashimoto, Masaji; Watanabe, Goro

2005-01-01

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

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

Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy

PubMed Central

Yang, Lili; Rozenfeld, Raphael; Wu, Defeng; Devi, Lakshmi A.; Zhang, Zhenfeng; Cederbaum, Arthur

2014-01-01

Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy. PMID:24398069

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.

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

PubMed

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

2009-01-01

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

The use of old donors in liver transplantation.

PubMed

Dasari, Bobby V M; Schlegel, Andrea; Mergental, Hynek; Perera, M Thamara P R

2017-04-01

The process of ageing has an impact on the entire human body including the organ systems. In transplantation, professionals are daily faced with risk assessment of suitable donor offers , whether to accept a liver graft for a specific recipient. In this context, livers from elderly donors are more frequently accepted for transplantation, to increase the donor pool and compensate the high waiting list mortality. In the current practice it is not unusual to accept 60-year old donor livers for transplantation, as the donor demographics have significantly changed over the years. However, controversy exists regarding the use of livers from donors above 70 or 80 years, particular in combination with other risk factors, e.g. liver steatosis, warm ischaemia or long cold storage. This review focuses first on the impact of ageing on liver morphology and function. Second, we will highlight outcome after transplantation from elderly donors. Finally, we describe further risk factors and donor-recipient selection under the scope of old donor organs and include our institutional experience and policy. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

The effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice after endoscopic treatment: a prospective, randomized, and controlled study.

PubMed

Fekaj, Enver; Gjata, Arben; Maxhuni, Mehmet

2013-09-22

In patients with obstructive jaundice, multi-organ dysfunction may develop. This trial is a prospective, open-label, randomized, and controlled study with the objective to evaluate the effect of ursodeoxycholic acid in liver functional restoration in patients with obstructive jaundice after endoscopic treatment. The aim of this study is to evaluate the effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice after endoscopic treatment. The hypothesis of this trial is that patients with obstructive jaundice, in which will be administered UDCA, in the early phase after endoscopic intervention will have better and faster functional restoration of the liver than patients in the control group.Patients with obstructive jaundice, randomly, will be divided into two groups: (A) test group in which will be administered ursodeoxycholic acid twenty-four hours after endoscopic procedure and will last fourteen days, and (B) control group.Serum-testing will include determination of bilirubin, alanine transaminase, aspartate transaminase, gama-glutamil transpeptidase, alkaline phosphatase, albumin, and cholesterol levels. These parameters will be determined one day prior endoscopic procedure, and on the third, fifth, seventh, tenth, twelfth and fourteenth days after endoscopic intervention. This trial is a prospective, open-label, randomized, and controlled study to asses the effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice in the early phase after endoscopic treatment.

Assessment of triglyceride and cholesterol in overweight people based on multiple linear regression and artificial intelligence model.

PubMed

Ma, Jing; Yu, Jiong; Hao, Guangshu; Wang, Dan; Sun, Yanni; Lu, Jianxin; Cao, Hongcui; Lin, Feiyan

2017-02-20

The prevalence of high hyperlipemia is increasing around the world. Our aims are to analyze the relationship of triglyceride (TG) and cholesterol (TC) with indexes of liver function and kidney function, and to develop a prediction model of TG, TC in overweight people. A total of 302 adult healthy subjects and 273 overweight subjects were enrolled in this study. The levels of fasting indexes of TG (fs-TG), TC (fs-TC), blood glucose, liver function, and kidney function were measured and analyzed by correlation analysis and multiple linear regression (MRL). The back propagation artificial neural network (BP-ANN) was applied to develop prediction models of fs-TG and fs-TC. The results showed there was significant difference in biochemical indexes between healthy people and overweight people. The correlation analysis showed fs-TG was related to weight, height, blood glucose, and indexes of liver and kidney function; while fs-TC was correlated with age, indexes of liver function (P < 0.01). The MRL analysis indicated regression equations of fs-TG and fs-TC both had statistic significant (P < 0.01) when included independent indexes. The BP-ANN model of fs-TG reached training goal at 59 epoch, while fs-TC model achieved high prediction accuracy after training 1000 epoch. In conclusions, there was high relationship of fs-TG and fs-TC with weight, height, age, blood glucose, indexes of liver function and kidney function. Based on related variables, the indexes of fs-TG and fs-TC can be predicted by BP-ANN models in overweight people.

Hepatotoxicity due to red bush tea consumption: a case report.

PubMed

Reddy, Shamantha; Mishra, Pragnyadipta; Qureshi, Sana; Nair, Singh; Straker, Tracey

2016-12-01

Many conventional drugs used today, including isoniazid, dapsone, and acetaminophen, are well recognized culprits of hepatotoxicity. With increasing use of complementary and alternative medical therapies, several herbal medicines, such as Ma-Huang, kava, and chaparral leaf, have been implicated as hepatotoxins. Hepatotoxicity may be the most frequent adverse reaction to these herbal remedies when taken in excessive quantities. A myriad of liver dysfunctions may occur including transient liver enzyme abnormalities due to acute and chronic hepatitis. These herbal products are often overlooked as the causal etiologic agent during the evaluation of a patient with elevated liver function tests. We describe a case of hepatotoxicity due to ingestion of red bush tea diagnosed during preoperative assessment of a patient scheduled for laparoscopic appendectomy. Elevated liver enzymes and thrombocytopenia detected in the patient's laboratory work up confounded the initial diagnosis of acute appendicitis and additional investigations were required to rule out cholecystitis and other causes of hepatitis. Open appendectomy was done uneventfully under spinal anesthesia without any further deterioration of hepatic function. Copyright © 2016. Published by Elsevier Inc.

Liver Function Tests

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 ...

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.

Is abnormal liver function correlated with food sensitisation in adults? US NHANES, 2005-2006.

PubMed

Shiue, I

2015-01-01

Associations between liver function and serum IgE levels have recently been observed in children. However, the relationship in adults is unclear. Therefore, it was aimed to study associations of liver function and serum total and food-specific IgE concentrations in a national and population-based study. Data were retrieved from the United States National Health and Nutrition Examination Surveys, 2005-2006 including demographics, liver status tests, biomarkers, lifestyle factors, and serum total and food-specific IgE concentrations. Participants aged 20 and above were included. Analyses included t-test, chi-square test, and survey-weighted regression modelling. After adjusting for age, sex, ethnicity, vitamin D, waist circumference, family poverty income ratio, total cholesterol, ever asthma, total protein, and survey weighting, abnormal gamma glutamyl transpeptidase was significantly associated with food sensitisation (peanut: OR 2.17, 95%CI 1.60-2.94, P<0.001; egg: OR 2.55, 95%CI 1.32-4.90, P=0.008; milk: OR 2.59, 95%CI 1.56-4.31, P=0.001; shrimp: OR 1.81, 95%CI 1.29-2.55, P=0.002). Moreover, both abnormal albumin and alanine transaminase were associated with egg sensitisation (OR 1.96, 95%CI 1.12-3.43, P=0.022 and OR 2.06, 95%CI 1.04-4.09, P=0.040, respectively). Abnormal liver status tests were correlated with serum food-specific IgE concentrations in adults. Future research with longitudinal design or in clinical settings may be warranted confirming or refuting the observations made in the present epidemiological study. Copyright © 2014 SEICAP. Published by Elsevier Espana. All rights reserved.

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

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.

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

PubMed

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

2005-09-01

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

Metabolic liver function measured in vivo by dynamic (18)F-FDGal PET/CT without arterial blood sampling.

PubMed

Horsager, Jacob; Munk, Ole Lajord; Sørensen, Michael

2015-01-01

Metabolic liver function can be measured by dynamic PET/CT with the radio-labelled galactose-analogue 2-[(18)F]fluoro-2-deoxy-D-galactose ((18)F-FDGal) in terms of hepatic systemic clearance of (18)F-FDGal (K, ml blood/ml liver tissue/min). The method requires arterial blood sampling from a radial artery (arterial input function), and the aim of this study was to develop a method for extracting an image-derived, non-invasive input function from a volume of interest (VOI). Dynamic (18)F-FDGal PET/CT data from 16 subjects without liver disease (healthy subjects) and 16 patients with liver cirrhosis were included in the study. Five different input VOIs were tested: four in the abdominal aorta and one in the left ventricle of the heart. Arterial input function from manual blood sampling was available for all subjects. K*-values were calculated using time-activity curves (TACs) from each VOI as input and compared to the K-value calculated using arterial blood samples as input. Each input VOI was tested on PET data reconstructed with and without resolution modelling. All five image-derived input VOIs yielded K*-values that correlated significantly with K calculated using arterial blood samples. Furthermore, TACs from two different VOIs yielded K*-values that did not statistically deviate from K calculated using arterial blood samples. A semicircle drawn in the posterior part of the abdominal aorta was the only VOI that was successful for both healthy subjects and patients as well as for PET data reconstructed with and without resolution modelling. Metabolic liver function using (18)F-FDGal PET/CT can be measured without arterial blood samples by using input data from a semicircle VOI drawn in the posterior part of the abdominal aorta.

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

PubMed

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

2015-04-28

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

Assessing alcohol intake & its dose-dependent effects on liver enzymes by 24-h recall and questionnaire using NHANES 2001-2010 data

DOE PAGES

Agarwal, Sanjiv; Fulgoni, III, Victor L.; Lieberman, Harris R.

2016-06-22

Alcohol is a significant component of the diet with dose-dependent risks and benefits. High doses of alcohol damage the liver and early symptoms of liver disease include changes in routinely assessed liver enzymes. Less is known regarding the mechanisms responsible for the benefits of moderate alcohol consumption, including their effects on the liver. The objectives of this study were to examine alcohol’s dose-dependent effects on markers of liver function (alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and bilirubin), as well as to compare the different methods of assessing alcohol intake using NHANES 2001–2010 adultmore » data (N =24,807). Three methods were used to estimate alcohol intake from all volunteers: 24-h recall; the National Cancer Institute (NCI) method of usual intake; and a specific alcohol intake questionnaire. Mean alcohol intake by 24-h recall, NCI method and questionnaire was 41.0 ± 0.8 g/d, 10.9 ± 0.2 g/d and 11.0 ± 0.2 g/d, respectively. Alcohol consumers had significantly lower levels of ALP and higher levels of AST, GGT and bilirubin compared to non-consumers (P < 0.01) and activities of ALT, AST, and GGT increased and of ALP decreased as alcohol intake increased, regardless of intake assessment method used. The most sensitive measure of alcohol consumption was GGT. Since alcohol had a graded linear effect on several liver enzymes, including at low and moderate doses, benefits as well as risks of alcohol intake may be related to liver function. In conclusion, since the NCI method and alcohol questionnaire yielded very similar alcohol intake estimates, this study cross-validated these methods and demonstrated the robustness of the NCI method for estimating intake of irregularly consumed foods.« less

Assessing alcohol intake & its dose-dependent effects on liver enzymes by 24-h recall and questionnaire using NHANES 2001-2010 data

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

Agarwal, Sanjiv; Fulgoni, III, Victor L.; Lieberman, Harris R.

Alcohol is a significant component of the diet with dose-dependent risks and benefits. High doses of alcohol damage the liver and early symptoms of liver disease include changes in routinely assessed liver enzymes. Less is known regarding the mechanisms responsible for the benefits of moderate alcohol consumption, including their effects on the liver. The objectives of this study were to examine alcohol’s dose-dependent effects on markers of liver function (alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and bilirubin), as well as to compare the different methods of assessing alcohol intake using NHANES 2001–2010 adultmore » data (N =24,807). Three methods were used to estimate alcohol intake from all volunteers: 24-h recall; the National Cancer Institute (NCI) method of usual intake; and a specific alcohol intake questionnaire. Mean alcohol intake by 24-h recall, NCI method and questionnaire was 41.0 ± 0.8 g/d, 10.9 ± 0.2 g/d and 11.0 ± 0.2 g/d, respectively. Alcohol consumers had significantly lower levels of ALP and higher levels of AST, GGT and bilirubin compared to non-consumers (P < 0.01) and activities of ALT, AST, and GGT increased and of ALP decreased as alcohol intake increased, regardless of intake assessment method used. The most sensitive measure of alcohol consumption was GGT. Since alcohol had a graded linear effect on several liver enzymes, including at low and moderate doses, benefits as well as risks of alcohol intake may be related to liver function. In conclusion, since the NCI method and alcohol questionnaire yielded very similar alcohol intake estimates, this study cross-validated these methods and demonstrated the robustness of the NCI method for estimating intake of irregularly consumed foods.« less

An Analysis of the Effects of Phenytoin in Treating Motion Sickness and the Effects of Motion Sickness on the Human Electroencephalogram

DTIC Science & Technology

1990-12-01

ears ( tinnitus ) and/or a reduced auditory acuity resulted from the dosing. These side effects have been shown to 29 occur in some subjects as a result of...examinations. 5. Complete blood count (CBC). 6. Blood biochemistry screen (Chem 18 including liver function tests). 7. Blood cholesterol and lipids . 8. Chest X...blood lipids and cholesterol, chest X-ray, urinalysis, visual acuity test, vestibular evaluation and liver function studies. Subjects will then take

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.

Image-guided intervention in the coagulopathic patient.

PubMed

Kohli, Marc; Mayo-Smith, William; Zagoria, Ronald; Sandrasegaran, Kumar

2016-04-01

Determining practice parameters for interventional procedures is challenging due to many factors including unreliable laboratory tests to measure bleeding risk, variable usage of standardized terminology for adverse events, poorly defined standards for administration of blood products, and the growing numbers of anticoagulant and antiplatelet medications. We aim to address these and other issues faced by radiologists performing invasive procedures through a review of available literature, and experiential guidance from three academic medical centers. We discuss the significant limitations with respect to using prothrombin-time and international normalized ratio to measure bleeding risk, especially in patients with synthetic defects due to liver function. Factors affecting platelet function including the impact of uremia; recent advances in laboratory testing, including platelet function testing; and thromboelastography are also discussed. A review of the existing literature of fresh-frozen plasma replacement therapy is included. The literature regarding comorbidities affecting coagulation including malignancy, liver failure, and uremia are also reviewed. Finally, the authors present a set of recommendations for laboratory thresholds, corrective transfusions, as well as withholding and restarting medications.

Liver Function Tests

MedlinePlus

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

Coding and non-coding gene regulatory networks underlie the immune response in liver cirrhosis

PubMed Central

Zhang, Xueming; Huang, Yongming; Yang, Zhengpeng; Zhang, Yuguo; Zhang, Weihui; Gao, Zu-hua; Xue, Dongbo

2017-01-01

Liver cirrhosis is recognized as being the consequence of immune-mediated hepatocyte damage and repair processes. However, the regulation of these immune responses underlying liver cirrhosis has not been elucidated. In this study, we used GEO datasets and bioinformatics methods to established coding and non-coding gene regulatory networks including transcription factor-/lncRNA-microRNA-mRNA, and competing endogenous RNA interaction networks. Our results identified 2224 mRNAs, 70 lncRNAs and 46 microRNAs were differentially expressed in liver cirrhosis. The transcription factor -/lncRNA- microRNA-mRNA network we uncovered that results in immune-mediated liver cirrhosis is comprised of 5 core microRNAs (e.g., miR-203; miR-219-5p), 3 transcription factors (i.e., FOXP3, ETS1 and FOS) and 7 lncRNAs (e.g., ENTS00000671336, ENST00000575137). The competing endogenous RNA interaction network we identified includes a complex immune response regulatory subnetwork that controls the entire liver cirrhosis network. Additionally, we found 10 overlapping GO terms shared by both liver cirrhosis and hepatocellular carcinoma including “immune response” as well. Interestingly, the overlapping differentially expressed genes in liver cirrhosis and hepatocellular carcinoma were enriched in immune response-related functional terms. In summary, a complex gene regulatory network underlying immune response processes may play an important role in the development and progression of liver cirrhosis, and its development into hepatocellular carcinoma. PMID:28355233

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.

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.

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.

A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches.

PubMed

Seki, Ekihiro; Brenner, David A; Karin, Michael

2012-08-01

c-Jun-N-terminal kinase (JNK) is a mitogen-activated protein kinase family member that is activated by diverse stimuli, including cytokines (such as tumor necrosis factor and interleukin-1), reactive oxygen species (ROS), pathogens, toxins, drugs, endoplasmic reticulum stress, free fatty acids, and metabolic changes. Upon activation, JNK induces multiple biologic events through the transcription factor activator protein-1 and transcription-independent control of effector molecules. JNK isozymes regulate cell death and survival, differentiation, proliferation, ROS accumulation, metabolism, insulin signaling, and carcinogenesis in the liver. The biologic functions of JNK are isoform, cell type, and context dependent. Recent studies using genetically engineered mice showed that loss or hyperactivation of the JNK pathway contributes to the development of inflammation, fibrosis, cancer growth, and metabolic diseases that include obesity, hepatic steatosis, and insulin resistance. We review the functions and pathways of JNK in liver physiology and pathology and discuss findings from preclinical studies with JNK inhibitors. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

[Epidemiology of infections after liver transplantation in children].

PubMed

Pawłowska, J

2001-01-01

One of the most important problems after solid organ transplantation including liver, remains infections. Multiple risk factors play a role among which the most important are: general patients health before transplantation, prolong operative time, graft function and type of immunosuppression. The most important problems with bacterial, fungal and viral infections was described as well as treatment and profilaxis.

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.

Creation of a solid organ transplant program in an underdeveloped country: Mexico's General Hospital transplantation program.

PubMed

García Covarrubias, L; Rossano García, A; Cicero Lebrija, A; Luque Hernández, A; Hinojosa Heredia, H; Fernández Ángel, D; Córdova, J; García Covarrubias, A; Bautista Olayo, R; Diliz Perez, H S

2013-05-01

With a population of >112 million persons, all Mexicans are entitled to receive medical care by the state and more than half have limited access to healthcare. From January 1985 to March 2009, 40 renal transplants were performed from living donors with a high percentage of complications. In April 2009, a new Solid Organ Transplantation Program was started; herein, we present this enterprise to the international community and briefly present a perspective on the Mexican transplant situation. We performed a retrospective chart review of kidney and liver transplant recipients from April 2009 to November 2011, including demographic features, immunosuppression, complications as well as initial and 1 month function. We performed 68 kidney (59 living and 9 deceased donors) and 5 liver transplants (cadaveric donors). The kidney transplant recipients were 73.5% males and showed an overall mean age of 29.77 years (range, 18-60). The donor mean age was 34.08 years. Mean recipient creatinine pretransplant was 13.32 mg/dL, while at day 5 it was 2.33 and at month one, 1.32 mg/dL. Five grafts were lost (7.3%): 4 due to death with a functioning graft and 1 due to acute pyelonephritis. Five patients experienced delayed graft function Basiliximab induction was required in all but one who received thymoglobulin owing to a high panel reactive antibody. Maintenance therapy included a calcineurin inhibitor, mycophenolate mofetil (MMF), and prednisone. Liver transplant recipients were 83.6% women. The etiologies were alcoholic cirrhosis (n = 2), primary billiary cirrhosis (n = 1) and hepatitis C virus infection (n = 2). Complications included: reperfusion syndrome (n = 1), convulsive crisis (medication; n = 1), acute respiratory distress syndrome (n = 1), and death (n = 1). Their Model for End-Stage Liver Disease scopes were 10-21. After basiliximab induction, they had maintenance therapy with tacrolimus, MMF, and steroids. The donor mean age was 26.2 years. All survivors show normal liver function tests currently. From 1985 to 2009, 40 kidney transplants were performed, with multiple complications including donor deaths. Our current results were comparable to international standards, with <15% complication rate. Copyright © 2013 Elsevier Inc. All rights reserved.

Liver failure in total artificial heart therapy.

PubMed

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

2016-07-01

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

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

PubMed

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

2014-02-01

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

A review of drug-induced liver injury databases.

PubMed

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

2017-09-01

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

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

PubMed

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

2018-06-19

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

The molecular functions of hepatocyte nuclear factors - In and beyond the liver.

PubMed

Lau, Hwee Hui; Ng, Natasha Hui Jin; Loo, Larry Sai Weng; Jasmen, Joanita Binte; Teo, Adrian Kee Keong

2018-05-01

The hepatocyte nuclear factors (HNFs) namely HNF1α/β, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function. The complex HNF transcriptional regulatory networks have largely been elucidated in rodent models, but less so in human biological systems. Several heterozygous mutations in these HNFs were found to cause diseases in humans but not in rodents, suggesting clear species-specific differences in mutational mechanisms that remain to be uncovered. In this review, we compare and contrast the expression patterns of the HNFs, the HNF cross-regulatory networks and how these liver-enriched transcription factors serve multiple functions in the liver and beyond, extending our focus to the pancreas and kidney. We also summarise the insights gained from both human and rodent studies of mutations in several HNFs that are known to lead to different disease conditions. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Biliary tract enhancement in gadoxetic acid-enhanced MRI correlates with liver function biomarkers.

PubMed

Noda, Yoshifumi; Goshima, Satoshi; Kajita, Kimihiro; Kawada, Hiroshi; Kawai, Nobuyuki; Koyasu, Hiromi; Matsuo, Masayuki; Bae, Kyongtae T

2016-11-01

To evaluate the association between gadoxetic-acid-enhanced magnetic resonance (MR) imaging measurements and laboratory and clinical biomarkers of liver function and fibrosis. One hundred thirty nine consecutive patients with suspected liver disease or liver tumor underwent gadoxetic-acid-enhanced MR imaging. MR imaging measurements during the hepatobiliary phase included biliary tract structure-to-muscle signal intensity ratio (SIR). These measurements were compared with Child-Pugh classification, end-stage liver disease (MELD) score, and aspartate aminotransferase-to-platelet ratio index (APRI). The SIRs of cystic duct and common bile duct were significantly correlated with Child-Pugh classification (P=0.012 for cystic duct and P<0.0001 for common bile duct), MELD score (P=0.0016 and P=0.0033), and APRI (P=0.0022 and P=0.0015). The sensitivity, specificity, and area under the receiver-operating-characteristic curve were: (74%, 88%, 0.86) with the SIR of common bile duct for the detection of patients with Child-Pugh class B or C; (100%, 87%, 0.94) with the SIR of cystic duct for MELD score (>10); (65%, 76%, 0.70) with the SIR of common bile duct for APRI (>1.5). Gadoxetic-acid contrast enhancement of cystic duct and common bile duct could be used as biomarkers to assess liver function. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In vitro recapitulation of the urea cycle using murine embryonic stem cell-derived in vitro liver model.

PubMed

Tamai, Miho; Aoki, Mami; Nishimura, Akihito; Morishita, Koji; Tagawa, Yoh-ichi

2013-12-01

Ammonia, a toxic metabolite, is converted to urea in hepatocytes via the urea cycle, a process necessary for cell/organismal survival. In liver, hepatocytes, polygonal and multipolar structures, have a few sides which face hepatic sinusoids and adjacent hepatocytes to form intercellular bile canaliculi connecting to the ductules. The critical nature of this three-dimensional environment should be related to the maintenance of hepatocyte function such as urea synthesis. Recently, we established an in vitro liver model derived from murine embryonic stem cells, IVL(mES), which included the hepatocyte layer and a surrounding sinusoid vascular-like network. The IVL(mES) culture, where the hepatocyte is polarized in a similar fashion to its in vivo counterpart, could successfully recapitulate in vivo results. L-Ornithine is an intermediate of the urea cycle, but supplemental L-ornithine does not activate the urea cycle in the apolar primary hepatocyte of monolayer culture. In the IVL(mES), supplemental L-ornithine could activate the urea cycle, and also protect against ammonium/alcohol-induced hepatocyte death. While the IVL(mES) displays architectural and functional properties similar to the liver, primary hepatocyte of monolayer culture fail to model critical functional aspects of liver physiology. We propose that the IVL(mES) will represent a useful, humane alternative to animal studies for drug toxicity and mechanistic studies of liver injury.

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

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

PubMed

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

2014-04-01

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

Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia.

PubMed

Ward, C; Lucas, M; Piris, J; Collier, J; Chapel, H

2008-09-01

Patients with common variable immunodeficiency disorders are monitored for liver function test abnormalities. A proportion of patients develop deranged liver function and some also develop hepatomegaly. We investigated the prevalence of abnormalities and types of liver disease, aiming to identify those at risk and determine outcomes. The local primary immunodeficiency database was searched for patients with a common variable immunodeficiency disorder and abnormal liver function and/or a liver biopsy. Patterns of liver dysfunction were determined and biopsies reviewed. A total of 47 of 108 patients had deranged liver function, most commonly raised alkaline phosphatase levels. Twenty-three patients had liver biopsies. Nodular regenerative hyperplasia was found in 13 of 16 with unexplained pathology. These patients were more likely to have other disease-related complications of common variable immunodeficiency disorders, in particular non-coeliac (gluten insensitive) lymphocytic enteropathy. However, five had no symptoms of liver disease and only one died of liver complications. Nodular regenerative hyperplasia is a common complication of common variable immunodeficiency disorders but was rarely complicated by portal hypertension.

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

PubMed Central

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

2012-01-01

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

Hepatitis B virus evasion from cGAS sensing in human hepatocytes.

PubMed

Verrier, Eloi R; Yim, Seung-Ae; Heydmann, Laura; El Saghire, Houssein; Bach, Charlotte; Turon-Lagot, Vincent; Mailly, Laurent; Durand, Sarah C; Lucifora, Julie; Durantel, David; Pessaux, Patrick; Manel, Nicolas; Hirsch, Ivan; Zeisel, Mirjam B; Pochet, Nathalie; Schuster, Catherine; Baumert, Thomas F

2018-04-20

Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic GMP-AMP synthase (cGAS) was identified as a DNA sensor. In this study, we aimed to investigate the functional role of cGAS in sensing of HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss- and gain-of-function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes and HBV-infected human liver chimeric mice. Here we show that cGAS is expressed in the human liver, primary human hepatocytes and human liver chimeric mice. While naked relaxed-circular HBV DNA is sensed in a cGAS-dependent manner in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the hepatocyte cGAS pathway is functionally active, as shown by reduction of viral cccDNA levels in gain-of-function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized mice. HBV exploits multiple strategies to evade sensing and antiviral activity of cGAS and its effector pathways. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Association between Helicobacter pylori and liver-to-spleen ratio: a randomized-controlled single-blind study.

PubMed

Doğan, Zeynal; Filik, Levent; Ergül, Bilal; Sarikaya, Murat; Akbal, Erdem

2013-01-01

Helicobacter pylori infection is reported to be associated with some extragastrointestinal manifestations, such as hematological diseases (thrombocytopenia, anemia), obesity, and fatty liver disease. The length or the volume ratio of liver to spleen was suggested to be changed in some hematological and hepatobiliary disorders. We hypothesized that the liver-to-spleen ratio may be affected in H. pylori-positive patients. In this respect, we aimed to evaluate the effect of H. pylori infection on the liver-to-spleen ratio and platelet indices. A total of 174 patients with functional dyspepsia were included in the study. Patients were divided into group 1 (H. pylori-positive gastritis) (n=95) and group 2 (H. pylori negative, control group) (n=79). Liver, spleen length measurement, and liver steatosis scores were performed by ultrasonography by the same physicians who were blinded to the H. pylori results. Blood count values including the platelet count and the mean platelet volume (MPV) were compared between the two groups. BMI was also evaluated as a potential confounding factor for fatty liver. The liver-to-spleen ratio, platelet-to-spleen ratio, MPV-to-spleen ratio, and the MPV-to-liver ratio were significantly lower in the H. pylori-positive group compared with the H. pylori-negative group (P<0.001, <0.001, <0.001, and 0.038, respectively). Fatty liver was significantly more frequent in H. pylori-positive patients. Liver-to-spleen ratio and the MPV-to-spleen ratio are important indices in the pathogenesis of H. pylori-linked liver and spleen manifestations, and thrombocytopenia.

Impact of liver volume and liver function on posthepatectomy liver failure after portal vein embolization- A multivariable cohort analysis.

PubMed

Alizai, Patrick H; Haelsig, Annabel; Bruners, Philipp; Ulmer, Florian; Klink, Christian D; Dejong, Cornelis H C; Neumann, Ulf P; Schmeding, Maximilian

2018-01-01

Liver failure remains a life-threatening complication after liver resection, and is difficult to predict preoperatively. This retrospective cohort study evaluated different preoperative factors in regard to their impact on posthepatectomy liver failure (PHLF) after extended liver resection and previous portal vein embolization (PVE). Patient characteristics, liver function and liver volumes of patients undergoing PVE and subsequent liver resection were analyzed. Liver function was determined by the LiMAx test (enzymatic capacity of cytochrome P450 1A2). Factors associated with the primary end point PHLF (according to ISGLS definition) were identified through multivariable analysis. Secondary end points were 30-day mortality and morbidity. 95 patients received PVE, of which 64 patients underwent major liver resection. PHLF occurred in 7 patients (11%). Calculated postoperative liver function was significantly lower in patients with PHLF than in patients without PHLF (67 vs. 109 μg/kg/h; p = 0.01). Other factors associated with PHLF by univariable analysis were age, future liver remnant, MELD score, ASA score, renal insufficiency and heart insufficiency. By multivariable analysis, future liver remnant was the only factor significantly associated with PHLF (p = 0.03). Mortality and morbidity rates were 4.7% and 29.7% respectively. Future liver remnant is the only preoperative factor with a significant impact on PHLF. Assessment of preoperative liver function may additionally help identify patients at risk for PHLF.

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

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

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

2010-07-02

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

Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance.

PubMed

Preidis, Geoffrey A; Kim, Kang Ho; Moore, David D

2017-04-03

The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.

Diagnostics and Treatment of Hepatocellular Carcinoma in 2016: Standards and Developments.

PubMed

Trojan, Jörg; Zangos, Stephan; Schnitzbauer, Andreas A

2016-04-01

Hepatocellular carcinoma (HCC) is a frequent complication of liver cirrhosis. Worldwide, HCC is one of the most common cancers, with a rising incidence. A selective literature search was conducted, taking into account current studies, reviews, meta-analyses, and guidelines. The diagnosis is established either non-invasively by dynamic imaging, showing a typical contrast enhancement and wash-out, or histopathologically. Pathological diagnosis of HCC is recommended for all atypical nodules in patients with cirrhosis and for those in non-cirrhotic patients. Tumor therapy as well as treatment of the underlying chronic liver disease and/or preservation of liver function are important for the management of patients with HCC. Standard stage-adapted treatments are based on the widely applied Barcelona Clinic Liver Cancer staging system including liver resection and transplantation, interventional treatments such as thermal ablation and transarterial therapies, and systemic treatment with the tyrosine kinase inhibitor sorafenib. After failure of sorafenib, anti-angiogenic drugs, MET inhibitors, and immunotherapeutics are currently under advanced clinical investigation. Treatment of HCC is multidisciplinary and therefore requires a close cooperation between various disciplines such as hepatology, visceral surgery, radiology, and oncology to achieve the best outcome depending on the tumor stage and degree of liver function impairment.

Meta-Omic Platforms to Assist in the Understanding of NAFLD Gut Microbiota Alterations: Tools and Applications

PubMed Central

Del Chierico, Federica; Gnani, Daniela; Vernocchi, Pamela; Petrucca, Andrea; Alisi, Anna; Dallapiccola, Bruno; Nobili, Valerio; Lorenza, Putignani

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide as a result of the increasing prevalence of obesity, starting from early life stages. It is characterized by a spectrum of liver diseases ranging from simple fatty liver (NAFL) to steatohepatitis (NASH), with a possible progression to fibrosis, thus increasing liver-related morbidity and mortality. NAFLD development is driven by the co-action of several risk factors, including obesity and metabolic syndrome, which may be both genetically induced and diet-related. Recently, particular attention has been paid to the gut-liver axis, which may play a physio-pathological role in the onset and progression of the disease. The gut microbiota is intended to act as a bioreactor that can guarantee autonomous metabolic and immunological functions and that can drive functional strategies within the environment of the body in response to external stimuli. The complexity of the gut microbiota suggests that it behaves as an organ. Therefore, the concept of the gut-liver axis must be complemented with the gut-microbiota-liver network due to the high intricacy of the microbiota components and metabolic activities; these activities form the active diet-driven power plant of the host. Such complexity can only be revealed using systems biology, which can integrate clinical phenomics and gut microbiota data. PMID:24402126

Parenteral Nutrition-Associated Liver Disease: The Role of the Gut Microbiota.

PubMed

Cahova, Monika; Bratova, Miriam; Wohl, Petr

2017-09-07

Parenteral nutrition (PN) provides life-saving nutritional support in situations where caloric supply via the enteral route cannot cover the necessary needs of the organism. However, it does have serious adverse effects, including parenteral nutrition-associated liver disease (PNALD). The development of liver injury associated with PN is multifactorial, including non-specific intestine inflammation, compromised intestinal permeability, and barrier function associated with increased bacterial translocation, primary and secondary cholangitis, cholelithiasis, short bowel syndrome, disturbance of hepatobiliary circulation, lack of enteral nutrition, shortage of some nutrients (proteins, essential fatty acids, choline, glycine, taurine, carnitine, etc.), and toxicity of components within the nutrition mixture itself (glucose, phytosterols, manganese, aluminium, etc.). Recently, an increasing number of studies have provided evidence that some of these factors are directly or indirectly associated with microbial dysbiosis in the intestine. In this review, we focus on PN-induced changes in the taxonomic and functional composition of the microbiome. We also discuss immune cell and microbial crosstalk during parenteral nutrition, and the implications for the onset and progression of PNALD. Finally, we provide an overview of recent advances in the therapeutic utilisation of pro- and prebiotics for the mitigation of PN-associated liver complications.

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.

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

The Role of Akt in Chronic Liver Disease and Liver Regeneration.

PubMed

Morales-Ruiz, Manuel; Santel, Ansgar; Ribera, Jordi; Jiménez, Wladimiro

2017-02-01

The liver is continuously exposed to diverse insults, which may culminate in pathological processes causing liver disease. An effective therapeutic strategy for chronic liver disease should control the causal factors of the disease and stimulate functional liver regeneration. Preclinical studies have shown that interventions aimed at maintaining Akt activity in a dysfunctional liver meet most of the criteria. Although the central function of Akt is cell survival, other cellular aspects such as glucose uptake, glycogen synthesis, cell-cycle progression, and lipid metabolism have been shown to be prominent functions of Akt in the context of hepatic physiology. In this review, the authors describe the benefits of the Akt signaling pathway, emphasizing its importance in coordinating proper cellular growth and differentiation during liver regeneration, hepatic function, and liver disease. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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.

[Liver and heart T2* measurement in secondary haemochromatosis].

PubMed

Barrera Portillo, M C; Uranga Uranga, M; Sánchez González, J; Alústiza Echeverría, J M; Gervás Wells, C; Guisasola Íñiguez, A

2013-01-01

To determine whether there is iron overload by calculating the T2* value in the liver and myocardium in patients with secondary haemochromatosis. To analyse the correlation of the values obtained with the iron levels in blood, with the liver iron concentration (LIC) calculated using magnetic resonance (MR) imaging, and the correlation between them. A total of 16 patients (13 males, 3 females), with a mean age of 61 years, were included and evaluated in the years 2008 and 2009. Fifteen of them had received multiple transfusions, and one was diagnosed with hereditary sideroblastic anaemia. The measurements included, blood ferritin, LIC by MRI, cardiac function using MRI and the T2* value by means of multi-echo sequences in the liver (TR/TE1/ΔTE/No of echos/α: 21/1,18/1.0/20/35°) and myocardium (26/1.04/0.8/30/60°). A correlation-regression analysis was performed by comparing the cardiac and liver T2* values with the ferritin, LIC and between each of them. A total of 13 patients had ferritin values greater than 1000ng/ml (median/minimum/maximum: 1762/294/3785ng/ml). An increased LIC greater than 80μmol/g (median/minimum/maximum: 125.4/41.2/241.5μmol/g) was observed in 13 patients. In all cases cardiac function was conserved, and in 15 cases the liver T2* value was less than 6.3ms. The myocardium T2* value was less than 20ms. in only one case. A high correlation was observed between the liver T2* values and the LIC (r:-0.912). The correlation was statistically significant between the liver T2* value and ferritin (r:-0.541). The correlations between myocardium T2* and ferritin, myocardium T2* and LIC, and myocardium T2* and liver T2* were not statistically significant. The liver T2* showed a high correlation with LIC and a statistically significant correlation with ferritin. No association was observed between the myocardium T2* values and ferritin in blood, the LIC or the liver T2* value. Copyright © 2011 SERAM. Published by Elsevier Espana. All rights reserved.

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.

Acute kidney injury after liver, heart, and lung transplants: dialysis modality, predictors of renal function recovery, and impact on survival.

PubMed

Pham, Phuong-Thu T; Slavov, Carmen; Pham, Phuong-Chi T

2009-07-01

Recipients of nonrenal organ transplants including the liver, heart, and lung are at risk for developing acute kidney injury (AKI) and chronic kidney disease (CKD). Underlying hepatic or cardiopulmonary failure, prolonged intraoperative hemodynamic instability, and the use of calcineurin inhibitors and nephrotoxic medications have all been suggested to be contributory. The incidence of perioperative AKI has been reported to occur in 17% to 95% in liver transplant recipients, 5% to 30% in heart transplant recipients, and 5% to 60% in recipients of lung transplants. Among those who develop AKI, renal replacement therapy is required in 5% to 35%, 5% to 15%, and 8% to 10% in liver, heart, and lung transplant recipients, respectively. The current article presents an overview of the literature on the choice of dialysis modality and its associated advantages and disadvantages in the management of AKI after liver, heart, and lung transplants. Predictive factors for renal function recovery and the impact of AKI and CKD on survival will also be discussed.

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

PubMed

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

2015-01-01

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

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

Otani, Satoshi; Kakinuma, Sei, E-mail: skakinuma.gast@tmd.ac.jp; Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo

Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures inmore » MMP-14–deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14–deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14–deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14–deficient livers. We demonstrate that MMP-14–mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes. - Highlights: • Loss of MMP-14 delayed formation of bile duct-like structures in perinatal liver. • Overexpression of MMP-14 in hepatobalsts promoted the biliary formation in vitro. • Loss of MMP-14 promoted hepatocyte maturation of hepatoblasts in vivo. • MMP-14–mediated signaling regulates terminal differentiation of hepatoblasts.« less

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.

Extracorporeal Bioartificial Liver for Treating Acute Liver Diseases

PubMed Central

Kumar, Ashok; Tripathi, Anuj; Jain, Shivali

2011-01-01

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

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.

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

PubMed

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

2013-05-01

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

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

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.

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.

Choriocarcinoma

MedlinePlus

... or genital tumor . Symptoms A possible symptom is abnormal or irregular vaginal bleeding in a woman who recently had a hydatidiform ... blood count Kidney function tests Liver function tests Imaging tests that may be done include: CT scan MRI You should be carefully monitored after a hydatidiform ...

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.

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.

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.

Reconstitution of hepatic tissue architectures from fetal liver cells obtained from a three-dimensional culture with a rotating wall vessel bioreactor.

PubMed

Ishikawa, Momotaro; Sekine, Keisuke; Okamura, Ai; Zheng, Yun-wen; Ueno, Yasuharu; Koike, Naoto; Tanaka, Junzo; Taniguchi, Hideki

2011-06-01

Reconstitution of tissue architecture in vitro is important because it enables researchers to investigate the interactions and mutual relationships between cells and cellular signals involved in the three-dimensional (3D) construction of tissues. To date, in vitro methods for producing tissues with highly ordered structure and high levels of function have met with limited success although a variety of 3D culture systems have been investigated. In this study, we reconstituted functional hepatic tissue including mature hepatocyte and blood vessel-like structures accompanied with bile duct-like structures from E15.5 fetal liver cells, which contained more hepatic stem/progenitor cells comparing with neonatal liver cells. The culture was performed in a simulated microgravity environment produced by a rotating wall vessel (RWV) bioreactor. The hepatocytes in the reconstituted 3D tissue were found to be capable of producing albumin and storing glycogen. Additionally, bile canaliculi between hepatocytes, characteristics of adult hepatocyte in vivo were also formed. Apart from this, bile duct structure secreting mucin was shown to form complicated tubular branches. Furthermore, gene expression analysis by semi-quantitative RT-PCR revealed the elevated levels of mature hepatocyte markers as well as genes with the hepatic function. With RWV culture system, we could produce functionally reconstituted liver tissue and this might be useful in pharmaceutical industry including drug screening and testing and other applications such as an alternative approach to experimental animals. Copyright © 2011 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

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

PubMed Central

Li, David; Madoff, David C.

2016-01-01

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

[Various pathways leading to the progression of chronic liver diseases].

PubMed

Egresi, Anna; Lengyel, Gabriella; Somogyi, Anikó; Blázovics, Anna; Hagymási, Krisztina

2016-02-21

As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression.

[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.

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

PubMed Central

Chen, Guo

2010-01-01

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

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.

Clinico-biochemical correlation to histological findings in alcoholic liver disease: a single centre study from eastern India.

PubMed

Ray, Sayantan; Khanra, Dibbendhu; Sonthalia, Nikhil; Kundu, Supratip; Biswas, Kaushik; Talukdar, Arunansu; Saha, Manjari; Bera, Himel

2014-10-01

Alcoholism is a health problem not only in developed countries but also in developing countries. Cirrhosis due to alcohol is a common cause of death among individuals abusing alcohol. A better knowledge of the spectrum of alcoholic liver diseases, its clinical, biochemical and histopathological features could result in early detection and prevention of alcoholic liver diseases before it's catastrophic and life threatening effects. A total of 200 patients with alcoholic liver diseases were studied with respect to alcohol consumption, clinical features, biochemical and histopathological changes. The clinical features, biochemical parameters, and histopathology of liver including Ishak's modified histological activity index (HAI) were correlated with the amount and duration of alcohol consumed. Majority of the patients were in the age group of 40-49 years and all the cases were males. Majority consumed alcohol of about 75-90 grams per day for a duration of 10-12 years. Anorexia and jaundice were the most common symptom and clinical finding respectively. Hyperbilirubinemia and hypoalbuminemia were the most common abnormalities observed in liver function tests. Advanced HAI stages with features of cirrhosis were most frequent histo-pathological finding noted in this study. Clinico-biochemical profile was significantly correlated with degree of alcohol ingestion as well as with liver histopathology. The wide prevalence of alcoholic liver disease including cirrhosis among Indian males was noted with significantly lower quantity and duration of alcohol ingestion. The severity of liver damage is directly proportional to the quantity and duration of alcohol consumed. Clinical features and biochemical changes may forecast the liver histopathology among the patients of alcoholic liver disease.

[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.

Tc-NGA imaging in liver transplantation: preliminary clinical experience

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

Woodle, E.S.; Ward, R.E.; Stadalnik, R.C.

1989-03-01

Technetium-99m galactosyl-neoglycoalbumin (Tc-NGA) is a new liver imaging agent that binds to hepatic-binding protein, a hepatocyte-specific membrane receptor. The purpose of this study was to determine the potential of Tc-NGA imaging in clinical liver transplantation. A total of 25 studies were performed in nine patients. Imaging studies performed in the early posttransplant period in patients with good hepatic allograft function revealed diffuse patchiness in tracer distribution, a manifestation of preservation damage. Left lobar infarction was demonstrated within a few hours of ischemic injury. Right posterior segmental infarction was seen in another patient. Comparison of kinetic, clinical, and biochemical data revealedmore » good correlation between hepatic allograft function and Tc-NGA kinetics. Major kinetic alterations were noted during periods of preservation injury, hepatic infarction, and acute rejection. These studies indicate: (1) major alterations in Tc-NGA kinetics occur during preservation injury, hepatic infarction, and acute rejection, and (2) Tc-NGA kinetic data appear to provide an accurate reflection of hepatic allograft function. Tc-NGA imaging has the advantages of being noninvasive and of utilizing standard nuclear medicine instrumentation, including portable imaging devices. In conclusion, Tc-NGA imaging provides a promising noninvasive approach for evaluation of liver function in patients undergoing hepatic transplantation.« less

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

PubMed

Potanos, Kristina; Kim, Heung Bae

2014-02-01

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

Gut microbiota in cirrhotic liver transplant candidates.

PubMed

Grąt, Michał; Hołówko, Wacław; Gałecka, Mirosława; Grąt, Karolina; Szachtaz, Patrycja; Lewandowsk, Zbigniew; Kosińska, Irena; Schmidts, Marcin; Olejnik-Schmidt, Agnieszka; Krawczyk, Marek

2014-09-01

The purpose of this study was to evaluate the gut microflora of liver transplant candidates. Fecal microflora of 20 cirrhotic liver transplant candidates was analyzed basing on prospectively collected stool samples. The results were compared with those of 20 non-cirrhotic patients with liver disease and/or abnormal liver function tests, 20 patients with Crohn’s disease, and 20 patients without any gastrointestinal disease. Moreover, correlations between particular counts of microbiota, as well as between microbial counts and stool pH were examined. The pattern of fecal microbiota of liver transplant candidates was characterized by increased counts of lactobacilli (p=0.001), including hydrogen peroxide producing strains (p=0.008). In these patients, lactobacilli were positively correlated to enterococci (p=0.006) and bifidobacteria (p=0.004). No correlations other than those observed for lactobacilli in general were observed between hydrogen peroxide producing lactobacilli and the remaining microbiota. Increased yeast and Escherichia coli counts were associated with a tendency towards lower (p=0.095) and higher (p=0.072) stool pH, respectively. Surprisingly, gut microflora of liver transplant candidates with cirrhosis is particularly enriched with lactobacilli, including hydrogen peroxide producing strains. Thus, the use of other potentially beneficial microorganisms, such as particular yeast strains, might be more appropriate for these patients.

NMR-based metabonomic and quantitative real-time PCR in the profiling of metabolic changes in carbon tetrachloride-induced rat liver injury.

PubMed

Li, Xiaowei; Zhang, Fusheng; Wang, Dongqin; Li, Zhenyu; Qin, Xuemei; Du, Guanhua

2014-02-01

Carbon tetrachloride (CCl4) is commonly used as a model toxicant to induce chronic and acute liver injuries. In this study, metabolite profiling and gene expression analysis of liver tissues were performed by nuclear magnetic resonance and quantitative real-time polymerase chain reaction to understand the responses of acute liver injury system in rats to CCl4. Acute liver injury was successfully induced by CCl4 as revealed by histopathological results and significant increase in alanine aminotransferase and serum aspartate aminotransferase. We found that CCl4 caused a significant increase in lactate, succinate, citrate, dimethylgycine, choline and taurine. CCl4 also caused a decrease in some of the amino acids such as leucine/isoleucine, glutamine/glutathione and betaine. Gene function analysis revealed that 10 relevant enzyme genes exhibited changes in expressions in the acute liver injury model. In conclusion, the metabolic pathways, including tricarboxylic acid cycle, antioxidant defense systems, fatty acid β-oxidation, glycolysis and choline and mevalonate metabolisms were impaired in CCl4-treated rat livers. These findings provided an overview of the biochemical consequences of CCl4 exposure and comprehensive insights into the metabolic aspects of CCl4-induced hepatotoxicity in rats. These findings may also provide reference of the mechanisms of acute liver injury that could be used to study the changes in functional genes and metabolites. Copyright © 2013 Elsevier B.V. All rights reserved.

Nadolol for lithium tremor in the presence of liver damage.

PubMed

Dave, M; Langbart, M M

1994-03-01

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

Examination of the liver in personnel working with liquid rocket propellant

PubMed Central

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

1970-01-01

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

Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats.

PubMed

Tan, Gang; Pan, Shangha; Li, Jie; Dong, Xuesong; Kang, Kai; Zhao, Mingyan; Jiang, Xian; Kanwar, Jagat R; Qiao, Haiquan; Jiang, Hongchi; Sun, Xueying

2011-01-01

Hydrogen sulfide (H(2)S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2)S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2)S in carbon tetrachloride (CCl(4))-induced hepatotoxicity, cirrhosis and portal hypertension. Sodium hydrosulfide (NaHS), a donor of H(2)S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine γ-lyase (CSE), were applied to the rats to investigate the effects of H(2)S on CCl(4)-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2)S, hepatic H(2)S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4) significantly reduced serum levels of H(2)S, hepatic H(2)S production and CSE expression. NaHS attenuated CCl(4)-induced acute hepatotoxicity by supplementing exogenous H(2)S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters. Exogenous H(2)S attenuates CCl(4)-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2)S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension.

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

PubMed

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

2017-02-01

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

UCSF Center for HIV Information

MedlinePlus

... This patient educational brochure offers a primer on hepatitis C, including information on the liver's functions, laboratory tests, and treatment. HIV and Aging Toolkit Subscribe Subscribe to receive ...

Stereotactic ablative radiotherapy for oligometastatic disease in liver.

PubMed

Kim, Myungsoo; Son, Seok Hyun; Won, Yong Kyun; Kay, Chul Seung

2014-01-01

Liver metastasis in solid tumors, including colorectal cancer, is the most frequent and lethal complication. The development of systemic therapy has led to prolonged survival. However, in selected patients with a finite number of discrete lesions in liver, defined as oligometastatic state, additional local therapies such as surgical resection, radiofrequency ablation, cryotherapy, and radiotherapy can lead to permanent local disease control and improve survival. Among these, an advance in radiation therapy made it possible to deliver high dose radiation to the tumor more accurately, without impairing the liver function. In recent years, the introduction of stereotactic ablative radiotherapy (SABR) has offered even more intensive tumor dose escalation in a few fractions with reduced dose to the adjacent normal liver. Many studies have shown that SABR for oligometastases is effective and safe, with local control rates widely ranging from 50% to 100% at one or two years. And actuarial survival at one and two years has been reported ranging from 72% to 94% and from 30% to 62%, respectively, without severe toxicities. In this paper, we described the definition and technical aspects of SABR, clinical outcomes including efficacy and toxicity, and related parameters after SABR in liver oligometastases from colorectal cancer.

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".

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

PubMed

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

2008-05-01

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

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

PubMed

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

2016-01-01

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

Role of exercise in optimizing the functional status of patients with nonalcoholic fatty liver disease.

PubMed

Gerber, Lynn H; Weinstein, Ali; Pawloski, Lisa

2014-02-01

Nonalcoholic fatty liver disease (NAFLD) is frequently concomitant with obesity. This article discusses factors that influence health and functional outcomes of people who develop NAFLD, including increased burden of illness, whole body function, performance, and perception of self-efficacy. Changes in macronutrients, amount of calories consumed, and decreased physical activity all negatively influence patient outcome. The benefits of exercise in this population are also discussed. To be effective, exercise must be performed, regularly and in conjunction with dietary and other behavioral change. Therefore, a lifelong commitment to exercise, activity, and diet are needed if NAFLD is to be successfully treated. Copyright © 2014 Elsevier Inc. All rights reserved.

An alternative medicine, Agaricus blazei, may have induced severe hepatic dysfunction in cancer patients.

PubMed

Mukai, Hirofumi; Watanabe, Toru; Ando, Masashi; Katsumata, Noriyuki

2006-12-01

We report three cases of patients with advanced cancer who showed severe hepatic damage, and two of whom died of fulminant hepatitis. All the patients were taking Agaricus blazei (Himematsutake) extract, one of the most popular complementary and alternative medicines among Japanese cancer patients. In one patient, liver functions recovered gradually after she stopped taking the Agaricus blazei, but she restarted taking it, which resulted in deterioration of the liver function again. The other patients who were admitted for severe liver damage had started taking the Agaricus blazei several days before admission. Although several other factors cannot be completely ruled out as the causes of liver damage, a strong causal relationship between the Agaricus blazei extract and liver damage was suggested and, at least, taking the Agaricus blazei extract made the clinical decision-making process much more complicated. Doctors who are aware of their patients taking the extract may accept it probably because they believe there is no harm in a complementary and alternative medicine. When unexpected liver damage is documented, however, doctors should consider the use of the Agaricus blazei extract as one of its causal factors. It is necessary to evaluate many modes of complementary and alternative medicines, including the Agaricus blazei extract, in rigorous, scientifically designed and peer-reviewed clinical trials.

Intestinal permeability in a patient with liver cirrhosis

PubMed Central

Aguirre Valadez, Jonathan Manuel; Rivera-Espinosa, Liliana; Méndez-Guerrero, Osvely; Chávez-Pacheco, Juan Luis; García Juárez, Ignacio; Torre, Aldo

2016-01-01

Liver cirrhosis is a worldwide public health problem, and patients with this disease are at high risk of developing complications, bacterial translocation from the intestinal lumen to the mesenteric nodes, and systemic circulation, resulting in the development of severe complications related to high mortality rate. The intestinal barrier is a structure with a physical and biochemical activity to maintain balance between the external environment, including bacteria and their products, and the internal environment. Patients with liver cirrhosis develop a series of alterations in different components of the intestinal barrier directly associated with the severity of liver disease that finally increased intestinal permeability. A “leaky gut” is an effect produced by damaged intestinal barrier; alterations in the function of tight junction proteins are related to bacterial translocation and their products. Instead, increasing serum proinflammatory cytokines and hemodynamics modification, which results in the appearance of complications of liver cirrhosis such as hepatic encephalopathy, variceal hemorrhage, bacterial spontaneous peritonitis, and hepatorenal syndrome. The intestinal microbiota plays a fundamental role in maintaining the proper function of the intestinal barrier; bacterial overgrowth and dysbiosis are two phenomena often present in people with liver cirrhosis favoring bacterial translocation. Increased intestinal permeability has an important role in the genesis of these complications, and treating it could be the base for prevention and partial treatment of these complications. PMID:27920543

Fuzhuan tea consumption imparts hepatoprotective effects and alters intestinal microbiota in high saturated fat diet-fed rats.

PubMed

Foster, Michelle T; Gentile, Christopher L; Cox-York, Kimberly; Wei, Yuren; Wang, Dong; Estrada, Andrea L; Reese, Lauren; Miller, Tirrel; Pagliassotti, Michael J; Weir, Tiffany L

2016-05-01

Nonalcoholic fatty liver disease is an obesity-related disorder characterized by lipid infiltration of the liver. Management is limited to lifestyle modifications, highlighting the need for alternative therapeutic options. The objective of this study was to examine if fermented Fuzhuan tea prevents metabolic impairments associated with development of hepatic steatosis. Rats consumed control (CON) or high saturated fat (SAT) diets with or without Fuzhuan tea for 8 weeks. Outcomes included enzymatic and gene expression measures of metabolic dysregulation in liver and adipose tissue. Pyrosequencing was used to assess intestinal microbiota adaptations. Fuzhuan tea prevented diet-induced inflammation in the liver. Liver triglycerides of ∼18 mg/g were observed in SAT-fed animals, but remained similar to CON diet levels (∼12 mg/g) when supplemented with Fuzhuan tea. In adipose tissue, tea treatment prevented SAT-induced inflammation and reduced plasma leptin approximately twofold. Fuzhuan tea also altered intestinal function and was associated with a threefold increase in two Lactobacillus spp. These data suggest that Fuzhuan tea protects against liver and adipose tissue stress induced by a high SAT diet and positively influences intestinal function. Further investigation of the molecular targets of Fuzhuan tea is warranted. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed

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

2017-02-01

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

Diagnostics and Treatment of Hepatocellular Carcinoma in 2016: Standards and Developments

PubMed Central

Trojan, Jörg; Zangos, Stephan; Schnitzbauer, Andreas A.

2016-01-01

Background Hepatocellular carcinoma (HCC) is a frequent complication of liver cirrhosis. Worldwide, HCC is one of the most common cancers, with a rising incidence. Methods A selective literature search was conducted, taking into account current studies, reviews, meta-analyses, and guidelines. Results The diagnosis is established either non-invasively by dynamic imaging, showing a typical contrast enhancement and wash-out, or histopathologically. Pathological diagnosis of HCC is recommended for all atypical nodules in patients with cirrhosis and for those in non-cirrhotic patients. Tumor therapy as well as treatment of the underlying chronic liver disease and/or preservation of liver function are important for the management of patients with HCC. Standard stage-adapted treatments are based on the widely applied Barcelona Clinic Liver Cancer staging system including liver resection and transplantation, interventional treatments such as thermal ablation and transarterial therapies, and systemic treatment with the tyrosine kinase inhibitor sorafenib. After failure of sorafenib, anti-angiogenic drugs, MET inhibitors, and immunotherapeutics are currently under advanced clinical investigation. Conclusion Treatment of HCC is multidisciplinary and therefore requires a close cooperation between various disciplines such as hepatology, visceral surgery, radiology, and oncology to achieve the best outcome depending on the tumor stage and degree of liver function impairment. PMID:27413729

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.

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

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.

Life-threatening postpartum hemolysis, elevated liver functions tests, low platelets syndrome versus thrombocytopenic purpura – Therapeutic plasma exchange is the answer

PubMed Central

Nasa, Prashant; Dua, J. M.; Kansal, Sudha; Chadha, Geeta; Chawla, Rajesh; Manchanda, Manav

2011-01-01

The differential diagnosis of life-threatening microangiopathic disorders in a postpartum female includes severe preeclampsia–eclampsia, hemolysis, elevated liver functions tests, low platelets syndrome and thrombotic thrombocytopenic purpura. There is considerable overlapping in the clinical and laboratory findings between these conditions, and hence an exact diagnosis may not be always possible. However, there is considerable maternal mortality and morbidity associated with these disorders. This case underlines the complexity of pregnancy-related microangiopathies regarding their differential diagnosis, multiple organ dysfunction and role of therapeutic plasma exchange in their management. PMID:21814380

Life-threatening postpartum hemolysis, elevated liver functions tests, low platelets syndrome versus thrombocytopenic purpura - Therapeutic plasma exchange is the answer.

PubMed

Nasa, Prashant; Dua, J M; Kansal, Sudha; Chadha, Geeta; Chawla, Rajesh; Manchanda, Manav

2011-04-01

The differential diagnosis of life-threatening microangiopathic disorders in a postpartum female includes severe preeclampsia-eclampsia, hemolysis, elevated liver functions tests, low platelets syndrome and thrombotic thrombocytopenic purpura. There is considerable overlapping in the clinical and laboratory findings between these conditions, and hence an exact diagnosis may not be always possible. However, there is considerable maternal mortality and morbidity associated with these disorders. This case underlines the complexity of pregnancy-related microangiopathies regarding their differential diagnosis, multiple organ dysfunction and role of therapeutic plasma exchange in their management.

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

The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

PubMed Central

Klintmalm, Goran B.; Nashan, Björn

2014-01-01

Despite the success of liver transplantation, long-term complications remain, including de novo malignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms, de novo tumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity. PMID:24719752

Hepatoprotective effects of litchi (Litchi chinensis) procyanidin A2 on carbon tetrachloride-induced liver injury in ICR mice

PubMed Central

Chen, Lih-Geeng; Chang, Cheng-Wei; Tsay, Jwu-Guh; Weng, Brian Bor-Chun

2017-01-01

Drug tolerance, lacking liver regenerative activity and inconclusive inhibition of steatosis and cirrhosis by silymarin treatment during chronic liver injury have increased the demand for novel alternative or synergistic treatments for liver damage. Litchi fruit is abundant in polyphenolic compounds and is used in traditional Chinese medicine for treatments that include the strengthening of hepatic and pancreatic functions. Unique polyphenolic compounds obtained from litchi pericarp extract (LPE) were studied in vitro and in vivo for hepatoprotection. Epicatechin (EC) and procyanidin A2 (PA2) of LPE were obtained by fractionated-extraction from pulverized litchi pericarps. All fractions, including LPE, were screened against silymarin in carbon tetrachloride (CCl4)-treated murine embryonic liver cell line (BNL). The effects of daily gavage-feeding of LPE, silymarin (200 mg/kg body weight) or H2O in CCl4-intoxicated male ICR mice were evaluated by studying serum chemicals, liver pathology and glutathione antioxidative enzymes. The effects of EC and PA2 on liver cell regenerative activity were investigated using a scratch wound healing assay and flow cytometric cell cycle analysis; the results of which demonstrated that LPE protected BNL from CCl4-intoxication. Gavage-feeding of LPE decreased serum glutamic oxaloacetate transaminase and glutamic pyruvic transaminase levels, and exhibited superior retention of the hexagonal structure of hepatocytes and reduced necrotic cells following liver histopathological examinations in CCl4-intoxicated ICR mice. Glutathione peroxidise and glutathione reductase activities were preserved as the normal control level in LPE groups. EC and PA2 were principle components of LPE. PA2 demonstrated liver cell regenerative activity in scratch wound healing assays and alcohol-induced liver cell injury in vitro. The present findings suggest that litchi pericarp polyphenolic extracts, including EC and PA2, may be a synergistic alternative to silymarin in hepatoprotection and liver cell regeneration. PMID:28587348

Hepatoprotective effects of litchi (Litchi chinensis) procyanidin A2 on carbon tetrachloride-induced liver injury in ICR mice.

PubMed

Chen, Lih-Geeng; Chang, Cheng-Wei; Tsay, Jwu-Guh; Weng, Brian Bor-Chun

2017-06-01

Drug tolerance, lacking liver regenerative activity and inconclusive inhibition of steatosis and cirrhosis by silymarin treatment during chronic liver injury have increased the demand for novel alternative or synergistic treatments for liver damage. Litchi fruit is abundant in polyphenolic compounds and is used in traditional Chinese medicine for treatments that include the strengthening of hepatic and pancreatic functions. Unique polyphenolic compounds obtained from litchi pericarp extract (LPE) were studied in vitro and in vivo for hepatoprotection. Epicatechin (EC) and procyanidin A2 (PA2) of LPE were obtained by fractionated-extraction from pulverized litchi pericarps. All fractions, including LPE, were screened against silymarin in carbon tetrachloride (CCl 4 )-treated murine embryonic liver cell line (BNL). The effects of daily gavage-feeding of LPE, silymarin (200 mg/kg body weight) or H 2 O in CCl 4 -intoxicated male ICR mice were evaluated by studying serum chemicals, liver pathology and glutathione antioxidative enzymes. The effects of EC and PA2 on liver cell regenerative activity were investigated using a scratch wound healing assay and flow cytometric cell cycle analysis; the results of which demonstrated that LPE protected BNL from CCl 4 -intoxication. Gavage-feeding of LPE decreased serum glutamic oxaloacetate transaminase and glutamic pyruvic transaminase levels, and exhibited superior retention of the hexagonal structure of hepatocytes and reduced necrotic cells following liver histopathological examinations in CCl 4- intoxicated ICR mice. Glutathione peroxidise and glutathione reductase activities were preserved as the normal control level in LPE groups. EC and PA2 were principle components of LPE. PA2 demonstrated liver cell regenerative activity in scratch wound healing assays and alcohol-induced liver cell injury in vitro . The present findings suggest that litchi pericarp polyphenolic extracts, including EC and PA2, may be a synergistic alternative to silymarin in hepatoprotection and liver cell regeneration.

Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt

PubMed Central

Abdel-Moneim, Adel; Morsy, Basant M.; Mahmoud, Ayman M.; Abo-Seif, Mohamed A.; Zanaty, Mohamed I.

2013-01-01

Hepatitis C is a major global health burden and Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. The current study was designed to evaluate the beneficial therapeutic effects of ethanolic extracts of Nigella sativa, Zingiber officinale and their mixture in Egyptian HCV patients. Sixty volunteer patients with proven HCV and fifteen age matched healthy subjects were included in this study. Exclusion criteria included patients on interferon alpha (IFN-α) therapy, infection with hepatitis B virus, drug-induced liver diseases, advanced cirrhosis, hepatocellular carcinoma (HCC) or other malignancies, blood picture abnormalities and major severe illness. Liver function enzymes, albumin, total bilirubin, prothrombin time and concentration, international normalized ratio, alpha fetoprotein and viral load were all assessed at baseline and at the end of the study. Ethanolic extracts of Nigella sativa and Zingiber officinale were prepared and formulated into gelatinous capsules, each containing 500 mg of Nigella sativa and/or Zingiber officinale. Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study. Both extracts as well as their mixture significantly ameliorated the altered viral load, alpha fetoprotein, liver function parameters; with more potent effect for the combined therapy. In conclusion, administration of Nigella sativa and/or Zingiber officinale ethanolic extracts to HCV patients exhibited potential therapeutic benefits via decreasing viral load and alleviating the altered liver function, with more potent effect offered by the mixture. PMID:27298610

Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt.

PubMed

Abdel-Moneim, Adel; Morsy, Basant M; Mahmoud, Ayman M; Abo-Seif, Mohamed A; Zanaty, Mohamed I

2013-01-01

Hepatitis C is a major global health burden and Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. The current study was designed to evaluate the beneficial therapeutic effects of ethanolic extracts of Nigella sativa, Zingiber officinale and their mixture in Egyptian HCV patients. Sixty volunteer patients with proven HCV and fifteen age matched healthy subjects were included in this study. Exclusion criteria included patients on interferon alpha (IFN-α) therapy, infection with hepatitis B virus, drug-induced liver diseases, advanced cirrhosis, hepatocellular carcinoma (HCC) or other malignancies, blood picture abnormalities and major severe illness. Liver function enzymes, albumin, total bilirubin, prothrombin time and concentration, international normalized ratio, alpha fetoprotein and viral load were all assessed at baseline and at the end of the study. Ethanolic extracts of Nigella sativa and Zingiber officinale were prepared and formulated into gelatinous capsules, each containing 500 mg of Nigella sativa and/or Zingiber officinale. Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study. Both extracts as well as their mixture significantly ameliorated the altered viral load, alpha fetoprotein, liver function parameters; with more potent effect for the combined therapy. In conclusion, administration of Nigella sativa and/or Zingiber officinale ethanolic extracts to HCV patients exhibited potential therapeutic benefits via decreasing viral load and alleviating the altered liver function, with more potent effect offered by the mixture.

Ciprofloxacin and statin interaction: a cautionary tale of rhabdomyolysis.

PubMed

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

2016-07-28

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

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.

Correlation between hepatic blood flow and liver function in alcoholic liver cirrhosis.

PubMed

Takahashi, Hideaki; Shigefuku, Ryuta; Yoshida, Yoshihito; Ikeda, Hiroki; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

2014-12-07

To elucidate the correlation between hepatic blood flow and liver function in alcoholic liver cirrhosis (AL-LC). The subjects included 35 patients with AL-LC (34 men, 1 woman; mean age, 58.9 ± 10.7 years; median age, 61 years; range: 37-76 years). All patients were enrolled in this study after obtaining written informed consent. Liver function was measured with tests measuring albumin (Alb), prothrombin time (PT), brain natriuretic peptide (BNP), branched amino acid and tyrosine ratio (BTR), branched chain amino acid (BCAA), tyrosine, ammonia (NH3), cholinesterase (ChE), immunoreactive insulin (IRI), total bile acid (TBA), and the retention rate of indocyanine green 15 min after administration (ICG R15). Hepatic blood flow, hepatic arterial tissue blood flow (HATBF), portal venous tissue blood flow (PVTBF), and total hepatic tissue blood flow (THTBF) were simultaneously calculated using xenon computed tomography. PVTBF, HATBF and THTBF were 30.2 ± 10.4, 20.0 ± 10.7, and 50.3 ± 14.9 mL/100 mL/min, respectively. Alb, PT, BNP, BTR, BCAA, tyrosine, NH3, ChE, IRI, TBA, and ICG R15 were 3.50 ± 0.50 g/dL, 72.0% ± 11.5%, 63.2 ± 56.7 pg/mL, 4.06 ± 1.24, 437.5 ± 89.4 μmol/L, 117.7 ± 32.8 μmol/L, 59.4 ± 22.7 μg/dL, 161.0 ± 70.8 IU/L, 12.8 ± 5.0 μg/dL, 68.0 ± 51.8 μmol/L, and 28.6% ± 13.5%, respectively. PVTBF showed a significant negative correlation with ICG R15 (r = -0.468, P <0.01). No significant correlation was seen between ICG 15R, HATBF and THTBF. There was a significant correlation between PVTBF and Alb (r = 0.2499, P < 0.05), and NH₃ tended to have an inverse correlation with PVTBF (r = -0.2428, P = 0.0894). There were also many significant correlations between ICG R15 and liver function parameters, including Alb, NH3, PT, BNP, TBA, BCAA, and tyrosine (r = -0.2156, P < 0.05; r = 0.4318, P < 0.01; r = 0.4140, P < 0.01; r = 0.3610, P < 0.05; r = 0.5085, P < 0.001; r = 0.4496, P < 0.01; and r = 0.4740, P < 0.05, respectively). Our investigation showed that there is a close correlation between liver function and hepatic blood flow.

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

PubMed

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

2014-02-01

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

Menstrual blood-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells*

PubMed Central

Mou, Xiao-zhou; Lin, Jian; Chen, Jin-yang; Li, Yi-fei; Wu, Xiao-xing; Xiang, Bing-yu; Li, Cai-yun; Ma, Ju-ming; Xiang, Charlie

2013-01-01

Orthotopic liver transplantation (OLT) is the only proven effective treatment for both end-stage and metabolic liver diseases. Hepatocyte transplantation is a promising alternative for OLT, but the lack of available donor livers has hampered its clinical application. Hepatocyte-like cells (HLCs) differentiated from many multi-potential stem cells can help repair damaged liver tissue. Yet almost suitable cells currently identified for human use are difficult to harvest and involve invasive procedures. Recently, a novel mesenchymal stem cell derived from human menstrual blood (MenSC) has been discovered and obtained easily and repeatedly. In this study, we examined whether the MenSCs are able to differentiate into functional HLCs in vitro. After three weeks of incubation in hepatogenic differentiation medium containing hepatocyte growth factor (HGF), fibroblast growth factor-4 (FGF-4), and oncostain M (OSM), cuboidal HLCs were observed, and cells also expressed hepatocyte-specific marker genes including albumin (ALB), α-fetoprotein (AFP), cytokeratin 18/19 (CK18/19), and cytochrome P450 1A1/3A4 (CYP1A1/3A4). Differentiated cells further demonstrated in vitro mature hepatocyte functions such as urea synthesis, glycogen storage, and indocyanine green (ICG) uptake. After intrasplenic transplantation into mice with 2/3 partial hepatectomy, the MenSC-derived HLCs were detected in recipient livers and expressed human ALB protein. We also showed that MenSC-derived HLC transplantation could restore the serum ALB level and significantly suppressed transaminase activity of liver injury animals. In conclusion, MenSCs may serve as an ideal, easily accessible source of material for tissue engineering and cell therapy of liver tissues. PMID:24190442

Rotating microgravity-bioreactor cultivation enhances the hepatic differentiation of mouse embryonic stem cells on biodegradable polymer scaffolds.

PubMed

Wang, Yingjie; Zhang, Yunping; Zhang, Shichang; Peng, Guangyong; Liu, Tao; Li, Yangxin; Xiang, Dedong; Wassler, Michael J; Shelat, Harnath S; Geng, Yongjian

2012-11-01

Embryonic stem (ES) cells are pluripotent cells that are capable of differentiating all the somatic cell lineages, including those in the liver tissue. We describe the generation of functional hepatic-like cells from mouse ES (mES) cells using a biodegradable polymer scaffold and a rotating bioreactor that allows simulated microgravity. Cells derived from ES cells cultured in the three-dimensional (3D) culture system with exogenous growth factors and hormones can differentiate into hepatic-like cells with morphologic characteristics of typical mature hepatocytes. Reverse-transcription polymerase chain-reaction testing, Western blot testing, immunostaining, and flow cytometric analysis show that these cells express hepatic-specific genes and proteins during differentiation. Differentiated cells on scaffolds further exhibit morphologic traits and biomarkers characteristic of liver cells, including albumin production, cytochrome P450 activity, and low-density lipoprotein uptake. When these stem cell-bearing scaffolds are transplanted into severe combined immunodeficient mice, the 3D constructs remained viable, undergoing further differentiation and maturation of hepatic-like cells in vivo. In conclusion, the growth and differentiation of ES cells in a biodegradable polymer scaffold and a rotating microgravity bioreactor can yield functional and organizational hepatocytes useful for research involving bioartificial liver and engineered liver tissue.

Influence of body habitus on feasibility and outcome of laparoscopic liver resections: a prospective study.

PubMed

Ratti, Francesca; D'Alessandro, Valentina; Cipriani, Federica; Giannone, Fabio; Catena, Marco; Aldrighetti, Luca

2016-06-01

The aim of the present study was to prospectively investigate whether the anthropometric measures of A Body Shape Index (ABSI, taking into account waist circumference adjusted for height and weight) affects feasibility and outcome of laparoscopic liver resections. One hundred patients undergoing laparoscopic liver resection were prospectively included in the study (2014-2015). Preoperative clinical parameters, including body mass index (BMI) and ABSI were evaluated for associations with intraoperative outcome and postoperative results (morbidity, mortality and functional recovery). Twenty-two and 78 patients underwent major and minor hepatectomies, respectively. Conversion rate was 9%, mean blood loss was 210 ± 115 ml. Postoperative morbidity was 15% and mortality was nil. Mean length of stay was 4 days. When considering the entire series, ABSI was not associated with intra and postoperative outcome. After stratification of patients according to difficulty score, Pearson's correlation demonstrated an association between ABSI and intraoperative blood loss (P = 0.03) and time for functional recovery (P = 0.05) in patients undergoing resections with high score of difficulty. Body habitus has an influence on outcome of laparoscopic liver resections with high degree of difficulty, while feasibility and outcome of low difficulty resections seem not to be affected by anthropometric measures. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Toward unraveling the complexity of simple epithelial keratins in human disease.

PubMed

Omary, M Bishr; Ku, Nam-On; Strnad, Pavel; Hanada, Shinichiro

2009-07-01

Simple epithelial keratins (SEKs) are found primarily in single-layered simple epithelia and include keratin 7 (K7), K8, K18-K20, and K23. Genetically engineered mice that lack SEKs or overexpress mutant SEKs have helped illuminate several keratin functions and served as important disease models. Insight into the contribution of SEKs to human disease has indicated that K8 and K18 are the major constituents of Mallory-Denk bodies, hepatic inclusions associated with several liver diseases, and are essential for inclusion formation. Furthermore, mutations in the genes encoding K8, K18, and K19 predispose individuals to a variety of liver diseases. Hence, as we discuss here, the SEK cytoskeleton is involved in the orchestration of several important cellular functions and contributes to the pathogenesis of human liver disease.

Toward unraveling the complexity of simple epithelial keratins in human disease

PubMed Central

Omary, M. Bishr; Ku, Nam-On; Strnad, Pavel; Hanada, Shinichiro

2009-01-01

Simple epithelial keratins (SEKs) are found primarily in single-layered simple epithelia and include keratin 7 (K7), K8, K18–K20, and K23. Genetically engineered mice that lack SEKs or overexpress mutant SEKs have helped illuminate several keratin functions and served as important disease models. Insight into the contribution of SEKs to human disease has indicated that K8 and K18 are the major constituents of Mallory-Denk bodies, hepatic inclusions associated with several liver diseases, and are essential for inclusion formation. Furthermore, mutations in the genes encoding K8, K18, and K19 predispose individuals to a variety of liver diseases. Hence, as we discuss here, the SEK cytoskeleton is involved in the orchestration of several important cellular functions and contributes to the pathogenesis of human liver disease. PMID:19587454

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)

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

PubMed

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

2013-01-01

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

Measurement of Blood Coagulation Factor Synthesis in Cultures of Human Hepatocytes.

PubMed

Heinz, Stefan; Braspenning, Joris

2015-01-01

An important function of the liver is the synthesis and secretion of blood coagulation factors. Within the liver, hepatocytes are involved in the synthesis of most blood coagulation factors, such as fibrinogen, prothrombin, factor V, VII, IX, X, XI, XII, as well as protein C and S, and antithrombin, whereas liver sinusoidal endothelial cells produce factor VIII and von Willebrand factor. Here, we describe methods for the detection and quantification of most blood coagulation factors in hepatocytes in vitro. Hepatocyte cultures indeed provide a valuable tool to study blood coagulation factors. In addition, the generation and expansion of hepatocytes or hepatocyte-like cells may be used in future for cell-based therapies of liver diseases, including blood coagulation factor deficiencies.

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/

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

PubMed

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

2014-06-17

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

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

PubMed Central

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

2014-01-01

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

Successful left hemihepatectomy and perioperative management of a patient with biliary cystadenocarcinoma, complicated with MELAS syndrome: report of a case.

PubMed

Ohno, Ayami; Mori, Akira; Doi, Ryuichiro; Yonenaga, Yoshikuni; Asano, Noboru; Uemoto, Shinji

2010-09-01

Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like syndrome (MELAS) is a rare, fetal disease caused by a mutation in mitochondrial DNA that leads to impaired oxidative metabolism in skeletal muscle, the central nervous system, and liver function. This report presents the case of a 50-year-old woman with biliary cystadenocarcinoma complicated by MELAS who underwent a successful left hemihepatectomy. In this case, the diagnostic key for the malignant tumor was an (18)F-fluorodeoxyglucose positron emission tomography study, which was useful even in a patient with MELAS, which causes abnormal glucose metabolism. The perioperative management of such patients includes special precautions to prevent lactic acidosis and deterioration of the reserved liver function after a hepatectomy, since the mitochondrial function in MELAS patients is abnormal. The patient in this report has remained free of liver dysfunctions and cancer recurrence for 2 years following the hepatectomy. This is the first report of a successful major hepatectomy for a patient with MELAS.

Some Biochemical and Hematological Parameters among Petrol Station Attendants: A Comparative Study

PubMed Central

Abou-ElWafa, Hala Samir; Albadry, Ahmed A.; Bazeed, Fagr B.

2015-01-01

Objective. To describe selected biochemical and hematological parameters (blood picture, liver enzymes, and kidney functions) in petrol station attendants in Mansoura city. Methods. This is a comparative cross-sectional study. The exposed group included 102 petrol station attendants. They were compared to a matched group of healthy 102 male service and office workers at the Faculty of Medicine, Mansoura University. The results of blood picture, liver enzymes, and kidney functions were compared between both groups. Results. Mean Red Blood Cells (RBCs) count, hemoglobin level, and Hematocrit (HCT) level were significantly lower in petrol station attendants than the comparison group. All other blood picture parameters showed nonsignificant difference between both groups. Liver enzymes, renal functions, serum albumin, and total protein showed statistically nonsignificant difference between both groups except for alanine aminotransferase (ALT) which was significantly higher in petrol station attendants. Conclusions. Some laboratory parameters among petrol station attendants showed changes that could be attributed to workplace exposure and should be given attention at preemployment and periodic medical examination. PMID:26634207

Development of the Liver in Alpaca (Vicugna pacos): A Microscopic and Macroscopic Description.

PubMed

Castro, A N C; Domínguez, M T; Gómez, S A; Mendoza Torres, G J; Llerena Zavala, C A; Ghezzi, M D; Barbeito, C G

2016-06-01

South American camelids have several biological, morphological and behavioural adaptations that allow them to live in geographical areas dominated by high altitudes. The liver has hematopoietic functions during the prenatal life, which could be modified in response to the unfavorable habitat. However, there are no previous data on the prenatal development of the liver in these species. In the present work, a study on the macroscopic and microscopic morphology of the liver of the alpaca during ontogeny was performed. Forty-one animals ranging in age from 20 days of embryonic development to adults were studied. Macroscopic and microscopic observations were performed on samples subjected to different techniques. Less than 7-g specimens were studied with stereoscopic magnifying glass. The general characteristics of the prenatal liver are similar to those of other mammals, and the structures related to hematopoietic function follow an ontogenic pattern similar to that of previously studied precocial species. However, there are differences in morphology when compared to descriptions for the Old World camelids, including the absence of relation between the caudate lobe and the right kidney and the lack of interlobular connective tissue. © 2015 Blackwell Verlag GmbH.

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.

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

PubMed

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

2012-01-18

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

Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis.

PubMed

Dong, Shu; Chen, Qi-Long; Song, Ya-Nan; Sun, Yang; Wei, Bin; Li, Xiao-Yan; Hu, Yi-Yang; Liu, Ping; Su, Shi-Bing

2016-01-01

The classic toxicity of carbon tetrachloride (CCl4) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl4-induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl4 in liver fibrosis. Wistar rats were treated with CCl4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl4-treated group were significantly higher than that of CCl4-untreated group. CCl4-treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change ≥ 1.5, P < 0.05) and 1412 proteins (fold change ≥ 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl4 treatment. Therefore, the toxicological mechanisms of CCl4-induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl4 detoxication in the liver.

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.

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 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.

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.

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

PubMed

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

2017-08-01

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

A Role for the Liver in Parturition and Preterm Birth.

PubMed

Mawson, Anthony R

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

A Role for the Liver in Parturition and Preterm Birth

PubMed Central

Mawson, Anthony R.

2016-01-01

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

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

PubMed

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

2013-06-26

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

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.

Comparative factor analysis of the effect of postoperative peripheral parenteral nutrition on recovery of right lobe liver donors.

PubMed

Hsieh, Chia-En; Lin, Kuo-Hua; Lin, Chia-Cheng; Hwu, Yueh-Juen; Lin, Ping-Yi; Lin, Hui-Chuan; Ko, Chih-Jan; Wang, Su-Han; Chen, Yao-Li

2015-04-01

Intensive nutritional support can reduce the catabolic response, improve protein synthesis, and promote liver regeneration. This study examined whether postoperative peripheral parenteral nutrition may improve recovery and reduce the length of hospital stay in right lobe liver donors. In this retrospective study, we enrolled liver donors with residual liver volume < 50%. Donors were classified into 2 groups: donors who received (n = 44) or did not receive (n = 40) postoperative peripheral parenteral nutrition. Liver function tests included alanine aminotransferase and total bilirubin levels, and postoperative complications included pleural effusion, atelectasis, and wound complications. Hospital length of stay was included as a potential risk factor for the evaluation of the effect of postoperative peripheral parenteral nutrition on recovery of right lobe liver donors. Male sex (β, 22.04; 95% confidence interval: 6.22 - 37.86) was a significant predictor of changes in postoperative alanine aminotransferase level. Male sex (β, 0.045; 95% confidence interval: 0.16 - 37.86) and receipt of peripheral parenteral nutrition (β, -0.045; 95% confidence interval: -0.72 - 0.17) were significant predictors of changes in total bilirubin level. Postoperative atelectasis (P < .001), pleural effusion (P < .011), and total complications (P = .015) had significantly lower incidence in the peripheral parenteral nutrition than control group. Multivariate logistic regression showed that recipients of peripheral parenteral nutrition (odds ratio, 0.161; 95% confidence interval: 0.043 - 0.598) and age (odds ratio, 0.870; 95% confidence interval: 0.782 - 0.968) were significant preoperative risk factors for postoperative complications. Postoperative peripheral parenteral nutrition is associated with a lower incidence of pleural effusion and atelectasis, a more rapid recovery of hyperbilirubinemia, and shorter length of stay in right lobe liver donors.

Liver function in workers exposed of the cosmetics industry.

PubMed

Casale, T; Caciari, T; Rosati, M V; Biagi, M; De Sio, S; Andreozzi, G; Schifano, M P; Capozzella, A; Pimpinella, B; Tomei, G; Tomei, F

2013-01-01

The purpose of this study is to assess whether occupational exposure to substances used in the cosmetic factories may cause effects on the liver and blood counts in exposed workers. The study included 48 exposed workers and 86 unexposed controls. All workers included in the study underwent blood count, white blood count, total, direct and indirect bilirubin, transaminases, alkaline phosphatase and cholinesterase. The differences between the means and frequencies were compared using the Student's t-test and chi-square test with Yates correction and were considered significant when the p value was <0.05. The analysis of the results shows that 35.4% of workers in the cosmetics industry had liver test values above the range. We noted a statistically significant higher prevalence of GPT (p <0.05) and total bilirubin (p <0.05) in the workers of the cosmetics industry compared with the control group. The results obtained suggest that occupational exposure to low doses of substances used in the cosmetic industry is able to influence some liver parameters in occupationally exposed workers.

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

PubMed

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

2018-05-11

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

Remote Sensing between Liver and Intestine: Importance of Microbial Metabolites

PubMed Central

Fu, Zidong Donna; Cui, Julia Yue

2017-01-01

Recent technological advancements including metagenomics sequencing and metabolomics have allowed the discovery of critical functions of gut microbiota in obesity, malnutrition, neurological disorders, asthma, and xenobiotic metabolism. Classification of the human gut microbiome into distinct “enterotypes” has been proposed to serve as a new paradigm for understanding the interplay between microbial variation and human disease phenotypes, as many organs are affected by gut microbiota modifications during the pathogenesis of diseases. Gut microbiota remotely interacts with liver and other metabolic organs of the host through various microbial metabolites that are absorbed into the systemic circulation. Purpose of review The present review summarizes recent literature regarding the importance of gut microbiota in modulating the physiological and pathological responses of various host organs, and describes the functions of the known microbial metabolites that are involved in this remote sensing process, with a primary focus on the gut microbiota-liver axis. Recent findings Under physiological conditions, gut microbiota modulates the hepatic transcriptome, proteome, and metabolome, most notably down-regulating cytochrome P450 3a mediated xenobiotic metabolism. Gut microbiome also modulates the rhythmicity in liver gene expression, likely through microbial metabolites, such as butyrate and propionate that serve as epigenetic modifiers. Additionally, the production of host hormones such as primary bile acids and glucagon like peptide 1 is altered by gut microbiota to modify intermediary metabolism of the host. Summary Dysregulation of gut microbiota is implicated in various liver diseases such as alcoholic liver disease, non-alcoholic steatohepatitis, liver cirrhosis, cholangitis, and liver cancer. Gut microbiota modifiers such as probiotics and prebiotics are increasingly recognized as novel therapeutic modalities for liver and other types of human diseases. PMID:28983453

Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation.

PubMed

Yu, Songfeng; Yu, Jun; Zhang, Wei; Cheng, Longyu; Ye, Yufu; Geng, Lei; Yu, Zhiyong; Yan, Sheng; Wu, Lihua; Wang, Weilin; Zheng, Shusen

2014-10-01

Liver grafts from hepatitis B surface antigen (HBsAg) positive donors could have potential to increase the donor pool. However, knowledge is extremely limited in this setting because currently available data are mostly from case reports. We aimed to assess the outcomes and experiences of liver transplantation from HBsAg positive donors in a single centre study. From January 2010 to February 2013, 42 adult patients underwent liver transplantation from HBsAg positive donors and 327 patients from HBsAg negative ones. The outcomes including complications and survival of two groups were compared and antiviral therapy retrospectively reviewed. HBsAg positive liver grafts were more likely to be allocated to patients with hepatitis B (HBV)-related diseases. Post-transplant evaluation showed similar graft function regaining pace and no differences in complications such as primary non-function, acute rejection and biliary complications. Patient and graft survivals were comparable to that of HBsAg negative grafts. Furthermore, HBsAg persisted after transplant in all patients that received positive grafts. The donor HBV serum status determined the one of the recipient after transplantation. No HBV flare-ups were observed under antiviral therapy of oral nucleotide analogues, regardless of using hepatitis B immunoglobulin combination. Utilization of HBsAg positive liver grafts seems not to increase postoperative morbidity and mortality. Therefore it is a safe way to expand the donor pool when no suitable donor is available. Our experience also suggests that hepatitis B immunoglobulin should be abandoned in recipients of HBsAg positive liver grafts, in whom HBV prophylaxis could be the only oral antiviral therapy. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology

NASA Astrophysics Data System (ADS)

Mederacke, Ingmar; Hsu, Christine C.; Troeger, Juliane S.; Huebener, Peter; Mu, Xueru; Dapito, Dianne H.; Pradere, Jean-Philippe; Schwabe, Robert F.

2013-11-01

Although organ fibrosis causes significant morbidity and mortality in chronic diseases, the lack of detailed knowledge about specific cellular contributors mediating fibrogenesis hampers the design of effective antifibrotic therapies. Different cellular sources, including tissue-resident and bone marrow-derived fibroblasts, pericytes and epithelial cells, have been suggested to give rise to myofibroblasts, but their relative contributions remain controversial, with profound differences between organs and different diseases. Here we employ a novel Cre-transgenic mouse that marks 99% of hepatic stellate cells (HSCs), a liver-specific pericyte population, to demonstrate that HSCs give rise to 82-96% of myofibroblasts in models of toxic, cholestatic and fatty liver disease. Moreover, we exclude that HSCs function as facultative epithelial progenitor cells in the injured liver. On the basis these findings, HSCs should be considered the primary cellular target for antifibrotic therapies across all types of liver disease.

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.

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

PubMed

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

2015-08-07

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

Branches of NF-κb signaling pathway regulate hepatocyte proliferation in rat liver regeneration.

PubMed

Chang, C F; Zhao, W M; Mei, J X; Zhou, Y; Pan, C Y; Xu, T T; Xu, C S

2015-07-13

Previous studies have demonstrated that the nuclear factor κB (NF-κB) pathway is involved in promoting cell proliferation. To further explore the regulatory branches and their sequence in the NF-κB pathway in the promotion of hepatocyte proliferation at the transcriptional level during rat liver regeneration, Rat Genome 230 2.0 array was used to detect the expression changes of the isolated hepatocytes. We found that many genes involved in the NF-κB pathway (including 73 known genes and 19 homologous genes) and cell proliferation (including 484 genes and 104 homologous genes) were associated with liver regeneration. Expression profile function (Ep) was used to analyze the biological processes. It was revealed that the NF-κB pathway promoted hepatocyte proliferation through three branches. Several methods of integrated statistics were applied to extract and screen key genes in liver regeneration, and it indicated that eight genes may play a vital role in rat liver regeneration. To confirm the above predicted results, Ccnd1, Jun and Myc were analyzed using qRT-PCR, and the results were generally consistent with that of microarray data. It is concluded that 3 branches and 8 key genes involved in the NF-κB pathway regulate hepatocyte proliferation during rat liver regeneration.

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

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.

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.

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.

[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.

Protective effects of extracts from Pomegranate peels and seeds on liver fibrosis induced by carbon tetrachloride in rats.

PubMed

Wei, Xiang-Lan; Fang, Ru-Tang; Yang, Yong-Hua; Bi, Xue-Yuan; Ren, Guo-Xia; Luo, A-Li; Zhao, Ming; Zang, Wei-Jin

2015-10-27

Liver fibrosis is a feature in the majority of chronic liver diseases and oxidative stress is considered to be its main pathogenic mechanism. Antioxidants including vitamin E, are effective in preventing liver fibrogenesis. Several plant-drived antioxidants, such as silymarin, baicalin, beicalein, quercetin, apigenin, were shown to interfere with liver fibrogenesis. The antioxidans above are polyphenols, flavonoids or structurally related compounds which are the main chemical components of Pomegranate peels and seeds, and the antioxidant activity of Pomegranate peels and seeds have been verified. Here we investigated whether the extracts of pomegranate peels (EPP) and seeds (EPS) have preventive efficacy on liver fibrosis induced by carbon tetrachloride (CCl4) in rats and explored its possible mechanisms. The animal model was established by injection with 50 % CCl4 subcutaneously in male wistar rats twice a week for four weeks. Meanwhile, EPP and EPS were administered orally every day for 4 weeks, respectively. The protective effects of EPP and EPS on biochemical metabolic parameters, liver function, oxidative markers, activities of antioxidant enzymes and liver fibrosis were determined in CCl4-induced liver toxicity in rats. Compared with the sham group, the liver function was worse in CCl4 group, manifested as increased levels of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin. EPP and EPS treatment significantly ameliorated these effects of CCl4. EPP and EPS attenuated CCl4-induced increase in the levels of TGF-β1, hydroxyproline, hyaluronic acid laminin and procollagen type III. They also restored the decreased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and inhibited the formation of lipid peroxidized products in rats treated with CCl4. The EPP and EPS have protective effects against liver fibrosis induced by CCl4, and its mechanisms might be associated with their antioxidant activity, the ability of decreasing the level of TGF-β1 and inhibition of collagen synthesis.

Protocol for Isolation of Primary Human Hepatocytes and Corresponding Major Populations of Non-parenchymal Liver Cells

PubMed Central

Pfeiffer, Elisa; Zeilinger, Katrin; Seehofer, Daniel; Damm, Georg

2016-01-01

Beside parenchymal hepatocytes, the liver consists of non-parenchymal cells (NPC) namely Kupffer cells (KC), liver endothelial cells (LEC) and hepatic Stellate cells (HSC). Two-dimensional (2D) culture of primary human hepatocyte (PHH) is still considered as the "gold standard" for in vitro testing of drug metabolism and hepatotoxicity. It is well-known that the 2D monoculture of PHH suffers from dedifferentiation and loss of function. Recently it was shown that hepatic NPC play a central role in liver (patho-) physiology and the maintenance of PHH functions. Current research focuses on the reconstruction of in vivo tissue architecture by 3D- and co-culture models to overcome the limitations of 2D monocultures. Previously we published a method to isolate human liver cells and investigated the suitability of these cells for their use in cell cultures in Experimental Biology and Medicine1. Based on the broad interest in this technique the aim of this article was to provide a more detailed protocol for the liver cell isolation process including a video, which will allow an easy reproduction of this technique. Human liver cells were isolated from human liver tissue samples of surgical interventions by a two-step EGTA/collagenase P perfusion technique. PHH were separated from the NPC by an initial centrifugation at 50 x g. Density gradient centrifugation steps were used for removal of dead cells. Individual liver cell populations were isolated from the enriched NPC fraction using specific cell properties and cell sorting procedures. Beside the PHH isolation we were able to separate KC, LEC and HSC for further cultivation. Taken together, the presented protocol allows the isolation of PHH and NPC in high quality and quantity from one donor tissue sample. The access to purified liver cell populations could allow the creation of in vivo like human liver models. PMID:27077489

Protocol for Isolation of Primary Human Hepatocytes and Corresponding Major Populations of Non-parenchymal Liver Cells.

PubMed

Kegel, Victoria; Deharde, Daniela; Pfeiffer, Elisa; Zeilinger, Katrin; Seehofer, Daniel; Damm, Georg

2016-03-30

Beside parenchymal hepatocytes, the liver consists of non-parenchymal cells (NPC) namely Kupffer cells (KC), liver endothelial cells (LEC) and hepatic Stellate cells (HSC). Two-dimensional (2D) culture of primary human hepatocyte (PHH) is still considered as the "gold standard" for in vitro testing of drug metabolism and hepatotoxicity. It is well-known that the 2D monoculture of PHH suffers from dedifferentiation and loss of function. Recently it was shown that hepatic NPC play a central role in liver (patho-) physiology and the maintenance of PHH functions. Current research focuses on the reconstruction of in vivo tissue architecture by 3D- and co-culture models to overcome the limitations of 2D monocultures. Previously we published a method to isolate human liver cells and investigated the suitability of these cells for their use in cell cultures in Experimental Biology and Medicine(1). Based on the broad interest in this technique the aim of this article was to provide a more detailed protocol for the liver cell isolation process including a video, which will allow an easy reproduction of this technique. Human liver cells were isolated from human liver tissue samples of surgical interventions by a two-step EGTA/collagenase P perfusion technique. PHH were separated from the NPC by an initial centrifugation at 50 x g. Density gradient centrifugation steps were used for removal of dead cells. Individual liver cell populations were isolated from the enriched NPC fraction using specific cell properties and cell sorting procedures. Beside the PHH isolation we were able to separate KC, LEC and HSC for further cultivation. Taken together, the presented protocol allows the isolation of PHH and NPC in high quality and quantity from one donor tissue sample. The access to purified liver cell populations could allow the creation of in vivo like human liver models.

Liver Transplant

MedlinePlus

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Impact of Hypocaloric Hyperproteic Diet on Gut Microbiota in Overweight or Obese Patients with Nonalcoholic Fatty Liver Disease: A Pilot Study.

PubMed

Pataky, Zoltan; Genton, Laurence; Spahr, Laurent; Lazarevic, Vladimir; Terraz, Sylvain; Gaïa, Nadia; Rubbia-Brandt, Laura; Golay, Alain; Schrenzel, Jacques; Pichard, Claude

2016-09-01

NAFLD is likely to become the most common cause of chronic liver disease. The first-line treatment includes weight loss. To analyze the impact of a hypocaloric hyperproteic diet (HHD) on gut microbiota in NAFLD patients. Fifteen overweight/obese patients with NAFLD were included. At baseline and after a 3-week HHD (Eurodiets(®), ~1000 kcal/day, ~125 g protein/day), we measured gut microbiota composition and function by shotgun metagenomics; body weight; body composition by bioelectrical impedance analysis; liver and visceral fat by magnetic resonance imaging; plasma C-reactive protein (CRP); and liver tests. Results between both time points, expressed as median (first and third quartile), were compared by Wilcoxon signed-rank tests. At baseline, age was 50 (47-55) years and body mass index 34.6 (32.4, 36.7) kg/m(2). HDD decreased body weight by 3.6 % (p < 0.001), percent liver fat by 65 % (p < 0.001), and CRP by 19 % (p = 0.014). HDD was associated with a decrease in Lachnospira (p = 0.019), an increase in Blautia (p = 0.026), Butyricicoccus (p = 0.024), and changes in several operational taxonomic units (OTUs) of Bacteroidales and Clostridiales. The reduced liver fat was negatively correlated with bacteria belonging to the Firmicutes and Bacteroidetes phyla (a Ruminococcaceae OTU, r = -0.83; Bacteroides, r = -0.73). The associated metabolic changes concerned mostly enzymes involved in amino acid and carbohydrate metabolism. In this pilot study, HHD changes gut microbiota composition and function in overweight/obese NAFLD patients, in parallel with decreased body weight, liver fat, and systemic inflammation. Future studies should aim to confirm these bacterial changes and understand their mode of action. Under clinicaltrials.gov: NCT01477307.

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

PubMed Central

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

2006-01-01

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

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

PubMed

Scheuher, Cynthia

2016-01-01

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

Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.

PubMed

Bacalini, Maria Giulia; Franceschi, Claudio; Gentilini, Davide; Ravaioli, Francesco; Zhou, Xiaoyuan; Remondini, Daniel; Pirazzini, Chiara; Giuliani, Cristina; Marasco, Elena; Gensous, Noémie; Di Blasio, Anna Maria; Ellis, Ewa; Gramignoli, Roberto; Castellani, Gastone; Capri, Miriam; Strom, Stephen; Nardini, Christine; Cescon, Matteo; Grazi, Gian Luca; Garagnani, Paolo

2018-03-15

The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt signaling pathways in the aging of human liver.

Unexplained abnormal liver function in patients with primary antibody deficiency: could it be chronic hepatitis E infection?

PubMed

Mohamed, Omar E; Jones, Julie; Osman, Husam; Huissoon, Aarnoud P

2017-08-09

Data from recent studies suggest rising incidence rate of hepatitis E virus (HEV) infection in the UK. HEV infection may take a severe and persistent course in immunocompromised patients, including transplant recipients on immunosuppressives, patients with HIV, haematological malignancies and in idiopathic CD4 + T lymphocytopenia. The prevalence of HEV in primary antibody deficiency (PAD) disorders is still unknown. The aim of this study was to investigate HEV infection in 27 patients with PAD with unexplained, persistently elevated liver enzymes. Although all the 27 patients tested negative for HEV-RNA, we would still strongly recommend that HEV should be considered in any immunodeficient patient with impaired liver function. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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.

Benign Liver Tumors

MedlinePlus

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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.

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.

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

PubMed

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

2014-03-01

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

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

PubMed

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

2016-05-01

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

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

PubMed Central

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

2016-01-01

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

Progression of Liver Disease

MedlinePlus

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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.

The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway

PubMed Central

Obeid, Rima

2013-01-01

Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism. Choline can be synthesized from phosphatidylcholine via the cytidine-diphosphate (CDP) pathway. Low dietary choline loweres methionine formation and causes a marked increase in S-adenosylmethionine utilization in the liver. The link between choline, betaine, and energy metabolism in humans indicates novel functions for these nutrients. This function appears to goes beyond the role of the nutrients in gene methylation and epigenetic control. Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders. Changes in plasma concentrations of total homocysteine (tHcy) reflect one aspect of the metabolic consequences of methyl group deficiency or nutrient supplementations. Folic acid supplementation spares betaine as a methyl donor. Betaine is a significant determinant of plasma tHcy, particularly in case of folate deficiency, methionine load, or alcohol consumption. Betaine supplementation has a lowering effect on post-methionine load tHcy. Hypomethylation and tHcy elevation can be attenuated when choline or betaine is available. PMID:24022817

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

NASA Astrophysics Data System (ADS)

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

2016-06-01

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

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

PubMed Central

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

2017-01-01

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

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.

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

Invariant Natural Killer T Cells are Reduced in Hereditary Hemochromatosis Patients.

PubMed

Maia, M L; Pereira, C S; Melo, G; Pinheiro, I; Exley, M A; Porto, G; Macedo, M F

2015-01-01

Invariant natural killer T (iNKT) cells are CD1d restricted-T cells that react to lipid antigens. iNKT cells were shown to be important in infection, autoimmunity and tumor surveillance. Alterations in the number and function of these cells were described in several pathological conditions including autoimmune and/or liver diseases. CD1d is critical for antigen presentation to iNKT cells, and its expression is increased in liver diseases. The liver is the major organ affected in Hereditary Hemochromatosis (HH), an autosomal recessive disorder caused by excessive iron absorption. Herein, we describe the study of iNKT cells of HH patients. Twenty-eight HH patients and 24 control subjects from Santo António Hospital, Porto, were included in this study. Patient's iron biochemical parameters (serum transferrin saturation and ferritin levels) and the liver function marker alanine transaminase (ALT) were determined at the time of study. Peripheral blood iNKT cells were analyzed by flow cytometry using an anti-CD3 antibody and the CD1d tetramer loaded with PBS57. We found a decrease in the percentage and number of circulating iNKT cells from HH patients when compared with control population independently of age. iNKT cell defects were more pronounced in untreated patients, relating with serum ferritin and transferrin saturation levels. No correlation was found with ALT, a marker of active liver dysfunction. Altogether, our results demonstrate that HH patients have reduced numbers of iNKT cells and that these are influenced by iron overload.

Obliterative portal venopathy without portal hypertension: an underestimated condition.

PubMed

Guido, Maria; Sarcognato, Samantha; Sonzogni, Aurelio; Lucà, Maria Grazia; Senzolo, Marco; Fagiuoli, Stefano; Ferrarese, Alberto; Pizzi, Marco; Giacomelli, Luciano; Colloredo, Guido

2016-03-01

Obliterative portal venopathy without portal hypertension has been described by a single study in a limited number of patients, thus very little is known about this clinical condition. This study aimed to investigate the prevalence of obliterative portal venopathy and its clinical-pathological correlations in patients with cryptogenic chronic liver test abnormalities without clinical signs of portal hypertension. We analysed 482 liver biopsies from adults with non-cirrhotic cryptogenic chronic liver disorders and without any clinical signs of portal hypertension, consecutively enrolled in a 5-year period. Twenty cases of idiopathic non-cirrhotic portal hypertension diagnosed in the same period, were included for comparison. Histological findings were matched with clinical and laboratory features. Obliterative portal venopathy was identified in 94 (19.5%) of 482 subjects and in all 20 cases of idiopathic non-cirrhotic portal hypertension: both groups shared the entire spectrum of histological changes described in the latter condition. The prevalence of incomplete fibrous septa and nodular regenerative hyperplasia was higher in the biopsies of idiopathic non-cirrhotic portal hypertension (P = 0.006 and P = 0.002), a possible hint of a more advanced stage of the disease. The two groups also shared several clinical laboratory features, including a similar liver function test profile, concomitant prothrombotic conditions and extrahepatic autoimmune disorders. Obliterative portal venopathy occurs in a substantial proportion of patients with unexplained chronic abnormal liver function tests without portal hypertension. The clinical-pathological profile of these subjects suggests that they may be in an early (non-symptomatic) stage of idiopathic non-cirrhotic portal hypertension. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

[Nutritional Assessment and Management for Patients with Chronic Liver Disease].

PubMed

Lee, Tae Hee

2018-04-25

When liver disease is severe, the prognosis can be worse if the patient is malnourished. Adequate nutritional support for patients with liver diseases can improve the patient's condition and prognosis. In the case of liver cirrhosis, malnutrition can occur due to a variety of causes, including poor oral intake, maldigestion, malabsorption, associated renal disease, and metabolic abnormalities. For a nutritional assessment, it is important to check the dietary intake, change in body composition, including anthropometry, and a functional assessment of muscle. Counselling and oral or enteral nutrition is preferred over parenteral nutrition as in other diseases. If esophageal varices are present, care should be taken when installing a feeding tube, but if there are ascites, percutaneous endoscopic gastrostomy is contraindicated because of the risk of complications. Calories of 30-35 kcal/kg/day and protein from 1.2 to 1.5 g/kg/day are appropriate. Protein restriction is unnecessary unless the hepatic encephalopathy is severe. A late evening snack and branched chain amino acids can be helpful. In the case of cholestasis, the supply of manganese and copper should be restricted. Sarcopenia in patients with liver cirrhosis is also prevalent and associated with the prognosis.

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.

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.

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.

Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite.

PubMed

Gust, Kurt A; Nanduri, Bindu; Rawat, Arun; Wilbanks, Mitchell S; Ang, Choo Yaw; Johnson, David R; Pendarvis, Ken; Chen, Xianfeng; Quinn, Michael J; Johnson, Mark S; Burgess, Shane C; Perkins, Edward J

2015-08-07

A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to develop holistic effects characterizations for the wildlife bird model, Northern bobwhite (Colinus virginianus) dosed with the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT). A subchronic 60 d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2A-DNT. Effects on global transcript expression were investigated in liver and kidney tissue using custom microarrays for C. virginianus in both sexes at all doses, while effects on proteome expression were investigated in liver for both sexes and kidney in males, at 30 mg/kg-d. As expected, transcript expression was not directly indicative of protein expression in response to 2A-DNT. However, a high degree of correspondence was observed among gene and protein expression when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Analysis of networks statistically enriched for both transcripts and proteins demonstrated common responses including inhibition of programmed cell death and arrest of cell cycle in liver tissues at 2A-DNT doses that caused liver necrosis and death in females. Additionally, both transcript and protein expression in liver tissue was indicative of induced phase I and II xenobiotic metabolism potentially as a mechanism to detoxify and excrete 2A-DNT. Nuclear signaling assays, transcript expression and protein expression each implicated peroxisome proliferator-activated receptor (PPAR) nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. Although the differential expression of transcripts and proteins was largely unique, the consensus of functional pathways and gene networks enriched among transcriptomic and proteomic datasets provided the identification of many critical metabolic functions underlying 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and trinitrotoluene exposures.

Donor-transmitted, donor-derived, and de novo cancer after liver transplant.

PubMed

Chapman, Jeremy R; Lynch, Stephen V

2014-03-01

Cancer is the third most common cause of death (after cardiovascular disease and infection) for patients who have a functioning kidney allograft. Kidney and liver transplant recipients have similar cancer risks because of immunosuppression but different risks because of differences in primary diseases that cause renal and hepatic failure and the inherent behavior of cancers in the liver. There are 4 types of cancer that may develop in liver allograft recipients: (1) recurrent cancer, (2) donor-transmitted cancer, (3) donor-derived cancer, and (4) de novo cancer. Identification of potential donor cancer transmission may occur at postmortem examination of a deceased donor or when a probable donor-transmitted cancer is identified in another recipient. Donor-transmitted cancer after liver transplant is rare in Australia, the United Kingdom, and the United States. Aging of the donor pool may increase the risk of subclinical cancer in donors. Liver transplant recipients have a greater risk of de novo cancer than the general population, and risk factors for de novo cancer in liver transplant recipients include primary sclerosing cholangitis, alcoholic liver disease, smoking, and increased age. Liver transplant recipients may benefit from cancer screening because they have a high risk, are clearly identifiable, and are under continuous medical supervision.

Selective enrichment of metal-binding proteins based on magnetic core/shell microspheres functionalized with metal cations.

PubMed

Fang, Caiyun; Zhang, Lei; Zhang, Xiaoqin; Lu, Haojie

2015-06-21

Metal binding proteins play many important roles in a broad range of biological processes. Characterization of metal binding proteins is important for understanding their structure and biological functions, thus leading to a clear understanding of metal associated diseases. The present study is the first to investigate the effectiveness of magnetic microspheres functionalized with metal cations (Ca(2+), Cu(2+), Zn(2+) and Fe(3+)) as the absorbent matrix in IMAC technology to enrich metal containing/binding proteins. The putative metal binding proteins in rat liver were then globally characterized by using this strategy which is very easy to handle and can capture a number of metal binding proteins effectively. In total, 185 putative metal binding proteins were identified from rat liver including some known less abundant and membrane-bound metal binding proteins such as Plcg1, Acsl5, etc. The identified proteins are involved in many important processes including binding, catalytic activity, translation elongation factor activity, electron carrier activity, and so on.

Experiment K-6-14. Hepatic function in rats after spaceflight

NASA Technical Reports Server (NTRS)

Merrill, A., Jr.; Hoel, M.; Wang, E.; Jones, D.; Hargrove, J.; Mullins, R.; Popova, I.

1990-01-01

To determine the possible biochemical consequences of prolonged weightlessness on liver function, tissue samples from rats that had flown aboard Cosmos 1887 were analyzed for hepatic protein, glycogen and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the hepatic glycogen content and HMG-CoA reductase activities of the rats flown on Cosmos 1887, and a decrease in the amount of microsomal cytochrome P sub 450 and the activity of aniline hydroxylase, a cytochrome P sub 450-dependent enzyme. Decreases in these two indices of the microsomal mixed-function oxidase system indicated that spaceflight may compromise the ability of liver to metabolize drugs and toxins. The higher HMG-CoA reductase correlated with elevated levels of serum cholestrol. Other changes included somewhat higher blood glucose, creatinine, SGOT, and much greater alkaline phosphatase and BUN. These results generally support the earlier observation of changes in these parameters (Merrill et al., Am. J. Physiol. 252:R22-R226, 1987). The importance of these alterations in liver function is not known; however, they have the potential to complicate long-term spaceflight.

A score model for the continuous grading of early allograft dysfunction severity.

PubMed

Pareja, Eugenia; Cortes, Miriam; Hervás, David; Mir, José; Valdivieso, Andrés; Castell, José V; Lahoz, Agustín

2015-01-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcomes. A lack of consensus on an EAD definition hinders comparisons of liver transplant outcomes and management of recipients among and within centers. We sought to develop a model for the quantitative assessment of early allograft function [Model for Early Allograft Function Scoring (MEAF)] after transplantation. A retrospective study including 1026 consecutive liver transplants was performed for MEAF score development. Multivariate data analysis was used to select a small number of postoperative variables that adequately describe EAD. Then, the distribution of these variables was mathematically modeled to assign a score for each actual variable value. A model, based on easily obtainable clinical parameters (ie, alanine aminotransferase, international normalized ratio, and bilirubin) and scoring liver function from 0 to 10, was built. The MEAF score showed a significant association with patient and graft survival at 3-, 6- and 12-month follow-ups. Hepatic steatosis and age for donors; cold/warm ischemia times and postreperfusion syndrome for surgery; and intensive care unit and hospital stays, Model for End-Stage Liver Disease and Child-Pugh scores, body mass index, and fresh frozen plasma transfusions for recipients were factors associated significantly with EAD. The model was satisfactorily validated by its application to an independent set of 200 patients who underwent liver transplantation at a different center. In conclusion, a model for the quantitative assessment of EAD severity has been developed and validated for the first time. The MEAF provides a more accurate graft function assessment than current categorical classifications and may help clinicians to make early enough decisions on retransplantation benefits. Furthermore, the MEAF score is a predictor of recipient and graft survival. The standardization of the criteria used to define EAD may allow reliable comparisons of recipients' treatments and transplant outcomes among and within centers. © 2014 American Association for the Study of Liver Diseases.

[Liver 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.

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.

mRNA N6-methyladenosine methylation of postnatal liver development in pig.

PubMed

He, Shen; Wang, Hong; Liu, Rui; He, Mengnan; Che, Tiandong; Jin, Long; Deng, Lamei; Tian, Shilin; Li, Yan; Lu, Hongfeng; Li, Xuewei; Jiang, Zhi; Li, Diyan; Li, Mingzhou

2017-01-01

N6-methyladenosine (m6A) is a ubiquitous reversible epigenetic RNA modification that plays an important role in the regulation of post-transcriptional protein coding gene expression. Liver is a vital organ and plays a major role in metabolism with numerous functions. Information concerning the dynamic patterns of mRNA m6A methylation during postnatal development of liver has been long overdue and elucidation of this information will benefit for further deciphering a multitude of functional outcomes of mRNA m6A methylation. Here, we profile transcriptome-wide m6A in porcine liver at three developmental stages: newborn (0 day), suckling (21 days) and adult (2 years). About 33% of transcribed genes were modified by m6A, with 1.33 to 1.42 m6A peaks per modified gene. m6A was distributed predominantly around stop codons. The consensus motif sequence RRm6ACH was observed in 78.90% of m6A peaks. A negative correlation (average Pearson's r = -0.45, P < 10-16) was found between levels of m6A methylation and gene expression. Functional enrichment analysis of genes consistently modified by m6A methylation at all three stages showed genes relevant to important functions, including regulation of growth and development, regulation of metabolic processes and protein catabolic processes. Genes with higher m6A methylation and lower expression levels at any particular stage were associated with the biological processes required for or unique to that stage. We suggest that differential m6A methylation may be important for the regulation of nutrient metabolism in porcine liver.

EpCAM and the biology of hepatic stem/progenitor cells

PubMed Central

Theise, Neil D.; Schmelzer, Eva; Boulter, Luke; Gires, Olivier; van Grunsven, Leo A.

2014-01-01

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is frequently and highly expressed on carcinomas, tumor-initiating cells, selected tissue progenitors, and embryonic and adult stem cells. During liver development, EpCAM demonstrates a dynamic expression, since it can be detected in fetal liver, including cells of the parenchyma, whereas mature hepatocytes are devoid of EpCAM. Liver regeneration is associated with a population of EpCAM-positive cells within ductular reactions, which gradually lose the expression of EpCAM along with maturation into hepatocytes. EpCAM can be switched on and off through a wide panel of strategies to fine-tune EpCAM-dependent functional and differentiative traits. EpCAM-associated functions relate to cell–cell adhesion, proliferation, maintenance of a pluripotent state, regulation of differentiation, migration, and invasion. These functions can be conferred by the full-length protein and/or EpCAM-derived fragments, which are generated upon regulated intramembrane proteolysis. Control by EpCAM therefore not only depends on the presence of full-length EpCAM at cellular membranes but also on varying rates of the formation of EpCAM-derived fragments that have their own regulatory properties and on changes in the association of EpCAM with interaction partners. Thus spatiotemporal localization of EpCAM in immature liver progenitors, transit-amplifying cells, and mature liver cells will decisively impact the regulation of EpCAM functions and might be one of the triggers that contributes to the adaptive processes in stem/progenitor cell lineages. This review will summarize EpCAM-related molecular events and how they relate to hepatobiliary differentiation and regeneration. PMID:25477371

Posttraumatic venous gas in the liver - a case report and review of the current literature.

PubMed

Fahrner, René; Rauchfuss, Falk; Scheuerlein, Hubert; Settmacher, Utz

2018-03-02

There are numerous causes of hepatic gas formation that range from serious pathologies to incidental findings, including mesenteric infarction, liver abscess, inflammatory bowel disease or minimally invasive hepatic interventions. We report a case of a 50-year-old man who was admitted to the emergency room after a car accident. The clinical examination and further diagnostics revealed a craniocerebral injury with a fracture of the skull, concomitant soft tissue lesions and subarachnoidal bleeding. Furthermore, a blunt thoracic trauma with hemopneumothorax due to rib fractures was treated with a chest tube. No obvious abdominal pathology was seen. While in the operating theatre for the surgical revision of the cranial soft tissue lesions, a femoral venous catheter was inserted without any complications. A routine ultrasound of the abdomen six hours after the trauma revealed unclear hepatic gas formation. A contrast-enhanced computer tomography (CT) scan of the abdomen was performed, and the gas formation was found to be localized within the left hepatic vein. Afterwards, there was no specific treatment of the hepatic venous gas formation, as no alterations of liver function or liver enzymes were seen. The further course of the patient was uneventful regarding the gas formation in the liver, and another ultrasound two days later revealed no further gas in the liver. The placement of a femoral venous catheter is a risk factor for gas formation in liver veins. No further treatment is needed in cases with stable liver function. To rule out serious pathologies, diagnostic findings (e.g., ultrasound, CT), clinical history and underlying diseases need to be analyzed carefully after the detection of intrahepatic gas formation. With contrast-enhanced CT, the localization of the gas and its potential causes might be detectable.

HRQOL using SF36 (generic specific) in liver cirrhosis.

PubMed

Janani, K; Varghese, Joy; Jain, Mayank; Harika, Kavya; Srinivasan, Vijaya; Michael, Tom; Jayanthi, Venkataraman

2017-07-01

Health-related quality of life (HRQOL) is influenced by the disease state, associated complications and their management. In patients with liver cirrhosis co-morbidity, severity of liver disease and their complications are likely to affect the QOL. The aim of the study was to determine the factors that are likely to influence the domains of HRQOL using SF-36 in patients with liver cirrhosis. For the study, 149 patients with liver cirrhosis were compared with age-gender matched healthy controls for physical and mental components of SF-36 score and the effects of age, co-morbidity severity of liver disease and complications of liver cirrhosis on HRQOL were assessed using the same questionnaire. Results of the study showed that except for body pain, all the patients had a significantly low individual and composite domain score (p-value <0.0001) compared to age-gender matched controls. Patients below 45 years, Child-Turcotte-Pugh (CTP) C, a high model for end-stage liver disease (MELD) and higher rates of complication had low scores for body pain (KW p <0.005) and those above 55 years, for physical function (p <0.05). Both the physical components had a major impact on mental composite score (MCS) (KW p <0.05). Co-morbidity that included diabetes, hypertension and hypothyroid states in various combinations had no effect on SF-36 scores while co-morbid conditions like musculoskeletal pain, arthralgia etc. affected physical domains (physical function, body pain and role physical) and physical component score (PCS) (KW p <0.01 to <0.0001). By linear regression, MELD had a direct and significant association with overall PCS and mental component score (MCS).

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

Hemochromatosis

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Galactosemia

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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.

Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug

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

Mosedale, Merrie; Wu, Hong; Kurtz, C. Lisa

A large number of antibiotics are known to cause drug-induced liver injury in the clinic; however, interpreting clinical risk is not straightforward owing to a lack of predictivity of the toxicity by standard preclinical species and a poor understanding of the mechanisms of toxicity. An example is PF-04287881, a novel ketolide antibiotic that caused elevations in liver function tests in Phase I clinical studies. In this study, a mouse diversity panel (MDP), comprised of 34 genetically diverse, inbred mouse strains, was utilized to model the toxicity observed with PF-04287881 treatment and investigate potential mechanisms that may mediate the liver response.more » Significant elevations in serum alanine aminotransferase (ALT) levels in PF-04287881-treated animals relative to vehicle-treated controls were observed in the majority (88%) of strains tested following a seven day exposure. The average fold elevation in ALT varied by genetic background and correlated with microscopic findings of hepatocellular hypertrophy, hepatocellular single cell necrosis, and Kupffer cell vacuolation (confirmed as phospholipidosis) in the liver. Global liver mRNA expression was evaluated in a subset of four strains to identify transcript and pathway differences that distinguish susceptible mice from resistant mice in the context of PF-04287881 treatment. The protein ubiquitination pathway was highly enriched among genes associated with PF-04287881-induced hepatocellular necrosis. Expression changes associated with PF-04287881-induced phospholipidosis included genes involved in drug transport, phospholipid metabolism, and lysosomal function. The findings suggest that perturbations in genes involved in protein degradation leading to accumulation of oxidized proteins may mediate the liver injury induced by this drug. - Highlights: • Identified susceptible and resistant mouse strains to liver injury induced by a CAD • Liver injury characterized by single cell necrosis, and phospholipidosis • Decreased gene expression associated with protein ubiquitination in sensitive mice • Altered protein ubiquitination may cause oxidized protein accumulation in the liver.« less

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

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

Structural and functional changes in acute liver injury.

PubMed

Smuckler, E A

1976-06-01

Carbon tetrachloride produces liver cell injury in a variety of animal species. The first structurally recognizable changes occur in the endoplasmic reticulum, with alteration in ribosome-membrane interactions. Later there is an increase in intracellular fat, and the formation of tangled nets of the ergastoplasm. At no time are there changes in mitochondria or single membrane limited bodies in cells with intact plasmalemma, although a relative increase in cell sap may appear. In dead cells (those with plasmalemma discontinuties) crystalline deposits of calcium phosphatase may be noted. Functional changes are related to the endoplasmic reticulum and the plasma membrane. An early decrease in protein synthesis takes place; an accumulation of neutral lipid is related to this change. Later alterations in the ergastoplasmic functions (e.g., mixed function oxidation) occurs. Carbon tetrachloride is not the active agent; rather, a product of its metabolism, probably the CC1, free radical, is. The mechanisms of injury include macromolecular adduction and peroxide propagation. A third possibility includes a cascade effect with the production of secondary and tertiary products, also toxic in nature, with the ability to produce more widespread damage to intracellular structures.

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.

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

Technetium-99m NGA functional hepatic imaging: preliminary clinical experience

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

Stadalnik, R.C.; Vera, D.R.; Woodle, E.S.

1985-11-01

Technetium-99m galactosyl-neoglycoalbumin ( (Tc)NGA) is a radiolabeled ligand to hepatic binding protein, a receptor which resides at the plasma membrane of hepatocytes. This receptor-binding radiopharmaceutical and its kinetic model provide a noninvasive method for the assessment of liver function. Eighteen patients were studied: seven with hepatoma, eight with liver metastases, four with cirrhosis, and one patient with acute fulminant non-A, non-B hepatitis. Technetium-99m NGA liver imaging provided anatomic information of diagnostic quality comparable to that obtained with other routine imaging modalities, including computed tomography, angiography, ultrasound, and (Tc)sulfur colloid scintigraphy. Kinetic modeling of dynamic (Tc)NGA data produced estimates of standardizedmore » hepatic blood flow, Q (hepatic blood flow divided by total blood volume), and hepatic binding protein concentration, (HBP). Significant rank correlation was obtained between (HBP) estimates and CTC scores. This correlation supports the hypothesis that (HBP) is a measure of functional hepatocyte mass. The combination of decreased Q and markedly reduced (HBP) may have prognostic significance; all three patients with this combination died of hepatic failure within 6 wk of imaging.« less

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.

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.

Alagille Syndrome

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Newborn Jaundice

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Reye Syndrome

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Basal values and changes of liver stiffness predict the risk of disease progression in compensated advanced chronic liver disease.

PubMed

Pons, Mònica; Simón-Talero, Macarena; Millán, Laura; Ventura-Cots, Meritxell; Santos, Begoña; Augustin, Salvador; Genescà, Joan

2016-10-01

Transient elastography has been proposed as a tool to predict the risk of decompensation in patients with chronic liver disease. We aimed to identify risk groups of disease progression, using a combination of baseline liver stiffness measurement (LSM) and its change over time (delta-LSM) in patients with compensated advanced chronic liver disease (cACLD). Ninety-four patients with baseline LSM ≥10kPa, Child-Pugh score 5 and without previous decompensation were included. A second LSM was performed during follow-up and data on liver function and liver-related events were collected. The primary endpoint was a composite that included death, liver decompensation and impairment in at least 1 point in Child-Pugh score. After a median follow-up of 43.6 months, 15% of patients presented the primary endpoint. Multivariate analysis identified baseline LSM (OR 1.12, P=0.002) and delta-LSM (OR 1.02, P=0.048) as independent predictors of the primary endpoint. A high risk group represented by patients with baseline LSM ≥21kPa and delta-LSM ≥10% (risk of progression 47.1%, 95% CI: 23-71%) was identified, while patients with LSM <21kPa and delta-LSM <10% presented zero risk of progression (P=0.03). Simple classification rules using baseline LSM and delta-LSM identify cACLD patients at low or high risk of disease progression. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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

PubMed

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

2012-01-01

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

The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver.

PubMed

Yin, Chunyue; Evason, Kimberley J; Maher, Jacquelyn J; Stainier, Didier Y R

2012-11-01

Hepatic stellate cells (HSCs) are liver-specific mesenchymal cells that play vital roles in liver development and injury. Our knowledge of HSC biology is limited by the paucity of in vivo data. HSCs and sinusoidal endothelial cells (SECs) reside in close proximity, and interactions between these two cell types are potentially critical for their development and function. Here, we introduce a transgenic zebrafish line, Tg(hand2:EGFP), that labels HSCs. We find that zebrafish HSCs share many similarities with their mammalian counterparts, including morphology, location, lipid storage, gene-expression profile, and increased proliferation and matrix production, in response to an acute hepatic insult. Using the Tg(hand2:EGFP) line, we conducted time-course analyses during development to reveal that HSCs invade the liver after SECs do. However, HSCs still enter the liver in mutants that lack most endothelial cells, including SECs, indicating that SECs are not required for HSC differentiation or their entry into the liver. In the absence of SECs, HSCs become abnormally associated with hepatic biliary cells, suggesting that SECs influence HSC localization during liver development. We analyzed factors that regulate HSC development and show that inhibition of vascular endothelial growth factor signaling significantly reduces the number of HSCs that enter the liver. We also performed a pilot chemical screen and identified two compounds that affect HSC numbers during development. Our work provides the first comprehensive description of HSC development in zebrafish and reveals the requirement of SECs in HSC localization. The Tg(hand2:EGFP) line represents a unique tool for in vivo analysis and molecular dissection of HSC behavior. Copyright © 2012 American Association for the Study of Liver Diseases.

New-onset diabetes mellitus after living-donor liver transplantation: association with graft synthetic function.

PubMed

Yagi, Shintaro; Kaido, Toshimi; Iida, Taku; Yoshizawa, Atsushi; Okajima, Hideaki; Uemoto, Shinji

2017-06-01

It is now known that post-transplant graft function after deceased-donor liver transplantation and living-donor liver transplantation (LDLT) differ; however, there is no report assessing the relationship between graft function and the development of new-onset diabetes mellitus after transplantation (NODAT). We conducted this study to identify the predictive risk factors for NODAT, including graft function after LDLT. The subjects of this study were 175 adult recipients who underwent LDLT at Kyoto University Hospital between 2006 and 2010, and survived for more than 3 months (median observation period, 1046 days). The 1-, 2-, and 3-year incidences of NODAT after LDLT were 26.1, 32.0, and 33.4%, respectively. Pre-transplant diabetes was associated with poor survival (p = 0.0048), whereas NODAT was not associated with patient survival. In the multivariate analysis, recipient age ≥40, a tacrolimus trough level ≥8 ng/mL 3 months after LDLT, and cholinesterase (ChE) <185 IU/L 3 months after LDLT were the independent risk factors for NODAT. Poor graft synthetic function 3 months after LDLT as well as older age of the recipient and a higher tacrolimus concentration were strongly associated with NODAT development after LDLT.

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.

The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep.

PubMed

Hogg, Kirsten; Wood, Charlotte; McNeilly, Alan S; Duncan, W Colin

2011-01-01

Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS). We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF) and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5) or testosterone propionate (TP; n = 9) twice weekly (100 mg; i.m) from d62-102 (gestation 147 days). In a novel treatment paradigm, a second cohort received a direct C (n = 4) or TP (20 mg; n = 7) fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05) and the histological presence of fatty liver (P<0.05) independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05), glucocorticoid receptor (GR; P<0.05), UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05) and IGF1 (P<0.01) expression were upregulated. The direct fetal intervention (C and TP) led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated in the fetal controls (P<0.05) and this was opposed by fetal TP (P<0.05). Hepatic estrogen receptor (ERα; P<0.05) and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05) were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.

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.

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.

Quality of life in patients with nonalcoholic fatty liver disease in combination with essential hypertension considering taste sensitivity to sodium chloride.

PubMed

Mashura, Hanna Y; Hanych, Taras M; Rishko, Alexander A

2016-01-01

Nonalcoholic fatty liver disease and hypertensive disease - is the most common combination of abnormalities that occur in people suffering from metabolic syndrome. Their combination not only causes concurrent damage of the liver and the heart, caused by common pathogenic beginning, and also mutually complicate the disease course of each other. The leading role in the development of nonalcoholic fatty liver disease belongs to abdominal obesity and insulin resistance, and is seen as a manifestation of liver disease in metabolic syndrome. Genetic predisposition, lifestyle, improper nutrition, including excessive use of sodium chloride, lead to excessive formation of visceral adipose tissue with development of abdominal obesity, which is a likely criterion of insulin resistance. The long course of nonalcoholic fatty liver disease in combination with essential hypertension in excessive consumption of sodium chloride may negatively affect their quality of life. The aim of the study is to find out the features of quality of life in patients with nonalcoholic fatty liver disease in combination with hypertensive disease with different taste sensitivity to sodium chloride. We have investigated the quality of life of 65 patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with different taste sensitivity to sodium chloride. Salt taste sensitivity threshold to sodium chloride is determined by the method of R. Henkin. Assessment of quality of life was performed using the Ukrainian version of the questionnaire Medical Outcomes Study Short Form 36 (MO S SF-36). Was revealed that in patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with high salt taste sensitivity threshold observed the decline in the quality of life that manifests as a decline in physical condition (especially of the physical functioning, physical role functioning and general health perceptions) and mental health (especially social functioning). Also the increased salt intake and salt appetite in patients with high salt taste sensitivity threshold were noted (p <0,05). Reducing the use of sodium chloride can be a preventive measure easier than a decrease in body weight, and one that will reduce the body weight, especially in people with nonalcoholic fatty liver disease in combination with hypertensive disease, can reduce the risk of complications and improve quality of life in patients.

The Origin of New-Onset Diabetes After Liver Transplantation: Liver, Islets, or Gut?

PubMed

Ling, Qi; Xu, Xiao; Wang, Baohong; Li, Lanjuan; Zheng, Shusen

2016-04-01

New-onset diabetes is a frequent complication after solid organ transplantation. Although a number of common factors are associated with the disease, including recipient age, body mass index, hepatitis C infection, and use of immunosuppressive drugs, new-onset diabetes after liver transplantation (NODALT) has the following unique aspects and thus needs to be considered its own entity. First, a liver graft becomes the patient's primary metabolic regulator after liver transplantation, but this would not be the case for kidney or other grafts. The metabolic states, as well as the genetics of the graft, play crucial roles in the development of NODALT. Second, dysfunction of the islets of Langerhans is common in cirrhotic patients and would be exacerbated by immunosuppressive agents, particularly calcineurin inhibitors. On the other hand, minimized immunosuppressive protocols have been widely advocated in liver transplantation because of liver tolerance (immune privilege). Third and last, through the "gut-liver axis," graft function is closely linked to gut microbiota, which is now considered an important metabolic organ and known to independently influence the host's metabolic homeostasis. Liver transplant recipients present with specific gut microbiota that may be prone to trigger metabolic disorders. In this review, we proposed 3 possible sites for the origin of NODALT, which are liver, islets, and gut, to help elucidate the underlying mechanism of NODALT.

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.

Primary Sclerosing Cholangitis (PSC)

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 ...

Type I Glycogen Storage 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 ...

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.

A novel thyroid function index associated with opposite therapeutic outcomes in advanced hepatocellular carcinoma patients receiving chemotherapy or sorafenib.

PubMed

Chu, Yu-De; Lin, Kwang-Huei; Huang, Ya-Hui; Lin, Chen-Chun; Hung, Chien-Fu; Yeh, Ta-Sen; Lee, Wei-Chen; Yeh, Chau-Ting

2018-05-21

A sustained proportion of advanced hepatocellular carcinoma (HCC) patients worldwide received either chemotherapy or sorafenib. However, to date, effective and convenient biomarkers to predict their therapeutic outcomes remained elusive. Hypothyroidism was associated with favorable anticancer treatment outcomes in several advanced cancers. Here, we aimed to investigate the potential of using thyroid-stimulating hormone (TSH) and free T4 (FT4) levels as biomarkers to predict clinical outcomes in HCC patients receiving chemotherapy or sorafenib. Total 123 advanced HCC patients at Barcelona Clinical Liver Cancer Stage C were included. They were separated into two cohorts, one treated by sorafenib (n = 62) and the other by chemotherapy (n = 61). Clinical data including TSH and FT4 were retrieved and correlated with treatment outcomes. Because of restriction in local insurance policy, the baseline liver function reserve was better in patients receiving sorafenib. Therefore, the two cohorts were analyzed separately. The results showed that a higher (> median) TSH × FT4 value was independently associated with favorable time-to-tumor progression (P = 0.006) and overall survival (P = 0.002) if chemotherapy was provided; whereas it was associated with unfavorable time-to-tumor progression (P = 0.017) and overall survival (P = 0.001) if sorafenib was administrated. These opposite associations remained valid when patients with Child-Pugh class A liver function from either cohort were included for analysis. A novel thyroid function index, TSH × FT4, significantly predicted opposite clinical outcomes in advanced HCC patients receiving sorafenib or chemotherapy treatment. © 2018 John Wiley & Sons Australia, Ltd.

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.

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.

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.

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.

A practice-changing culture method relying on shaking substantially increases mitochondrial energy metabolism and functionality of human liver cell lines.

PubMed

Adam, Aziza A A; van der Mark, Vincent A; Donkers, Joanne M; Wildenberg, Manon E; Oude Elferink, Ronald P J; Chamuleau, Robert A F M; Hoekstra, Ruurdtje

2018-01-01

Practice-changing culturing techniques of hepatocytes are highly required to increase their differentiation. Previously, we found that human liver cell lines HepaRG and C3A acquire higher functionality and increased mitochondrial biogenesis when cultured in the AMC-Bioartificial liver (BAL). Dynamic medium flow (DMF) is one of the major contributors to this stimulatory effect. Recently, we found that DMF-culturing by shaking of HepaRG monolayers resulted in higher mitochondrial biogenesis. Here we further investigated the effect of DMF-culturing on energy metabolism and hepatic functionality of HepaRG and C3A monolayers. HepaRG and C3A DMF-monolayers were incubated with orbital shaking at 60 rpm during the differentiation phase, while control monolayers were maintained statically. Subsequently, energy metabolism and hepatic functionality were compared between static and DMF-cultures. DMF-culturing of HepaRG cells substantially increased hepatic differentiation; transcript levels of hepatic structural genes and hepatic transcription regulators were increased up to 15-fold (Cytochrome P450 3A4) and nuclear translocation of hepatic transcription factor CEBPα was stimulated. Accordingly, hepatic functions were positively affected, including ammonia elimination, urea production, bile acid production, and CYP3A4 activity. DMF-culturing shifted energy metabolism from aerobic glycolysis towards oxidative phosphorylation, as indicated by a decline in lactate production and glucose consumption, and an increase in oxygen consumption. Similarly, DMF-culturing increased mitochondrial energy metabolism and hepatic functionality of C3A cells. In conclusion, simple shaking of monolayer cultures substantially improves mitochondrial energy metabolism and hepatic differentiation of human liver cell lines. This practice-changing culture method may prove to prolong the in-vitro maintenance of primary hepatocytes and increase hepatic differentiation of stem cells.

Acute toxicity of functionalized single wall carbon nanotubes: A biochemical, histopathologic and proteomics approach.

PubMed

Ahmadi, Homa; Ramezani, Mohammad; Yazdian-Robati, Rezvan; Behnam, Behzad; Razavi Azarkhiavi, Kamal; Hashem Nia, Azadeh; Mokhtarzadeh, Ahad; Matbou Riahi, Maryam; Razavi, Bibi Marjan; Abnous, Khalil

2017-09-25

Recently carbon nanotubes (CNTs) showed promising potentials in different biomedical applications but their safe use in humans and probable toxicities are still challenging. The aim of this study was to determine the acute toxicity of functionalized single walled carbon nanotubes (SWCNTs). In this project, PEGylated and Tween functionalized SWCNTs were prepared. BALB/c mice were randomly divided into nine groups, including PEGylated SWCNTs (75,150μg/mouse) and PEG, Tween80 suspended SWCNTs, Tween 80 and a control group (intact mice). One or 7 days after intravenous injection, the mice were killed and serum and livers were collected. The oxidative stress markers, biochemical and histopathological changes were studied. Subsequently, proteomics approach was used to investigate the alterations of protein expression profiles in the liver. Results showed that there were not any significant differences in malondealdehyde (MDA), glutathione (GSH) levels and biochemical enzymes (ALT and AST) between groups, while the histopathological observations of livers showed some injuries. The results of proteomics analysis revealed indolethylamine N-Methyltransferase (INMT), glycine N-Methyltransferase (GNMT), selenium binding protein (Selenbp), thioredoxin peroxidase (TPx), TNF receptor associated protein 1(Trap1), peroxiredoxin-6 (Prdx6), electron transport flavoprotein (Etf-α), regucalcin (Rgn) and ATP5b proteins were differentially expressed in functionalized SWCNTs groups. Western blot analyses confirmed that the changes in Prdx6 were consistent with 2-DE gel analysis. In summary, acute toxicological study on two functionalized SWCNTs did not show any significant toxicity at selected doses. Proteomics analysis also showed that following exposure to functionalized SWCNTs, the expression of some proteins with antioxidant activity and detoxifying properties were increased in liver tissue. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Marine collagen peptides protect against early alcoholic liver injury in rats.

PubMed

Lin, Bing; Zhang, Feng; Yu, Yongchao; Jiang, Qinghao; Zhang, Zhaofeng; Wang, Junbo; Li, Yong

2012-04-01

Marine collagen peptides (MCP) have been reported to exhibit antioxidative activity, which is the common property of numerous hepatoprotective agents. Previous studies have shown that MCP have biological functions including anti-hypertension, anti-ulcer, anti-skin ageing and extending the life span. However, its role in alcoholic liver injury remains unknown. The present study aimed to investigate the effects of MCP on early alcoholic liver injury in rats. Rats were administered with alcohol at a dose of 6 g/kg body weight intragastrically per d to induce early liver injury, which was then evaluated by serum markers and histopathological examination. Treatment with MCP could reverse the increased level of serum aminotransferase and reduce hepatic histological damage. In addition, MCP attenuated the alteration in serum superoxide dismutase and malondialdehyde levels. MCP also counteracted the increased levels of total cholesterol and TAG. However, no significant difference was observed in the contents of alcohol dehydrogenase both in liver and serum protein of rats. These findings suggest that MCP have a protective effect on early alcoholic liver injury in rats by their antioxidative activity and improving lipid metabolism.

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

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.

OY-TES-1 may regulate the malignant behavior of liver cancer via NANOG, CD9, CCND2 and CDCA3: a bioinformatic analysis combine with RNAi and oligonucleotide microarray.

PubMed

Hu, Qiping; Fu, Jun; Luo, Bin; Huang, Miao; Guo, Wenwen; Lin, Yongda; Xie, Xiaoxun; Xiao, Shaowen

2015-04-01

Given its tumor-specific expression, including liver cancer, OY-TES-1 is a potential molecular marker for the diagnosis and immunotherapy of liver cancers. However, investigations of the mechanisms and the role of OY-TES-1 in liver cancer are rare. In the present study, based on a comprehensive bioinformatic analysis combined with RNA interference (RNAi) and oligonucleotide microarray, we report for the first time that downregulation of OY-TES-1 resulted in significant changes in expression of NANOG, CD9, CCND2 and CDCA3 in the liver cancer cell line BEL-7404. NANOG, CD9, CCND2 and CDCA3 may be involved in cell proliferation, migration, invasion and apoptosis, yet also may be functionally related to each other and OY-TES-1. Among these molecules, we identified that NANOG, containing a Kazal-2 binding motif and homeobox, may be the most likely candidate protein interacting with OY-TES-1 in liver cancer. Thus, the present study may provide important information for further investigation of the roles of OY-TES-1 in liver cancer.

Hepatocellular carcinoma: Western and Eastern surgeons' points of view.

PubMed

Vibert, E; Ishizawa, T

2012-10-01

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Developed on a pathological liver in 90% of cases, theoretically liver transplantation (LT) is its best treatment because it cures both malignancy and cause of malignancy, the underlying pathological liver. Cadaveric donors are the main source of liver in Western countries as France and living donors are the rules in Eastern countries as Japan. Because organ shortage could impact choices in HCC treatments, it was interesting to compare a Western and Eastern surgeon's points of view about treatment of HCC to assess if the source of organs has modified therapeutic strategies. Hence, aim of this work was to compare points of view of two hepatobiliary and transplant surgeons specialized in the treatment of HCC in France and Japan concerning five keys points that are decisive to choose one of the two curative treatments in HCC on pathological liver: liver resection or LT. These questions included the definition of an oncological treatment of HCC, the assessment of liver function, the treatment of HCC recurrences, the incidence of pathological information on therapeutic strategy and potential future therapeutics strategies. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

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

PubMed

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

2017-06-01

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

Therapeutic effect 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.

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

PubMed

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

2018-04-04

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

Normothermic machine perfusion of donor livers without the need for human blood products

PubMed Central

Matton, Alix P. M.; Burlage, Laura C.; van Rijn, Rianne; de Vries, Yvonne; Karangwa, Shanice A.; Nijsten, Maarten W.; Gouw, Annette S. H.; Wiersema‐Buist, Janneke; Adelmeijer, Jelle; Westerkamp, Andrie C.; Lisman, Ton

2018-01-01

Normothermic machine perfusion (NMP) enables viability assessment of donor livers prior to transplantation. NMP is frequently performed by using human blood products including red blood cells (RBCs) and fresh frozen plasma (FFP). Our aim was to examine the efficacy of a novel machine perfusion solution based on polymerized bovine hemoglobin‐based oxygen carrier (HBOC)‐201. Twenty‐four livers declined for transplantation were transported by using static cold storage. Upon arrival, livers underwent NMP for 6 hours using pressure‐controlled portal and arterial perfusion. A total of 12 livers were perfused using a solution based on RBCs and FFPs (historical cohort), 6 livers with HBOC‐201 and FFPs, and another 6 livers with HBOC‐201 and gelofusine, a gelatin‐based colloid solution. Compared with RBC + FFP perfused livers, livers perfused with HBOC‐201 had significantly higher hepatic adenosine triphosphate content, cumulative bile production, and portal and arterial flows. Biliary secretion of bicarbonate, bilirubin, bile salts, and phospholipids was similar in all 3 groups. The alanine aminotransferase concentration in perfusate was lower in the HBOC‐201–perfused groups. In conclusion, NMP of human donor livers can be performed effectively using HBOC‐201 and gelofusine, eliminating the need for human blood products. Perfusing livers with HBOC‐201 is at least similar to perfusion with RBCs and FFP. Some of the biomarkers of liver function and injury even suggest a possible superiority of an HBOC‐201–based perfusion solution and opens a perspective for further optimization of machine perfusion techniques. Liver Transplantation 24 528–538 2018 AASLD. PMID:29281862

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

PubMed

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

2017-12-07

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

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.

Overexpression of Peroxiredoxin 4 Affects Intestinal Function in a Dietary Mouse Model of Nonalcoholic Fatty Liver Disease

PubMed Central

Noguchi, Hirotsugu; Mazaki, Yuichi; Kurahashi, Toshihiro; Izumi, Hiroto; Wang, Ke-Yong; Guo, Xin; Uramoto, Hidetaka; Kohno, Kimitoshi; Taniguchi, Hatsumi; Tanaka, Yoshiya; Fujii, Junichi; Sasaguri, Yasuyuki; Tanimoto, Akihide; Nakayama, Toshiyuki

2016-01-01

Background Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear. Methods & Results Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wild-type (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-α, but lower expression of microsomal triglyceride-transfer protein. Conclusion Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4. PMID:27035833

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.

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

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

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

Neuropsychological functioning in preschool-aged children undergoing evaluation for organ transplant.

PubMed

Antonini, Tanya N; Beer, Stacey S; Miloh, Tamir; Dreyer, William J; Caudle, Susan E

2017-02-01

The purpose of this study was to review the current literature on neuropsychological functioning in two groups of children requiring organ transplants (liver or heart) and present recent clinical data collected through the liver and cardiac transplantation programs at a large pediatric academic medical center. Data included in this study came from 18 patients who completed evaluations for heart transplant (n = 8) or liver transplant (n = 10) between the ages of 2 and 6 years (inclusive). Measures examining neurocognitive, emotional-behavioral, and adaptive functioning were collected as part of standard pre-transplant clinical neuropsychological evaluations. Within each organ group, mean scores were calculated and compared with normative population mean scores using one sample t-tests. In addition, non-parametric binomial tests were calculated to examine whether the proportion of individuals falling more than one standard deviation below the population mean was significantly greater in the patient groups than the normative population base rate of 16%. Patients in both groups performed below normative expectation in several neurocognitive and adaptive domains. However, neither group showed significant difficulties in behavioral or emotional regulation. Results from this study document cognitive delays in preschool-aged children undergoing evaluations for liver transplant or heart transplant, highlighting the importance of intervention and long-term monitoring of these two patient populations, as well as the need for neuropsychologist involvement with transplant teams.

Outbreak of carbon tetrachloride poisoning in a color printing factory related to the use of isopropyl alcohol and an air conditioning system in Taiwan.

PubMed

Deng, J F; Wang, J D; Shih, T S; Lan, F L

1987-01-01

Three workers from a color printing factory were admitted to community hospitals in 1985 with manifestations of acute hepatitis. One of the three had superimposed acute renal failure and pulmonary edema. An investigation was subsequently conducted at the plant to determine the etiology of the outbreak and the prevalence of liver disease among the remaining workers. Comprehensive medical evaluations were conducted, which included physical examinations, liver function tests, and serological screening for hepatitis. Seventeen of 25 workers from the plant had abnormal liver function tests 10 days after the outbreak, and a significant association was found between the presence of abnormal liver function tests and a history of recently having worked inside any of three rooms in which an interconnecting air conditioning system had been installed to cool the printing machines. After further investigation, it was determined that the incident occurred following inadvertent use of carbon tetrachloride to clean a pump in the printing machine. A simulation of the pump cleaning operation revealed ambient air levels of carbon tetrachloride of 300-500 ppm. Ultimately, it was concluded that the outbreak was in all likelihood due to the combined use of carbon tetrachloride and isopropyl alcohol in the cleaning operation. This outbreak underscores the importance of adopting appropriate industrial hygiene measures in a rapidly industrializing nation such as Taiwan.

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.

Amprenavir and ritonavir plasma concentrations in HIV-infected patients treated with fosamprenavir/ritonavir with various degrees of liver impairment.

PubMed

Seminari, Elena; De Bona, Anna; Gentilini, Gianluca; Galli, Laura; Schira, Giulia; Gianotti, Nicola; Uberti-Foppa, Caterina; Soldarini, Armando; Dorigatti, Fernanda; Lazzarin, Adriano; Castagna, Antonella

2007-10-01

The purpose of this study was to evaluate the steady-state pharmacokinetics of amprenavir and ritonavir in HIV-infected patients with different degrees of hepatic impairment. HIV-positive patients receiving fosamprenavir/ritonavir (700/100 mg twice daily) were included. Patients were classified into three groups: (i) chronic hepatitis; (ii) liver cirrhosis; (iii) normal liver function. Serial blood samples for steady-state amprenavir and ritonavir pharmacokinetics (>14 days on treatment) were collected in the fasting state before the morning dose (C(trough)) and then 1, 2, 3, 4, 6, 8, 10 and 12 h after drug intake. Amprenavir and ritonavir plasma concentrations were determined by HPLC. Twenty-one HIV-infected patients were included. Seven had chronic hepatitis, eight had liver cirrhosis and six patients were in the control group. Amprenavir AUC(0-12), AUC(0-infinity), C(max) and C(ss) were increased by 50% to 60% in the cirrhotic group when compared with controls, whereas CL/F was decreased by 40%. Patients with chronic hepatitis showed a significant increase in AUC(0-12), C(max) and C(ss) values when compared with controls. Ritonavir pharmacokinetics was different only in cirrhotic patients when compared with controls. Liver function parameters at weeks 4, 12 and 24 were not different from baseline in any of the groups. Overall, a significant correlation between amprenavir AUC(0-12) and total bilirubin values on the day of pharmacokinetic analysis was found (r = 0.64, P = 0.003). On the basis of these data and also of data available in the literature, it seems reasonable to adapt the dose of fosamprenavir and/or ritonavir exclusively in the presence of adverse events, possibly related to protease inhibitors (i.e. liver toxicity), in subjects with high drug plasma levels. Therapeutic drug monitoring is advised in the management of these patients.

Serum levels of advanced glycation end-products (AGEs) and the decoy soluble receptor for AGEs (sRAGE) can identify non-alcoholic fatty liver disease in age-, sex- and BMI-matched normo-glycemic adults.

PubMed

Palma-Duran, Susana A; Kontogianni, Meropi D; Vlassopoulos, Antonis; Zhao, Shudong; Margariti, Aikaterini; Georgoulis, Michael; Papatheodoridis, George; Combet, Emilie

2018-06-01

Non-alcoholic fatty liver disease (NAFLD) is a serious health problem affecting ~25% of the global population. While NAFLD pathogenesis is still unclear, multiple NAFLD parameters, including reduced insulin sensitivity, impaired glucose metabolism and increased oxidative stress are hypothesised to foster the formation of advanced glycation end-products (AGEs). Given the link of AGEs with end organ damage, there is scope to examine the role of the AGE/RAGE axis activation in liver injury and NAFLD. Age, sex and body mass index matched normo-glycemic NAFLD adults (n = 58) and healthy controls (n = 58) were enrolled in the study. AGEs were analysed by liquid chromatography-mass spectrometry (CML, CEL), fluorescence (pentosidine, AGE fluorescence), colorimetry (fructosamine) and ELISA (sRAGE). Their association with liver function, inflammation, fibrosis and stage of NAFLD was examined. Early and advanced glycation end-products, except N ε -carboxymethyl-L-lysine (CML), were 10-30% higher, sRAGE levels 1.7-fold lower, and glycation/sRAGE ratios 4-fold higher in the NAFLD cases compared to controls. While AGEs presented weak to moderate correlations with indices of liver function and damage (AST/ALT, HOMA-IR, TNF-α and TGF-β1), including sRAGE to characterize the AGEs/sRAGE axis strengthened the associations observed. High glycation/sRAGE ratios were associated with 1.3 to 14-fold likelihood of lower AST/ALT ratios. The sum of AGEs/sRAGE ratios accurately distinguished between healthy controls and NAFLD patients (area under the curve of 0.85). Elevated AGEs/sRAGE (>7.8 mmol/pmol) was associated with a 12-fold likelihood of the presence of NAFLD. These findings strengthen the involvement of AGEs-RAGE axis in liver injury and the pathogenesis of NAFLD. Copyright © 2018 Elsevier Inc. All rights reserved.

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

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.

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

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.

Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease.

PubMed

Wieland, A; Frank, D N; Harnke, B; Bambha, K

2015-11-01

The human intestinal microbiota is a key regulator of host metabolic and immune functions and alterations in the microbiome ('dysbiosis') have been implicated in several human diseases. Because of the anatomical links between the intestines and the liver, dysbiosis may also disrupt hepatic function and thereby contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). To perform a comprehensive review of the medical literature investigating associations between intestinal dysbiosis and NAFLD, with a particular emphasis on studies that characterise the microbiome in NAFLD. We conducted a search of PubMed, Embase, and Web of Science using multiple search terms including: 'NAFLD, NASH, fatty liver, steatohepatitis' combined with 'metagenome, microbiom*, microbiota*, fecal flora, intestinal flora, gut bacteria'. Results were manually reviewed and studies selected based on relevance to intestinal microbiota and NAFLD. We also included studies that addressed potential mechanistic models of pathways linking the dysbiosis to NAFLD. Nine studies (five human and four animal models) were identified in our search that assessed associations between specific intestinal microbiota composition and NAFLD. We reviewed and summarised the results of additional investigations that more broadly addressed the mechanisms by which the microbiome may impact NAFLD pathogenesis. Investigations in humans and animals demonstrate associations between intestinal dysbiosis and NAFLD; however, causality has not been proven and mechanistic links require further delineation. As the field of microbiome research matures in techniques and study design, more detailed insights into NAFLD pathogenesis and its associations with the intestinal microbiota will be elucidated. © 2015 John Wiley & Sons Ltd.

A large outbreak of Campylobacter jejuni infection in a university college caused by chicken liver pâté, Australia, 2013.

PubMed

Moffatt, C R M; Greig, A; Valcanis, M; Gao, W; Seemann, T; Howden, B P; Kirk, M D

2016-10-01

In October 2013, public health authorities were notified of a suspected outbreak of gastroenteritis in students and guests following a catered function at a university residential college. A retrospective cohort study was undertaken to examine whether foods served at the function caused illness. A total of 56 cases of gastroenteritis, including seven laboratory-confirmed cases of Campylobacter jejuni infection, were identified in 235 eligible respondents. Univariate analysis showed a significant association with a chicken liver pâté entrée [relative risk (RR) 3·64, 95% confidence interval (CI) 2·03-6·52, P < 0·001], which retained significance after adjustment for confounding via multivariable analysis (adjusted RR 2·80, 95% CI 1·26-6·19, P = 0·01). C. jejuni and C. coli were also isolated in chicken liver pâté recovered from the college's kitchen. Subsequent whole genome multilocus sequence typing (wgMLST) of clinical and food-derived C. jejuni isolates showed three genetically distinct sequence types (STs) comprising ST528, ST535 (both clinically derived) and ST991 (food derived). The study demonstrates the value of utilizing complementary sources of evidence, including genomic data, to support public health investigations. The use of wgMLST highlights the potential for significant C. jejuni diversity in epidemiologically related human and food isolates recovered during outbreaks linked to poultry liver.

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.

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

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

Xu, Wenxuan; Lu, Chunfeng; Yao, Lu

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

Liver-inherent immune system: its role in blood-stage malaria

PubMed Central

Wunderlich, Frank; Al-Quraishy, Saleh; Dkhil, Mohamed A.

2014-01-01

The liver is well known as that organ which is obligately required for the intrahepatocyte development of the pre-erythrocytic stages of the malaria-causative agent Plasmodium. However, largely neglected is the fact that the liver is also a central player of the host defense against the morbidity- and mortality-causing blood stages of the malaria parasites. Indeed, the liver is equipped with a unique immune system that acts locally, however, with systemic impact. Its main “antipodal” functions are to recognize and to generate effective immunoreactivity against pathogens on the one hand, and to generate tolerance to avoid immunoreactivity with “self” and harmless substances as dietary compounds on the other hand. This review provides an introductory survey of the liver-inherent immune system: its pathogen recognition receptors including Toll-like receptors (TLRs) and its major cell constituents with their different facilities to fight and eliminate pathogens. Then, evidence is presented that the liver is also an essential organ to overcome blood-stage malaria. Finally, we discuss effector responses of the liver-inherent immune system directed against blood-stage malaria: activation of TLRs, acute phase response, phagocytic activity, cytokine-mediated pro- and anti-inflammatory responses, generation of “protective” autoimmunity by extrathymic T cells and B-1 cells, and T cell-mediated repair of liver injuries mainly produced by malaria-induced overreactions of the liver-inherent immune system. PMID:25408684

Conversion From Sirolimus to Everolimus in Long-Term Liver Graft Recipients.

PubMed

Weiler, Nina; Bilge, Nigar; Troetschler, Sven; Vermehren, Johannes; Schnitzbauer, Andreas Anton; Herrmann, Eva; Sarrazin, Christoph; Zeuzem, Stefan; Welker, Martin-Walter

2017-07-01

Immunosuppression by inhibition of the mechanistic target of rapamycin (mTOR) is a promising approach after liver transplantation. The mTOR inhibitor sirolimus was used in selected liver graft recipients despite safety concerns and lack of approval. Everolimus is another mTOR inhibitor approved after liver transplantation. It is currently unknown, whether conversion of sirolimus to everolimus is safe in long-term liver graft recipients. Long-term liver graft recipients treated with sirolimus were converted to everolimus. A systematical analysis of biochemical and clinical data before and after conversion was performed. Sixteen patients were included (female/male, 8/8). Median (range) age at conversion was 66 years (49-78 years), and patients were converted at a median (range) of 10.1 years (4.0-22.3 years) after liver transplantation. In the majority of patients, no dose adjustment was needed after conversion. No rejection and no cytomegalovirus replication episodes were observed. Furthermore, no differences were found with respect to kidney function, diabetes mellitus, or blood pressure before and after conversion. Bilirubin serum concentration was lower, whereas aspartate aminotransaminase, alanine aminotransferase, and triglycerides serum concentrations were higher after conversion to everolimus. Neither clinical- nor graft-associated significant complications were observed after conversion from sirolimus to everolimus in long-term liver graft recipients. Everolimus-based immunosuppression may be offered to patients after liver transplantation formerly treated with sirolimus. © 2017, The American College of Clinical Pharmacology.

The prognostic value of acute-on-chronic liver failure during the course of severe alcoholic hepatitis.

PubMed

Sersté, Thomas; Cornillie, Alexia; Njimi, Hassane; Pavesi, Marco; Arroyo, Vicente; Putignano, Antonella; Weichselbaum, Laura; Deltenre, Pierre; Degré, Delphine; Trépo, Eric; Moreno, Christophe; Gustot, Thierry

2018-03-08

A better identification of factors predicting death is needed in alcoholic hepatitis (AH). Acute-on-chronic liver failure (ACLF) occurs during the course of liver disease and can be identified when AH is diagnosed (prevalent ACLF [pACLF]) or during follow-up (incidental ACLF [iACLF]). This study analyzed the impact of ACLF on outcomes in AH and the role of infection on the onset of ACLF and death. Patients admitted from July 2006 to July 2015 suffering from biopsy-proven severe (s)AH with a Maddrey discriminant function (mDF) ≥32 were included. Infectious episodes, ACLF, and mortality were assessed during a 168-day follow-up period. Results were validated on an independent cohort. One hundred sixty-five patients were included. Mean mDF was 66.3 ± 20.7 and mean model for end-stage liver disease score was 26.8 ± 7.4. The 28-day cumulative incidence of death (CID) was 31% (95% CI 24-39%). Seventy-nine patients (47.9%) had pACLF. The 28-day CID without pACLF and with pACLF-1, pACLF-2, and pACLF-3 were 10.4% (95% CI 5.1-18.0), 30.8% (95% CI 14.3-49.0), 58.3% (95% CI 35.6-75.5), and 72.4% (95% CI 51.3-85.5), respectively, p <0.0001. Twenty-nine patients (17.5%) developed iACLF. The 28-day relative risk of death in patients developing iACLF was 41.87 (95% CI 5.2-335.1; p <0.001). A previous infection was the only independent risk factor for developing iACLF during the follow-up. Prevalence, incidence, and impact on prognosis of ACLF were confirmed in a validation cohort of 97 patients with probable sAH. ACLF is frequent during the course of sAH and is associated with high mortality. Infection strongly predicts the development of ACLF in this setting. In patients with chronic liver disease, an acute deterioration of liver function combined with single or multiple organ failures is known as acute-on-chronic liver failure. This study shows that acute-on-chronic liver failure is frequent during the course of severe alcoholic hepatitis. In severe alcoholic hepatitis, acute-on-chronic liver failure is associated with high mortality and frequently occurs after an infection. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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.

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.

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.

Prolactin receptor, growth hormone receptor, and putative somatolactin receptor in Mozambique tilapia: tissue specific expression and differential regulation by salinity and fasting.

PubMed

Pierce, A L; Fox, B K; Davis, L K; Visitacion, N; Kitahashi, T; Hirano, T; Grau, E G

2007-01-01

In fish, pituitary growth hormone family peptide hormones (growth hormone, GH; prolactin, PRL; somatolactin, SL) regulate essential physiological functions including osmoregulation, growth, and metabolism. Teleost GH family hormones have both differential and overlapping effects, which are mediated by plasma membrane receptors. A PRL receptor (PRLR) and two putative GH receptors (GHR1 and GHR2) have been identified in several teleost species. Recent phylogenetic analyses and binding studies suggest that GHR1 is a receptor for SL. However, no studies have compared the tissue distribution and physiological regulation of all three receptors. We sequenced GHR2 from the liver of the Mozambique tilapia (Oreochromis mossambicus), developed quantitative real-time PCR assays for the three receptors, and assessed their tissue distribution and regulation by salinity and fasting. PRLR was highly expressed in the gill, kidney, and intestine, consistent with the osmoregulatory functions of PRL. PRLR expression was very low in the liver. GHR2 was most highly expressed in the muscle, followed by heart, testis, and liver, consistent with this being a GH receptor with functions in growth and metabolism. GHR1 was most highly expressed in fat, liver, and muscle, suggesting a metabolic function. GHR1 expression was also high in skin, consistent with a function of SL in chromatophore regulation. These findings support the hypothesis that GHR1 is a receptor for SL. In a comparison of freshwater (FW)- and seawater (SW)-adapted tilapia, plasma PRL was strongly elevated in FW, whereas plasma GH was slightly elevated in SW. PRLR expression was reduced in the gill in SW, consistent with PRL's function in freshwater adaptation. GHR2 was elevated in the kidney in FW, and correlated negatively with plasma GH, whereas GHR1 was elevated in the gill in SW. Plasma IGF-I, but not GH, was reduced by 4 weeks of fasting. Transcript levels of GHR1 and GHR2 were elevated by fasting in the muscle. However, liver levels of GHR1 and GHR2 transcripts, and liver and muscle levels of IGF-I transcripts were unaffected by fasting. These results clearly indicate tissue specific expression and differential physiological regulation of GH family receptors in the tilapia.

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.

Overactivity of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus: Electrophysiological Findings in db/db Mice

PubMed Central

Gao, Hong; Molinas, Adrien J.R.; Qiao, Xin

2017-01-01

Preautonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus play a large role in the regulation of hepatic functions via the autonomic nervous system. Activation of hepatic sympathetic nerves increases glucose and lipid metabolism and contributes to the elevated hepatic glucose production observed in the type 2 diabetic condition. This augmented sympathetic output could originate from altered activity of liver-related PVN neurons. Remarkably, despite the importance of the brain-liver pathway, the cellular properties of liver-related neurons are not known. In this study, we provide the first evidence of overall activity of liver-related PVN neurons. Liver-related PVN neurons were identified with a retrograde, trans-synaptic, viral tracer in male lean and db/db mice and whole-cell patch-clamp recordings were conducted. In db/db mice, the majority of liver-related PVN neurons fired spontaneously; whereas, in lean mice the majority of liver-related PVN neurons were silent, indicating that liver-related PVN neurons are more active in db/db mice. Persistent, tonic inhibition was identified in liver-related PVN neurons; although, the magnitude of tonic inhibitory control was not different between lean and db/db mice. In addition, our study revealed that the transient receptor potential vanilloid type 1-dependent increase of excitatory neurotransmission was reduced in liver-related PVN neurons of db/db mice. These findings demonstrate plasticity of liver-related PVN neurons and a shift toward excitation in a diabetic mouse model. Our study suggests altered autonomic circuits at the level of the PVN, which can contribute to autonomic dysfunction and dysregulation of neural control of hepatic functions including glucose metabolism. SIGNIFICANCE STATEMENT A growing body of evidence suggests the importance of the autonomic control in the regulation of hepatic metabolism, which plays a major role in the development and progression of type 2 diabetes mellitus. Despite the importance of the brain-liver pathway, the overall activity of liver-related neurons in control and diabetic conditions is not known. This is a significant gap in knowledge, which prevents developing strategies to improve glucose homeostasis via altering the brain-liver pathway. One of the key findings of our study is the overall shift toward excitation in liver-related hypothalamic neurons in the diabetic condition. This overactivity may be one of the underlying mechanisms of elevated sympathetic activity known in metabolically compromised patients and animal models. PMID:29038244

Overactivity of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus: Electrophysiological Findings in db/db Mice.

PubMed

Gao, Hong; Molinas, Adrien J R; Miyata, Kayoko; Qiao, Xin; Zsombok, Andrea

2017-11-15

Preautonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus play a large role in the regulation of hepatic functions via the autonomic nervous system. Activation of hepatic sympathetic nerves increases glucose and lipid metabolism and contributes to the elevated hepatic glucose production observed in the type 2 diabetic condition. This augmented sympathetic output could originate from altered activity of liver-related PVN neurons. Remarkably, despite the importance of the brain-liver pathway, the cellular properties of liver-related neurons are not known. In this study, we provide the first evidence of overall activity of liver-related PVN neurons. Liver-related PVN neurons were identified with a retrograde, trans-synaptic, viral tracer in male lean and db/db mice and whole-cell patch-clamp recordings were conducted. In db/db mice, the majority of liver-related PVN neurons fired spontaneously; whereas, in lean mice the majority of liver-related PVN neurons were silent, indicating that liver-related PVN neurons are more active in db/db mice. Persistent, tonic inhibition was identified in liver-related PVN neurons; although, the magnitude of tonic inhibitory control was not different between lean and db/db mice. In addition, our study revealed that the transient receptor potential vanilloid type 1-dependent increase of excitatory neurotransmission was reduced in liver-related PVN neurons of db/db mice. These findings demonstrate plasticity of liver-related PVN neurons and a shift toward excitation in a diabetic mouse model. Our study suggests altered autonomic circuits at the level of the PVN, which can contribute to autonomic dysfunction and dysregulation of neural control of hepatic functions including glucose metabolism. SIGNIFICANCE STATEMENT A growing body of evidence suggests the importance of the autonomic control in the regulation of hepatic metabolism, which plays a major role in the development and progression of type 2 diabetes mellitus. Despite the importance of the brain-liver pathway, the overall activity of liver-related neurons in control and diabetic conditions is not known. This is a significant gap in knowledge, which prevents developing strategies to improve glucose homeostasis via altering the brain-liver pathway. One of the key findings of our study is the overall shift toward excitation in liver-related hypothalamic neurons in the diabetic condition. This overactivity may be one of the underlying mechanisms of elevated sympathetic activity known in metabolically compromised patients and animal models. Copyright © 2017 the authors 0270-6474/17/3711140-11$15.00/0.

Genetics Home Reference: Joubert syndrome

MedlinePlus

... sensing the physical environment and in chemical signaling. Primary cilia are important for the structure and function of many types of cells, including brain cells (neurons) and certain cells in the kidneys and liver. Primary cilia are also necessary for the perception ...

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

Potential use of metabolic breath tests to assess liver disease and prognosis: has the time arrived for routine use in the clinic?

PubMed

Stravitz, R Todd; Ilan, Yaron

2017-03-01

The progression of liver disease may be unique among organ system diseases in that progressive fibrosis compromises not only the sufficiency of hepatocyte mass but also impairs blood flow to the liver, resulting in porto-systemic shunting. Although liver biopsy as an assessment of fibrosis has become the key biomarker of and target for new therapies, it is invasive and subject to sampling error, and cannot quantify metabolic function or porto-systemic shunting. Measurement of the hepatic venous pressure gradient accommodates some of the deficiencies of biopsy but requires expertise not widely available and misses minor changes in hepatocellular mass and thereby information about metabolic function. Thus, an unmet need in clinical hepatology remains unfulfilled: a noninvasive biomarker which quantitates both the hepatocellular insufficiency and porto-systemic shunting inherent in progressive hepatic fibrosis. Ideally, such a biomarker should correlate with clinical endpoints including liver-related survival and cirrhotic complications, be performed at the point-of-care, and be affordable and easy to use. This review, an expert opinion, summarizes background and recent data suggesting that metabolic breath tests may now meet these requirements and have a valid place in clinical hepatology to supplant the time-honoured assessment of hepatic fibrosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Development of Stem Cell-Based Treatment for Liver Failure.

PubMed

Zhu, Tiantian; Li, Yuwen; Guo, Yusheng; Zhu, Chuanlong

2017-01-01

Liver failure is a devastating clinical syndrome with a persistently mortality rate despite advanced care. Orthotopic liver transplantation protected patients from hepatic failure. Yet, limitations including postoperative complications, high costs, and shortages of donor organs defect its application. The development of stem cell therapy complements the deficiencies of liver transplantation, due to the inherent ability of stem cells to proliferate and differentiate. Understand the source of stem cells, as well as the advantages and disadvantages of stem cell therapy. Based on published papers, we discussed the cell sources and therapeutic effect of stem cells. We also summarized the pros and cons, as well as optimization of stem cell-based treatment. Finally outlook future prospects of stem cell therapy. Stem cells may be harvested from a variety of human tissues, and then used to promote the convalescence of hepatocellular function. The emergence of the co-cultured system, tissueengineered technology and genetic modfication has further enhanced the functionality of stem cells. However, the tumorigenicity, the low survival rate and the scarcity of long-term treatment effect are obstacles for the further development of stem cell therapy. In this review, we highlight current research findings and present the future prospects in the area of stem cell-based treatment for liver failure. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

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.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

PubMed

Godoy, Patricio; Hewitt, Nicola J; Albrecht, Ute; Andersen, Melvin E; Ansari, Nariman; Bhattacharya, Sudin; Bode, Johannes Georg; Bolleyn, Jennifer; Borner, Christoph; Böttger, Jan; Braeuning, Albert; Budinsky, Robert A; Burkhardt, Britta; Cameron, Neil R; Camussi, Giovanni; Cho, Chong-Su; Choi, Yun-Jaie; Craig Rowlands, J; Dahmen, Uta; Damm, Georg; Dirsch, Olaf; Donato, María Teresa; Dong, Jian; Dooley, Steven; Drasdo, Dirk; Eakins, Rowena; Ferreira, Karine Sá; Fonsato, Valentina; Fraczek, Joanna; Gebhardt, Rolf; Gibson, Andrew; Glanemann, Matthias; Goldring, Chris E P; Gómez-Lechón, María José; Groothuis, Geny M M; Gustavsson, Lena; Guyot, Christelle; Hallifax, David; Hammad, Seddik; Hayward, Adam; Häussinger, Dieter; Hellerbrand, Claus; Hewitt, Philip; Hoehme, Stefan; Holzhütter, Hermann-Georg; Houston, J Brian; Hrach, Jens; Ito, Kiyomi; Jaeschke, Hartmut; Keitel, Verena; Kelm, Jens M; Kevin Park, B; Kordes, Claus; Kullak-Ublick, Gerd A; LeCluyse, Edward L; Lu, Peng; Luebke-Wheeler, Jennifer; Lutz, Anna; Maltman, Daniel J; Matz-Soja, Madlen; McMullen, Patrick; Merfort, Irmgard; Messner, Simon; Meyer, Christoph; Mwinyi, Jessica; Naisbitt, Dean J; Nussler, Andreas K; Olinga, Peter; Pampaloni, Francesco; Pi, Jingbo; Pluta, Linda; Przyborski, Stefan A; Ramachandran, Anup; Rogiers, Vera; Rowe, Cliff; Schelcher, Celine; Schmich, Kathrin; Schwarz, Michael; Singh, Bijay; Stelzer, Ernst H K; Stieger, Bruno; Stöber, Regina; Sugiyama, Yuichi; Tetta, Ciro; Thasler, Wolfgang E; Vanhaecke, Tamara; Vinken, Mathieu; Weiss, Thomas S; Widera, Agata; Woods, Courtney G; Xu, Jinghai James; Yarborough, Kathy M; Hengstler, Jan G

2013-08-01

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

Weighted gene co-expression network analysis of colorectal cancer liver metastasis genome sequencing data and screening of anti-metastasis drugs.

PubMed

Gao, Bo; Shao, Qin; Choudhry, Hani; Marcus, Victoria; Dong, Kung; Ragoussis, Jiannis; Gao, Zu-Hua

2016-09-01

Approximately 9% of cancer-related deaths are caused by colorectal cancer (CRC). CRC patients are prone to liver metastasis, which is the most important cause for the high CRC mortality rate. Understanding the molecular mechanism of CRC liver metastasis could help us to find novel targets for the effective treatment of this deadly disease. Using weighted gene co-expression network analysis on the sequencing data of CRC with and with metastasis, we identified 5 colorectal cancer liver metastasis related modules which were labeled as brown, blue, grey, yellow and turquoise. In the brown module, which represents the metastatic tumor in the liver, gene ontology (GO) analysis revealed functions including the G-protein coupled receptor protein signaling pathway, epithelial cell differentiation and cell surface receptor linked signal transduction. In the blue module, which represents the primary CRC that has metastasized, GO analysis showed that the genes were mainly enriched in GO terms including G-protein coupled receptor protein signaling pathway, cell surface receptor linked signal transduction, and negative regulation of cell differentiation. In the yellow and turquoise modules, which represent the primary non-metastatic CRC, 13 downregulated CRC liver metastasis-related candidate miRNAs were identified (e.g. hsa-miR-204, hsa-miR-455, etc.). Furthermore, analyzing the DrugBank database and mining the literature identified 25 and 12 candidate drugs that could potentially block the metastatic processes of the primary tumor and inhibit the progression of metastatic tumors in the liver, respectively. Data generated from this study not only furthers our understanding of the genetic alterations that drive the metastatic process, but also guides the development of molecular-targeted therapy of colorectal cancer liver metastasis.

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.

Liver irradiation causes distal bystander effects in the rat brain and affects animal behaviour.

PubMed

Kovalchuk, Anna; Mychasiuk, Richelle; Muhammad, Arif; Hossain, Shakhawat; Ilnytskyy, Slava; Ghose, Abhijit; Kirkby, Charles; Ghasroddashti, Esmaeel; Kovalchuk, Olga; Kolb, Bryan

2016-01-26

Radiation therapy can not only produce effects on targeted organs, but can also influence shielded bystander organs, such as the brain in targeted liver irradiation. The brain is sensitive to radiation exposure, and irradiation causes significant neuro-cognitive deficits, including deficits in attention, concentration, memory, and executive and visuospatial functions. The mechanisms of their occurrence are not understood, although they may be related to the bystander effects.We analyzed the induction, mechanisms, and behavioural repercussions of bystander effects in the brain upon liver irradiation in a well-established rat model.Here, we show for the first time that bystander effects occur in the prefrontal cortex and hippocampus regions upon liver irradiation, where they manifest as altered gene expression and somewhat increased levels of γH2AX. We also report that bystander effects in the brain are associated with neuroanatomical and behavioural changes, and are more pronounced in females than in males.

Acute hepatic decompensation precipitated by pregnancy-related catabolic stress: a rare mimic of acute liver failure.

PubMed

Sinclair, Marie; Ket, Shara; Testro, Adam; Gow, Paul J; Angus, Peter W

2014-02-01

Abnormal liver function tests are common in pregnancy; however, liver failure is rare. Pregnancy is a catabolic state that can precipitate illness in patients with underlying metabolic disorders. A 19-year-old woman presented at 14 weeks of gestation with an alanine transaminase of 2,252 international units/L (less than 30), an international normalized ratio of 6.9 (0.9-1.2), and an ammonia of 58 micromole/L (11-51 micromole/L). No cause was identified on routine investigations including liver biopsy. Biochemical and clinical deterioration prompted investigation for a metabolic disorder. Urinary orotic acid was elevated, consistent with the urea cycle disorder type 1 citrullinemia. Appropriate management (arginine supplementation and dietary protein restriction) led to rapid improvement and later delivery of a healthy neonate. This is an unusual presentation that reminds us of the importance of considering metabolic disorders during the catabolic stress of pregnancy.

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.

Predictors of Liver Toxicity Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

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

Velec, Michael; Haddad, Carol R.; Craig, Tim

Purpose: To identify risk factors associated with a decline in liver function after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma. Methods and Materials: Data were analyzed from patients with hepatocellular carcinoma treated on clinical trials of 6-fraction SBRT. Liver toxicity was defined as an increase in Child-Pugh (CP) score ≥2 three months after SBRT. Clinical factors, SBRT details, and liver dose-volume histogram (DVH) parameters were tested for association with toxicity using logistic regression. CP class B patients were analyzed separately. Results: Among CP class A patients, 101 were evaluable, with a baseline score of A5 (72%) or A6 (28%).more » Fifty-three percent had portal vein thrombus. The median liver volume was 1286 cc (range, 766-3967 cc), and the median prescribed dose was 36 Gy (range, 27-54 Gy). Toxicity was seen in 26 patients (26%). Thrombus, baseline CP of A6, and lower platelet count were associated with toxicity on univariate analysis, as were several liver DVH-based parameters. Absolute and spared liver volumes were not significant. On multivariate analysis for CP class A patients, significant associations were found for baseline CP score of A6 (odds ratio [OR], 4.85), lower platelet count (OR, 0.90; median, 108 × 10{sup 9}/L vs 150 × 10{sup 9}/L), higher mean liver dose (OR, 1.33; median, 16.9 Gy vs 14.7 Gy), and higher dose to 800 cc of liver (OR, 1.11; median, 14.3 Gy vs 6.0 Gy). With 13 CP-B7 patients included or when dose to 800 cc of liver was replaced with other DVH parameters (eg, dose to 700 or 900 cc of liver) in the multivariate analysis, effective volume and portal vein thrombus were associated with an increased risk. Conclusions: Baseline CP scores and higher liver doses (eg, mean dose, effective volume, doses to 700-900 cc) were strongly associated with liver function decline 3 months after SBRT. A lower baseline platelet count and portal vein thrombus were also associated with an increased risk.« less

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.

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

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.

Liver Transplantation and Donor Body Mass Index >30: Use or Refuse?

PubMed

Andert, Anne; Becker, Niklas; Ulmer, Florian; Schöning, Wenzel; Hein, Marc; Rimek, Alexandra; Neumann, Ulf; Schmeding, Maximilian

2016-03-31

Organ shortage is a major problem in liver transplantation. The use of extended criteria donors has become the most important strategy for increasing the donor pool. However, the role of donor body mass index has not yet been thoroughly investigated. The aim of our study was to compare outcomes after liver transplantation in patients who received a liver from a donor with a BMI <30, 30-39, and ≥40, with special regard to the incidence of early allograft dysfunction (EAD) and primary non-function (PNF). One hundred and sixty-three patients who underwent liver transplantation at the University Hospital Aachen between June 2010 and January 2014 were included in this analysis. The outcome of liver transplantation was evaluated by the 30-day and 1-year patient and graft survival rates and the incidences of post-reperfusion syndrome (PRS), EAD, and PNF. The BMI 30-39 group had a higher incidence of EAD than the BMI <30 and BMI ≥40 groups. We observed 5 cases of PNF in the BMI <30 group. The incidence of acute renal failure was significantly higher in the BMI 30-39 and BMI ≥40 groups than in the BMI <30 group. Patient and graft survival did not differ significantly among the 3 groups. Based on the findings of this study, grafts from obese donors with a BMI >30 can be safely transplanted. Therefore, the donor pool can be enlarged to include such obese donors without a negative impact on the long-term patient outcome after liver transplantation.

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.

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.

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

Ethnicity and the diagnosis gap in liver disease: a population-based study.

PubMed

Alazawi, William; Mathur, Rohini; Abeysekera, Kushala; Hull, Sally; Boomla, Kambiz; Robson, John; Foster, Graham R

2014-11-01

Liver disease is a major cause of morbidity and mortality worldwide. Large numbers of liver function tests (LFTs) are performed in primary care, with abnormal liver biochemistry a common finding. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. Metabolic syndrome, common in people from South Asia, is an important risk factor for NAFLD. It is hypothesised that a large gap exists between numbers of patients with abnormal LFTs and those with recorded liver diagnoses, and that NAFLD is more common among adults of South Asian ethnic groups. A cross-sectional study of 690,683 adults in coterminous general practices in a region with high ethnic diversity. Data were extracted on LFTs, liver disease, and process of care measures from computerised primary care medical records. LFTs were performed on 218,032 patients, of whom 31 627 had elevated serum transaminases. The prevalence of abnormal LFTs was highest among individuals of Bangladeshi ethnicity. Of the patients with abnormal LFTs, 88.4% did not have a coded liver diagnosis. NAFLD was the most frequently recorded liver disease and was most common among Bangladeshi patients. In a multivariate analysis, independent risk factors for NAFLD included Bangladeshi ethnicity, diabetes, raised BMI, hypertension, and hypercholesterolaemia. Abnormal LFTs are common in the population, but are underinvestigated and often remain undiagnosed. Bangladeshi ethnicity is an important independent risk factor for NAFLD. © British Journal of General Practice 2014.

Discharge Disposition After Stroke in Patients With Liver Disease.

PubMed

Parikh, Neal S; Merkler, Alexander E; Schneider, Yecheskel; Navi, Babak B; Kamel, Hooman

2017-02-01

Liver disease is associated with both hemorrhagic and thrombotic processes, including an elevated risk of intracranial hemorrhage. We sought to assess the relationship between liver disease and outcomes after stroke, as measured by discharge disposition. Using administrative claims data, we identified a cohort of patients hospitalized with stroke in California, Florida, and New York from 2005 to 2013. The predictor variable was liver disease. All diagnoses were defined using validated diagnosis codes. Ordinal logistic regression was used to analyze the association between liver disease and worsening discharge disposition: home, nursing/rehabilitation facility, or death. Secondarily, multiple logistic regression was used to analyze the association between liver disease and in-hospital mortality. Models were adjusted for demographics, vascular risk factors, and comorbidities. We identified 121 428 patients with intracerebral hemorrhage and 703 918 with ischemic stroke. Liver disease was documented in 13 584 patients (1.7%). Liver disease was associated with worse discharge disposition after both intracerebral hemorrhage (global odds ratio, 1.28; 95% confidence interval, 1.19-1.38) and ischemic stroke (odds ratio, 1.23; 95% confidence interval, 1.17-1.29). Similarly, liver disease was associated with in-hospital death after both intracerebral hemorrhage (odds ratio, 1.33; 95% confidence interval, 1.23-1.44) and ischemic stroke (odds ratio, 1.60; 95% confidence interval, 1.51-1.71). Liver disease was associated with worse hospital discharge disposition and in-hospital mortality after stroke, suggesting worse functional outcomes. © 2016 American Heart Association, Inc.

Apoptosis and Necrosis in the Liver

PubMed Central

Guicciardi, Maria Eugenia; Malhi, Harmeet; Mott, Justin L.; Gores, Gregory J.

2013-01-01

Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of “programmed” necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article. PMID:23720337

Apoptosis and necrosis in the liver.

PubMed

Guicciardi, Maria Eugenia; Malhi, Harmeet; Mott, Justin L; Gores, Gregory J

2013-04-01

Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of "programmed" necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.

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

Effects of an Agaricus blazei aqueous extract pretreatment on paracetamol-induced brain and liver injury in rats.

PubMed

Soares, Andréia A; de Oliveira, Andrea L; Sá-Nakanishi, Anacharis B; Comar, Jurandir F; Rampazzo, Ana P S; Vicentini, Fernando A; Natali, Maria R M; Gomes da Costa, Sandra M; Bracht, Adelar; Peralta, Rosane M

2013-01-01

The action of an Agaricus blazei aqueous extract pretreatment on paracetamol injury in rats was examined not only in terms of the classical indicators (e.g., levels of hepatic enzymes in the plasma) but also in terms of functional and metabolic parameters (e.g., gluconeogenesis). Considering solely the classical indicators for tissue damage, the results can be regarded as an indication that the A. blazei extract is able to provide a reasonable degree of protection against the paracetamol injury in both the hepatic and brain tissues. The A. blazei pretreatment largely prevented the increased levels of hepatic enzymes in the plasma (ASP, ALT, LDH, and ALP) and practically normalized the TBARS levels in both liver and brain tissues. With respect to the functional and metabolic parameters of the liver, however, the extract provided little or no protection. This includes morphological signs of inflammation and the especially important functional parameter gluconeogenesis, which was impaired by paracetamol. Considering these results and the long list of extracts and substances that are said to have hepatoprotective effects, it would be useful to incorporate evaluations of functional parameters into the experimental protocols of studies aiming to attribute or refute effective hepatoprotective actions to natural products.

Effects of an Agaricus blazei Aqueous Extract Pretreatment on Paracetamol-Induced Brain and Liver Injury in Rats

PubMed Central

Soares, Andréia A.; de Oliveira, Andrea L.; Sá-Nakanishi, Anacharis B.; Comar, Jurandir F.; Rampazzo, Ana P. S.; Vicentini, Fernando A.; Natali, Maria R. M.; Gomes da Costa, Sandra M.; Peralta, Rosane M.

2013-01-01

The action of an Agaricus blazei aqueous extract pretreatment on paracetamol injury in rats was examined not only in terms of the classical indicators (e.g., levels of hepatic enzymes in the plasma) but also in terms of functional and metabolic parameters (e.g., gluconeogenesis). Considering solely the classical indicators for tissue damage, the results can be regarded as an indication that the A. blazei extract is able to provide a reasonable degree of protection against the paracetamol injury in both the hepatic and brain tissues. The A. blazei pretreatment largely prevented the increased levels of hepatic enzymes in the plasma (ASP, ALT, LDH, and ALP) and practically normalized the TBARS levels in both liver and brain tissues. With respect to the functional and metabolic parameters of the liver, however, the extract provided little or no protection. This includes morphological signs of inflammation and the especially important functional parameter gluconeogenesis, which was impaired by paracetamol. Considering these results and the long list of extracts and substances that are said to have hepatoprotective effects, it would be useful to incorporate evaluations of functional parameters into the experimental protocols of studies aiming to attribute or refute effective hepatoprotective actions to natural products. PMID:23984368

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

Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection.

PubMed

Fukuda, Yutaka; Momoi, Nobuo; Akaihata, Mitsuko; Nagasawa, Katsutoshi; Mitomo, Masaki; Aoyagi, Yoshimichi; Endoh, Kisei; Hosoya, Mitsuaki

2015-08-01

Chronic active Epstein-Barr virus (EBV) infection (CAEBV), characterized by persistent infectious mononucleosis-like symptoms, can lead to cardiovascular complications including coronary artery aneurysm or myocarditis. Here, we present the case of an 11-year-old boy with pulmonary arterial hypertension (PAH) and junctional ectopic tachycardia associated with CAEBV. The patient did not have any major symptoms attributed to CAEBV, such as fever, lymphadenopathy or splenomegaly when the PAH developed. Mild liver dysfunction was found at the first examination, and it persisted. Two years after the PAH symptoms appeared, CAEBV was evident, based on deteriorated liver function, hepatosplenomegaly, and coronary artery aneurysms. CAEBV should be considered as a cause of secondary PAH, particularly when liver dysfunction coexists. © 2015 Japan Pediatric Society.

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

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.

Early graft function and carboxyhemoglobin level in liver transplanted patients.

PubMed

Ali, Yasser; Negmi, H; Elmasry, N; Sadek, M; Riaz, A; Al Ouffi, H; Khalaf, H

2007-10-01

Heme-Oxygenase-1 catalyzes hemoglobin into bilirubin, iron, and carbon monoxide, a well known vasodilator. Heme-Oxygenase-1 expression and carbon monoxide production as measured by blood carboxyhemoglobin levels, increase in end stage liver disease patients. We hypothesized that there may be a correlation between carboxyhemoglobin level and early graft function in patients undergoing liver transplant surgeries. In a descriptive retrospective study, 39 patients who underwent liver transplantation between the year 2005 and 2006 at KFSH&RC, are included in the study. All patients received general anesthesia with isoflurane in 50% oxygen and air. Levels of oxyhemoglobin, carboxyhemoglobin and methemoglobin concentration in percentage were recorded at preoperative time, anhepatic phase, end of surgery, ICU admission and 24 hr after surgery. The level of lactic acid, prothrombin time (PT), partial thrombin time (PTT), serum total bilirubin and ammonia were also recorded at ICU admission and 24 hr after surgery. The numbers of blood units transfused were recorded. 39 patients were included in the study with 13/39 for living donor liver transplant (LDLT) compared to 26/39 patients scheduled for deceased donor liver transplant (DDLT). The mean age was 35.9 +/- 16.9 years while the mean body weight was 60.3 +/- 20.9 Kg. Female to male ratio was 21/18. The median packed red blood cell (PRBC) units was 4 (Rang 0-40). There was a significant increase in carboxyhemoglobin level during the anhepatic phase, end of surgery and on ICU admission compared with preoperative value (p<0.005). However, there was insignificant changes in methemoglobin level and significant decrease in oxyhemoglobin levels throughout the study period compared to the preoperative value (p<0.005). The changes in carboxyhemoglobin level on ICU admission and 24 hrs postoperatively were positively correlated with the changes in serum total bilirubin and prothrombin time (R = 0.35, 0.382, 0.325 and 0.31) respectively p<0.05) but not with the changes in serum lactic acid. The same strong correlation was found when analysing LDLT and DDLT patients separately between carboxyhemoglobin concentration and PT and total bilirubin while still the correlation with lactic acid was weak. There was no correlation between average perioperative carboxyhemoglobin concentration during different timing of measurements and average units of transfused blood (R = -0.02) p>0.05. The changes in carboxyhemoglobin level significantly correlate with the Changes in graft functions particularly prothrombin time and serum total bilirubin and may be used as an early, rapid and simple test for early evaluation of graft function.

Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis.

PubMed

Wehr, Alexander; Baeck, Christer; Heymann, Felix; Niemietz, Patricia Maria; Hammerich, Linda; Martin, Christian; Zimmermann, Henning W; Pack, Oliver; Gassler, Nikolaus; Hittatiya, Kanishka; Ludwig, Andreas; Luedde, Tom; Trautwein, Christian; Tacke, Frank

2013-05-15

Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6(+/gfp) and Cxcr6(gfp/gfp) mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6(-/-) mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6(-/-) mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.

Academic potential and cognitive functioning of long-term survivors after childhood liver transplantation.

PubMed

Ee, L C; Lloyd, O; Beale, K; Fawcett, J; Cleghorn, G J

2014-05-01

This cross-sectional study assessed intellect, cognition, academic function, behaviour, and emotional health of long-term survivors after childhood liver transplantation. Eligible children were >5 yr post-transplant, still attending school, and resident in Queensland. Hearing and neurocognitive testing were performed on 13 transplanted children and six siblings including two twin pairs where one was transplanted and the other not. Median age at testing was 13.08 (range 6.52-16.99) yr; time elapsed after transplant 10.89 (range 5.16-16.37) yr; and age at transplant 1.15 (range 0.38-10.00) yr. Mean full-scale IQ was 97 (81-117) for transplanted children and 105 (87-130) for siblings. No difficulties were identified in intellect, cognition, academic function, and memory and learning in transplanted children or their siblings, although both groups had reduced mathematical ability compared with normal. Transplanted patients had difficulties in executive functioning, particularly in self-regulation, planning and organization, problem-solving, and visual scanning. Thirty-one percent (4/13) of transplanted patients, and no siblings, scored in the clinical range for ADHD. Emotional difficulties were noted in transplanted patients but were not different from their siblings. Long-term liver transplant survivors exhibit difficulties in executive function and are more likely to have ADHD despite relatively intact intellect and cognition. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

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.

Donation after cardiac death liver transplantation: predictors of outcome.

PubMed

Mathur, A K; Heimbach, J; Steffick, D E; Sonnenday, C J; Goodrich, N P; Merion, R M

2010-11-01

We aimed to identify recipient, donor and transplant risk factors associated with graft failure and patient mortality following donation after cardiac death (DCD) liver transplantation. These estimates were derived from Scientific Registry of Transplant Recipients data from all US liver-only DCD recipients between September 1, 2001 and April 30, 2009 (n = 1567) and Cox regression techniques. Three years post-DCD liver transplant, 64.9% of recipients were alive with functioning grafts, 13.6% required retransplant and 21.6% died. Significant recipient factors predictive of graft failure included: age ≥ 55 years, male sex, African-American race, HCV positivity, metabolic liver disorder, transplant MELD ≥ 35, hospitalization at transplant and the need for life support at transplant (all, p ≤ 0.05). Donor characteristics included age ≥ 50 years and weight >100 kg (all, p ≤ 0.005). Each hour increase in cold ischemia time (CIT) was associated with 6% higher graft failure rate (HR 1.06, p < 0.001). Donor warm ischemia time ≥ 35 min significantly increased graft failure rates (HR 1.84, p = 0.002). Recipient predictors of mortality were age ≥ 55 years, hospitalization at transplant and retransplantation (all, p ≤ 0.006). Donor weight >100 kg and CIT also increased patient mortality (all, p ≤ 0.035). These findings are useful for transplant surgeons creating DCD liver acceptance protocols. ©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.

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.

Relation of Insulin Resistance and Liver Fibrosis Progression in Patients with Chronic Hepatitis C Virus Infection

PubMed Central

Mohamed, Hassan R; Abdel-Azziz, Mohamed Yaqoot; Zalata, Kkaled Refaat; Abdel-Razik, Ahmed M M

2009-01-01

Background: Hepatitis C virus (HCV) infection can predispose to the development of insulin resistance before diabetes occurs. Such a potential link is particularly cogent in light of recent data indicate that diabetes may be associated with increased hepatic fibrosis progression in patients with chronic HCV infection. The aim of the study is to determine the prevalence of insulin resistance in non diabetic patients with chronic hepatitis C and its relation to liver fibrosis. Methods: Thirty eight patients with chronic liver diseases. They subdivided into 2 groups; chronic hepatitis C (CHC) with elevated liver enzymes and CHC with normal liver enzymes. Age and sex matched 12 healthy subjects as control group. All subjects were subjected to Careful history and copmlete examination with stress upon symptoms and signs of chronic liver diseases. Investigations include liver function tests; viral markers (Anti HCV antibodies & PCR for HCV). Serum fasting glucose; serum fasting insulin; homeostasis model assessment (HOMA), liver biopsy and abdominal ultrasound. Results: No correlation between viral load and hepatic fibrosis in HCV infected patients. Liver fibrosis is considerably higher among HCV patients with elevated serum transaminase levels. Insulin resistance is present in HCV infected cases compared with control group and it is positively correlated with liver fibrosis. Conclusion: The present data support the hypothesis that insulin resistance may increase the rate of fibrosis progression in non diabetic patients with chronic HCV. Follow up of hyperinsulinemia by serial measurement of HOMA test in non diabetic HCV infected patients may be a biochemical indicator for progression of liver fibrosis. PMID:21475535

[The liver and the immune system].

PubMed

Jakab, Lajos

2015-07-26

The liver is known to be the metabolic centre of the organism and is under the control of the central nervous system. It has a peculiar tissue structure and its anatomic localisation defines it as part of the immune system having an individual role in the defence of the organism. The determinant of its particular tissue build-up is the sinusoid system. In addition to hepatocytes, one cell row "endothelium", stellate cells close to the external surface, Kupffer cells tightly to its inner surface, as well as dendritic cells and other cell types (T and B lymphocytes, natural killer and natural killer T-cells, mast cells, granulocytes) are present. The multitudes and variety of cells make it possible to carry out the tasks according to the assignment of the organism. The liver is a member of the immune system having immune cells largely in an activated state. Its principal tasks are the assurance of the peripheral immune tolerance of the organism with the help of the haemopoetic cells and transforming growth factor-β. The liver takes part in the determination of the manner of the non-specific immune response of the organism. In addition to acute phase reaction of the organism, the liver has a role in the adaptive/specific immune response. These functions include retardation of the T and B lymphocytes and the defence against harmful pathogens. With the collaboration of transforming growth factor-β, immunoglobulins and their subclasses are inhibited just as the response of the T lymphocytes. The only exception is the undisturbed immunoglobulin A production. Particularly important is the intensive participation of the liver in the acute phase reaction of the organism, which is organised and guided by the coordinated functions of the cortico-hypothalamo-hypophysis-adrenal axis. Beside cellular elements, hormones, adhesion molecules, chemokines and cytokines are also involved in the cooperation with the organs. Acute phase reactants play a central role in these processes. Until recently the α2-macroglobulin was not considered as an acute reactant of the organism, but it is now functionally included in the acute phase reaction presumably due to its close connection with the transforming growth factor-β. Transforming growth factor-β has extraordinarily important roles in all phases of inflammation and in the specific immune response. The peripheral immune tolerance of the organism involves tightly coupled regulation of proliferation, differentiation and survival of lymphocytes.

Morphometric analysis of primary graft non-function in liver transplantation.

PubMed

Vertemati, M; Sabatella, G; Minola, E; Gambacorta, M; Goffredi, M; Vizzotto, L

2005-04-01

Primary graft non-function (PNF) is a life-threatening condition that is thought to be the consequence of microcirculation injury. The aim of the present study was to assess, with a computerized morphometric model, the morphological changes at reperfusion in liver biopsy specimens from patients who developed PNF after liver transplantation. Biopsy specimens were obtained at maximum ischaemia and at the end of reperfusion. Morphology included many stereological parameters, such as volumes of all parenchymal components, surface density, size distribution and mean diameter of hepatocytes. Other variables examined were intensive care unit stay, degree of steatosis, serum liver function tests and ischaemic time. In the postoperative period, the PNF group showed elevated serum levels of alanine transferase, decreased daily rate of bile production and prothrombin activity. Blood lactates were significantly higher in the PNF group than in a control group. When comparing groups, the volumetric parameters related to hepatocytes and sinusoids and the surface densities of the hepatic cells showed an inverse relationship. At the end of reperfusion, in PNF group the volume fraction of hepatocyte cytoplasm was decreased; in contrast, the volume fraction of sinusoidal lumen was markedly increased. The cell profiles showed the same inverse trend: the surface density of the parenchymal border of hepatocytes was decreased in PNF when compared with the control group, while the surface density of the vascular border was increased. In the PNF group, the surface density of the sinusoidal bed was directly correlated with alanine transferase, daily rate of bile production, prothrombin activity and cold ischaemic time. The alterations in hepatic architecture, as demonstrated by morphometric analysis in liver transplant recipients that developed PNF, provide additional information that may represent useful viability markers of the graft to complement conventional histological analysis.

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

PubMed Central

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

2013-01-01

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

Non-invasive diagnosis of advanced fibrosis and cirrhosis

PubMed Central

Sharma, Suraj; Khalili, Korosh; Nguyen, Geoffrey Christopher

2014-01-01

Liver cirrhosis is a common and growing public health problem globally. The diagnosis of cirrhosis portends an increased risk of morbidity and mortality. Liver biopsy is considered the gold standard for diagnosis of cirrhosis and staging of fibrosis. However, despite its universal use, liver biopsy is an invasive and inaccurate gold standard with numerous drawbacks. In order to overcome the limitations of liver biopsy, a number of non-invasive techniques have been investigated for the assessment of cirrhosis. This review will focus on currently available non-invasive markers of cirrhosis. The evidence behind the use of these markers will be highlighted, along with an assessment of diagnostic accuracy and performance characteristics of each test. Non-invasive markers of cirrhosis can be radiologic or serum-based. Radiologic techniques based on ultrasound, magnetic resonance imaging and elastography have been used to assess liver fibrosis. Serum-based biomarkers of cirrhosis have also been developed. These are broadly classified into indirect and direct markers. Indirect biomarkers reflect liver function, which may decline with the onset of cirrhosis. Direct biomarkers, reflect extracellular matrix turnover, and include molecules involved in hepatic fibrogenesis. On the whole, radiologic and serum markers of fibrosis correlate well with biopsy scores, especially when excluding cirrhosis or excluding fibrosis. This feature is certainly clinically useful, and avoids liver biopsy in many cases. PMID:25492996

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.

Piggyback technique in adult orthotopic liver transplantation: an analysis of 1067 liver transplants at a single center

PubMed Central

Nakamura, Noboru; Vaidya, Anil; Levi, David M.; Kato, Tomoaki; Nery, Jose R.; Madariaga, Juan R.; Molina, Enrique; Ruiz, Phillip; Gyamfi, Anthony; Tzakis, Andreas G.

2006-01-01

Background. Orthotopic liver transplantation (OLT) in adult patients has traditionally been performed using conventional caval reconstruction technique (CV) with veno-venous bypass. Recently, the piggyback technique (PB) without veno-venous bypass has begun to be widely used. The aim of this study was to assess the effect of routine use of PB on OLTs in adult patients. Patients and methods. A retrospective analysis was undertaken of 1067 orthotopic cadaveric whole liver transplantations in adult patients treated between June 1994 and July 2001. PB was used as the routine procedure. Patient demographics, factors including cold ischemia time (CIT), warm ischemia time (WIT), operative time, transfusions, blood loss, and postoperative results were assessed. The effects of clinical factors on graft survival were assessed by univariate and multivariate analyses.In all, 918 transplantations (86%) were performed with PB. Blood transfusion, WIT, and usage of veno-venous bypass were less with PB. Seventy-five (8.3%) cases with PB had refractory ascites following OLT (p=NS). Five venous outflow stenosis cases (0.54%) with PB were noted (p=NS). The liver and renal function during the postoperative periods was similar. Overall 1-, 3-, and 5-year patient survival rates were 85%, 78%, and 72% with PB. Univariate analysis showed that cava reconstruction method, CIT, WIT, amount of transfusion, length of hospital stay, donor age, and tumor presence were significant factors influencing graft survival. Multivariate analysis further reinforced the fact that CIT, donor age, amount of transfusion, and hospital stay were prognostic factors for graft survival. Conclusions. PB can be performed safely in the majority of adult OLTs. Results of OLT with PB are as same as for CV. Liver function, renal function, morbidity, mortality, and patient and graft survival are similar to CV. However, amount of transfusion, WIT, and use of veno-venous bypass are less with PB. PMID:18333273

Effect of Dietary Vitamin A on Reproductive Performance and Immune Response of Broiler Breeders

PubMed Central

Guo, Yuming; Wang, Yongwei; Guo, Shuangshuang

2014-01-01

The effects of dietary vitamin A supplementation on reproductive performance, liver function, fat-soluble vitamin retention, and immune response were studied in laying broiler breeders. In the first phase of the experiment, 1,120 Ross-308 broiler breeder hens were fed a diet of corn and soybean meal supplemented with 5,000 to 35,000 IU/kg vitamin A (retinyl acetate) for 20 weeks. In the second phase, 384 Ross-308 broiler breeder hens were fed the same diet supplemented with 5,000 to 135,000 IU/kg vitamin A (retinyl acetate) for 24 weeks. The hens' reproductive performance, the concentrations of vitamins A and E in liver and egg yolk, liver function, mRNA expression of vitamin D receptor in duodenal mucosa, antibody titers against Newcastle disease virus vaccine, and T-cell proliferation responses were evaluated. Supplementation of vitamin A at levels up to and including 35,000 IU/kg did not affect reproductive performance and quadratically affected antibody titer to Newcastle disease virus vaccine (p<0.05). Dietary addition of vitamin A linearly increased vitamin A concentration in liver and yolk and linearly decreased α-, γ-, and total tocopherol concentration in yolk (p<0.01) and α-tocopherol in liver (p<0.05). Supplementation of vitamin A at doses of 45,000 IU/kg and above significantly decreased egg weight, yolk color, eggshell thickness and strength, and reproductive performance. Dietary vitamin A significantly increased mRNA expression of vitamin D receptor in duodenal mucosa (p<0.05), increased aspartate amino transferase activity, and decreased total bilirubin concentration in serum. Supplementation of vitamin A at 135,000 IU/kg decreased the proliferation of peripheral blood lymphocytes (p<0.05). Therefore, the maximum tolerable dose of vitamin A for broiler breeders appears to be 35,000 IU/kg, as excessive supplementation has been shown to impair liver function, reproductive performance, and immune response. PMID:25148198

Echocardiography and NAFLD (non-alcoholic fatty liver disease).

PubMed

Trovato, Francesca M; Martines, Giuseppe F; Catalano, Daniela; Musumeci, Giuseppe; Pirri, Clara; Trovato, Guglielmo M

2016-10-15

Non-alcoholic-fatty-liver-disease (NAFLD) is associated with atherosclerosis, increased cardiovascular risks and mortality. We investigated if, independently of insulin resistance, diet, physical activity and obesity, fatty liver involvement has any relationship with echocardiographic measurements in NAFLD. 660 NAFLD and 791 non-NAFLD subjects, referred to the same out-patients medical unit for lifestyle-nutritional prescription, were studied. Congestive heart failure, myocardial infarction, malignancies, diabetes mellitus, extreme obesity, underweight-bad-nourished subjects and renal insufficiency were exclusion criteria. Liver steatosis was assessed by Ultrasound-Bright-Liver-Score (BLS), left ventricular ejection fraction (LVEF), trans-mitral E/A doppler ratio (diastolic relaxation) and left ventricular myocardial mass (LVMM/m(2)) by echocardiography. Doppler Renal artery Resistive Index (RRI), insulin resistance (HOMA) and lifestyle profile were also included in the clinical assessment. LVMM/m(2) is significantly greater in NAFLD, 101.62±34.48 vs. 88.22±25.61, p<0.0001 both in men and in women. Ejection fraction is slightly smaller only in men with NAFLD; no significant difference was observed for the E/A ratio. BMI (30.42±5.49 vs. 24.87±3.81; p<0.0001) and HOMA (2.90±1.70 vs. 1.85±1.25; p: 0.0001) were significantly greater in NAFLD patients. By Multiple-Linear-Regression, NAFLD and unhealthy dietary profile are associated also in lean non-diabetic subjects with lower systolic function, independently of BMI, dietary profile, physical activity, RRI and insulin resistance. NAFLD may be a meaningful early clue suggestive of diminishing heart function, with similar determining factors. NAFLD is amenable to management and improvement by lifestyle change counseling, addressing a dual target: reducing fatty liver, which is easily monitored by ultrasound, and, independently, maintaining a normal heart function. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Fisetin inhibits liver cancer growth in a mouse model: Relation to dopamine receptor.

PubMed

Liu, Xiang-Feng; Long, Hai-Jiao; Miao, Xiong-Ying; Liu, Guo-Li; Yao, Hong-Liang

2017-07-01

Fisetin (3,3',4',7-tetrahydroxyflavone), a natural abundant flavonoid, is produced in different vegetables and fruits. Fisetin has been reported to relate to various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. Dopamine receptors (DRs) belonging to G protein‑coupled receptor family, are known as the target of ~50% of all modern medicinal drugs. DRs consist of various proteins, functioning as transduction of intracellular signals for extracellular stimuli. We found that fisetin performed as DR2 agonist to suppress liver cancer cells proliferation, migration and invasion. Caspase-3 signaling was activated to induce apoptosis for fisetin administration. Furthermore, TGF‑β1 was also inhibited in fisetin-treated liver cancer cells, reducing epithelial-mesenchymal transition (EMT). Additionally, fisetin downregulated VEGFR1, p-ERK1/2, p38 and pJNK, ameliorating liver cancer progression. In vivo, the orthotopically implanted tumors from mice were inhibited by fisetin adminisatration accompanied by prolonged survival rate and higher levels of dopamine. Together, the results indicated a novel therapeutic strategy to suppress liver cancer progression associated with DR2 regulation, indicating that dopamine might be of importance in liver cancer progression.

Fisetin inhibits liver cancer growth in a mouse model: Relation to dopamine receptor

PubMed Central

Liu, Xiang-Feng; Long, Hai-Jiao; Miao, Xiong-Ying; Liu, Guo-Li; Yao, Hong-Liang

2017-01-01

Fisetin (3,3′,4′,7-tetrahydroxyflavone), a natural abundant flavonoid, is produced in different vegetables and fruits. Fisetin has been reported to relate to various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. Dopamine receptors (DRs) belonging to G protein-coupled receptor family, are known as the target of ~50% of all modern medicinal drugs. DRs consist of various proteins, functioning as transduction of intracellular signals for extracellular stimuli. We found that fisetin performed as DR2 agonist to suppress liver cancer cells proliferation, migration and invasion. Caspase-3 signaling was activated to induce apoptosis for fisetin administration. Furthermore, TGF-β1 was also inhibited in fisetin-treated liver cancer cells, reducing epithelial-mesenchymal transition (EMT). Additionally, fisetin downregulated VEGFR1, p-ERK1/2, p38 and pJNK, ameliorating liver cancer progression. In vivo, the orthotopically implanted tumors from mice were inhibited by fisetin adminisatration accompanied by prolonged survival rate and higher levels of dopamine. Together, the results indicated a novel therapeutic strategy to suppress liver cancer progression associated with DR2 regulation, indicating that dopamine might be of importance in liver cancer progression. PMID:28560391

Update on liver transplants in Lebanon.

PubMed

Faraj, Walid; Haydar, Ali; Nounou, Ghina El; Naaj, Abdallah Abou El; Khoury, Ghattas; Jabbour, Samar; Khalife, Mohamed

2015-09-01

Objective-To review all liver transplants performed at the American University of Beirut Medical Center from 1998 to present. Materials and Methods-From 1998 to present, 21 liver transplants (15 into adults and 6 into children) were performed at the American University of Beirut Medical Center. Of the 21 transplants, 5 were living related liver transplants. Results-Patient survival was 76% at 1, 5, and 10 years. Five recipients died at a median of 9 (range, 1-56) days after transplant. Causes of death included 1 case of severe cellular rejection, 1 case of portal and hepatic artery thrombosis, 1 case of intraoperative cardiac arrest, and 2 cases of primary nonfunction. Two biliary complications and 2 major vascular complications also occurred. All 16 survivors are well, with normal findings on liver function tests at a median follow-up time of 93 (range, 10-185) months after transplant. Conclusions-Although our numbers are small, the 10-year survival rate is comparable to reported rates for other series around the world. Deceased organ donations must be encouraged so that we can perform more transplants. As a source of organs, living related liver transplant is important; however, it cannot replace deceased donation.

Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease.

PubMed

Targher, Giovanni; Byrne, Christopher D

2017-05-01

Non-alcoholic fatty liver disease (NAFLD) is caused by an accumulation of fat in the liver; the condition can progress over time to increase the risk of developing cirrhosis, end-stage liver disease and hepatocellular carcinoma. The prevalence of NAFLD is increasing rapidly owing to the global epidemics of obesity and type 2 diabetes mellitus (T2DM), and NAFLD has been predicted to become the most important indication for liver transplantation over the next decade. It is now increasingly clear that NAFLD not only affects the liver but can also increase the risk of developing extra-hepatic diseases, including T2DM, cardiovascular disease and chronic kidney disease (CKD), which have a considerable impact on health-care resources. Accumulating evidence indicates that NAFLD exacerbates insulin resistance, predisposes to atherogenic dyslipidaemia and releases a variety of proinflammatory factors, prothrombotic factors and profibrogenic molecules that can promote vascular and renal damage. Furthermore, communication or 'crosstalk' between affected organs or tissues in these diseases has the potential to further harm function and worsen patient outcomes, and increasing amounts of evidence point to a strong association between NAFLD and CKD. Whether a causal relationship between NAFLD and CKD exists remains to be definitively established.

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-01-01

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

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.

Liver enzymes and histology in obese patients with obstructive sleep apnea.

PubMed

Kallwitz, Eric R; Herdegen, James; Madura, James; Jakate, Shriram; Cotler, Scott J

2007-01-01

Recent studies have shown an association between obstructive sleep apnea (OSA) and elevated liver enzymes in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the current study was to compare biochemical and histologic findings in patients with NAFLD as a function of OSA status. Subjects consisted of 85 patients who had a sleep study followed by a liver biopsy performed at the time of obesity surgery. The diagnosis of OSA was based on an apnea hypopnea index of >/=15. Demographic and laboratory data were collected retrospectively. Liver biopsies were systematically evaluated for features of NAFLD including degree of steatosis, inflammation, and fibrosis. All but one patient had histologic evidence of NAFLD and 51% of the study population had OSA. A higher proportion of patients with OSA had elevated alanine aminotransferase levels (13/39) compared with those without OSA (3/34) (P=0.01). Only 19% of subjects had fibrosis on liver biopsy and still fewer (5%) had bridging fibrosis or cirrhosis. There was a trend toward a higher prevalence of OSA in patients with evidence of progressive liver disease, as indicated by inflammation plus fibrosis (11/15), compared with those with inflammation alone (22/48) (P=0.06). In obese patients with NAFLD, OSA was associated with elevated alanine aminotransferase levels and a trend toward histologic evidence of progressive liver disease.

Pretreatment with propylene glycol alginate sodium sulfate ameliorated concanavalin A-induced liver injury by regulating the PI3K/Akt pathway in mice.

PubMed

Xu, Shizan; Wu, Liwei; Zhang, Qinghui; Feng, Jiao; Li, Sainan; Li, Jingjing; Liu, Tong; Mo, Wenhui; Wang, Wenwen; Lu, Xiya; Yu, Qiang; Chen, Kan; Xia, Yujing; Lu, Jie; Xu, Ling; Zhou, Yingqun; Fan, Xiaoming; Guo, Chuanyong

2017-09-15

Propylene glycol alginate sodium sulfate (PSS), a sulfated polysaccharide possesses anti-inflammatory effects. Here, we investigated the effect of PSS on concanavalin A (Con A)-induced liver injury in mice and examined the underlying mechanisms. Balb/C mice were injected intravenously with Con A (25mg/kg) to generate a model of acute liver injury. PSS (25 or 50mg/kg) was injected intraperitoneally 1h before the Con A administration. The levels of serum liver enzymes, inflammatory cytokines, and other marker proteins were determined, and liver injury was assessed histopathologically 2, 8, and 24h after Con A injection. Pretreatment with PSS reduced the levels of serum liver enzymes, inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and attenuated histopathological damage in Con A-induced liver injury in mice. The effects of Con A were mediated by apoptosis and autophagy, as indicated by changes in protein and gene expression of related factors after Con A injection. PSS activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway and showed a protective function against apoptosis and autophagy. PSS ameliorated Con A-induced liver injury by downregulating inflammatory cytokines including TNF-α and IL-1β and regulating apoptosis and autophagy via the PI3K/Akt pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg.

PubMed

Arab, Juan P; Martin-Mateos, Rosa M; Shah, Vijay H

2018-02-01

The term gut-liver axis is used to highlight the close anatomical and functional relationship between the intestine and the liver. The intestine has a highly specialized epithelial membrane which regulates transport across the mucosa. Due to dysbiosis, impairment of the intestinal barrier and altered immunity status, bacterial products can reach the liver through the portal vein, where they are recognized by specific receptors, activate the immune system and lead to a proinflammatory response. Gut microbiota and bacterial translocation play an important role in the pathogenesis of chronic liver diseases, including alcoholic and non-alcoholic fatty liver disease, cirrhosis, and its complications, such as portal hypertension, spontaneous bacterial peritonitis and hepatic encephalopaty. The gut microbiota also plays a critical role as a modulator of bile acid metabolism which can also influence intestinal permeability and portal hypertension through the farnesoid-X receptor. On the other hand, cirrhosis and portal hypertension affect the microbiota and increase translocation, leading to a "chicken and egg" situation, where translocation increases portal pressure, and vice versa. A myriad of therapies targeting gut microbiota have been evaluated specifically in patients with chronic liver disease. Further studies targeting intestinal microbiota and its possible hemodynamic and metabolic effects are needed. This review summarizes the current knowledge about the role of gut microbiota in the pathogenesis of chronic liver diseases and portal hypertension.

Liver transplantation from a deceased donor with β-thalassemia intermedia is not contraindicated: A case report.

PubMed

Gumus, Ersin; Abbasoglu, Osman; Tanyel, Cahit; Gumruk, Fatma; Ozen, Hasan; Yuce, Aysel

2017-05-01

The use of extended criteria donors who might have previously been deemed unsuitable is an option to increase the organ supply for transplantation. This report presents a pediatric case of a successful liver transplantation from a donor with β-thalassemia intermedia. A patient, 6-year-old female, with a diagnosis of cryptogenic liver cirrhosis underwent deceased donor liver transplantation from a thalassemic donor. Extreme hyperferritinemia was detected shortly after transplantation. The most probable cause of hyperferritinemia was iron overload secondary to transplantation of a hemosiderotic liver. Hepatocellular injury due to acute graft rejection might have contributed to elevated ferritin levels by causing release of stored iron from the hemosiderotic liver graft. Iron chelation and phlebotomy therapies were started simultaneously in the early postoperative period to avoid iron-related organ toxicity and transplant failure. Follow-up with monthly phlebotomies after discharge yielded a favorable outcome with normal transplant functions. Thalassemia intermedia patients can be candidates of liver donors to decrease pretransplant waitlist mortality. After transplantation of a hemosiderotic liver, it is important to monitor the recipient in terms of iron overload and toxicity. Early attempts to lower iron burden including chelation therapy and/or phlebotomy should be considered to avoid organ toxicity and transplant failure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Role of transmethylation reactions in alcoholic liver disease

PubMed Central

Kharbanda, Kusum K

2007-01-01

Alcoholic liver disease is a major health care problem worldwide. Findings from many laboratories, including ours, have demonstrated that ethanol feeding impairs several of the many steps involved in methionine metabolism. Ethanol consumption predominantly results in a decrease in the hepatocyte level of S-adenosylmethionine and the increases in two toxic metabolites, homocysteine and S-adenosylhomocysteine. These changes, in turn, result in serious functional consequences which include decreases in essential methylation reactions via inhibition of various methyltransferases. Of particular interest to our laboratory is the inhibition of three important enzymes, phosphatidylethanolamine methyltransferase, isoprenylcysteine carboxyl methyltransferase and protein L-isoaspartate methyltransferase. Decreased activity of these enzymes results in increased fat deposition, increased apoptosis and increased accumulation of damaged proteins-all of which are hallmark features of alcoholic liver injury. Of all the therapeutic modalities available, betaine has been shown to be the safest, least expensive and most effective in attenuating ethanol-induced liver injury. Betaine, by virtue of aiding in the remethylation of homocysteine, removes both toxic metabolites (homocysteine and S-adenosylhomocysteine), restores S-adenosylmethionine level, and reverses steatosis, apoptosis and damaged proteins accumulation. In conclusion, betaine appears to be a promising therapeutic agent in relieving the methylation and other defects associated with alcoholic abuse. PMID:17854136

Deconvoluting hepatic processing of carbon nanotubes

NASA Astrophysics Data System (ADS)

Alidori, Simone; Bowman, Robert L.; Yarilin, Dmitry; Romin, Yevgeniy; Barlas, Afsar; Mulvey, J. Justin; Fujisawa, Sho; Xu, Ke; Ruggiero, Alessandro; Riabov, Vladimir; Thorek, Daniel L. J.; Ulmert, Hans David S.; Brea, Elliott J.; Behling, Katja; Kzhyshkowska, Julia; Manova-Todorova, Katia; Scheinberg, David A.; McDevitt, Michael R.

2016-07-01

Single-wall carbon nanotubes present unique opportunities for drug delivery, but have not advanced into the clinic. Differential nanotube accretion and clearance from critical organs have been observed, but the mechanism not fully elucidated. The liver has a complex cellular composition that regulates a range of metabolic functions and coincidently accumulates most particulate drugs. Here we provide the unexpected details of hepatic processing of covalently functionalized nanotubes including receptor-mediated endocytosis, cellular trafficking and biliary elimination. Ammonium-functionalized fibrillar nanocarbon is found to preferentially localize in the fenestrated sinusoidal endothelium of the liver but not resident macrophages. Stabilin receptors mediate the endocytic clearance of nanotubes. Biocompatibility is evidenced by the absence of cell death and no immune cell infiltration. Towards clinical application of this platform, nanotubes were evaluated for the first time in non-human primates. The pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans.

Cystathionine γ-Lyase Deficiency Exacerbates CCl4-Induced Acute Hepatitis and Fibrosis in the Mouse Liver.

PubMed

Ci, Lei; Yang, Xingyu; Gu, Xiaowen; Li, Qing; Guo, Yang; Zhou, Ziping; Zhang, Mengjie; Shi, Jiahao; Yang, Hua; Wang, Zhugang; Fei, Jian

2017-07-20

The present study examined the role of cystathionine γ-lyase (CSE) in carbon tetrachloride (CCl 4 )-induced liver damage. A CSE gene knock-out and luciferase gene knock-in (KI) mouse model was constructed to study the function of CSE and to trace its expression in living status. CCl 4 or lipopolysaccharide markedly downregulated CSE expression in the liver of mice. CSE-deficient mice showed increased serum alanine aminotransferase and aspartate aminotransferase levels, and liver damage after CCl 4 challenge, whereas albumin and endogenous hydrogen sulfide (H 2 S) levels decreased significantly. CSE knockout mice showed increased serum homocysteine levels, upregulation of inflammatory cytokines, and increased autophagy and IκB-α degradation in the liver in response to CCl 4 treatment. The increase in pro-inflammatory cytokines, including tumor necrosis factor-alpha in CSE-deficient mice after CCl 4 challenge, was accompanied by a significant increase in liver tissue hydroxyproline and α-smooth muscle actin and histopathologic changes in the liver. However, H 2 S donor pretreatment effectively attenuated most of these imbalances. Here, a CSE knock-out and luciferase KI mouse model was established for the first time to study the transcriptional regulation of CSE expression in real time in a non-invasive manner, providing information on the effects and potential mechanisms of CSE on CCl 4 -induced liver injury. CSE deficiency increases pro-inflammatory cytokines in the liver and exacerbates acute hepatitis and liver fibrosis by reducing H 2 S production from L-cysteine in the liver. The present data suggest the potential of an H 2 S donor for the treatment of liver diseases such as toxic hepatitis and fibrosis. Antioxid. Redox Signal. 27, 133-149.

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

PubMed

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

2017-10-01

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

Genetic and epigenetic changes in fibrosis-associated hepatocarcinogenesis in mice

PubMed Central

Chappell, Grace; Kutanzi, Kristy; Uehara, Takeki; Tryndyak, Volodymyr; Hong, Hue-Hua; Hoenerhoff, Mark; Beland, Frederick A.; Rusyn, Ivan; Pogribny, Igor P.

2014-01-01

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis-associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and non-tumor liver samples from B6C3F1 mice treated with N-nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl4; 0.2 ml/kg, 2 times/week ip starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. H-ras, Ctnnb1, and Hnf1α genes were not mutated in tumors in mice treated with DEN+CCl4. In contrast, the increased tumor incidence in mice treated with DEN+CCl4 was associated with marked epigenetic changes in liver tumors and non-tumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3), and promoter hypermethylation and functional down-regulation of Riz1, a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements (LINE) 1 and short interspersed nucleotide elements (SINE) B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer-related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis-associated liver cancer. PMID:24242335

Novel developmental biology-based protocol of embryonic stem cell differentiation to morphologically sound and functional yet immature hepatocytes.

PubMed

Bukong, Terence N; Lo, Tracie; Szabo, Gyongyi; Dolganiuc, Angela

2012-05-01

Liver diseases are common in the United States and often require liver transplantation; however, donated organs are limited and thus alternative sources for liver cells are in high demand. Embryonic stem cells (ESC) can provide a continuous and readily available source of liver cells. ESC differentiation to liver cells is yet to be fully understood and comprehensive differentiation protocols are yet to be defined. Here, we aimed to achieve human (h)ESC differentiation into mature hepatocytes using defined recombinant differentiation factors and metabolites. Embryonic stem cell H1 line was sub-cultured on feeder layer. We induced hESCs into endodermal differentiation succeeded by early/late hepatic specification and finally into hepatocyte maturation using step combinations of Activin A and fibroblast growth factor (FGF)-2 for 7 days; followed by FGF-4 and bone morphogenic protein 2 (BMP2) for 7 days, succeeded by FGF-10 + hepatocyte growth factor 4 + epidermal growth factor for 14 days. Specific inhibitors/stimulators were added sequentially throughout differentiation. Cells were analysed by PCR, flow cytometry, microscopy or functional assays. Our hESC differentiation protocol resulted in viable cells with hepatocyte shape and morphology. We observed gradual changes in cell transcriptome, including up-regulation of differentiation-promoting GATA4, GATA6, POU5F1 and HNF4 transcription factors, steady levels of stemness-promoting SOX-2 and low levels of Nanog, as defined by PCR. The hESC-derived hepatocytes expressed alpha-antitrypsin, CD81, cytokeratin 8 and low density lipoprotein (LDL) receptor. The levels of alpha-fetoprotein and proliferation marker Ki-67 in hESC-derived hepatocytes remained elevated. Unlike stem cells, the hESC-derived hepatocytes performed LDL uptake, produced albumin and alanine aminotransferase and had functional alcohol dehydrogenase. We report a novel protocol for hESC differentiation into morphological and functional yet immature hepatocytes as an alternative method for hepatocyte generation. © 2012 John Wiley & Sons A/S.

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.

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.

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.

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.

Preoperative galactose elimination capacity predicts complications and survival after hepatic resection.

PubMed

Redaelli, Claudio A; Dufour, Jean-François; Wagner, Markus; Schilling, Martin; Hüsler, Jürg; Krähenbühl, Lukas; Büchler, Markus W; Reichen, Jürg

2002-01-01

To analyze a single center's 6-year experience with 258 consecutive patients undergoing major hepatic resection for primary or secondary malignancy of the liver, and to examine the predictive value of preoperative liver function assessment. Despite the substantial improvements in diagnostic and surgical techniques that have made liver surgery a safer procedure, careful patient selection remains mandatory to achieve good results in patients with hepatic tumors. In this prospective study, 258 patients undergoing hepatic resection were enrolled: 111 for metastases, 78 for hepatocellular carcinoma (HCC), 21 for cholangiocellular carcinoma, and 48 for other primary hepatic tumors. One hundred fifty-eight patients underwent segment-oriented liver resection, including hemihepatectomies, and 100 had subsegmental resections. Thirty-two clinical and biochemical parameters were analyzed, including liver function assessment by the galactose elimination capacity (GEC) test, a measure of hepatic functional reserve, to predict postoperative (60-day) rates of death and complications and long-term survival. All variables were determined within 5 days before surgery. Data were subjected to univariate and multivariate analysis for two patient subgroups (HCC and non-HCC). The cutoffs for GEC in both groups were predefined. Long-term survival (>60 days) was subjected to Kaplan-Meier analysis and the Cox proportional hazard model. In the entire group of 258 patients, a GEC less than 6 mg/min/kg was the only preoperative biochemical parameter that predicted postoperative complications and death by univariate and stepwise regression analysis. A GEC of more than 6 mg/min/kg was also significantly associated with longer survival. This predictive value could also be shown in the subgroup of 180 patients with tumors other than HCC. In the subgroup of 78 patients with HCC, a GEC less than 4 mg/min/kg predicted postoperative complications and death by univariate and stepwise regression analysis. Further, a GEC of more than 4 mg/min/kg was also associated with longer survival. This prospective study establishes the preoperative determination of the hepatic reserve by GEC as a strong independent and valuable predictor for short- and long-term outcome in patients with primary and secondary hepatic tumors undergoing resection.