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Background: End-stage liver diseases (ESLDs) are a significant global health challenge due to their high prevalence and severe health impacts. Despite the severe outcomes associated with ESLDs, therapeutic options remain limited. Targeting the activation of hepatic stellate cells (HSCs), key drivers of extracellular matrix accumulation during liver injury presents a novel therapeutic approach. In ESLDs patients, branched-chain amino acids (BCAAs, leucine, isoleucine and valine) levels are decreased, and supplementation has been proposed to attenuate liver fibrosis and improve regeneration. However, their effects on HSCs require further investigation., Objective: To evaluate the efficacy of BCAAs and their metabolites, branched-chain α-keto acids (BCKAs), in modulating HSCs activation in human and rat models., Methods: Primary HSCs from rats and cirrhotic and non-cirrhotic human livers, were cultured and treated with BCAAs or BCKAs to assess their effects on both preventing (from day 1 of isolation) and reversing (from day 7 of isolation) HSCs activation., Results: In rat HSCs, leucine and BCKAs significantly reduced fibrotic markers and cell proliferation. In human HSCs, the metabolite of isoleucine decreased cell proliferation around 85% and increased the expression of branched-chain ketoacid dehydrogenase. The other metabolites also showed antifibrotic effects in HSCs from non-cirrhotic human livers., Conclusion: BCAAs and their respective metabolites inhibit HSC activation with species-specific responses. Further research is needed to understand how BCAAs influence liver fibrogenesis. BCKAs supplementation could be a strategic approach for managing ESLDs, considering the nutritional status and amino acid profiles of patients., (© 2024. The Author(s).)

To address the challenge of limited throughput with traditional toxicity testing, a newly developed high-throughput transcriptomics (HTT) platform, together with a 5-day in vivo rat model, offers an alternative approach to estimate chemical exposures and provide reasonable estimates of toxicological endpoints. This study contains an HTT analysis of 18 environmental chemicals with known liver toxicity. They were evaluated using male Sprague Dawley rats exposed to various concentrations daily for five consecutive days via oral gavage, with data collected on the sixth day. Here, we further explored the 5-day rat model to identify potential gene signatures that can differentiate between toxic and non-toxic liver responses and provide us with a potential histopathological endpoint of chemical exposure. We identified a distinct gene expression pattern that differentiated non-hepatotoxic compounds from hepatotoxic compounds in a dose-dependent manner, and an analysis of the significantly altered common genes indicated that toxic chemicals predominantly upregulated most of the genes and several pathways in amino acid and lipid metabolism. Finally, our liver injury module analysis revealed that several liver-toxic compounds showed similarities in the key injury phenotypes of cellular inflammation and proliferation, indicating potential molecular initiating processes that may lead to a specific end-stage liver disease.

Our purpose was to compare the efficacy of liver and splenic volumetry (LV and SV), extracellular volume (ECV) on dual-layer spectral-detector CT scoring systems for estimating liver fibrosis (LF) in 45 patients with pathologically staged LF. ECV measured on CT value (HU-ECV), iodine density (ID-ECV), atomic number (Zeff-ECV), and electron density (ED-ECV), LV or SV/body surface area (BSA), albumin bilirubin grade (ALBI), model for end-stage liver disease (MELD) score, aspartate aminotransferase platelet ratio index (APRI), and fibrosis index based on the four factors (FIB-4) were recorded. Transient elastography was measured in 22 patients, and compared to ECV. No correlation was found between transient elastography and all ECVs. Area under the curve (AUC) for estimating F4 on transient elastography was 0.885 (95% CI 0.745-1.000). ALBI was weakly associated with LF (p = 0.451), while MELD (p < 0.001), APRI (p = 0.010), and FIB-4 (p = 0.010) were significantly associated with LF. SV/BSA had a higher AUC than MELD, APRI, and FIB-4 for estimating F4 (AUC = 0.815, 95% CI 0.63-0.999), but MELD (AUC = 0.799, 95% CI 0.634-0.965), APRI (AUC = 0.722, 95% CI 0.561-0.883), and FIB-4 (AUC = 0.741, 95% CI 0.582-0.899) had higher AUCs than ALBI. SV/BSA significantly contributed to differentiation for estimating F4; odds ratio (OR) was 1.304-1.353 (Reader 1-2; R1-R2), whereas MELD significantly contributed to the differentiation between F0-2 and F3-4; OR was 1.528-1.509 (R1-R2). AUC for SV/BSA and MELD combined was 0.877 (95% CI 0.748-1.000). In conclusion, SV/BSA allows for a higher estimation of liver cirrhosis (F4). MELD is more suitable for assessing severe LF (≥ F3-4). The combination of SV/BSA and MELD had a higher AUC than SV/BSA alone for liver cirrhosis (F4)., (© 2023. The Author(s).)

Objectives: Milan criteria is the most commonly used criteria for patients with hepatocellular carcinoma awaiting liver transplant. The effects of locoregional therapy on downstaging or bridging before liver transplant on survival remain controversial. Considering that the tumor size may change with locoregional therapy and formalin fixation after explantation, we aimed to evaluate the effects of locoregional therapy on radiological and pathological Milan criteria and survival., Materials and Methods: Demographic data, etiology, preoperative alpha-fetoprotein value, Child-Pugh and Model for End-Stage Liver Disease-Na scores, status of being inside or outside of radiological Milan criteria, status of being inside or outside of Milan criteria in explant (pathological Milan criteria), and the locoregional therapy types and combinations were evaluated for their effects on inclusion in Milan criteria and survival., Results: During the study period, 396 patients underwent liver transplant at our center, with 97 because of cirrhosis and hepatocellular carcinoma. When we viewed patients according to preoperative radiologic evaluations, 67.9% were within Milan criteria and 32.1% were outside. When we viewed according to explant (pathological) evaluations, 80.7% of patients were within Milan criteria. Among 97 patients, 71 (73.2%) had locoregional therapy (22 [30.9%] for downstaging, 49 [69.0%] for bridging to transplant), and 12 patients (12.3%) were within Milan criteria on explant examination while outside of Milan criteria before LT. One-year, 3-year, and 5-year survival rates were 80.7%, 76.1%, and 71.6%, respectively., Conclusions: As a result of radiological evaluations, in patients who were outside of Milan criteria and underwent locoregional therapy, explant pathology within Milan criteria had a positive effect on survival; however, after locoregional therapy, there was no significant effect on survival in patients who were still outside of Milan criteria.

Objective: To determine the sensitivity of combining the model for end-stage liver disease (MELD) scoring with new inflammatory indexes in determining the priority for liver transplantation and demonstrating its potential usability in solid tumour visceral crisis., Study Design: Descriptive study. Place and Duration of the Study: Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkiye, from June 2017 to June 2022., Methodology:  Patients hospitalised in the medical oncology clinic for hepatic dysfunction were included. The MELD scores of these patients were calculated, and the predictive contribution of the systemic immune-inflammatory index (SII) to prognosis and mortality was evaluated., Results: A total of 295 patients (158 (53.6%) men and 137 (46.4%) women) were included. When compared for primary tumour types, colorectal cancers were the most common with 55 (18.6%) cases, followed by breast cancers at 52 (17.6%), pancreatic carcinoma at 50 (16.9%), and stomach cancers at 40 (13.6%) cases. In the survival analyses of all three MELD scores (MELD-Original, MELD-Na, and MELD 3.0) between <20 groups and ≥20 groups, the median Overall Survival (OS) for MELD-Original was 1.44 vs. 0.88 months (p<0.001), for MELD- Na it was 1.64 vs. 0.85 months (p<0.001), and for MELD 3.0 it was 2.16 vs. 1.28 months (p=0.039). In the ROC analysis, the SII parameter cut-off was ≥626.28 for the estimation of mortality, SII sensitivity was 78.7%, and specificity was 100% (p=0.013)., Conclusion: Combined use of MELD and SII scores in patients with solid tumours with hepatic visceral crises will be practical, cost-effective, and easy to access, eliminate gender-based disparities, and contribute to clinical follow-ups with objective data., Key Words: Malignant neoplasm, MELD score, MELD-Na, MELD 3.0, SII.

Liver transplantation offers live-saving therapy for patients with complications of cirrhosis and stage T2 hepatocellular carcinoma. The demand for organs far outstrips the supply, and innovations aimed at increasing the number of usable deceased donors as well as alternative donor sources are a major focus. The etiologies of cirrhosis are shifting over time, with more need for transplantation among patients with alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease and less for viral hepatitis, although hepatitis B remains an important indication for transplant in countries with high endemicity. The rise in transplantation for alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease has brought attention to how patients are selected for transplantation and the strategies needed to prevent recurrent disease. In this review, we present a status report on the most pressing topics in liver transplantation and future challenges., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Cirrhosis is a diffuse pathology characterized by fibrosis of the liver and is the last stage of chronic liver diseases. It is a serious medical condition which seriously impacts reproduction and reproductive life span. The aim of this study is to evaluate the outcomes of pregnancies complicated with liver cirrhosis., Methods: Retrospective chart review of the fetal and maternal results of 20 pregnant women with liver cirrhosis who had undergone antenatal follow-up and delivery at a tertiary center in a 12-year period was performed., Results: Chronic hepatitis B was found to be the leading cause of liver cirrhosis in the study group, with a rate of 25% (n: 5/20). The average MELD score was calculated as 8.8 ± 3.5. Only three patients developed hepatic decompensation during pregnancy. Fetal demise was observed in 10% of the cases (n: 2/20, MELD scores 8 and 17). MELD score was significantly higher in the patients with adverse perinatal outcomes., Conclusion: Even though pregnancy is rarely observed in women with liver cirrhosis, many patients are able to achieve favorable maternal and fetal results without developing hepatic decompensation with appropriate management and close follow-up. The Model for End-Stage Liver Disease (MELD) score is a clinical tool utilized to estimate the severity and survival for chronic liver disease and was previously found to be associated with unfavorable outcomes in pregnant patients. Our study confirms this finding with the current experience from a tertiary care center., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Childhood obesity is a global public health problem. Worldwide, 41 million children under 5 years and 340 million children and adolescents between 5 and 19 years are overweight. In addition, the recent COVID-19 epidemic has further amplified this social phenomenon. Obesity is a condition associated with various comorbidities, such as nonalcoholic fatty liver disease (NAFLD). The pathophysiology of NAFLD in obesity is intricate and involves the interaction and dysregulation of several mechanisms, such as insulin resistance, cytokine signaling, and alteration of the gut microbiota. NAFLD is defined as the presence of hepatic steatosis in more than 5% of hepatocytes, evaluated by histological analysis. It can evolve from hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and end-stage liver failure. Body weight reduction through lifestyle modification remains the first-line intervention for the management of pediatric NAFLD. Indeed, studies suggest that diets low in fat and sugar and conversely rich in dietary fibers promote the improvement of metabolic parameters. This review aims to evaluate the existing relationship between obesity and NAFLD in the pediatric population and to assess the dietary patterns and nutritional supplementations that can be recommended to prevent and manage obesity and its comorbidities.

Background: Polycystic liver disease (PLD) is characterized by the progressive development of polycystic lesions in the kidney and the liver, possibly resulting in dual organ failure. We indicated living donor liver transplantation (LDLT) for a patient with end-stage liver and kidney disease (ELKD) due to PLD on uncomplicated chronic hemodialysis., Case Presentation: A 63-year-old man with ELKD and uncontrolled massive ascites due to PLD and hepatitis B on uncomplicated chronic hemodialysis was referred to us with a single possible 47-year-old female living donor. Because of the necessity of right lobe liver procurement from this small middle-aged donor and uncomplicated hemodialysis on this recipient, we considered LDLT, rather than dual organ transplantation, could be the most well-balanced option to save the life of this recipient with acceptable risk limits for this donor. A right lobe graft with 0.91 for graft recipient weight ratio was implanted with an uneventful operative procedure under intra- and postoperative continuous hemodiafiltration. The recipient was rescheduled on routine hemodialysis on day 6 after transplantation and recovered with a gradual decrease in ascites output. He was discharged on day 56. He continues to have a very good liver function and quality of life without ascites and uncomplicated routine hemodialysis 1 year after transplantation. The living donor was discharged 3 weeks after surgery and is also doing well., Conclusion: Although combined liver-kidney transplantation from a deceased donor could be the best option for ELKD due to PLD, LDLT can also be an acceptable option for ELKD with uncomplicated hemodialysis, considering the double equipoise theory for both lifesaving of the recipient and acceptable donor risk., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that affects approximately one-quarter of the global adult population, posing a significant threat to human health with wide-ranging social and economic implications. The main characteristic of NAFLD is considered that the excessive fat is accumulated and deposited in hepatocytes without excess alcohol intake or some other pathological causes. NAFLD is a progressive disease, ranging from steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Therefore, NAFLD will probably emerge as the leading cause of end-stage liver disease in the coming decades. Unlike other highly prevalent diseases, NAFLD has received little attention from the global public health community. Liver biopsy is currently considered the gold standard for the diagnosis and staging of NAFLD because of the absence of noninvasive and specific biomarkers. Due to the complex pathophysiological mechanisms of NAFLD and the heterogeneity of the disease phenotype, no specific pharmacological therapies have been approved for NAFLD at present, although several drugs are in advanced stages of development. This review summarizes the current evidence on the pathogenesis, diagnosis and treatment of NAFLD.

Background: Subcutaneous and visceral adipose tissues are important body components, but their effects on the mortality in patients with liver cirrhosis remain controversial based on the current evidence., Methods: We retrospectively identified 372 eligible patients in whom subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI) could be measured by computed tomography images at the third lumbar vertebra. The association of SATI and VATI with the risk of death was evaluated on a continuous scale with restricted cubic spline curves based on Cox proportional hazards models. Cumulative probability of mortality was estimated by Nelson-Aalen cumulative risk curve analyses. Independent predictors of death were evaluated by competing risk analyses after adjusting for age, sex, and model for end-stage liver disease score., Results: Majority of patients were male (69.4%) with a mean age of 55.40 ± 10.68 years. SATI had a U-shaped association with mortality (P for non-linearity <0.001). Cutoff values of SATI were 19.7 and 51.8 cm 2 /m 2 at the points where hazard ratios were just <1.2. SATI was categorized as low (<19.7 cm 2 /m 2 ), moderate (19.7-51.8 cm 2 /m 2 ), and high (>51.8 cm 2 /m 2 ) level. There was no significant difference in the cumulative probability of mortality between low versus moderate SATI groups (Gray's test, P = 0.052) and high versus moderate SATI groups (Gray's test, P = 0.054). Competing risk analyses demonstrated that low SATI could increase the mortality compared with moderate SATI (subdistribution hazard ratio [sHR] = 1.66, 95% confidence interval [CI]: 0.992-2.78, P = 0.054) and was an independent predictor of death (sHR = 1.86, 95% CI: 1.059-3.28, P = 0.031). Competing risk analyses also demonstrated that high SATI could significantly increase the mortality compared with moderate SATI (sHR = 1.6, 95% CI: 1-2.54, P = 0.049), and was an independent predictor of death (sHR = 2.007, 95% CI: 1.195-3.37, P = 0.0085). VATI had an irregularly shaped association with mortality (P for non-linearity <0.001). Cutoff values of VATI were 9.8 and 40.2 cm 2 /m 2 at the points where hazard ratios were just <1.2. VATI was categorized as low (<9.8 cm 2 /m 2 ), moderate (9.8-40.2 cm 2 /m 2 ), and high (>40.2 cm 2 /m 2 ) level. There was no significant difference in the cumulative probability of mortality between low versus moderate VATI groups (Gray's test, P = 0.381) and high versus moderate VATI groups (Gray's test, P = 0.787). Competing risk analyses demonstrated that neither low (sHR = 1.27, 95% CI: 0.599-2.7, P = 0.53) nor high VATI (sHR = 0.848, 95% CI: 0.539-1.34, P = 0.48) was an independent predictor of death compared with moderate VATI., Conclusions: Both excessive deficiency and accumulation of subcutaneous adipose tissues negatively influence the outcomes of cirrhotic patients., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Objectives: Sarcopenia is an important metabolic disorder associated with end-stage liver disease and is an independent predictor of mortality in liver transplant candidates. We evaluated effects of pretransplant muscle mass, muscle quality, and visceral adipose tissue on mortality after liver transplant., Materials and Methods: For 2015-2020, we included 65 liver transplant recipients whose records contained pretransplant liver computed tomography images. We calculated skeletal muscle mass index (muscle tissue area in centimeters squared divided by height in meters squared), visceral-to-subcutaneous fat ratio (visceral adiposity indicator), and intramuscular adipose tissue content ratio (muscle quality indicator)., Results: Median age was 55 years (IQR, 45-63 years), and 48 (73.8%) patients were men. During follow-up, 53 (81.5%) study group patients survived; mean survival time was 71.73 ± 3.81 months. The deceased patient group had a statistically higher pretransplant visceral-to-subcutaneous fat ratio than the survival group (P = .046). Survival was 100% for 1 positive indicator, 86.2% for 2 positive indicators, and 70.4% for 3 positive indicators (P = .096). Positive correlation was confirmed between pretransplant skeletal muscle mass index and age (P = .043) and pretransplant body mass index (weight in kilograms divided by height in meters squared) (P < .001). There was a moderate positive correlation between pretransplant intramuscular adipose tissue content ratio and age (R = 0.529, P ≤ .001) and a weak positive correlation with pretransplant body mass index (R = 0.361, P = .003). Furthermore, pretransplant visceral- tosubcutaneous fat ratio showed a weak positive correlation with age (R = 0.306, P = .013) and a weak negative correlation with the Model for End-Stage Liver Disease score (R = -0.301, P = .016)., Conclusions: Pretransplant sarcopenia is an important indicator to predict mortality and morbidity in posttransplant follow-up. Visceral-to-subcutaneous fat ratio is an important parameter to evaluate sarcopenia in liver transplant patients.

Aim: To investigate predictors affecting survival in patients with spontaneously ruptured hepatocellular carcinoma (srHCC)., Methods: One-hundred-and-twenty-seven patients experiencing srHCC between January 2010 and December 2020 were enrolled. The clinical features, treatments, and outcomes were reviewed. Statistics included univariate analysis, Kaplan-Meier analysis, multivariate analysis using Cox proportional hazards model and logistic regression model, and receiver operating characteristic (ROC) curve analysis., Results: Of the 127 srHCC patients, 24, 42, and 61 patients received conservative treatment, surgical treatment, and transarterial chemoembolization/embolization (TACE/TAE) treatment at HCC rupture, respectively. The largest tumor size [hazard ratio (HR) 1.127; p < 0.001], Barcelona-Clinic Liver Cancer (BCLC) stage (HR 2.184, p = 0.023), international normalized ratio (INR; HR 3.895; p = 0.012), total bilirubin level (TBil; HR 1.014; p = 0.014), TACE after rupture (compared with conservative treatment) (HR 0.549; p = 0.029), TACE/TAE and surgery at rupture, and albumin level (HR 0.949; p = 0.017) were independent predictors affecting overall survival. A survival predictive model for HCC rupture (SPHR) using these predictors was created. ROC analysis showed that the area under the curve (AUC) of the SPHR model for 30 day survival was 0.925, and the AUCs of the model for end-stage liver disease (MELD) score and Child-Pugh score for 30 day survival were 0.767 and 0.757, respectively., Conclusion: The largest tumor size, advanced BCLC stage, higher INR and TBil, lower albumin, and conservative treatment were negative independent predictors for overall survival. The SPHR model may be more suitable than the MELD score and Child-Pugh score for predicting 30 day survival in srHCC., (© 2022. The Author(s).)

Acute liver injury is a common and serious syndrome caused by multiple factors and unclear pathogenesis. If the injury persists, liver injury can lead to cirrhosis and liver failure and ultimately results in the development of liver cancer. Emerging evidence has indicated that long noncoding RNAs (lncRNAs) play an important role in the development of liver injury. However, the role of antisense Igf2r RNA (Airn) in acute liver injury and its underlying mechanism remain largely unclear. In this study, we show that Airn is upregulated in liver tissue and primary hepatocytes from an acute liver injury mouse model. Consistently, Airn is also overexpressed in serum samples of patients with acute-on-chronic liver failure and is negatively correlated with the Model for End-Stage Liver Disease (MELD) score. Moreover, gene knockout and rescue assays reveal that Airn alleviates CCl 4 -induced liver injury by inhibiting hepatocyte apoptosis and oxidative stress in vivo . Further investigation reveals that Airn decreases H 2 O 2 -induced hepatocyte apoptosis in vitro . Mechanistically, we reveal that Airn represses CCl 4 - and H 2 O 2 -induced enhancement of phosphorylation of p65 and IκBα, suggesting that Airn inhibits hepatocyte apoptosis by inactivating the NF-κB pathway. In conclusion, our results demonstrate that Airn can alleviate acute liver injury by inhibiting hepatocyte apoptosis via inactivating the NF-κB signaling pathway, and Airn could be a potential biomarker for acute liver injury.

Background and Aims: Minimal hepatic encephalopathy (MHE) is a common neuropsychiatric complication in patients with cirrhosis. Alterations in monoamine neurotransmitters have been associated with the pathogenesis of MHE. We investigated the levels of hippocampal noradrenergic neurotransmitter in a rat model of thioacetamide-induced chronic liver failure-related MHE, and their role in cognitive impairment., Materials: 18 male Sprague-Dawley (SD) rats were equally divided in MHE and control groups. A rat model of MHE was established by intraperitoneal injection of thioacetamide (TAA) for 12 weeks. Cognitive function was assessed using the Morris water maze (MWM) test and locomotor activity and exploratory behavior assessed with open field test. The concentration of hippocampal noradrenaline (NE) was detected by ELISA, and the magnetic susceptibility value in the hippocampus was detected by quantitative susceptibility mapping. Hippocampal iron content was quantified by Prussian blue staining., Results: MHE rats performed significantly poorer than their control counterparts in the MWM test, as seen by decreased number of platform crossings and time in the target quadrant, and increased path length to reach the target zone (P < 0.05 for all parameters). In the open field test, the MHE group exhibited lower locomotor activity and exploratory behavior than the control group (P < 0.05 for all parameters). We detected pronounced iron staining in the hippocampus of MHE rats, whereas no iron-stained particles were found in control rats. We observed an imbalance of inflammatory (increased pro- and decreased anti-) cytokines in the hippocampus of MHE rats. Further analysis of the data showed that the level of hippocampal noradrenaline in MHE rats was significantly lower than that of control rats (P < 0.05). We observed a correlation between the level of inflammatory cytokine and noradrenaline land susceptibility value in the rat hippocampus of the MHE group., Conclusion: Our results suggest that MHE associated with TAA-induced chronic liver failure is associated with alterations in noradrenergic neurotransmission. We propose that iron imbalance in the brain might lead to reduction in the levels of noradrenaline, and cognitive impairment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background/aims: Sarcopenia negatively affects the prognosis of cirrhotic patients, but clinical implications of changes in muscle mass remain unclear. We aimed to elucidate its role in the prognosis of outpatients with cirrhosis., Methods: Patients with cirrhosis who underwent annual abdominal computed tomography (CT) for hepatocellular carcinoma surveillance were included in the prospective cohort. The L3 skeletal muscle index (SMI) was adopted as a proxy for the amount of skeletal muscle, and the rate of SMI change between inclusion and after 1 year (ΔSMI/yr%) was calculated., Results: In total, 595 patients underwent a second CT after 1 year. Among them, 109 and 64 patients had sarcopenia and Child-Pugh class B/C decompensation at inclusion, which changed to 103 and 45 at the 1-year follow-up, respectively. During a median follow-up of 30.1 months after 1 year, 86 patients had at least one cirrhosis complication, and 18 died or received liver transplantation. In the development of cirrhosis complications, ΔSMI/yr% was independently associated, even after adjusting for the Child-Pugh and model for end stage liver disease (MELD)-Na scores. In addition, ΔSMI/yr% showed a good predictive performance for the development of cirrhosis complications within 6 months after 1-year follow-up in all subgroups, with a cut-off of -2.62 (sensitivity, 83.9%; specificity, 74.5%) in the overall population. SMI at 1-year and Child-Pugh score were independent factors associated with survival. In addition, changes in sarcopenia status significantly stratified survival., Conclusion: ΔSMI/yr% was a good predictor of the development of cirrhosis complications in outpatients with cirrhosis, independent of Child-Pugh and MELD scores.

Introduction: Chronic liver disease (CLD) represents different liver disorders of varying severity and etiology in which hepatic inflammation and fibrosis continue at least for 6 months. Portal hypertension is one of the important complications of CLD and its early recognition is of paramount importance. Though liver biopsy remains the gold standard for diagnosing liver fibrosis and upper gastrointestinal (GI) endoscopy plays an important role in diagnosing different findings of portal hypertension, various noninvasive methods like FibroScan are being increasingly used to diagnose liver fibrosis., Aims and Objectives: Study the FibroScan and endoscopic findings in patients of CLDs and the objectives are to find the prevalence of portal hypertension and to find various grades of esophageal varix and portal hypertensive gastropathy (PHG) and its relationship with liver fibrosis by FibroScan., Materials and Methods: A total of 114 patients of CLD and compensated cirrhosis having childturcotte- pugh (CTP) stages A and B were included in the study fulfilling inclusion and exclusion criteria, after calculating the sample size of 100. All the patients underwent detailed history, physical and gastrointestinal examination. Complete blood count (CBC), liver function test (LFT), kidney function test (KFT), viral markers were done. Aspartate aminotransferase (AST) to platelet ratio index (APRI) score was calculated, liver fibrosis was estimated by FibroScan and evidence of portal hypertension was documented by upper GI endoscopy. Cutoff value of FibroScan, APRI score, and model for end-stage liver disease (MELD) score for portal hypertension was decided by receiver operating characteristic (ROC) curve., Results: Alcoholic liver disease (ALD) was the most common cause (43%) of CLD closely followed by nonalcoholic fatty liver disease (NAFLD) in 42% cases followed by chronic viral hepatitis, 75% patients had evidence of portal hypertension with PHG being the most common followed by esophageal varix. F4 fibrosis was found in 73% of cases followed by F3, F2, and F1 fibrosis. FibroScan value of 12.2 kPa was predictive of presence of portal hypertension and value of 26.6 mm predicted the presence of large esophageal varices., (© Journal of the Association of Physicians of India 2011.)

Hepatic dysfunction represents a wide spectrum of pathological changes, which can be frequently found in hepatitis, cholestasis, metabolic diseases, and focal liver lesions. As hepatic dysfunction is often clinically silent until advanced stages, there remains an unmet need to identify affected patients at early stages to enable individualized intervention which can improve prognosis. Passive liver function tests include biochemical parameters and clinical grading systems ( e.g ., the Child-Pugh score and Model for End-Stage Liver Disease score). Despite widely used and readily available, these approaches provide indirect and limited information regarding hepatic function. Dynamic quantitative tests of liver function are based on clearance capacity tests such as the indocyanine green (ICG) clearance test. However, controversial results have been reported for the ICG clearance test in relation with clinical outcome and the accuracy is easily affected by various factors. Imaging techniques, including ultrasound, computed tomography, and magnetic resonance imaging, allow morphological and functional assessment of the entire hepatobiliary system, hence demonstrating great potential in evaluating hepatic dysfunction noninvasively. In this article, we provide a state-of-the-art summary of noninvasive imaging modalities for hepatic dysfunction assessment along the pathophysiological track, with special emphasis on the imaging modality comparison and selection for each clinical scenario., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interests related to this study., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) affects 25% of adults in the general population and is a disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) to end-stage liver disease. NAFLD is an independent risk factor for cardiovascular disease, diabetes mellitus, and all-cause mortality, and NASH cirrhosis is a frequent indication for liver transplantation. In persons with human immunodeficiency virus (PWH), chronic liver disease is the second leading cause of non-human immunodeficiency virus-related mortality. Between 20% and 63% of PWH have NASH, and 14% to 63% have NASH with fibrosis. However, little is known about the optimal diagnostic strategies, risk factors for, and treatment of NAFLD in PWH. Here, we review current data on and identify knowledge gaps in the epidemiology, pathophysiology, diagnosis, and management of NAFLD in PWH and highlight priorities for research., (Copyright © 2022 AGA Institute. All rights reserved.)

Background and Aims: Liver transplantation (LT) in alcohol-associated hepatitis (AH) remains controversial, in part because spontaneous recovery (SR) can occur. There is a paucity of data on SR in patients with severe AH who undergo LT evaluation. The purpose of this study was to determine factors associated with SR and survival in patients with severe AH who undergo LT evaluation., Approach and Results: This is a retrospective study of ALD patients with Model for End-Stage Liver Disease (MELD) >25 and <90 days abstinence who underwent LT evaluation at a single center between 2012 and 2018. One hundred forty-four patients (median age, 45.5 years; 68.1% male) were included. Forty-nine (34%) underwent LT and 95 (66%) patients did not undergo LT, and of those, 34 (23.6%) experienced SR. Factors associated with recovery were younger age (OR, 0.92; p = 0.004), lower index international normalized ratio (INR; 0.31; p = 0.03), and lower peak MELD (OR, 0.83; p = 0.02). Only 7 patients (20.6%) achieved a compensated state with a MELD <15 and absence of therapy for ascites or HE. Survival was improved in patients who underwent early LT when compared to SR. Survival was impaired in SR following relapse to alcohol use when compared to SR patients who abstained and LT recipients. Among all 6-month survivors of AH, alcohol use trended toward an association with mortality (HR, 2.05; p = 0.17), but only LT was associated with decreased mortality risk (HR, 0.20; p = 0.005)., Conclusions: SR from AH after LT evaluation is associated with age, index INR, and lower peak MELD. Most recovered patients continue to experience end-stage complications. LT is the only factor associated with lower mortality., (© 2021 by the American Association for the Study of Liver Diseases.)

Aim: Hepatic fibrosis in injured liver is characterized by the activation of hepatic stellate cells (HSCs) from their quiescent state. Survivin (BIRC5) is one of the key genes that are upregulated during activation of HSCs but their role in HSC activation and fibrosis progression is unknown. Here, we have investigated the role of survivin protein in early fibrogenic activation of HSCs and fibrosis progression in chronic liver injury., Materials & Methods: Primary quiescent HSCs were isolated from healthy mice liver through perfusion and cultured for fibrogenic activation. Survivin expression was suppressed by its pharmacological suppressant, YM155. We developed chronic liver injury induced fibrotic mice model through administrating repeated dose of CCl 4 for 2 weeks and 4 weeks. Mice were pre-treated with YM155 a week before CCl 4 administration till 2nd week of dosing and then discontinued. Hepatic parameters were characterized and underlying mechanisms were investigated., Key Findings: Survivin expression gradually increased along with the expression of αSMA, collagen I activation maker in HSCs during their activation from quiescent state. Survivin suppression through YM155 downregulated αSMA, collagen I. Pre-treatment of YM155 in mice ceased the early activation of HSCs and onset of fibrosis in injured liver. However, discontinuation of YM155 initiated the activation of HSCs and fibrosis progression that shows survivin expression in HSCs is essential for their early activation and onset of liver fibrosis., Significance: Survivin expression induces with activation of HSCs and drives onset of liver fibrosis in injured liver. Targeting survivin protein in activated HSCs could be a potential anti-fibrotic therapeutic approach in chronic liver injury., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Autologous liver transplantation (ALT) to cure end-stage hepatic alveolar echinococcosis (HAE) requires that hepatobiliary surgeons understand the invasion of intrahepatic structure and adjacent tissues or organs. Triphase contrast-enhanced CT of the liver has been widely used for diagnosis and preoperative evaluation of HAE. Three-dimensional (3D) reconstruction allows for accurate measurement of remnant liver volume (RLV). The objective of the study was to evaluate value of triphase contrast-enhanced CT together with 3D reconstruction in preoperative evaluation of indications for ALT in patients with end-stage HAE. This cohort include twenty-one consecutive patients with end-stage HAE, who preoperatively underwent triphase enhanced CT together with 3D reconstruction for ALT. To depict the indications, the 2D image data were reviewed statistically focusing on porta hepatis invasion, retrohepatic vena cava (RHVC) involvement and degrees of intrahepatic vessel invasion, and the 3D reconstruction was performed to obtain ratio of RLV to standard liver volume (SLV). The results showed that 95.24% patients (20/21) had porta hepatis invasion. When lesions located in right liver lobe, porta hepatis invasion occurred most commonly in the second and third porta hepatis (7/10), whereas the first, second and third porta hepatis were most commonly invaded by lesions in the right and caudate / left medial liver lobes (7/11) (P < 0.05). The mean value of longitudinal invasion of RHVC was 8.0 cm, and 95.2% (20/21) of patients had RHVC invasion with ≥ 180° circumferential invasion. As for the important vascular events, moderate and severe invasion occurred most commonly in the right hepatic vein, right branch of portal vein and RHVC each in 95.2% (20/21) patients (P < 0.05). We also found that preoperative CT had a good agreement with intraoperative findings in assessing intrahepatic vascular involvement by HAE (kappa index = 0.77). The estimated average ratio of RLV to SLV was 0.95 (range, 0.43-1.62). In conclusion, the 2D contrast-enhanced CT could well depict anatomic location and size of HAE, and invasion of porta hepatis and vascular by this disease, and involvement of other adjacent organs and tissues. Above all, 3D reconstruction could accurately measure RLV in patients with end-stage HAE for ALT., (© 2021. The Author(s).)

Background and Aims: NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology., Approach and Results: We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response., Conclusion: Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects., (© 2021 by the American Association for the Study of Liver Diseases.)

Raman spectroscopy has shown to be a promising method for the examination of biomedical samples. However, until now, its efficacy has not been established in clinical diagnostics. In this study, Raman spectroscopy's potential application in medical laboratories is evaluated for a large variety (38) of biomarkers. Given 234 serum samples from a cohort of patients with different stages of liver disease, we performed Raman spectroscopy at 780nm excitation wavelength. The Raman spectra were analyzed in combination with the results of routine diagnostics using specifically developed complex mathematical algorithms, including fluorescence filtering, frequency subset selection and several overfitting circumventing strategies, such as independent validation. With the results of this cohort, which were validated in 328 independent samples, a significant proof-of-concept study was completed. This study highlights the need to prevent overfitting and to use independent data for validation. The results reveal that Raman spectroscopy has high potential for use in medical laboratory diagnostics to simultaneously quantify multiple biomarkers., Competing Interests: The authors have declared that no competing interests exist.

Background: Early diagnosis of hepatic encephalopathy (HE) in chronic liver disease (CLD) is difficult clinically., Objective: The aim of this study was to evaluate whether serum matrix metalloproteinase-9 (MMP-9) levels could identify early HE in patients with CLD., Methods: Serum MMP-9 levels in 1,187 patients with CLD were measured at baseline. A total of 1,187 patients with CLD were followed for a mean of 48 months (range: 4-50). The association between MMP-9 and the risk of HE was evaluated by logistic regression analysis and Cox regression analysis., Results: Patients with higher serum MMP-9 levels had higher rates of HE history and HE events during follow-up (all P <0.001). The multivariate logistic regression analysis revealed that MMP-9 (OR=2.84, 95% CI 1.63-7.11, P =0.004) was independently associated with HE history, with an increased grade of aggravation on liver fibrosis at baseline. Multivariate Cox proportional hazard analysis revealed that MMP-9 (HR=2.21, 95% CI 1.09-5.02, P <0.001) was an independent predictor for HE events by sensitivity analysis. The Kaplan-Meier analysis demonstrated that patients with MMP-9 above the median value (176.2 mg/d) had a higher rate of new HE events than patients who had MMP-9 levels below the median value ( P <0.001)., Conclusions: Elevated serum RBP4 levels were associated with a higher risk of HE events during follow-up. These results may suggest that serum MMP-9 has good predictive value for detecting HE in patients with CLD, which provides some clinical reference value to clinicians for the early diagnosis of HE., (© 2021 by the Association of Clinical Scientists, Inc.)

In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut-liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.

Background and Aims: Our aim was to evaluate the impact of direct-acting antivirals (DAAs) on decompensated cirrhosis (DCC) and HCC in patients with chronic HCV and substance use disorder (SUD) compared with those without an SUD., Approach and Results: This retrospective cohort study used the MarketScan database (2013-2018) to identify 29,228 patients with chronic HCV, where 22% (n = 6,385) had ≥1 SUD diagnosis. The inverse probability of treatment weighted multivariable Cox proportional hazard models were used to compare the risk of developing DCC and HCC. Among the those who were noncirrhotic, treatment reduced the DCC risk among SUD (adjusted hazard ratio [aHR] 0.13; 95% CI, 0.06-0.30) and non-SUD (aHR 0.11; 95% CI, 0.07-0.18), whereas the risk for HCC was not reduced for the SUD group (aHR 0.91; 95% CI, 0.33-2.48). For those with cirrhosis, compared with patients who were untreated, treatment reduced the HCC risk among SUD (aHR, 0.33; 95% CI, 0.13-0.88) and non-SUD (aHR, 0.40; 95% CI, 0.25-0.65), whereas the risk for DCC was not reduced for the SUD group (aHR, 0.64; 95% CI, 0.37-1.13). Among patients with cirrhosis who were untreated, the SUD group had a higher risk of DCC (aHR, 1.52; 95% CI, 1.03-2.24) and HCC (aHR, 1.69; 95% CI, 1.05-2.72) compared with non-SUD group., Conclusions: Among the HCV SUD group, DAA treatment reduced the risk of DCC but not HCC for those who were noncirrhotic, whereas DAA treatment reduced the risk of HCC but not DCC for those with cirrhosis. Among the nontreated, patients with an SUD had a significantly higher risk of DCC and HCC compared with those without an SUD. Thus, DAA treatment should be considered for all patients with HCV and an SUD while also addressing the SUD., (© 2021 by the American Association for the Study of Liver Diseases.)

Background and Aims: Biliary atresia (BA) is a devastating cholangiopathy of infancy. Upon diagnosis, surgical reconstruction by Kasai hepatoportoenterostomy (HPE) restores biliary drainage in a subset of patients, but most patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling that of human BA. High-mobility group box 1 (HMGB1) is an important member of the danger-associated molecular patterns capable of mediating inflammation during infection-associated responses. In this study, we investigated the role of HMGB1 in BA pathogenesis., Approach and Results: In cholangiocytes, RRV induced the expression and release of HMGB1 through the p38 mitogen-activated protein kinase signaling pathway, and inhibition of p38 blocked HMGB1 release. Treatment of cholangiocytes with ethyl pyruvate suppressed the release of HMGB1. Administration of glycyrrhizin in vivo decreased symptoms and increased survival in the murine model of BA. HMGB1 levels were measured in serum obtained from infants with BA enrolled in the PROBE and START studies conducted by the Childhood Liver Disease Research Network. High HMGB1 levels were found in a subset of patients at the time of HPE. These patients had higher bilirubin levels 3 months post-HPE and a lower survival of their native liver at 2 years., Conclusions: These results suggest that HMGB1 plays a role in virus induced BA pathogenesis and could be a target for therapeutic interventions in a subset of patients with BA and high HMGB1., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: The 13 C-methacetin breath test (MBT) is a noninvasive, quantitative hepatic metabolic function test. The aim of this prospective, multicenter study was to determine the utility of initial and serial 13 C-MBT in predicting 21-day outcomes in adults with acute liver failure (ALF) and non-acetaminophen acute liver injury (ALI)., Approach and Results: The 13 C-MBT BreathID device (Exalenz Biosciences, Ltd.) provided the percent dose recovery (PDR) for a duration of 60 minutes after administration of 13 C-methacetin solution as the change in exhaled 13 CO 2 / 12 CO 2 compared with pre-ingestion ratio on study days 1, 2, 3, 5, and 7. Results were correlated with 21-day transplant-free survival and other prognostic indices. A total of 280 subjects were screened for enrollment between May 2016 and August 2019. Median age of the 62 enrolled patients with adequate data was 43 years, 79% were Caucasian, 76% had ALF with the remaining 24% having ALI. The mean PDR peak on day 1 or day 2 was significantly lower in nonsurvivors compared with transplant-free survivors (2.3%/hour vs. 9.1%/hour; P < 0.0001). In addition, serial PDR peaks were consistently lower in nonsurvivors versus survivors (P < 0.0001). The area under the receiver operating characteristic curve (AUROC) of the 13 C-MBT in the combined cohort was 0.88 (95% CI: 0.79-0.97) and higher than that provided by King's College (AUROC = 0.70) and Model for End-Stage Liver Disease scores (AUROC = 0.83). The 13 C-MBT was well tolerated with only two gastrointestinal adverse events reported., Conclusions: The 13 C-MBT is a promising tool to estimate the likelihood of hepatic recovery in patients with ALF and ALI. Use of the PDR peak data from the 13 C-MBT point-of-care test may assist with medical decision making and help avoid unnecessary transplantation in critically ill patients with ALF and ALI., (© 2021 by the American Association for the Study of Liver Diseases.)

Background and Aims: Estimates of racial disparity in cirrhosis have been limited by lack of large-scale, longitudinal data, which track patients from diagnosis to death and/or transplant., Approach and Results: We analyzed a large, metropolitan, population-based electronic health record data set from seven large health systems linked to the state death registry and the national transplant database. Multivariate competing risk analyses, adjusted for sex, age, insurance status, Elixhauser score, etiology of cirrhosis, HCC, portal hypertensive complication, and Model for End-Stage Liver Disease-Sodium (MELD-Na), examined the relationship between race, transplant, and cause of death as defined by blinded death certificate review. During the study period, 11,277 patients met inclusion criteria, of whom 2,498 (22.2%) identified as Black. Compared to White patients, Black patients had similar age, sex, MELD-Na, and proportion of alcohol-associated liver disease, but higher comorbidity burden, lower rates of private insurance, and lower rates of portal hypertensive complications. Compared to White patients, Black patients had the highest rate all-cause mortality and non-liver-related death and were less likely to be listed or transplanted (P < 0.001 for all). In multivariate competing risk analysis, Black patients had a 26% increased hazard of liver-related death (subdistribution HR, 1.26; 95% CI, [1.15-1.38]; P < 0.001)., Conclusions: Black patients with cirrhosis have discordant outcomes. Further research is needed to determine how to address these real disparities in the field of hepatology., (© 2021 by the American Association for the Study of Liver Diseases.)

Aim: Stereotactic-body radiotherapy (SBRT) is a treatment option for portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC). Here, we report on our experience of treating PVTT using SBRT in patients with concomitant underlying chronic liver disease., Methods: This study included 24 patients. The initial prescription dose was 45 Gy in three fractions in 17 (70.8%) patients, but it was modified in the remaining seven (29.2%) patients, with the dose ranging from 39 to 42 Gy in 3-4 fractions. After SBRT, transarterial chemoembolization (TACE) was performed in 16 (66.7%) patients., Results: Of the 24 patients, 2 (8.3%) showed complete response, while 11 (45.8%) showed partial response. After a median follow-up of 8.4 months (range: 2.6-56.5 months), the 1-year overall survival (OS) and the median survival were 67.5% and 20.8 months, respectively. Both combined SBRT and TACE and grade ≥3 hepatic toxicity affected the 1-year OS (SBRT alone vs SBRT + TACE: 14.6% vs 71.4%, P < .001; presence of hepatic toxicity vs absence: 0% vs 81.1%, P = .002)., Conclusions: Overall, SBRT, especially in combination with TACE, is an effective treatment for patients with HCC and PVTT. An optimal dose schedule must be followed to reduce hepatic toxicity while maintaining tumor response., (© 2020 John Wiley & Sons Australia, Ltd.)

Nonalcoholic fatty liver disease (NAFLD) affects up to 70% of children with obesity and has become the number one etiology for liver transplant in the United States. Early, effective intervention is critical to prevent disease progression into adulthood. Yet, it is seldom achieved through lifestyle modification alone. Thus, children must be included in NAFLD pharmacology trials, which, to date, continue to focus primarily on adult populations. This commentary serves as a call to action., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background and Aims: Frailty, as measured by the Liver Frailty Index (LFI), is associated with liver transplant (LT) waitlist mortality. We sought to identify an optimal LFI cutoff that predicts waitlist mortality., Approach and Results: Adults with cirrhosis awaiting LT without hepatocellular carcinoma at nine LT centers in the United States with LFI assessments were included. Multivariable competing risk analysis assessed the relationship between LFI and waitlist mortality. We identified a single LFI cutoff by evaluating the fit of the competing risk models, searching for the cutoff that gave the best model fit (as judged by the pseudo-log-likelihood). We ascertained the area under the curve (AUC) in an analysis of waitlist mortality to find optimal cutoffs at 3, 6, or 12 months. We used the AUC to compare the discriminative ability of LFI+Model for End Stage Liver Disease-sodium (MELDNa) versus MELDNa alone in 3-month waitlist mortality prediction. Of 1,405 patients, 37 (3%), 82 (6%), and 135 (10%) experienced waitlist mortality at 3, 6, and 12 months, respectively. LFI was predictive of waitlist mortality across a broad LFI range: 3.7-5.2. We identified an optimal LFI cutoff of 4.4 (95% confidence interval [CI], 4.0-4.8) for 3-month mortality, 4.2 (95% CI, 4.1-4.4) for 6-month mortality, and 4.2 (95% CI, 4.1-4.4) for 12-month mortality. The AUC for prediction of 3-month mortality for MELDNa was 0.73; the addition of LFI to MELDNa improved the AUC to 0.79., Conclusions: LFI is predictive of waitlist mortality across a wide spectrum of LFI values. The optimal LFI cutoff for waitlist mortality was 4.4 at 3 months and 4.2 at 6 and 12 months. The discriminative performance of LFI+MELDNa was greater than MELDNa alone. Our data suggest that incorporating LFI with MELDNa can more accurately represent waitlist mortality in LT candidates., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease in the western world. Steatosis can be accompanied by inflammation and cell damage (non-alcoholic steatohepatitis, NASH), and even liver fibrosis. Sphingolipids are a heterogeneous class of lipids and essential components of the plasma membrane and plasma lipoproteins. The atypical class of deoxy-sphingolipids has been implicated in the metabolic syndrome and type 2 diabetes., Aim: To determine if circulating (deoxy)sphingolipids are associated with NAFLD and its different entities, steatosis, inflammatory changes (inflammation and ballooning) and fibrosis., Methods: Sphingolipids were analysed by LC-MS after hydrolysing the N-acyl and O-linked headgroups in plasma of obese adults who underwent a liver biopsy in suspicion of NAFLD., Results: Two-hundred and eighty-eight patients were included. There was no association between typical sphingolipids and NAFLD and its different entities. There was a significant association between the presence of steatosis and the concentrations of deoxy-sphinganine [exp(B) 11.163 with CI (3.432, 36.306) and p < 0.001] and deoxy-sphingosine [exp(B) 8.486 with CI (3.437, 20.949) and p < 0.001]. There was no association between these deoxy-sphingolipids and activity of the steatohepatitis, nor was there any association with fibrosis. Differences in deoxy-sphingolipids also correlated independently with the presence of the metabolic syndrome, but not diabetes., Conclusion: Deoxy-sphingolipids are elevated in patients with steatosis compared to those without fatty liver, but not different between the different NAFLD subtypes, suggesting that deoxy-sphingolipid bases might be involved in steatogenesis, but not in the further progression of NAFLD to NASH nor in fibrogenesis.

Hepatopulmonary syndrome (HPS) is defined as three distinct features: liver disease, hypoxemia, and intrapulmonary vasodilation. The purpose of this study was to investigate the clinical outcomes of pediatric HPS and to identify the risk factors for HPS in children with biliary atresia (BA). We performed a retrospective cohort study of all children who were diagnosed with HPS between 2000 and 2018 at Seoul National University Hospital. The clinical features and outcomes of the 10 patients diagnosed with HPS were reviewed. To clarify the risk factors of HPS in patients with BA, we reviewed 120 patients diagnosed with BA. Underlying liver disease was BA in 8 patients, portal vein agenesis in 1 patient, and portal vein thrombosis in 1 patient. A total of 7 patients underwent liver transplantation (LT). Currently, all seven patients, including 3 patients with severe HPS, survived after LT. The prevalence of HPS in children with BA was 7%. Polysplenia/interrupted inferior vena was the only risk factor for HPS in BA patients in multivariate analysis. The Pediatric End-Stage Liver Disease score was not associated with the development of HPS. Children with severe HPS undergoing LT had excellent outcomes. Screening for HPS in children with BA is required regardless of the severity of liver diseases.

Pruritus is known to be a common complication in hepatitis patients, but the exact frequency and degree are not fully elucidated. Thus, we evaluated pruritus of 450 patients with chronic liver disease at our hospital. Pruritus was observed in 240 (53%) of the patients. Pruritus was significantly associated with males (OR = 1.51, P = 0.038) and patients with alkaline phosphatase (ALP) ≥ 200 U/L (OR = 1.56, P = 0.0495) and was significantly less in HBsAg-positive patients (OR = 0.449, P = 0.004). Seasonally, there was no difference in the frequency of pruritus between summer and winter. Of the 24 refractory pruritus patients treated with nalfurafine, 17 (71%) indicated improvement of itch, which is defined as a decrease in the visual analog scale score ≥ 30 mm. Pruritus was improved by nalfurafine both during daytime and nighttime in the Kawashima's scores evaluation. All patients who received nalfurafine exhibited improved Kawashima's scores ≥ 1 point during the daytime or nighttime. In conclusion, pruritus occurred in > 50% of patients with chronic liver disease, and predictors of pruritus were males and ALP ≥ 200 U/L. Nalfurafine may be useful for pruritus, regardless of whether daytime or nighttime.

Objective: Muscle depletion in patients undergoing liver transplantation affects the recipients' prognosis and therefore cannot be overlooked. We aimed to evaluate whether changes in muscle and fat mass during the preoperative period are associated with prognosis after deceased donor liver transplantation (DDLT)., Materials and Methods: This study included 72 patients who underwent DDLT and serial computed tomography (CT) scans. Skeletal muscle index (SMI) and fat mass index (FMI) were calculated using the muscle and fat area in CT performed 1 year prior to surgery (1 yr Pre-LT), just before surgery (Pre-LT), and after transplantation (Post-LT). Simple aspects of serial changes in muscle and fat mass were analyzed during three measurement time points. The rate of preoperative changes in body composition parameters were calculated (preoperative ΔSMI [%] = [SMI at Pre-LT - SMI at 1 yr Pre-LT] / SMI at Pre-LT × 100; preoperative ΔFMI [%] = [FMI at Pre-LT - FMI at 1 yr Pre-LT] / FMI at Pre-LT × 100) and assessed for correlation with patient survival., Results: SMI significantly decreased during the preoperative period (mean preoperative ΔSMI, -13.04%, p < 0.001). In the multivariable analysis, preoperative ΔSMI ( p = 0.016) and model for end-stage liver disease score ( p = 0.011) were independent prognostic factors for overall survival. The mean survival time for patients with a threshold decrease in the preoperative ΔSMI (≤ -30%) was significantly shorter than for other patients ( p = 0.007). Preoperative ΔFMI was not a prognostic factor but FMI increased during the postoperative period ( p = 0.009) in all patients., Conclusion: A large reduction in preoperative SMI was significantly associated with reduced survival after DDLT. Therefore, changes in muscle mass during the preoperative period can be considered as a prognostic factor for survival after DDLT., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2021 The Korean Society of Radiology.)

Background and Aims: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease., Approach and Results: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients., Conclusions: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Serum levels of procalcitonin (PCT) are considered a useful biomarker for the diagnosis of bacterial infection or inflammation. There are few reports of high PCT levels in end-stage liver disease regardless of bacterial infection. Here, we present a case of extremely high PCT levels (> 100 ng/mL) in a patient with severe cirrhosis combined with hepatic carcinoma., Case Presentation: A 65-year-old man developed end-stage cirrhosis with hepatic carcinoma. Radiographic imaging showed a massive hepatocellular carcinoma with multiple loci lack of indications of resection. Hence, transcatheter hepatic arterial chemoembolization was performed three times over a period of 4 months. Before and after interventional therapies, the biochemistry laboratory results were only slightly abnormal except for persistently high PCT concentrations (> 100 ng/mL), irrespective of the evidence for bacterial infection or sepsis., Conclusions: This case suggests that continuously high levels of PCT (> 100 ng/mL) may be present in advanced liver disease, particularly in complex situations such as decompensated cirrhosis and liver cancer, in the absence of severe infection or sepsis. This knowledge could expand the significance of PCT in liver disease.

Background: Secondary biliary cirrhosis (SBC) represents a unique form of cirrhosis that develops in the liver secondary to persistent biliary obstruction. This study aimed to review the living donor liver transplants (LDLTs) performed at our center for patients with SBC and end-stage liver disease and to share the perioperative strategies undertaken to achieve satisfactory outcomes., Methods: The medical records of 29 patients who underwent LDLT for SBC between December 1994 and July 2018 at the Asan Medical Center (Seoul, South Korea) were retrospectively reviewed. Their clinical data were extracted and statistically analyzed. Survival curves were computed., Results: The perioperative and in-hospital morbidity rates were 72.4% and 10.3%, respectively. The overall mean recipient follow-up was 80.0 (SD, 66.4) months (range, 0.8-246.8 months). Patient survival rates after 1, 3, 5, and 10 years after transplant were 82.8%, 79.3%, 79.3%, and 79.3%, respectively. For liver grafts, the survival rates were 82.8%, 75.8%, 75.8%, and 75.8% at 1, 3, 5, and 10 years, respectively., Conclusions: LDLT is potentially a final lifesaving resort for patients with SBC with portal hypertension. However, considering the difficulty of surgery and perioperative management, LDLT should be performed by experienced transplant surgeons in a center where a multidisciplinary approach is possible., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Hepatic encephalopathy (HE) is associated with marked increases in morbidity and mortality for patients with cirrhosis. We aimed to determine the risk of and predictors for HE in contemporary patients., Methods: We prospectively enrolled 294 subjects with Child A-B (70% Child A) cirrhosis and portal hypertension without previous HE from July 2016 to August 2018. The primary outcome was the development of overt HE (grade >2). We assessed the predictive power of model for end-stage liver disease-sodium (MELD-Na) score, the Inhibitory Control Test, the Sickness Impact Profile score, and the Bilirubin-Albumin-Beta-Blocker-Statin score. We also derived a novel predictive model incorporating MELD-Na score, impact of cirrhosis on daily activity (Likert 1-9), frailty (chair-stands per 30 seconds), and health-related quality of life (Short-Form 8, 0-100)., Results: The cohort's median age was 60 years, 56% were men, and the median MELD-Na score was 9. During a follow-up of 548 ± 281 days, 62 (21%) had incident overt HE with 1-year probability of 14% ± 2%, 10% ± 2%, and 25% ± 5% for Child A and B. The best model for predicting the risk of overt HE included MELD-Na, Short-Form 8, impact on activity rating, and chair-stands within 30 seconds. This model-MELDNa-Actvity-Chairstands-Quality of Life Hepatic Encephalopathy Score-offered an area under the receiver operating curve (AUROC) for HE development at 12 months of 0.82 compared with 0.55, 0.61, 0.70, and 0.72 for the Inhibitory Control Test, Sickness Impact Profile, Bilirubin-Albumin-Beta-Blocker-Statin, and MELD-Na, respectively. The AUROC for HE-related hospitalization was 0.92., Discussion: This study provides the incidence of HE in a well-characterized cohort of contemporary patients. Bedside measures such as activity, quality of life, and physical function accurately stratified the patient's risk for overt HE.

Background and Aims: Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) policy mandates a 6-month waiting period before exception scores are granted to liver transplant candidates with hepatocellular carcinoma (HCC). This study aims to evaluate waitlist and posttransplant outcomes in patients with HCC, before and after implementation of the 6-month waiting rule., Approach and Results: We examined two groups from the UNOS registry: Group 1 (pre-6-month rule) consisted of patients registered as transplant candidates with HCC from January 1, 2013, to October 7, 2015 (n = 4,814); group 2 (post-6-month rule) consisted of patients registered from October 8, 2015, to June 30, 2018 (n = 3,287). As expected, the transplant probability was higher in the first 6 months after listing in group 1 than group 2 at 42.0% versus 6.3% (P < 0.001). However, the 6-month waitlist mortality/dropout rate was lower in group 2 at 1.2% than group 1 at 4.1% (P < 0.001). To assess regional parity of transplant, UNOS regions were categorized into three groups based on Model for End-Stage Liver Disease score at transplant: lower-score (regions 3, 10, and 11), middle-score (1, 2, 6, 8, and 9), and higher-score region groups (4, 5, and 7). Outcomes were compared from the time exception points were given, which we defined as conditional waitlist outcomes. Conditional waitlist mortality/dropout decreased, and transplant probability increased in all region groups, but the benefits of the policy were more pronounced in the higher and middle-score groups, compared with the lower-score group. The decline in waitlist mortality/dropout was only significant in the high Model for End-Stage Liver Disease group (P < 0.001). No effect was observed on posttransplant mortality or percent of patients within Milan criteria on explant., Conclusions: The HCC policy change was associated with decreased waitlist mortality/dropout and increased transplant probability. The policy helped to decrease but did not eliminate regional disparities in transplant opportunity without an effect on posttransplant outcomes., (© 2020 by the American Association for the Study of Liver Diseases.)

Introduction: Liver transplantation is the definitive treatment modality of the patients having an end-stage liver disease with hepatocellular carcinoma., Discussion: The number of living donor liver transplantations has been increased because of the deceased donor organ shortage, especially in Asian countries., Conclusion: Reports of different clinics about the postoperative course and tumor recurrence rates comparing living donor versus deceased donor liver transplantations, besides patient selection criteria, are reviewed along with our clinic's experiences.

Background and Aims: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013)., Approach and Results: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001)., Conclusions: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation., (© 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: Hepatologists often determine whether transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) is preferred for patients with cirrhosis and severe aortic stenosis. The goal of this cohort study is to compare outcomes following TAVR and SAVR in patients with cirrhosis to inform the preferred intervention., Approach and Results: Prospectively collected data on 105 consecutive patients with cirrhosis and aortic stenosis who underwent TAVR (n = 55) or SAVR (n = 50) between 2008 and 2016 were reviewed retrospectively. Two control groups were included: 2,680 patients without cirrhosis undergoing TAVR and SAVR and 17 patients with cirrhosis who received medical therapy alone. Among the 105 patients with cirrhosis, the median Society of Thoracic Surgeons score was 3.8% (1.5, 6.9), and the median Model for End-Stage Liver Disease (MELD) score was 11.6 (9.4, 14.0). The TAVR group had similar in-hospital (1.8% vs. 2.0%) and 30-day mortality (3.6% vs. 4.2%) as the SAVR group. During the median follow-up of 3.8 years (95% confidence interval, 3.0-6.9), there were 63 (60%) deaths. MELD score (adjusted hazard ratio, 1.13; 95% confidence interval, 1.05-1.21; P = 0.002) was an independent predictor of long-term survival. In the subgroup of patients with MELD score <12, the TAVR group had reduced survival compared with the SAVR group (median survival of 2.8 vs. 4.4 years; P = 0.047). However, in those with MELD score ≥12, survival after TAVR, SAVR, and medical therapy was similar (1.3 vs. 2.1 vs. 1.6 years, respectively; P = 0.53)., Conclusion: In select patients with cirrhosis, both TAVR and SAVR have acceptable and comparable short-term outcomes. MELD score, but not Society of Thoracic Surgeons score, independently predicts long-term survival after TAVR and SAVR. For patients with MELD score <12, SAVR is a preferred procedure; however, neither procedure appears superior to medical therapy in patients with MELD score ≥12., (© 2020 by the American Association for the Study of Liver Diseases.)

Background and Aim: The alcoholic hepatitis histologic score has been proposed as a new prognostic tool to assess the risk of death in alcoholic hepatitis. We aimed to evaluate its prognostic value in patients with severe alcoholic hepatitis., Methods: Liver biopsies were analysed independently by two pathologists according to the alcoholic hepatitis histologic score. The Laennec staging system was also used to evaluate fibrosis., Results: One hundred and seven patients were included, and 89% of the patients received corticosteroids. The alcoholic hepatitis histologic score was available in 105 patients. Histologic scoring showed mild, moderate and severe scores in 10, 29 and 66 patients, respectively. Laennec staging was available for 53 patients, among whom 49 had cirrhosis, including 7 with Laennec 4A, 15 with 4B and 27 with 4C. Survival rates in mild, moderate and severe alcoholic hepatitis histologic score groups were 90%, 72% and 69% at 28 days ( p  = 0.6), 80%, 52% and 63% at 3 months ( p  = 0.3), and 70%, 41% and 58% at 6 months ( p  = 0.3), respectively. Within the alcoholic hepatitis histologic score, fibrosis demonstrated the best interobserver reproducibility (agreement = 100%, Κ = 1.00). Compared to patients with Laennec 4B or 4C cirrhosis, survival rates for patients without cirrhosis or with Laennec 4A cirrhosis were 100% vs 83% at 28 days ( p  = 0.16), 91% vs 68% at 3 months ( p  = 0.13), and 82% vs 64% at 6 months ( p  = 0.2), respectively. In multivariate analysis adjusted for age and for model for end-stage liver disease score, the alcoholic hepatitis histologic score and Laennec stage were not associated with 6-month mortality., Conclusions: The alcoholic hepatitis histologic score is not predictive of short-term survival in this cohort of patients with severe alcoholic hepatitis.

Inflammation is commonly cited as a mechanism of delayed effects of acute radiation exposure (DEARE). Confirmation of its presence could provide significant insight to targeted use of treatments or mitigators of DEARE. We sought to quantify the presence of cellular inflammation in kidneys of non-human primates that developed acute and chronic kidney injury after a partial body irradiation exposure. We show herein that cellular inflammation is not found as a component of either acute or chronic kidney injury. Other mechanistic pathways of injury must be sought.

Background/aims: An increased post-operative mortality risk has been reported among patients who undergo living donor liver transplantation (LDLT) with higher model for end-stage liver disease (MELD) scores. In this study, we investigated the effect of MELD score reduction on post-operative outcomes in patients with a high MELD (≥20) score by pre-transplant management., Materials and Methods: We retrospectively analyzed 386 LDLT cases, and patients were divided into low-MELD (<20, n=293) vs. high-MELD (≥20, n=93) groups according to their MELD score at the time of index hospitalization. Patients in the high-MELD group were managed specifically according to a treatment algorithm in an effort to decrease the MELD score. Patients in the high-MELD group were further divided into 2 subgroups: (1) responders (n=34) to pre-transplant treatment with subsequent reduction of the MELD score by a minimum of 1 point vs. (2) non-responders (n=59), whose MELD score remained unchanged or further increased on the day of LDLT. Responders vs. non-responders were compared according to etiology, demographics, and survival.

Objective: The National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) is a programme of infrastructure development across NIHR Biomedical Research Centres. The aim of the NIHR HIC is to improve the quality and availability of routinely collected data for collaborative, cross-centre research. This is demonstrated through research collaborations in selected therapeutic areas, one of which is viral hepatitis., Design: The collaboration in viral hepatitis identified a rich set of datapoints, including information on clinical assessment, antiviral treatment, laboratory test results and health outcomes. Clinical data from different centres were standardised and combined to produce a research-ready dataset; this was used to generate insights regarding disease prevalence and treatment response., Results: A comprehensive database has been developed for potential viral hepatitis research interests, with a corresponding data dictionary for researchers across the centres. An initial cohort of 960 patients with chronic hepatitis B infections and 1404 patients with chronic hepatitis C infections has been collected., Conclusion: For the first time, large prospective cohorts are being formed within National Health Service (NHS) secondary care services that will allow research questions to be rapidly addressed using real-world data. Interactions with industry partners will help to shape future research and will inform patient-stratified clinical practice. An emphasis on NHS-wide systems interoperability, and the increased utilisation of structured data solutions for electronic patient records, is improving access to data for research, service improvement and the reduction of clinical data gaps., Competing Interests: Competing interests: LND reports grants from National Institute for Health Research, during the conduct of the study. KA reports personal fees from Vir, Gilead, Springbank, Roche, Janssen, Biotest, Aligos, Arbutus, Assembly and Shinoigi, grants from Merck Sharp & Dohme, outside the submitted work. GC reports personal fees from Gilead and Merck Sharp & Dohme outside the submitted work. BG reports other from Imperial National Institute for Health Research (NIHR) Biomedical Research Centres (BRC), during the conduct of the study. ATS reports grants from NIHR Health Informatics Collaborative, other from NIHR BRC, during the conduct of the study. EN reports grants from ViiV healthcare, grants from GlaxoSmithKline, grants from Gilead, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Alcoholic hepatitis should be suspected in every patient with excessive chronic alcohol consumption and recent onset of jaundice. Diagnosis of alcoholic hepatitis is based on clinical and laboratory findings, and confirmed by a liver biopsy when available. Several scores are available to assess severity and prognosis of alcoholic hepatitis. The 1-month mortality of patients with severe alcoholic hepatitis, as defined by Maddrey's discriminant function, is 20-30%. Therefore, severe alcoholic hepatitis should be treated with a 28-day course of oral prednisolone after systematic screening for infection. In this review, we discuss diagnosis of alcoholic hepatitis, the different scores to assess severity of the disease, indications for corticosteroid therapy and alternative therapeutic options for non-responders to medical therapy.