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Daniel Pievsky,1 Nikolaos Pyrsopoulos2 1Department of Internal Medicine, 2Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, University Hospital, Newark, NJ, USA Abstract: Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related death in the United States and carries a very poor prognosis, with a median survival time of

Background: Protein-energy malnutrition is associated with poor surgical outcomes in liver transplant patients, but its impact on healthcare use has not been precisely characterized. We sought to quantify the burden of protein-energy malnutrition in hospitalized patients undergoing liver transplantation., Methods: Current Procedural Terminology codes were used to identify United States hospitalizations between 2011 and 2018 for liver transplantation using the Nationwide Inpatient Sample. Patients <18 years old were excluded. Protein-energy malnutrition was identified by International Classification of Diseases Ninth and Tenth Revision codes. Multivariable regression was used to determine associations between protein-energy malnutrition and hospital outcomes, including hospital length of stay and hospital charges/costs., Results: Of 9856 hospitalizations, 2835 (29%) had protein-energy malnutrition. Patients with protein-energy malnutrition had greater comorbidity burden and in-hospital acuity (eg, dialysis, sepsis, vasopressors, or mechanical ventilation). The adjusted median difference of protein-energy malnutrition vs no protein-energy malnutrition for length of stay was 6.4 days (95% CI, 5.6-7.1; P < 0.001), for hospital charges was $108,063 (95% CI, $93,172-$122,953; P < 0.001), and for hospital costs was $23,636 (95% CI, $20,390-$26,882; P < 0.001)., Conclusion: Among patients undergoing liver transplantation, protein-energy malnutrition was associated with increased length of stay and hospital charges/costs. The additional cost of protein-energy malnutrition to liver transplantation programs was $23,636 per protein-energy malnutrition hospitalization. Our data justify the development of and investment in personnel and programs dedicated to reversing-or even preventing-protein-energy malnutrition in patients awaiting liver transplantation., (© 2024 American Society for Parenteral and Enteral Nutrition.)

Background: Autoimmune liver diseases (AiLD) encompass a variety of disorders that target either the liver cells (autoimmune hepatitis, AIH) or the bile ducts [(primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC)]. These conditions can progress to chronic liver disease (CLD), which is characterized by fibrosis, cirrhosis, and hepatocellular carcinoma. Recent studies have indicated a rise in hospitalizations and associated costs for CLD in the US, but information regarding inpatient admissions specifically for AiLD remains limited., Aim: To examine the trends and mortality of inpatient hospitalization of AiLD from 2011 to 2017., Methods: This study is a retrospective analysis utilizing the National Inpatient Sample (NIS) databases. All subjects admitted between 2011 and 2017 with a diagnosis of AiLD (AIH, PBC, PSC) were identified using the International Classification of Diseases (ICD-9) and ICD-10 codes. primary AiLD admission was defined if the first admission code was one of the AiLD codes. secondary AiLD admission was defined as having the AiLD diagnosis anywhere in the admission diagnosis (25 diagnoses). Subjects aged 21 years and older were included. The national estimates of hospitalization were derived using sample weights provided by NIS. χ 2 tests for categorical data were used. The primary trend characteristics were in-hospital mortality, hospital charges, and length of stay., Results: From 2011 to 2017, hospitalization rates witnessed a significant decline, dropping from 83263 admissions to 74850 admissions ( P < 0.05). The patients hospitalized were predominantly elderly (median 53% for age > 65), mostly female (median 59%) ( P < 0.05), and primarily Caucasians (median 68%) ( P < 0.05). Medicare was the major insurance (median 56%), followed by private payer (median 27%) ( P < 0.05). The South was the top geographical distribution for these admissions (median 33%) ( P < 0.05), with most admissions taking place in big teaching institutions (median 63%) ( P < 0.05). Total charges for admissions rose from 66031 in 2011 to 78987 in 2017 ( P < 0.05), while the inpatient mortality rate had a median of 4.9% ( P < 0.05), rising from 4.67% in 2011 to 5.43% in 2017. The median length of stay remained relatively stable, changing from 6.94 days (SD = 0.07) in 2011 to 6.51 days (SD = 0.06) in 2017 ( P < 0.05). Acute renal failure emerged as the most common risk factor associated with an increased death rate, affecting nearly 68% of patients ( P < 0.05)., Conclusion: AiLD-inpatient hospitalization showed a decrease in overall trends over the studied years, however there is a significant increase in financial burden on healthcare with increasing in-hospital costs along with increase in mortality of hospitalized patient with AiLD., Competing Interests: Conflict-of-interest statement: All authors have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Ursodeoxycholic acid (UDCA) is the first-line treatment of primary biliary cholangitis (PBC). Long-term UDCA use significantly reduces progression to cirrhosis. UDCA improves liver enzymes and transplant-free survival rates. Despite the association between PBC and hyperlipidemia, treatment is indicated under specific circumstances with statins and fibrates being safe options. Osteoporosis, which is frequently seen, is usually managed based on data from postmenopausal women. Sicca syndrome is treated similarly to its standalone condition with the use of hydroxypropyl methylcellulose eye drops and anticholinergic drugs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Understanding the interaction between the heart and liver is pivotal for managing patients in whom both organs are affected. Studies have shown that cardio-hepatic interactions are bidirectional and that their identification, assessment, and treatment remain challenging. Congestive hepatopathy is a condition that develops in the setting of long-standing systemic venous congestion. If left untreated, congestive hepatopathy may lead to hepatic fibrosis. Acute cardiogenic liver injury develops as a combination of venous stasis and sudden arterial hypoperfusion due to cardiac, circulatory, or pulmonary failure. The treatment of both conditions should be directed toward optimizing the cardiac substrate. Hyperdynamic syndrome may develop in patients with advanced liver disease and lead to multiorgan failure. Cirrhotic cardiomyopathy or abnormalities in pulmonary vasculature, such as hepatopulmonary syndrome and portopulmonary hypertension may also develop. Each complication has unique treatment challenges and implications for liver transplantation. The presence of atrial fibrillation and atherosclerosis in liver disease brings another layer of complexity, particularly in terms of anticoagulation and statin use. This article provides an overview of cardiac syndromes in liver disease, focusing on current treatment options and future perspectives., Competing Interests: NP has been an associate editor of Journal of Clinical and Translational Hepatology since 2021. The other authors have no conflict of interests related to this publication., (© 2023 Authors.)

Background and Aim: Hepatic decompensation is a major complication of liver cirrhosis. We validated the predictive performance of the newly proposed CHESS-ALARM model to predict hepatic decompensation in patients with hepatitis B virus (HBV)-related cirrhosis and compared it with other transient elastography (TE)-based models such as liver stiffness-spleen size-to-platelet (LSPS), portal hypertension (PH), varices risk scores, albumin-bilirubin (ALBI), and albumin-bilirubin-fibrosis-4 (ALBI-FIB-4)., Methods: Four hundred eighty-two patients with HBV-related liver cirrhosis between 2006 and 2014 were recruited. Liver cirrhosis was clinically or morphologically defined. The predictive performance of the models was assessed using a time-dependent area under the curve (tAUC)., Results: During the study period, 48 patients (10.0%) developed hepatic decompensation (median 93 months). The 1-year predictive performance of the LSPS model (tAUC = 0.8405) was higher than those of the PH model (tAUC = 0.8255), ALBI-FIB-4 (tAUC = 0.8168), ALBI (tAUC = 0.8153), CHESS-ALARM (tAUC = 0.8090), and variceal risk score (tAUC = 0.7990). The 3-year predictive performance of the LSPS model (tAUC = 0.8673) was higher than those of the PH risk score (tAUC = 0.8670), CHESS-ALARM (tAUC = 0.8329), variceal risk score (tAUC = 0.8290), ALBI-FIB-4 (tAUC = 0.7730), and ALBI (tAUC = 0.7451). The 5-year predictive performance of the PH risk score (tAUC = 0.8521) was higher than those of the LSPS (tAUC = 0.8465), varices risk score (tAUC = 0.8261), CHESS-ALARM (tAUC = 0.7971), ALBI-FIB-4 (tAUC = 0.7743), and ALBI (tAUC = 0.7541). However, there was no significant difference in the predictive performance among all models at 1, 3, and 5 years (P > 0.05)., Conclusions: The CHESS-ALARM score was able to reliably predict hepatic decompensation in patients with HBV-related liver cirrhosis and showed similar performance to the LSPS, PH, varices risk scores, ALBI, and ALBI-FIB-4., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Acute-on-chronic liver failure (ACLF) results from an acute decompensation of cirrhosis due to exogenous insult. The condition is characterized by a severe systemic inflammatory response, inappropriate compensatory anti-inflammatory response, multisystem extrahepatic organ failure, and high short-term mortality. Here, the authors evaluate the current status of potential treatments for ACLF and assess their efficacy and therapeutic potential., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Mortality caused by cirrhosis is now the 14th most common cause of death worldwide and 12th most common in the United States. We studied trends in inpatient mortality and hospitalization charges associated with cirrhotic decompensation from esophageal variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome from 2007 to 2017., Materials and Methods: Using the National Inpatient Sample databases, we first isolated patients 18 years or older with the diagnosis of cirrhosis using International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, Tenth Revision (ICD-10) codes. We then identified patients with the admission diagnosis of esophageal variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. Time-series regression was used to determine whether a trend occurred over the study period. We also evaluated for patient-related demographic changes over the study period., Results: A total of 259,897 cirrhotic patients with the studied decompensations were captured. During the study period, time-series regression confirmed downtrends in mortality rates and length of stay for all types of decompensations. Conversely, we found increases in hospitalization charges for all types of decompensations. Patient age increased over the study period. Patients were also more likely to be White and pay with., Conclusion: From 2007 to 2017, inpatient mortality rates and lengths of stay decreased for cirrhotic decompensations for all causes of decompensation. Total charges, conversely, increased for all causes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) remains a deadly disease, with patients' best hope for a cure being liver transplantation; however, access to health care resources, such as donor organs, between ethnic groups has historically been unbalanced. Ensuring equitable access to donor livers is crucial to minimize disparities in HCC outcomes. As a result, we sought to better elucidate the differences in transplantation rates among various ethnic groups., Materials and Methods: The National Inpatient Sample (NIS) was utilized to evaluate for disparities in liver transplantation in patients whose primary or secondary diagnosis was recorded as HCC or hepatoma. The study included admissions between 2007 and 2014 to centers with at least 1 documented liver transplant., Results: A total of 7244 transplants were performed over 70,406 weighted admissions. Black race was associated with lower transplantation rates, with an adjusted odds ratio of 0.46 (95% confidence interval: 0.42-0.51, P <0.01) when accounting for a number of possible confounders including socioeconomic and geographic factors., Conclusions: Our study observed decreased rates of liver transplant in blacks compared with whites for HCC. Furthermore, improved economic status and private insurance had a significantly higher odds ratio for transplantation. Hospital-level studies are needed to clarify confounding factors not apparent in large administrative datasets and help better investigate factors that lead to less optimal transplant rates among blacks. Interventions may include more optimal screening policies and procedures, improved interdisciplinary management, and earlier referrals., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Severe alcoholic hepatitis (AH) is one of the most lethal manifestations of alcohol-associated liver disease. In light of the increase in alcohol consumption worldwide, the incidence of AH is on the rise, and data examining the trends of AH admission is needed., Aim: To examine inpatient admission trends secondary to AH, along with their clinical outcomes and epidemiological characteristics., Methods: The National Inpatient Sample (NIS) database was utilized, and data from 2011 to 2017 were reviewed. We included individuals aged ≥ 21 years who were admitted with a primary or secondary diagnosis of AH using the International Classification of Diseases (ICD)-9 and its correspondent ICD-10 codes. Hepatitis not related to alcohol was excluded. The national estimates of inpatient admissions were obtained using sample weights provided by the NIS., Results: AH-related hospitalization demonstrated a significant increase in the USA from 281506 (0.7% of the total admission in 2011) to 324050 (0.9% of the total admission in 2017). The median age was 54 years. The most common age group was 45-65 years (range 57.8%-60.7%). The most common race was white (63.2%-66.4%), and patients were predominantly male (69.7%-71.2%). The primary healthcare payers were Medicare (29.4%-30.7%) and Medicaid (21.5%-32.5%). The most common geographical location was the Southern USA (33.6%-34.4%). Most patients were admitted to a tertiary care center (50.2%-62.3%) located in urban areas. Mortality of AH in this inpatient sample was 5.3% in 2011 and 5.5% in 2017. The most common mortality-associated risk factors were acute renal failure (59.6%-72.1%) and gastrointestinal hemorrhage (17.2%-20.3%). The total charges were noted to range between $25242.62 and $34874.50., Conclusion: The number of AH inpatient hospitalizations significantly increased from 2011 to 2017. This could have a substantial financial impact with increasing healthcare costs and utilization. AH-mortality remained the same., Competing Interests: Conflict-of-interest statement: All authors have no relevant conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours' standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child-Turcotte-Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose-dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%-60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE., (© 2022 Hadassah Medical Center. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Hepatitis E virus (HEV) originally identified as a cause of acute icteric hepatitis in developing countries has grown to be a cause of zoonotic viral hepatitis in developed countries such as the United States. While there are eight identified genotypes to date, genotype 1 (HEV1), HEV2, HEV3, HEV4 are the most common to infect humans. HEV1 and HEV2 are most common in developing countries including Latina America, Africa and Asia, and are commonly transmitted through contaminated water supplies leading to regional outbreaks. In contrast HEV3 and HEV4 circulate freely in many mammalian animals and can lead to occasional transmission to humans through fecal contamination or consumption of undercooked meat. The incidence and prevalence of HEV in the United States is undetermined given the absence of FDA approved serological assays and the lack of commercially available testing. In majority of cases, HEV infection is a self-limiting hepatitis requiring only symptomatic treatment. However, this is not the case in immunocompromised individuals, including those that have undergone solid organ or stem cell transplantation. In this subset of patients, chronic infection can be life threatening as hepatic insult can lead to inflammation and fibrosis with subsequent cirrhosis and death. The need for re-transplantation as a result of post-transplant hepatitis is of great concern. In addition, there have been many reported incidents of extrahepatic manifestations, for which the exact mechanisms remain to be elucidated. The cornerstone of treatment in immunocompromised solid organ transplant recipients is reduction of immunosuppressive therapies, while attempting to minimize the risk of organ rejection. Subsequent treatment options include ribavirin, and pegylated interferon alpha in those who have demonstrated ribavirin resistance. Further investigation assessing safety and efficacy of anti-viral therapy is imperative given the rising global health burden. Given this concern, vaccination has been approved in China with other investigations underway throughout the world. In this review we introduce the epidemiology, diagnosis, clinical manifestations, and treatment of HEV, with emphasis on immunocompromised individuals in the United States., Competing Interests: Conflict-of-interest statement: The authors do not have any conflicts of interest relevant to this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Cannabinoid receptors are potential therapeutic targets in a variety of gastrointestinal tract disorders. The authors hypothesize that the use of cannabis use is associated with better control of symptoms associated with irritable bowel syndrome (IBS). This study aimed to examine the utilization of inpatient services by patients with IBS who did and did not report the use of cannabis., Methods: This is a retrospective cohort study that utilized the 2016 Nationwide Readmissions Database. Inclusion criteria included a principal diagnosis of IBS. The primary outcome was 30-day hospital readmission rates for IBS-specific causes. Secondary outcomes included the 30-day hospital readmission rates for all causes, resource utilization, and the 5 most common principal diagnoses and independent risk factors associated with readmission., Results: Of the 7163 patients with IBS identified in the National Readmission Database, 357 reported the use of cannabis. The 30-day IBS-specific readmission rates were 1.5% in patients who reported cannabis use and 1.1% in those who did not report cannabis use (P=0.53). Among the cannabis users, none of the variables evaluated served as a significant predictor of IBS-specific readmission; median income was a predictor for readmission among those who did not report cannabis use (odds ratio, 2.77; 95% confidence interval, 1.15-6.67; P=0.02). The 30-day readmission rates for all causes were 8.1% and 12.7% for patients who did and did not report cannabis use, respectively. After adjusting for confounders, the odds of 30-day readmission for all causes were lower among patients who reported cannabis use compared with those who did not (adjusted odds ratio, 0.53; 95% confidence interval, 0.28-0.99; P=0.04). The 5 most frequent diagnoses at readmission among patients who did not report cannabis use were enterocolitis because of Clostridioides difficile, IBS without diarrhea, sepsis, noninfective gastroenteritis and colitis, and acute kidney failure. By contrast, the 5 most frequent readmission diagnoses for cannabis users were cyclical vomiting, IBS with diarrhea, endometriosis, right upper quadrant abdominal pain, and nausea with vomiting. A discharge disposition of "against medical advice" was identified as an independent risk factor for 30-day hospital readmission for all causes among patients who reported cannabis use. By contrast, higher comorbidity scores and discharges with home health care were independent predictors of 30-day hospital readmission for all causes among patients who did not report cannabis use. Private insurance was an independent factor associated with lower rates of readmission for all causes among those who did not report cannabis use., Conclusion: Our review of the National Readmission Database revealed no statistically significant differences in 30-day readmission rates for IBS-specific causes when comparing patients who reported cannabis use with those who did not. However, the authors found that cannabis use was associated with reduced 30-day hospital readmission rates for all causes., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aim: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant., Methods: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16., Results: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation., Conclusions: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS., Gov Identifier: NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group., Competing Interests: Conflict of interest DP, FS, JB are employees of Zydus Discovery DMCC. No conflict of interest relevant to the current trial were reported by the rest of the authors listed for this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new acronym adopted from the consensus of international experts. Given the increasing prevalence of MAFLD in pre-transplant settings, de novo and recurrent graft steatosis/MAFLD are common in post-transplant settings. The impact of graft steatosis on long-term outcomes is unclear. The current knowledge of incidence rate, risk factors, diagnosis, long-term outcomes, and management of graft steatosis (both de novo and recurrent) is discussed in this review., Competing Interests: Conflict-of-interest statement: Authors have nothing to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background & Aims: Hepatic encephalopathy (HE) is associated with increased morbidity, mortality, and health care resource use. In this phase 2b study, we evaluated the efficacy and safety of ornithine phenylacetate (OP), an ammonia scavenger, in hospitalized patients with cirrhosis, increased levels of ammonia at screening, and acute or overt HE., Methods: We conducted a double-blind study of 231 patients with cirrhosis and HE at multiple sites in North America, Europe, Israel, and Australia from January 7, 2014, through December 29, 2016. Patients were assigned randomly to groups that received placebo or OP (10, 15, or 20 g/d, based on the severity of liver disease), plus each institution's standard of care (eg, lactulose to achieve 2-3 bowel movements with or without rifaximin, in accordance with guidelines). The primary end point was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stages 3/4 or improvement to HEST stages 0/1 from baseline stage 2, in the intent-to-treat population (all patients with increased levels of ammonia at screening, determined by a local laboratory)., Results: Median times to clinical improvement, based on ammonia measurements at local laboratories, did not differ significantly between the groups given OP vs the placebo group (P = .129). Analyses of central laboratory-confirmed increases in levels of ammonia at baseline (n = 201) showed clinical improvement in HE at a median of 21 hours sooner in groups given OP vs placebo. The percentages of patients with any specific adverse event did not differ significantly between groups. Serious adverse events occurred in 25% of patients in the OP group and in 29% in the placebo group (P = .552)., Conclusions: In a randomized controlled trial of patients with cirrhosis and HE, we found no significant difference in time to clinical improvement between patients given OP vs placebo. However, OP appears to be safe and should undergo further testing for treatment of hyperammonemia in hospitalized patients receiving treatment for the underlying precipitant of acute or overt HE. ClinicalTrials.gov no: NCT01966419., (Copyright © 2021 by the AGA Institute. Published by Elsevier, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease with increasing prevalence worldwide. Clostridioides difficile infection (CDI) remains the most common cause of nosocomial diarrhea in developed countries., Aim: To assess the impact of NAFLD on the outcomes of hospitalized patients with CDI., Methods: This study was a retrospective cohort study. The Nationwide Inpatient Sample database was used to identify a total of 7239 adults admitted as inpatients with a primary diagnosis of CDI and coexisting NAFLD diagnosis from 2010 to 2014 using ICD-9 codes. Patients with CDI and coexisting NAFLD were compared to those with CDI and coexisting alcoholic liver disease (ALD) and viral liver disease (VLD), individually. Primary outcomes included mortality, length of stay, and total hospitalization charges. Secondary outcomes were in-hospital complications. Multivariate regression was used for outcome analysis after adjusting for possible confounders., Results: CDI with NAFLD was independently associated with lower rates of acute respiratory failure (2.7% vs 4.2%, P < 0.01; 2.7% vs 4.2%, P < 0.05), shorter length of stay (days) (5.75 ± 0.16 vs 6.77 ± 0.15, P < 0.001; 5.75 ± 0.16 vs 6.84 ± 0.23, P < 0.001), and lower hospitalization charges (dollars) (38150.34 ± 1757.01 vs 46326.72 ± 1809.82, P < 0.001; 38150.34 ± 1757.01 vs 44641.74 ± 1660.66, P < 0.001) when compared to CDI with VLD and CDI with ALD, respectively. CDI with NAFLD was associated with a lower rate of acute kidney injury (13.0% vs 17.2%, P < 0.01), but a higher rate of intestinal perforation ( P < 0.01) when compared to VLD. A lower rate of mortality (0.8% vs 2.7%, P < 0.05) but a higher rate of intestinal obstruction (4.6% vs 2.2%, P = 0.001) was also observed when comparing CDI with NAFLD to ALD., Conclusion: Hospitalized CDI patients with NAFLD had more intestinal complications compared to CDI patients with VLD and ALD. Gut microbiota dysbiosis may contribute to the pathogenesis of intestinal complications., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest related to this publication., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

The incidence of alcoholic hepatitis is increasing while the mortality rate remains high. The single current available therapy for severe alcoholic hepatitis is administration of corticosteroids for patients with severe alcoholic hepatitis, which has demonstrated limited benefits, providing a short-term mortality benefit with a marginal response rate. There is a need for developing safe and effective therapies. This article reviews novel therapies targeting various mechanisms in the pathogenesis of alcoholic hepatitis, such as the gut-liver axis, inflammatory cascade, oxidative stress, and hepatic regeneration. Current ongoing clinical trials for alcoholic hepatitis also are described., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are hepatobiliary diseases of presumed immune-mediated origin that have been shown to overlap. The aim of this retrospective trial was to use national data to examine the characteristics and outcomes of patients hospitalized with overlapping PBC and AIH (PBC/AIH)., Methods: The National Inpatient Sample was used to identify hospitalized adult patients with PBC, AIH, and PBC/AIH from 2010 to 2014 by International Classification of Diseases-Ninth Edition Revision codes; patients with hepatitis B virus and hepatitis C virus infection were excluded. Primary outcomes measures were in-hospital outcomes that included mortality, respiratory failure, septic shock, length of stay, and total hospital charges. Secondary outcomes were the clinical characteristics of PBC/AIH, including the comorbid extrahepatic autoimmune disease pattern and complications of cirrhosis., Results: A total of 3,478 patients with PBC/AIH were included in the study. PBC/AIH was associated with higher rates of Sjögren's syndrome ( p <0.001; p <0.001), lower rates of Crohn's disease ( p <0.05; p <0.05), and higher rates of cirrhosis-related complications when compared to PBC or AIH alone. There were similar rates of mortality between the PBC/AIH, PBC, and AIH groups. The PBC/AIH group had higher rates of septic shock when compared to the PBC group ( p <0.05) and AIH group ( p <0.05) after adjusting for possible confounders., Conclusions: PBC/AIH is associated with a lower rate of Crohn's disease, a higher rate of Sjögren's syndrome, higher rates of cirrhosis-related complications, and significantly increased risk of septic shock compared to PBC and AIH individually., Competing Interests: The authors have no conflict of interests related to this publication., (© 2021 Authors.)

Despite numerous advances and emerging data, liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications. In an era of persistent organ shortage and increasing organ demand, allocation of liver grafts must be considered carefully. While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation, tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes. As more studies seeking to expand the oncologic indications for liver transplantation are emerging, it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes. In addition, time from diagnosis to transplantation appears to correlate with survival, as stable disease over time portends better outcomes post-operatively. Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques. While tumor size and stage are important prognostic predictors for most malignancies, patient and tumor selection protocols are necessary. As the fields of medical and surgical oncology continue to evolve, it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively. Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms. Current data evaluating liver transplantation for expanded oncologic indications such as: expanded criteria hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed tumors, and liver limited metastatic colorectal carcinomas, incorporate multi-modal therapies and evaluation of tumor treatment response. While further investigation is necessary, initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology., Competing Interests: Conflict-of-interest statement: The authors of this manuscript have no relevant conflicts of interest or disclosures to report., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is unfortunately associated with an overall poor prognosis and high mortality. Early and intermediate stages of HCC allow for treatment with surgical resection, ablation and even liver transplantation, however disease progression warrants conventional systemic therapy. For years treatment options were limited to molecular-targeting medications, of which sorafenib remains the standard of care. The recent development and success of immune checkpoint inhibitors has proven to be a breakthrough in the treatment of HCC, but there is an urgent need for the development of further novel therapeutic treatments that prolong overall survival and minimize recurrence. Current investigation is focused on adoptive cell therapy including chimeric antigen receptor-T cells (CAR-T cells), T cell receptor (TCR) engineered T cells, dendritic cells, natural killer cells, and tumor infiltrating lymphocyte cells, which have shown remarkable success in the treatment of hematological and solid tumor malignancies. In this review we briefly introduce readers to the currently approved systemic treatment options and present clinical and experimental evidence of HCC immunotherapeutic treatments that will hopefully one day allow for revolutionary change in the treatment modalities used for unresectable HCC. We also provide an up-to-date compilation of ongoing clinical trials investigating CAR-T cells, TCR engineered T cells, cancer vaccines and oncolytic viruses, while discussing strategies that can help overcome commonly faced challenges when utilizing cellular based treatments., Competing Interests: Conflict-of-interest statement: The authors do not have any conflicts of interest relevant to this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Globally, the rise in prevalence of obesity and metabolic syndrome as a whole has been linked to increased access to processed foods, such as refined sugars and saturated fats. Consequently, nonalcoholic fatty liver disease (NAFLD) is on the rise in both developed and developing nations. However, much is still unknown on the NAFLD phenotype with regards to the effect of ethnic diversity. Despite similarities in dietary habits, it appears that certain ethnicities are more protected against NAFLD than others. However, manifestations of the same genetic polymorphisms in different groups of people increase those individuals' predisposition to NAFLD. Diets from different regions have been associated with a lower prevalence of NAFLD and have even been linked to regression of hepatic steatosis. Socioeconomic variations amongst different regions of the world also contribute to NAFLD prevalence and associated complications. Thus, a thorough understanding of ethnic variability in NAFLD is essential to tailoring treatment recommendations to patients of different backgrounds., Competing Interests: The authors have no conflict of interests related to this publication., (© 2021 Authors.)

Recent progress in our understanding of the pathways linked to progression from hepatic insult to cirrhosis has led to numerous novel therapies being investigated as potential cures and inhibitors of hepatic fibrogenesis. Liver cirrhosis is the final result of prolonged fibrosis, which is an intimate balance between fibrogenesis and fibrinolysis. A number of these complex mechanisms are shared across the various etiologies of liver disease. Thankfully, investigation has yielded some promising results in regard to reversal of fibrosis, particularly the indirect benefits associated with antiviral therapy for the treatment of hepatitis B and C and the farnesoid receptor agonist for the treatment of primary biliary cholangitis and metabolic associated fatty liver disease. A majority of current clinical research is focused on targeting metabolic associated fatty liver disease and its progression to metabolic steatohepatitis and ultimately cirrhosis, with some hope of potential standardized therapeutics in the near future. With our ever-evolving understanding of the underlying pathophysiology, these therapeutics focus on either controlling the primary disease (the initial trigger of fibrogenesis), interrupting receptor ligand interactions and other intracellular communications, inhibiting fibrogenesis, or even promoting resolution of fibrosis. It is imperative to thoroughly test these potential therapies with the rigorous standards of clinical therapeutic trials in order to ensure the highest standards of patient safety. In this article we will briefly review the key pathophysiological pathways that lead to liver fibrosis and present current clinical and experimental evidence that has shown reversibility of liver fibrosis and cirrhosis, while commenting on therapeutic safety., Competing Interests: Conflict-of-interest statement: The authors do not have any conflicts of interest relevant to this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: It has been reported that transjugular intrahepatic portosystemic shunting (TIPS) might be utilized as a salvage option for hepatorenal syndrome (HRS), while randomized controlled trials are pending and real-world contemporary data on inpatient mortality is lacking., Methods: We conducted an observational retrospective cohort study from the National Inpatient Sample from 2005 to 2014. We included all adult patients admitted with HRS and cirrhosis, using ICD 9-CM codes. We excluded cases with variceal bleeding, Budd-Chiari, end-stage renal disease, liver transplant and transfers to acute-care facilities. TIPS' association with inpatient mortality was assessed using multivariable mixed-effects logistic regression, as well as exact-matching, thus mitigating for TIPS selection bias. The exact-matched analysis was repeated among TIPS-only versus dialysis-only patients., Results: A total of 79,354 patients were included. Nine hundred eighteen (1.2%) underwent TIPS. Between TIPS and non-TIPS groups, mean age (58 years) and gender (65% males) were similar. Overall mortality was 18% in TIPS and 48% in dialysis-only cases (n = 10,379; 13.1%). Ninety six (10.5%) TIPS patients underwent dialysis. In-hospital mortality in TIPS patients was twice less likely than in non-TIPS patients (adjusted odds ratio [aOR] = 0.43, 95% CI 0.30-0.62; p < 0.001), with similar results in matched analysis [exact-matched (em) OR = 0.39, 95% CI 0.17-0.89; p < 0.024; groups = 96; unweighted n = 463]. Head-to-head comparison showed that TIPS-only patients were 3.3 times less likely to succumb inpatient versus dialysis-only patients (contrast aOR = 0.31, 95% CI 0.20-0.46; p < 0.001), with similar findings post-matching (emOR = 0.22, 95% CI 0.15-0.33; p < 0.001; groups = 54, unweighted n = 1457)., Conclusions: Contemporary, real-world data reveal that TIPS on its own, and when compared to dialysis, is associated with decreased inpatient mortality when utilized in non-bleeders-HRS patients. Further randomized studies are needed to establish the long-term benefit of TIPS in these patients.

Background: Acute variceal bleeding is a major complication of portal hypertension and is a leading cause of death in patients with cirrhosis. There is limited data on the outcomes of patients with esophageal variceal bleeding in teaching versus nonteaching hospitals. Because esophageal variceal bleeding requires complex management, it may be hypothesized that teaching hospitals have lower mortality., Aim: To assess the differences in mortality, hospital length of stay (LOS) and cost of admission for patients admitted for variceal bleed in teaching versus nonteaching hospitals across the US., Methods: The National Inpatient Sample is the largest all-payer inpatient database consisting of approximately 20% of all inpatient admissions to nonfederal hospitals in the United States. We collected data from the years 2008 to 2014. Cases of variceal bleeding were identified using the International Classification of Diseases, Ninth Edition, Clinical Modification codes. Differences in mortality, LOS and cost were evaluated for patients with esophageal variceal bleed between teaching and nonteaching hospitals and adjusted for patient characteristics and comorbidities., Results: Between 2008 and 2014, there were 58362 cases of esophageal variceal bleeding identified. Compared with teaching hospitals, mortality was lower in non-teaching hospitals (8.0% vs 5.3%, P < 0.001). Median LOS was shorter in nonteaching hospitals as compared to teaching hospitals (4 d vs 5 d, P < 0.001). A higher proportion of non-white patients were managed in teaching hospitals. As far as procedures in nonteaching vs teaching hospitals, portosystemic shunt insertion (3.1% vs 6.9%, P < 0.001) and balloon tamponade (0.6% vs 1.2%) were done more often in teaching hospitals while blood transfusions (64.2% vs 59.9%, P = 0.001) were given more in nonteaching hospitals. Using binary logistic regression models and adjusting for baseline patient demographics and comorbid conditions the mortality, LOS and cost in teaching hospitals remained higher., Conclusion: In patients admitted for esophageal variceal bleeding, mortality, length of stay and cost were higher in teaching hospitals versus nonteaching hospitals when controlling for other confounding factors., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interest for this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Drug induced liver injury (DILI) is a common cause of acute liver injury. Paracetamol, also known as acetaminophen, is a widely used anti-pyretic that has long been established to cause liver toxicity once above therapeutic levels. Hepatotoxicity from paracetamol overdose, whether intentional or non-intentional, is the most common cause of DILI in the United States and remains a global issue. Given the increased prevalence of combination medications in the form of pain relievers and antihistamines, paracetamol can be difficult to identify and remains a significant cause of acute hepatotoxicity, as evidenced by its contribution to over half of all acute liver failure cases in the United States. This is especially concerning given that, when co-ingested with other medications, the rise in serum paracetamol levels may be delayed past the 4-hour post-ingestion mark that is currently used to determine patients that require medical therapy. This review serves to describe the clinical and pathophysiologic features of hepatotoxicity secondary to paracetamol and provide an update on current available knowledge and treatment options., Competing Interests: Conflict-of-interest statement: Dr. Pyrsopoulos reports grants from Allergan, grants from Bayer, grants from Beigene, grants from Bristol Myers, grants from Confirm, grants from Conatus, grants from Intercept, grants from Mallinckrodt, grants from Novartis, grants from Resusix, grants from Saro, grants from Valeant, grants from Gilead, grants from Exelixis, grants from Hologic, grants from Shire, grants from Genfit, grants from Prometheus, outside the submitted work. Dr. Rotundo certifies that she has no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: Liver biopsy remains the gold standard for staging of chronic liver disease following orthotopic liver transplantation. Noninvasive assessment of fibrosis with Fibro-test (FT) is well-studied in immunocompetent populations with chronic hepatitis C virus infection. The aim of this study is to investigate the diagnostic value of FT in the assessment of hepatic fibrosis in the allografts of liver transplant recipients with evidence of recurrent hepatitis C. Methods: We retrospectively compared liver biopsies and FT performed within a median of 1 month of each other in orthotopic liver transplantation recipients with recurrent hepatitis C. Results: The study population comprised 22 patients, most of them male (19/22), and with median age of 62 years. For all patients, there was at least a one-stage difference in fibrosis as assessed by liver biopsy compared to FT, while for the majority (16/22) there was at least a two-stage difference. The absence of correlation between the two modalities was statistically demonstrated (Mann-Whitney U test, p = 0.01). In detecting significant fibrosis (a METAVIR stage of F2 and above), an FT cut-off of 0.5 showed moderate sensitivity (77%) and negative predictive value (80%), but suboptimal specificity (61%) and positive predictive value (58%). Conclusions: In post-transplant patients with recurrent hepatitis C, FT appears to be inaccurately assessing the degree of allograft fibrosis, therefore limiting its reliability as a staging tool., Competing Interests: Nikolaos Pyrsopoulos is a recipient of research grants from Gilead, Abbvie, Merck and Roche. The other authors have no conflict of interests related to this publication., (© 2020 Authors.)

Nonalcoholic fatty liver disease (NAFLD) is the accumulation of fat in the liver in the absence of secondary causes. NAFLD is a multifactorial disease that results from the interaction of genetic predisposition and metabolic, inflammatory and environmental factors. Among these factors, dysregulation of gut microbiome has been linked to the development of fatty liver disease. The microbiome composition can be modified by dietary habits leading to gut microbiome dysbiosis, especially when a diet is rich in saturated fats, animal products and fructose sugars. Different species of bacteria in the gut metabolize nutrients differently, triggering different pathways that contribute to the accumulation of fat within the liver and triggering inflammatory cascades that promote liver damage. In this review, we summarize the current understanding of the roles of gut microbiota in mediating NAFLD development and discuss possible gut microbiota-targeted therapies for NAFLD. We summarize experimental and clinical evidence, and draw conclusions on the therapeutic potential of manipulating gut microbiota to decrease the incidence and prevalence of fatty liver disease., Competing Interests: Nikolaos Pyrsopoulos declares separate research grants from Gilead Sciences, Intercept, Shire, Genfit, Prometheus, Conatus. The other authors have no conflict of interests related to this publication.