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IMPORTANCE: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure. OBJECTIVE: To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports. DESIGN, SETTING, AND PARTICIPANTS: This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023. EXPOSURES: Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity. MAIN OUTCOMES AND MEASURES: Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports. RESULTS: The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports. CONCLUSIONS AND RELEVANCE: In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.

ABSTRACTIntroductionThe growing prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and its association with obesity as a metabolic disease contributes to harmful outcomes and healthcare resource burden worldwide. For this reason, there is an urgent need to develop new therapies. Identification of treatment targets, research design, endpoints definitions and assessments, and supportive regulatory pathways for drug approval all play prominent roles in shaping efforts in drug discovery, investigation, and approval.Areas coveredIn this perspective, the authors enumerate key challenges of NAFLD clinical research and offer a conceptual framework to address these issues which arise during clinical trials.Expert opinionWith the anticipated significant healthcare and costs burden that NAFLD will impose throughout the world, the diagnostics and drug development processes need to be accelerated. Important measures to improve clinical trial research include standardization of case definitions, comprehensive and granular covariate data collection, quality study development incorporating novel trial designs, and quality data reporting. The authors believe that these actions will accelerate understanding, development, and ultimately approval of efficacious treatments.

Budd-Chiari syndrome (BCS), or hepatic venous outflow obstruction, is a rare cause of liver disease that should not be missed. Variable clinical presentation among patients with BCS necessitates a high index of suspicion to avoid missing this life-threatening diagnosis. BCS is characterized as primary or secondary, depending on etiology of venous obstruction. Most patients with primary BCS have several contributing risk factors leading to a prothrombotic state. A multidisciplinary stepwise approach is integral in treating BCS. Lifelong anticoagulation is recommended. Long-term monitoring of patients for development of cirrhosis, complications of portal hypertension, hepatocellular carcinoma, and progression of underlying diseases is important.

Chronic hepatitis C virus infection remains a national and global public health burden and is associated with significant morbidity and mortality. Oral direct-acting antiviral combination regimens have excellent tolerability and efficacy with rates exceeding 90%. Sustained virologic response is associated with significant improvements in clinical outcomes. However, translation of sustained virologic response rates from trials to community settings has been poor with interferon-based regimens. We review and summarize key datasets from major real-world observational cohort studies. We review preliminary data from oral generic direct-acting antiviral formulations. Future real-world studies are needed to further clarify optimal treatment strategies for difficult-to-treat populations.

Hepatic encephalopathy (HE) is one of the major clinical decompensations of cirrhosis, with a high impact on health care resource utilization and cost. For an effective and comprehensive management of HE, the clinicians need to understand the pathophysiologic mechanisms of HE. This review describes the multiorgan processes involved in HE and how several HE precipitants and treatment strategies act on ammonia production, excretion, and neurotoxicity, including the impact of diabetes and use of cannabinoids. The authors also discuss the current and future role of gut microbiome, systemic/central inflammation, and various neurotransmitters for the pathogenesis and treatment of HE.

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ABSTRACTIntroduction: Currently, hepatitis C virus (HCV) infection remains the most common indication for liver transplant in the United States (US) with almost universal HCV recurrence in the post-liver transplant setting. Previous interferon (IFN)-related efficacy and tolerability concerns about worsening liver function have limited treatment options for many patients with HCV-associated decompensated liver disease and post-liver transplant recipients. However, the last decade has seen a seen a radical shift in the management of HCV with multiple direct-acting antiviral (DAA) treatments that provide more effective, all-oral, IFN-free alternatives.Areas covered: This review will serve to highlight the various pharmacotherapies available to clinicians for patients with HCV recurrence post-liver transplant. A brief history of prior regimens is provided with evidence for newer treatments presented. Also detailed are updated guidelines from societal organizations. Finally, timing of HCV treatment is discussed as the decision to treat patients in a pre or post-liver transplant setting remains challenging.Expert opinion: While there are many potential available therapies for HCV recurrence in the post-liver transplant setting, daclatasvir/sofosbuvir and ledipasvir/sofosbuvir have been the most extensively studied. Newer, pangenotypic generation drugs require more evidence before routine utilization in post-liver transplant recipients.

Clinicians are required to assess abnormal liver chemistries on a daily basis. The most common liver chemistries ordered are serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin. These tests should be termed liver chemistries or liver tests. Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels. Cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels. The majority of bilirubin circulates as unconjugated bilirubin and an elevated conjugated bilirubin implies hepatocellular disease or cholestasis. Multiple studies have demonstrated that the presence of an elevated ALT has been associated with increased liver-related mortality. A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females and levels above this should be assessed. The degree of elevation of ALT and or AST in the clinical setting helps guide the evaluation. The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson’s disease, and alpha-1 antitrypsin deficiency. In addition, a history of prescribed and over-the-counter medicines should be sought. For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken. Total bilirubin elevation can occur in either cholestatic or hepatocellular diseases. Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings. A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible.

ObjectiveDue to a high efficacy in clinical trials, sofosbuvir (SOF) and ribavirin (RBV) for 12 or 16 weeks is recommended for treatment of patients with HCV genotype (GT) 2 infection. We investigated safety and effectiveness of these regimens for GT2 in HCV-TARGET participants.DesignHCV-TARGET, an international, prospective observational study evaluates clinical practice data on novel antiviral therapies at 44 academic and 17 community medical centres in North America and Europe. Clinical data were centrally abstracted from medical records. Selection of treatment regimen and duration was the investigator's choice. The primary efficacy outcome was sustained virological response 12 weeks after therapy (SVR12).ResultsBetween December 2013 and April 2015, 321 patients completed 12 weeks (n=283) or 16 weeks (n=38) of treatment with SOF and RBV. Prior treatment experience and cirrhosis was more frequent among patients in the 16-week regimen compared with 12 weeks (52.6% vs 27.6% and 63.2% vs 21.9%, respectively). Overall, SVR12 was 88.2%. The SVR12 in patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0% and 83%. In the multivariate analysis, liver cirrhosis, lower serum albumin and RBV dose at baseline were significantly associated with SVR12. Common adverse events (AEs) included fatigue, anaemia, nausea, headache, insomnia, rash and flu-like symptoms. Discontinuation due to AEs occurred in 2.8%.ConclusionsIn this clinical practice setting, SOF and RBV was safe and effective for treatment of patients with HCV GT2 infection.Trial registration numberNCT01474811.

Chronic hepatitis B virus (HBV) infection is a bloodborne infection which affects approximately 1.6 million persons in the U.S. and 292 million persons worldwide and is associated with significant morbidity and mortality due to cirrhosis and hepatocellular carcinoma. HBV disproportionately affects foreign-persons from endemic regions such as sub-Saharan Africa and the Asian-Pacific region. Chronic HBV is diagnosed with positive HBsAg and detectable HBV DNA. Patients with immunoactive disease (elevated HBV DNA and serum ALT) may require antiviral therapy with peg-interferon or oral nucleos(t)ide analogues which suppress viral replication, and are associated with a decreased risk for liver events.

OBJECTIVES:Data from the United States are lacking regarding the impact of entecavir (ETV) on the risk of hepatocellular carcinoma (HCC). Our aim is to determine whether treatment with ETV is associated with a reduced HCC risk by calculating the expected HCC incidence based on the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model and comparing it with the observed HCC incidence.METHODS:The incidence of HCC in US patients treated with ETV between 2005 and 2013 in a retrospective cohort was obtained. The predicted HCC incidence was calculated using the REACH-B model. The standardized incidence ratios (SIRs) were calculated as a ratio of observed over predicted HCC cases.RESULTS:Of 841 patients, 646 (65% male, 84% Asian, median age 47 years, 36% hepatitis B e antigen positive, 9.4% with cirrhosis) met the inclusion criteria. Over a median follow-up of 4 years, 17 (2.6%) cases of HCC were diagnosed, including 8 out of 61 (13.1%) patients with cirrhosis and 9 out of 585 (1.5%) without cirrhosis. Compared with those without HCC, the 17 patients with HCC were older at 53 years vs. 47 years and more likely to have cirrhosis at 47.1% vs. 8.4%. Among patients without cirrhosis, the observed HCC incidence was significantly lower than predicted by the fourth year (SIR, 0.37; 95% confidence interval: 0.166–0.82). A sensitivity analysis that comprised all patients, including those with cirrhosis, showed that at the maximum follow-up time of 8.2 years, a significantly lower than predicted HCC incidence was noted with an SIR of 0.56 (95% confidence interval: 0.35–0.905).CONCLUSIONS:Based on the REACH-B model, long-term ETV therapy was associated with a lower than predicted HCC incidence. However, the risk of HCC persisted, and careful HCC surveillance remains warranted despite the anti-viral treatment.

Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir.

Chronic hepatitis C infection remains a global public health burden and has important clinical implications due to progressive liver fibrosis and development of cirrhosis and its complications. The role of antiviral therapy in infected children is an area of controversy due to an indolent clinical course in the majority of children, and a low likelihood of viral eradication in response to an intensive interferon-based treatment course that is associated with a wide spectrum of adverse effects. This review summarizes new concepts in the epidemiology, natural history, and management of chronic hepatitis C infection in children.

To determine the relative impact of chronic hepatitis C (CHC) and comorbid psychiatric illness on the health-related quality of life (HRQoL).

Background:Warts are a common pediatric skin infection caused by human papillomavirus (HPV). Spontaneous clearance of warts involves anti-HPV immunity, which may be enhanced by contact sensitizers. Squaric acid dibutylester (SADBE) is a nonmutagenic sensitizing agent useful for immunotherapy of alopecia areata. Objective:We hypothesized that SADBE home application might be effective therapy for warts. Methods:An open-label, retrospective study of 61 children with warts was performed. Sensitization with 2% SADBE on the forearm was followed with home application of 0.2% SADBE to warts 3 to 7 nights per week for at least 3 months. Results:Complete clearing occurred in 34 patients (58%), with a mean duration of therapy of 7 weeks. Partial clearing occurred in 11 (18%), and no response in 14 (24%). Clearance correlated with plantar distribution, wart duration under 2 years (P<.05), and first-line therapy with SADBE. Mild side effects occurred in one third of patients, were limited most commonly to mild erythema at the site of sensitization, and necessitated discontinuation of therapy in only 2 patients. Conclusion:SADBE topical immunotherapy is a safe, effective option for home therapy of warts in children. (J Am Acad Dermatol 2000;42:803-8.)

IMPORTANCE: People with HIV (PWH) are often coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), leading to increased risk of developing hepatocellular carcinoma (HCC), but few cohort studies have had sufficient power to describe the trends of HCC incidence and risk among PWH in the combination antiretroviral therapy (cART) era. OBJECTIVE: To determine the temporal trends of HCC incidence rates (IRs) and to compare rates by risk factors among PWH in the cART era. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study, which was conducted between 1996 and 2015. NA-ACCORD pooled individual-level data from 22 HIV clinical and interval cohorts of PWH in the US and Canada. PWH aged 18 years or older with available CD4 cell counts and HIV RNA data were enrolled. Data analyses were completed in March 2020. EXPOSURES: HBV infection was defined as detection of either HBV surface antigen, HBV e antigen, or HBV DNA in serum or plasma any time during observation. HCV infection was defined by detection of anti-HCV seropositivity, HCV RNA, or detectable genotype in serum or plasma at any time under observation. MAIN OUTCOMES AND MEASURES: HCC diagnoses were identified on the basis of review of medical records or cancer registry linkage. RESULTS: Of 109?283 PWH with 723?441 person-years of follow-up, the median (interquartile range) age at baseline was 43 (36-51) years, 93?017 (85.1%) were male, 44?752 (40.9%) were White, 44?322 (40.6%) were Black, 21?343 (19.5%) had HCV coinfection, 6348 (5.8%) had HBV coinfection, and 2082 (1.9%) had triple infection; 451 individuals received a diagnosis of HCC by 2015. Between the early (1996-2000) and modern (2006-2015) cART eras, the crude HCC IR increased from 0.28 to 0.75 case per 1000 person-years. HCC IRs remained constant among HIV-monoinfected persons or those coinfected with HBV, but from 1996 to 2015, IRs increased among PWH coinfected with HCV (from 0.34 cases/1000 person-years in 1996 to 2.39 cases/1000 person-years in 2015) or those with triple infection (from 0.65 cases/1000 person-years in 1996 to 4.49 cases/1000 person-years in 2015). Recent HIV RNA levels greater than or equal to 500 copies/mL (IR ratio, 1.8; 95% CI, 1.4-2.4) and CD4 cell counts less than or equal to 500 cells/µL (IR ratio, 1.3; 95% CI, 1.0-1.6) were associated with higher HCC risk in the modern cART era. People who injected drugs had higher HCC risk compared with men who had sex with men (IR ratio, 2.0; 95% CI, 1.3-2.9), adjusted for HBV-HCV coinfection. CONCLUSIONS AND RELEVANCE: HCC rates among PWH increased significantly over time from 1996 to 2015. PWH coinfected with viral hepatitis, those with higher HIV RNA levels or lower CD4 cell counts, and those who inject drugs had higher HCC risk.

Congestive hepatopathy is a known complication of cardiac disease and is typically identified in the context of an established cardiac diagnosis and profound cardiopulmonary symptoms. We report the case of a 28-year-old man with liver disease secondary to asymptomatic constrictive pericarditis. This case highlights the need for gastroenterologists to consider occult cardiac disease as a cause of unexplained liver dysfunction.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.