Naga Chalasani

Background and Aims Little is known about the clinical characteristics and prognosis of hospitalized patients with moderate alcohol‐associated hepatitis (mAH) as compared to severe alcohol‐associated hepatitis (sAH). Therefore, we aimed to describe the clinical characteristics and risk factors associated with mortality in hospitalized mAH patients. Methods Patients hospitalized with alcohol‐associated hepatitis (AH) from 1 January 2010 to 31 December 2020 at a large US healthcare system [11 hospitals, one liver transplant centre] were retrospectively analysed for outcomes. Primary outcome was 90‐day mortality. AH and mAH were defined according to NIAAA Alcoholic Hepatitis Consortia and Model for End‐stage Liver Disease Score ≤ 20 respectively. Multivariable Cox regression analysis was performed to identify independent risk factors associated with 90‐day mortality. Results 1504 AH patients were …

AimsWe investigated the utility of SSM in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) for detecting cirrhosis, esophageal varices (EV), and high-risk EV.Methods154 study participants with MASLD underwent simultaneous liver stiffness measurement (LSM) and SSM. 96 (62%) participants had an upper endoscopy (73 participants, ie, 47% undergoing within a year). The diagnostic performance of SSM, as well as the BAVENO VII proposed SSM cutoffs (≥ 21 kPa,> 40 kPa, and> 50 kPa), was examined.ResultsThe failure rate for SSM was 19% compared to 5% for LSM. An invalid SSM was statistically significantly associated with a higher body mass index, a larger waist circumference, and a lower fibrosis stage. The area under the receiver operating characteristics for SSM to diagnose cirrhosis, EV, and high-risk EV was 0.78 (95% CI 0.70–0.85), 0.74 (95% CI 0.61–0.84), and 0.82 …

Background Metabolic dysfunction‐associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD. Aims To assess the effects of this new nomenclature on the prevalence and distribution of different SLD categories in people with HIV (PWH) and identified factors associated with MASLD and clinically significant fibrosis (CSF). Methods PWH were prospectively enrolled from 9 US centres and underwent clinical evaluation and vibration‐controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). SLD was defined as CAP ≥ 263 dB/m, CSF as LSM of ≥8 kPa, and advanced fibrosis (AF) as LSM ≥ 12 kPa. The prevalence of SLD, MASLD, metabolic dysfunction and alcohol‐associated liver disease (MetALD), ALD, cryptogenic (cSLD), CSF and AF were determined. Uni‐ and multivariate logistic regression …

Background & AimsPNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD.MethodsA total of 1047 children and 2057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥3). Regression analyses were performed after controlling for relevant covariates. An additive model was used to assess the effect of PNPLA3 G-allele (CC vs CG vs GG).ResultsPNPLA3 G-allele was significantly associated with advanced fibrosis in children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16–2.09) and adults (OR, 1.55; 95% CI, 1.16–1.54). Across the cohort …

Background Causality assessment of suspected drug‐induced liver injury (DILI) during metabolic dysfunction‐associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non‐invasive testing may be provided on histology. Aim To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting. Methods From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment. Results Expert opinion, guidance and recommendations on the role …

1. Nicoletti P, Dellinger A, Li YJ, et al. HLAB* 53: 01 is a significant risk factor for liver injury due to phenytoin and other anti epileptic drugs in African Americans. Am J Gastroenterol 2024; 119 (1): 200-2. 2. National Academies of Sciences, Engineering, and Medicine. Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field. The National Academies Press: Washington, DC (https://doi. org/10.17226/26902)(2023). 3. Naito T, Suzuki K, Hirata J, et al. A deep learning method for HLA imputation and trans-ethnic MHC fine-mapping of type 1 diabetes. Nat Commun 2021; 12: 1639. 4. Arrieta-Bolaños E, Hernández-Zaragoza DI, Barquera R. An HLA map of the world: A comparison of HLA frequencies in 200 worldwide populations reveals diverse patterns for class I and class II. Front Genet 2023; 14: 866407. 5. Gourraud PA, Khankhanian P, Cereb N, et al. HLA diversity in …

ObjectiveTo describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA’s surveillance database.MethodsHepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020.ResultsAmong DILIN’s 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver …

Conclusions:The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by advanced fibrosis, age, T2DM, and sex.

BackgroundIntravenous vancomycin therapy can cause liver injury as well as “drug reaction with eosinophilia and systemic symptoms” (DRESS) syndrome. This study aimed to better define the clinical features and HLA associations of vancomycin-induced liver injury.ObjectiveTo describe clinical, biochemical, and temporal characteristics of vancomycin-induced liver injury.MethodsCases of liver injury with recent exposure to vancomycin who were enrolled in the US Drug-induced Liver Injury Network between 2004 and 2020 were assessed. Sequencing of HLA alleles was performed on stored blood samples.ResultsAmong 1697 cases of drug-induced liver injury identified between 2004 and 2021, 9 (0.5%) were attributed to intravenous vancomycin. The 9 cases included 6 men, median age 60 years (range, 23-85 days), and treatment for 26 days (range, 1-34 days). The clinical presentation was DRESS syndrome …

A 68-year-old female presented with abdominal pain, nausea, and loss of appetite which progressively worsened over the month prior to presentation. She was in her usual state of health leading up to this presentation without any recent illnesses, travel, or new medications or supplements. Her past medical history was notable for a remote stroke, hypertension, migraine headaches, idiopathic urticaria, asthma, osteoarthritis, osteoporosis, and recurrent urinary tract infections. Her surgical history included hysterectomy with bladder suspension 20 years ago. She had a known drug allergy to penicillin, causing hives. She was a non-smoker and drank one alcoholic beverage 3-4 times a week. Her family history was notable for a brother who required surgery for liver cysts in adulthood and a younger brother with an enlarged liver. She had 3 healthy children. She did not take any herbal or dietary supplements. She has …

BackgroundThere are two sub-phenotypes of large-duct primary sclerosing cholangitis (PSC): isolated intrahepatic PSC (IIPSC) and extrahepatic disease with or without intrahepatic (extra/intrahepatic).AimsThis study examined the differences in outcomes in patients with IIPSC compared to extra/intrahepatic and small-duct PSC.MethodsPatients with PSC treated at our institution from 1998 to 2019 were investigated. Biochemistries, clinical events, and survival were assessed by chart review and National Death Index. Cox-proportional hazards were used to determine the risk of clinical outcomes based on biliary tract involvement.ResultsOur cohort comprised 442 patients with large-duct PSC (57 had IIPSC, 385 had extra/intrahepatic PSC) and 23 with small-duct PSC. Median follow-up in the IIPSC group was not significantly different from the extra/intrahepatic group [7 vs. 6 years, P = 0.06]. Except for lower age …

Abstract Background & Aims Food insecurity (FI) is a risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis in the general population, but its impact on liver disease in people with HIV (PWH) is unknown. Methods We examined the association of FI with prevalence of NAFLD and fibrosis in a diverse cohort of PWH. PWH aged≥ 18 years on antiretroviral therapy, HIV RNA< 200 copies/mL, and without other known liver diseases were screened for NAFLD (CAP≥ 263 decibels/meter) and advanced fibrosis (LSM≥ 11 kilopascals) by vibration controlled transient elastography at eight US centers. Participants were categorized as food insecure using the Six-Item Short Form Household Food Security Survey. We used multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) of NAFLD and advanced fibrosis by FI status. Results Among 654 PWH, NAFLD was …

Background & Aims Patients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF. Methods We studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002–2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30‐day waitlist mortality (Competing risk), and post‐LT mortality (Cox‐proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30‐day waitlist mortality. Results About 3212 adults with ALF were waitlisted …

Occult liver disease refers to the presence of unrecognized chronic liver disease and cirrhosis. Liver disease is currently the eleventh cause of death globally, representing 4% of all deaths in the world. Alcohol consumption is the leading cause of cirrhosis globally, accounting for approximately 60% of cases. The estimated global prevalence of non-alcoholic fatty liver disease (NAFLD) is 32.4% and has been steadily increasing over the last years. Viral hepatitis B and C accounted for 1.3 million deaths in 2020.Several studies in populations at high risk of chronic liver disease (elevated liver enzymes, type 2 diabetes, excessive alcohol consumption) have found an elevated prevalence of occult liver disease. Attempts should be made to assess the prevalence of occult liver disease in Latin America, a region with one of the highest rates of metabolic diseases and excessive alcohol consumption.Screening for NAFLD in …

Alcohol consumption is one of the leading causes of the global burden of disease and results in high healthcare and economic costs. Heavy alcohol misuse leads to alcohol-related liver disease, which is responsible for a significant proportion of alcohol-attributable deaths globally. Other than reducing alcohol consumption, there are currently no effective treatments for alcohol-related liver disease. Oxidative stress refers to an imbalance in the production and elimination of reactive oxygen species and antioxidants. It plays important roles in several aspects of alcohol-related liver disease pathogenesis. Here, we review how chronic alcohol use results in oxidative stress through increased metabolism via the cytochrome P450 2E1 system producing reactive oxygen species, acetaldehyde and protein and DNA adducts. These trigger inflammatory signaling pathways within the liver leading to expression of pro-inflammatory mediators causing hepatocyte apoptosis and necrosis. Reactive oxygen species exposure also results in mitochondrial stress within hepatocytes causing structural and functional dysregulation of mitochondria and upregulating apoptotic signaling. There is also evidence that oxidative stress as well as the direct effect of alcohol influences epigenetic regulation. Increased global histone methylation and acetylation and specific histone acetylation inhibits antioxidant responses and promotes expression of key pro-inflammatory genes. This review highlights aspects of the role of oxidative stress in disease pathogenesis that warrant further study including mitochondrial stress and epigenetic regulation. Improved understanding of these …

Background & AimsThe hospital frailty risk score (HFRS) identifies older patients at risk of poor outcomes and may have value in cirrhosis. We compared the Charlson (CCI), Elixhauser (ECI), and cirrhosis (CirCom) comorbidity indices with the HFRS in predicting outcomes for cirrhosis hospitalisations.MethodsUsing the National Inpatient Sample (quarter 4 of 2015–2019), we analysed cirrhosis hospitalisations. For each index, we described the prevalence of comorbid conditions and inpatient mortality. We compared the ability of CCI, ECI, CirCom, and HFRS to predict inpatient mortality. Raw and adjusted models predicting inpatient mortality were compared using the area under the receiver operating characteristic curve and the Akaike information criterion.ResultsThe cohort’s (N = 626,553) median age was 61 years (IQR 52–68 years), 60% were male, cirrhosis was caused by alcohol in 43%, and 38% had ascites …

Background & AimsSevere alcohol-associated hepatitis (SAH) is associated with high 90-day mortality. Glucocorticoid therapy for 28 days improves 30- but not 90-day survival. We assessed the efficacy and safety of a combination of anakinra, an IL-1 antagonist, plus zinc (A+Z) compared to prednisone using the Day-7 Lille score as a stopping rule in patients with SAH.MethodsIn this phase IIb double-blind randomized trial in adults with SAH and MELD scores of 20-35, participants were randomized to receive either daily anakinra 100 mg subcutaneously for 14 days plus daily zinc sulfate 220 mg orally for 90 days, or daily prednisone 40 mg orally for 30 days. Prednisone or prednisone placebo was stopped if Day-7 Lille score was >0.45. All study drugs were stopped for uncontrolled infection or ≥5 point increase in MELD score. The primary endpoint was overall survival at 90 days.ResultsSeventy-three participants …

LINKED CONTENT This article is linked to Gawrieh et al papers. To view these articles, visit https://doi.org/10.1111/apt.17849 and https://doi.org/10.1111/apt.17886

Hormonal agents are crucial in medical therapy for a range of indications, notably in women's health. Oral contraceptives (OCs) have been used since the 1960s, and hormone replacement therapy (HRT) for chronic postmenopausal conditions from the late 1990s. 1– 3 Early OCs, with high doses of estrogens (50 mg mestranol or 20–50 mg ethinyl estradiol) plus a progestin, evolved to lower-estrogen formula to reduce estrogen-related side effects. 1, 2 When the initial analysis of the Women's Health Initiative showed more detrimental than beneficial effects, hormone replacement therapy fell out of favor. 3, 4 Subsequently, nonhormonal options were developed to act as agonists for some target tissues and antagonists for receptors in other organs. These include selective estrogen receptor modulators (SERMs), which have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic …

Background: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular outcomes. Assessment of the impact of NASH therapy on cardiovascular risk is an important element of NASH drug development but is challenging particularly in early phase trials. Aptamer-based proteomic profiles (Somalogic®) in serum have been used to develop and validate a risk score as a surrogate for cardiovascular (CV) risk. Hypothesis: Improvement in NASH histology will result in improved proteomic cardiovascular risk scores. Methods: A post-hoc analysis of proteomic profiles of serum samples, using the Somalogic® platform, from the Pioglitazone vs. Vitamin E vs. Placebo for Treatment of Nonalcoholic Fatty Liver Disease (PIVENS) trial was conducted. PIVENS was a 96-week trial of nondiabetic participants with (NASH). We applied the proteomic CV risk scores to samples from baseline, on therapy and end …