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Joseph K Lim, Basile Njei Yale Liver Center and Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USACorrespondence: Joseph K Lim, Yale Liver Center and Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT, 06520, USA, Email joseph.lim@yale.eduAbstract: The COVID-19 pandemic has had a profound impact on global health, necessitating a comprehensive understanding of its diverse manifestations. Cholangiopathy, a condition characterized by biliary dysfunction, has emerged as a significant complication in COVID-19 patients. In this review, we report the epidemiology of COVID-19, describe the hepatotropism of SARS-CoV-2, and present the histopathology of acute liver injury (ALI) in COVID-19. Additionally, we explore the relationship between pre-existing chronic liver disease and COVID-19, shedding light on the increased susceptibility of these individuals to develop cholangiopathy. Through an in-depth analysis of cholangiopathy in COVID-19 patients, we elucidate its clinical manifestations, diagnostic criteria, and underlying pathogenesis involving inflammation, immune dysregulation, and vascular changes. Furthermore, we provide a summary of studies investigating post-COVID-19 cholangiopathy, highlighting the long-term effects and potential management strategies for this condition, and discussing opportunities for intervention, including therapeutic targets, diagnostic advancements, supportive care, and future research needs.Keywords: cholangiopathy, COVID-19, long-COVID-19, histopathology, interventions

Background: Current endoscopic retrograde cholangiopancreatography (ERCP) and cholangioscopic-based diagnostic sampling for indeterminant biliary strictures remain suboptimal. Artificial intelligence (AI)-based algorithms by means of computer vision in machine learning have been applied to cholangioscopy in an effort to improve diagnostic yield. The aim of this study was to perform a systematic review and meta-analysis to evaluate the diagnostic performance of AI-based diagnostic performance of AI-associated cholangioscopic diagnosis of indeterminant or malignant biliary strictures., Methods: Individualized searches were developed in accordance with PRISMA and MOOSE guidelines, and meta-analysis according to Cochrane Diagnostic Test Accuracy working group methodology. A bivariate model was used to compute pooled sensitivity and specificity, likelihood ratio, diagnostic odds ratio, and summary receiver operating characteristics curve (SROC)., Results: Five studies (n=675 lesions; a total of 2,685,674 cholangioscopic images) were included. All but one study analyzed a deep learning AI-based system using a convoluted neural network (CNN) with an average image processing speed of 30 to 60 frames per second. The pooled sensitivity and specificity were 95% (95% CI: 85-98) and 88% (95% CI: 76-94), with a diagnostic accuracy (SROC) of 97% (95% CI: 95-98). Sensitivity analysis of CNN studies (4 studies, 538 patients) demonstrated a pooled sensitivity, specificity, and accuracy (SROC) of 95% (95% CI: 82-99), 88% (95% CI: 72-95), and 97% (95% CI: 95-98), respectively., Conclusions: Artificial intelligence-based machine learning of cholangioscopy images appears to be a promising modality for the diagnosis of indeterminant and malignant biliary strictures., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) has a global prevalence of 25%. Studies on incident liver and cardiovascular outcomes in lean (Body mass index: BMI < 25 kg/m 2 , or < 23 kg/m 2 for Asians) vs. non-lean individuals with MASLD have reported mixed results. We aimed to compare incident clinical outcomes and mortality between lean and non-lean individuals with compensated MASLD cirrhosis in a large national cohort., Methods: This was a retrospective cohort study of patients with newly diagnosed compensated MASLD cirrhosis in the Veterans Health Administration between 01/2008 and 05/2021. The primary outcome was incident hepatic decompensation, and secondary outcomes were incident major adverse cardiovascular events (MACE) and all-cause mortality. Multivariable Cox proportional hazard models were used to assess association. Fine and Gray competing risk regression was used where applicable., Results: The study included 15155 patients with MASLD cirrhosis: 1,597 lean and 13558 non-lean patients. Included patients were mostly male (95%), median age was 67 years, and 72.8% were non-Hispanic white. At baseline, the prevalence of diabetes was lower in lean vs. non-lean individuals (46.7 vs. 73.9%, p < 0.001). In multivariable models, lean status was associated with a 64% increased risk of all-cause mortality (aHR = 1.64) but decreased risk of hepatic decompensation (aSHR = 0.67). Lean individuals experienced significantly higher rates of cardiovascular-related mortality (aHR = 1.40)., Conclusion: Lean MASLD patients with compensated cirrhosis had a higher mortality risk but a lower risk of hepatic decompensation than non-lean patients. Despite having a better baseline cardiometabolic profile and similar rates of MACE, lean individuals with MASLD cirrhosis have a higher risk of cardiovascular mortality., Competing Interests: Declarations. Conflict of interest: BN is supported by NIH CTSA Grant Number TL1 TR001864 and Yale Liver Center award NIH P30 DK034989; XX. NM is supported by an NIH K08 Grant (DK-124577-01). He also has investigator-initiated funding from Grifols unrelated to this work., (© 2025. The Author(s).)

Objectives: Liver fibrosis represents a common sequela of nonalcoholic fatty liver disease (NAFLD) and other chronic liver diseases. Noninvasive liver fibrosis scores (LFSs) aim to evaluate the severity of liver fibrosis. Whether LFSs can predict the risk of future cardiovascular events (CVEs) remains unclear. This systematic review aimed to clarify the association between liver fibrosis and CVEs by studying the value of LFSs, namely the Fibrosis-4 (FIB-4) Index for Liver Fibrosis score and the NAFLD Fibrosis Score (NFS), for predicting CVEs., Methods: PubMed, Scopus, Web of Science, and Cochrane Library were searched for relevant prospective studies. Retrieved articles were screened to confirm their eligibility for the systematic review. We evaluated the quality of the included studies using the National Institutes of Health tool., Results: Twelve studies of high to fair quality were included in this systematic review. Of note, 10/12 studies reported an independent association between high LFSs and the risk of CVEs, cardiovascular mortality, and all-cause mortality (all P < 0.05). In addition, an advanced histological grade of liver fibrosis (grade 3 or 4) was suggestive of CVE occurrence. NAFLD also appeared to be associated with a higher risk of CVEs at any severity of fibrosis (all P < 0.05)., Conclusions: The findings of this review suggest that liver fibrosis in patients with NAFLD is an independent predictor of future adverse CVEs, cardiovascular mortality, and all-cause mortality. Noninvasive and easy-to-perform LFSs, including FIB-4 score and the NFS, appear useful in predicting such events in patients with a spectrum of cardiovascular diseases and the general population without known cardiovascular disease.

Background: Studies evaluating the hepatic safety of medications have been limited by the inability to control for confounding from receipt of other hepatotoxic drugs., Objective: The objective of this study was to develop an index (Hepatotoxicity Score) to adjust for concomitant hepatotoxic medication exposure within pharmacoepidemiology studies., Methods: We identified 193 medications with ≥ 4 reports of hepatotoxicity and created cohorts of outpatient initiators in the Veterans Health Administration (2000-2021). Exposure occurred from initiation through 30 days after discontinuation or up to 1 year. We measured age-/sex-adjusted rates of hospitalization for severe acute liver injury (ALI) by chronic liver disease (CLD), identified drugs with high rates, and used these rates as weights in the score. To demonstrate real-world use, we calculated the score for proton pump inhibitor (PPI) initiators. We summed the weights of the drugs dispensed within 90 days prior to PPI initiation. Hazard ratios (HRs) of severe ALI (95% confidence intervals) were measured with and without adjustment for Hepatotoxicity Score., Results: Among 89 512 PPI initiators with CLD, HRs of severe ALI were higher for lansoprazole (HR = 2.17 [95% CI, 1.24-3.82]), but not pantoprazole (HR = 0.83 [95% CI, 0.61-1.13]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.99 [95% CI, 1.13-3.50]). Among 2 462 414 PPI initiators without CLD, HRs were not significantly higher for lansoprazole (HR = 1.66 [95% CI, 0.99-2.77]) but were significantly lower for pantoprazole (HR = 0.59 [95% CI, 0.37-0.95]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.52 [95% CI, 0.91-2.54])., Conclusions: The Hepatotoxicity Score provides a tool to adjust for confounding due to concomitant hepatotoxic drug exposure within hepatic safety studies., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aim: Elevated body mass index (BMI) presents a significant public health challenge in the United States, contributing to considerable morbidity, mortality and economic burden. This study investigates the health burden of overweight and obesity in the United States from 1990 to 2021, leveraging the Global Burden of Disease data set to analyse trends, disparities and potential determinants of high BMI-related health outcomes., Materials and Methods: Our study focused on the United States, analysing trends in disability-adjusted life years (DALY) and deaths attributable to high BMI, defined as a BMI of 25 kg/m 2 or higher for adults. Statistical analyses included estimated annual percentage change (EAPC) in age-standardized DALY rates and age-standardized death rates. Pearson correlation was performed between EAPCs and the socio-demographic index (SDI), with significance set at p < 0.05., Results: From 1990 to 2021, age-standardized DALY rates attributable to high BMI increased by 24.9%, whereas the age-standardized death rates increased by 5.2%. Age disparities showed DALYs peaking at 60-64 years for males and 65-69 years for females, with deaths peaking at 65-69 years for males and 90-94 years for females. A strong negative correlation was found between the EAPC in age-standardized DALY and death rates and the SDI., Conclusions: Overweight and obesity significantly impact public health in the United States, especially among older adults and lower socio-demographic regions. Comprehensive public health strategies integrating behavioural, technological and environmental interventions are crucial. Future research should focus on longitudinal studies, personalized interventions and policy-driven approaches to address the multifaceted influences on high BMI., (© 2024 John Wiley & Sons Ltd.)

Background: Cirrhosis comprises a significant health challenge in the Middle East and North African (MENA) region impacting healthcare systems and communities. This study sought to investigate trends in the burden of cirrhosis and other chronic liver disease, different etiologies, deaths, and the disability burden utilizing data from the Global Burden of Disease (GBD) database., Methods: Analyzing epidemiological trends from 1990 to 2021 across 21 MENA countries, this research utilized data on age-standardized incidence rates (ASIR), age-standardized death rates, and age-standardized disability-adjusted life years (DALYs) to evaluate the burden of cirrhosis and other chronic liver disease. The study also examined national variations and sociodemographic relationships., Results: The study identified a 114.9% increase in cirrhosis and other chronic liver disease incidence within the MENA region between 1990 and 2021, with 7,344,030 incident cases reported in 2021. The ASIR showed a steeper rise in females (9.6%) compared to males (7.0%). Etiology-specific analysis revealed an increase in the ASIR for MASLD related cirrhosis and other chronic liver disease by 22.2%, while those due to alcohol as well as hepatitis B and C decreased by 28.1%, 59.3%, and 30%, respectively. Despite the rising incidence, overall age-standardized death rates across all etiologies decreased by 54.3%, with DALYs showing a 51.4% decrease during the same period. Country-specific trends varied significantly, with Oman recording the highest annual ASIR increase (0.64%), and Qatar observing the most substantial annual reduction in age-standardized death rates (-2.88%)., Conclusion: The study highlights evolving trends in cirrhosis and other chronic liver disease within the MENA region, emphasizing the necessity for comprehensive, etiology, and gender-specific interventions. Despite an increasing incidence, the observed improvements in mortality rates and age-standardized disability burden indicate progress in public health efforts to mitigate cirrhosis's impact. These findings point to the complex nature of cirrhosis outcomes and the urgent need for tailored strategies to manage its increasing burden effectively., (© 2024. The Author(s).)

Lean metabolic dysfunction-associated steatotic liver disease (MASLD) defies traditional views of fatty liver diseases by manifesting in nonobese individuals. The renaming from nonalcoholic fatty liver disease to MASLD underscores a broader understanding of its pathophysiology, highlighting the complex interplay of metabolic factors beyond obesity. Despite its clinical importance, diagnosing and managing lean MASLD remains challenging due to its historical ties to obesity and a general lack of awareness about its unique characteristics. On December 4, 2023, a systematic literature search was conducted across six databases, focusing on peer-reviewed studies in English related to the diagnosis and management of lean MASLD. This study was registered with the International Prospective Register of Systematic Reviews (CRD42023489308). Out of 95 studies following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 43 addressed diagnosis and surveillance, whereas 52 explored management strategies. The results revealed the difficulties in diagnosing lean MASLD, pointing out the limitations of traditional markers and the potential of advanced imaging techniques. Management strategies discussed included lifestyle changes and possible pharmacological treatments tailored to the specific metabolic features of this patient group. The study highlights the necessity for increased clinical awareness, regular monitoring, and personalized therapeutic approaches for lean MASLD. It calls for further research to refine diagnostic criteria and develop targeted treatments, aiming to enhance care for individuals with lean MASLD., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Njei et al.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Njei et al.)

Background: Recipient functional status prior to transplantation has been found to impact post-transplant outcomes in heart, liver and kidney transplants. However, information on how functional status, before and after transplant impacts post-transplant survival outcomes is lacking., Aim: To investigate the impact of recipient functional status on short and long term intestinal transplant outcomes in United States adults., Methods: We conducted a retrospective cohort study on 1254 adults who underwent first-time intestinal transplantation from 2005 to 2022. The primary outcome was mortality. Using the Karnofsky Performance Status, functional impairment was categorized as severe, moderate and normal. Analyses were conducted using Kaplan-Meier curves and multivariable Cox regression., Results: The median age was 41 years, majority (53.4%) were women. Severe impairment was present in 28.3% of recipients. The median survival time was 906.6 days. The median survival time was 1331 and 560 days for patients with normal and severe functional impairment respectively. Recipients with severe impairment had a 56% higher risk of mortality at one year [Hazard ratio (HR) = 1.56; 95%CI: 1.23-1.98; P < 0.001] and 58% at five years (HR = 1.58; 95%CI: 1.24-2.00; P < 0.001) compared to patients with no functional impairment. Recipients with worse functional status after transplant also had poor survival outcomes., Conclusion: Pre- and post-transplant recipient functional status is an important prognostic indicator for short- and long-term intestinal transplant outcomes., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest, financial or otherwise, to disclose in relation to this study. There are no funding sources for the manuscript., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the global population, with a significant risk of advancing to liver cirrhosis and hepatocellular carcinoma. The roles of ammonia and glutamine in MASLD's pathogenesis are increasingly recognized, prompting this systematic review. This systematic review was conducted through a meticulous search of literature on December 21, 2023, across five major databases, focusing on studies that addressed the relationship between ammonia or glutamine and MASLD. The quality of the included studies was evaluated using CASP checklists. This study is officially registered in the PROSPERO database (CRD42023495619) and was conducted without external funding or sponsorship. Following PRISMA guidelines, 13 studies were included in this review. The studies were conducted globally, with varying sample sizes and study designs. The appraisal indicated a mainly low bias, confirming the reliability of the evidence. Glutamine's involvement in MASLD emerged as multifaceted, with its metabolic role being critical for liver function and disease progression. Variable expressions of glutamine synthetase and glutaminase enzymes highlight metabolic complexity whereas ammonia's impact through urea cycle dysfunction suggests avenues for therapeutic intervention. However, human clinical trials are lacking. This review emphasizes the necessity of glutamine and ammonia in understanding MASLD and identifies potential therapeutic targets. The current evidence, while robust, points to the need for human studies to corroborate preclinical findings. A personalized approach to treatment, informed by metabolic differences in MASLD patients, is advocated, alongside future large-scale clinical trials for a deeper exploration into these metabolic pathways., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

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.

BACKGROUND Long-term patient survival after intestinal transplantation (IT) remains low compared with other organ transplants despite years of advancement in clinical experience. While patients with extremely high or low body mass index (BMI) are often considered ineligible for IT, the impact of BMI on post-transplant IT survival remains understudied. MATERIAL AND METHODS Using the United Network for Organ Sharing Standard Transplant database, we conducted a retrospective cohort study on patients who underwent IT between April 11, 1994, and September 29, 2021. We assessed the association of recipient and donor BMI at transplant with post-transplant mortality using Kaplan-Meier survival curves and univariate and multivariate Cox regression analyses. RESULTS A total of 1541 patients were included in our final sample. Of these patients, 806 were females (52.5%) and most were in the normal-weight BMI subgroup (54.2%). Obese class II (mean; 36.8±10.92 years) and underweight patients (mean; 37.6±13.37 years) were significantly younger than patients in other BMI categories. The adjusted multivariate model demonstrated an increased risk of mortality in underweight IT recipients compared to normal-weight IT recipients (aHR=1.25, 95% confidence interval [CI], 1.02-1.54; P=0.032).There was no significant association between donor BMI categories and survival in IT recipients. CONCLUSIONS Recipient BMI below normal is associated with an increased risk of mortality after intestinal transplantation and represents a potentially modifiable patient characteristic to improve survival outcomes.

Introduction: This study review aimed to consolidate current knowledge on the electrocardiographic abnormalities observed in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD)., Methods: This was a systematic review of studies on the association between MASLD and electrocardiographic abnormalities, published between January 1, 1946, and October 31, 2023. Data from eligible studies were extracted, analyzed, synthesized, and summarized., Results: We evaluated a total of 27 studies with 8,607,500 participants overall and 1,005,101 participants with MASLD. There was a statistically significant association between MASLD and prevalent atrial fibrillation (pooled OR: 1.34 95 % CI: 1.20-1.49, p < 0.001, n = 12), shorter QRS duration (pooled SMD: -0.073, 95 % CI: -0.144 - -0.001, n = 2, p = 0.048, n = 2), QTc prolongation (p < 0.001, n = 2), LVH (pooled OR: 1.48, 95 % CI: 1.25-1.75, p < 0.001, n = 3), low voltage (p < 0.001, n = 1), ST changes (OR: 1.41, 95 % CI: 1.04-1.91, p = 0.027, n = 1), T wave inversion (p < 0.001, n = 1), axis deviation (OR: 3.21, 95 % CI: 1.99-5.17, p < 0.001, n = 1), conduction defect (OR: 2.79, 95 % CI: 1.83-4.26, p < 0.001, n = 1) and bundle branch block (OR: 2.90, 95 % CI: 1.82-4.61, p < 0.001, n = 1), any persistent heart block (p < 0.001, n = 1), fragmented QRS (p < 0.001, n = 1), and p wave dispersion (p < 0.001, n = 1) CONCLUSION: MASLD is associated with multiple ECG abnormalities which are potential markers of early cardiac involvement, highlighting the multisystemic nature of MASLD. These specific ECG abnormalities could be used in screening and management algorithms to improve cardiac risk stratification in MASLD patients., Prospero Registration: CRD42023477501., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Basile Njei reports a relationship with NIH CTSA Grant Number TL1 TR001864 that includes: funding grants. Basile Njei reports a relationship with Yale Liver Center award NIH P30 DK034989 that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to increased cardiovascular (CV) risks, notably congestive heart failure (CHF). We evaluated the influence of MASLD on CHF and mortality among hospitalized cirrhotic patients., Methods: We analyzed the National Inpatient Sample from 2016 to 2020, identifying adult cirrhosis patients. We focused on CHF and in-hospital mortality, plus hospital stay length, costs, and discharge status. Propensity score matching created balanced cohorts for comparison. Poisson and logistic regression provided adjusted CHF risks and mortality odds ratios (ORs) for MASLD patients., Results: Before matching, 4.1% of 672,625 cirrhotic patients had MASLD. Post-matching, each group had 23,161 patients. Patients with MASLD showed higher CHF risk (OR 1.14, 95% CI 1.10-1.21, p<0.001) but lower in-hospital mortality (OR 0.57, 95% CI 0.52-0.63, p<0.01) and decreased costs (median $24,447 vs. $28,630, OR 0.86, 95% CI 0.85-0.87, p<0.001)., Conclusion: In this nationwide study of patients with cirrhosis, MASLD was associated with a higher prevalence of CHF and lower in-patient mortality. These findings mirror the "adiposity paradox" phenomenon, where obese/overweight individuals with cardiometabolic dysfunction may experience less severe or beneficial health outcomes than those with a normal weight. Further investigation is warranted to decode the intricate interplay between MASLD, cirrhosis, CHF, and in-hospital mortality and its clinical practice implications., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ugwendum et al.)

Competing Interests: Mario Strazzabosco consults for Engitix. The remaining authors have no conflicts to report.

Background: Lean metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by a BMI < 25 kg/m² (or < 23 kg/m² in Asians), presents a challenging prognosis compared to non-lean MASLD. This study examines cardiovascular outcomes in both lean and non-lean MASLD cohorts., Methods: In this meta-analysis, pooled odds ratios (ORs) within 95 % confidence intervals (CIs) were calculated for primary outcomes (cardiovascular mortality and major adverse cardiovascular events [MACE]) and secondary outcomes (cardiovascular disease [CVD], all-cause mortality, hypertension, and dyslipidemia). Studies comparing lean and non-lean MASLD within the same cohorts were analyzed, prioritizing those with larger sample sizes or recent publication dates., Results: Twenty-one studies were identified, encompassing lean MASLD patients (n = 7153; mean age 52.9 ± 7.4; 56 % male) and non-lean MASLD patients (n = 23,514; mean age 53.2 ± 6.8; 63 % male). Lean MASLD exhibited a 50 % increase in cardiovascular mortality odds compared to non-lean MASLD (OR: 1.5, 95 % CI 1.2-1.8; p < 0.0001). MACE odds were 10 % lower in lean MASLD (OR: 0.9, 95 % CI 0.7-1.2; p = 0.7), while CVD odds were 40 % lower (p = 0.01). All-cause mortality showed a 40 % higher odds in lean MASLD versus non-lean MASLD (p = 0.06). Lean MASLD had 30 % lower odds for both hypertension (p = 0.01) and dyslipidemia (p = 0.02) compared to non-lean MASLD., Conclusion: Despite a favorable cardiometabolic profile and comparable MACE rates, lean individuals with MASLD face elevated cardiovascular mortality risk., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Basile Njei reports a relationship with NIH CTSA Grant Number TL1 TR001864 that includes: funding grants. Basile Njei reports a relationship with Yale Liver Center award NIH P30 DK034989 that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is an important cause of cirrhosis and end-stage liver disease. In addition, there have been reports of worse extrahepatic outcomes, especially cardiovascular events, in patients with lean patients' fatty liver disease compared to the non-lean group. There is limited data on hepatic, cardiac, and renal outcomes in lean compared to non-lean patients with MASH. This study aims to evaluate the cardiovascular, renal, and hepatic outcomes in hospitalized US adults with MASH, focusing on a comprehensive comparison between lean and non-lean patients., Methods: The National Inpatient Sample (NIS) database was queried from 2016 to 2020 to identify hospitalizations with MASH. Hospitalizations with a history of overweight and obesity (lean body mass index (BMI) <25 vs. lean BMI >25) were also identified. The primary outcome was in-hospital mortality. Secondary outcomes were major adverse cardiovascular outcomes (MACE: a composite of acute myocardial infarction, cardiac arrest, stroke, heart failure, and atrial fibrillation); major adverse kidney outcome (MAKE: a composite outcome of acute kidney injury (AKI), renal replacement therapy, and renal cancer), and hepatic decompensation (esophageal varices with bleeding, ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy, and hepatorenal syndrome) Multivariate logistic regression analysis was used to derive risk ratios for clinical outcomes., Results: We included 539,275 MASH patients in our sample; 324,330 (60%) were lean. The included patients were mostly female (61%), the mean age was 64 years, and 76% were White. At baseline, non-lean patients had a higher prevalence of heart failure, hypertension, and hyperlipidemia. There was no difference in the prevalence of smoking among both groups. In a multivariate analysis, with adjustment for age, sex, race, sarcopenia, cardiometabolic risk factors, hospital characteristics, admission type, socioeconomic factors, and all comorbidities (including 31 Elixhauser comorbidities), lean status was associated with a 40% increased risk of mortality (adjusted odds ratio (aOR) 1.40, confidence interval (CI) 1.29-1.53), 19% increased risk of MACE (aOR 1.19; 95% CI 1.14-1.24), 20% increased risk of renal decompensation (aOR 1.25; 95% CI 1.20-1.30), and 33% increased risk of hepatic decompensation (aOR 1.33 CI 1.28-1.38)., Conclusion: Lean patients with MASH are at higher risk of cardiovascular and renal outcomes and may benefit from enhanced screening for early identification and treatment to improve outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ezeani et al.)

Early identification of high-risk metabolic dysfunction-associated steatohepatitis (MASH) can offer patients access to novel therapeutic options and potentially decrease the risk of progression to cirrhosis. This study aimed to develop an explainable machine learning model for high-risk MASH prediction and compare its performance with well-established biomarkers. Data were derived from the National Health and Nutrition Examination Surveys (NHANES) 2017-March 2020, which included a total of 5281 adults with valid elastography measurements. We used a FAST score ≥ 0.35, calculated using liver stiffness measurement and controlled attenuation parameter values and aspartate aminotransferase levels, to identify individuals with high-risk MASH. We developed an ensemble-based machine learning XGBoost model to detect high-risk MASH and explored the model's interpretability using an explainable artificial intelligence SHAP method. The prevalence of high-risk MASH was 6.9%. Our XGBoost model achieved a high level of sensitivity (0.82), specificity (0.91), accuracy (0.90), and AUC (0.95) for identifying high-risk MASH. Our model demonstrated a superior ability to predict high-risk MASH vs. FIB-4, APRI, BARD, and MASLD fibrosis scores (AUC of 0.95 vs. 0.50, 0.50, 0.49 and 0.50, respectively). To explain the high performance of our model, we found that the top 5 predictors of high-risk MASH were ALT, GGT, platelet count, waist circumference, and age. We used an explainable ML approach to develop a clinically applicable model that outperforms commonly used clinical risk indices and could increase the identification of high-risk MASH patients in resource-limited settings., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Fatty liver disease, also known as hepatic steatosis, poses a significant global health concern due to the excessive accumulation of fat within the liver. If left untreated, this condition can give rise to severe complications. Recent advances in artificial intelligence (AI, specifically AI-based ultrasound imaging) offer promising tools for diagnosing this condition. This review endeavors to explore the current state of research concerning AI's role in diagnosing fatty liver disease, with a particular emphasis on imaging methods. To this end, a comprehensive search was conducted across electronic databases, including Google Scholar and Embase, to identify relevant studies published between January 2010 and May 2023, with keywords such as "fatty liver disease" and "artificial intelligence (AI)." The article selection process adhered to the PRISMA framework, ultimately resulting in the inclusion of 13 studies. These studies leveraged AI-assisted ultrasound due to its accessibility and cost-effectiveness, and they hailed from diverse countries, including India, China, Singapore, the United States, Egypt, Iran, Poland, Malaysia, and Korea. These studies employed a variety of AI classifiers, such as support vector machines, convolutional neural networks, multilayer perceptron, fuzzy Sugeno, and probabilistic neural networks, all of which demonstrated a remarkable level of precision. Notably, one study even achieved a diagnostic accuracy rate of 100%, underscoring AI's potential in diagnosing fatty liver disease. Nevertheless, the review acknowledged certain limitations within the included studies, with the majority featuring relatively small sample sizes, often encompassing fewer than 100 patients. Additionally, the variability in AI algorithms and imaging techniques added complexity to the comparative analysis. In conclusion, this review emphasizes the potential of AI in enhancing the diagnosis and management of fatty liver disease through advanced imaging techniques. Future research endeavors should prioritize the execution of large-scale studies that employ standardized AI algorithms and imaging techniques to validate AI's utility in diagnosing this prevalent health condition., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Nduma et al.)

Background: Non-alcoholic fatty liver disease (NAFLD) is common in obese individuals, but its occurrence in lean individuals and the underlying mechanisms are not well understood. This study aimed to systematically review the literature on the genetic and epigenetic factors influencing NAFLD in lean individuals., Methods: A comprehensive search was conducted on April 2 nd , 2023, in seven databases using specific criteria. Only peer-reviewed studies in English, focusing on genetic or epigenetic effects on NAFLD in lean individuals, were included for qualitative synthesis. The Newcastle Ottawa Scale (NOS) was used for quality assessment. This study is registered with PROSPERO (CRD42023413809)., Results: Following PRISMA guidelines, 18 studies were included in this review. The studies were conducted globally, with varying sample sizes and study designs. The NOS quality assessment revealed a moderate overall quality with variations in risk of bias and limitations in comparability and ascertainments of exposure among contributing studies. Genetic determinants related to lipid metabolism, inflammation, and oxidative stress pathways were identified, including PNPLA3 and TM6SF2 gene variants associated with increased NAFLD risk in lean individuals. Epigenetic modifications, particularly depletion of histone variants, were also implicated. However, some studies found no significant associations between genetic or clinical characteristics and lean NAFLD. Less frequent genetic risk factors, such as CETP and APOC3 gene variants, were reported., Conclusions: This systematic review underscores the importance of investigating genetic and epigenetic factors in lean NAFLD. The findings highlight the role of PNPLA3 and TM6SF2 gene variants and suggest potential epigenetic contributions. Further research is needed to fully understand the genetic and epigenetic mechanisms underlying NAFLD in lean individuals., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-31/coif). The authors have no conflicts of Interest to declare., (2024 Translational Gastroenterology and Hepatology. All rights reserved.)

Introduction: Artificial intelligence (AI), by means of computer vision in machine learning, is a promising tool for cholangiocarcinoma (CCA) diagnosis. The aim of this study was to provide a comprehensive overview of AI in medical imaging for CCA diagnosis., Methods: A systematic review with scientometric analysis was conducted to analyze and visualize the state-of-the-art of medical imaging to diagnosis CCA., Results: Fifty relevant articles, published by 232 authors and affiliated with 68 organizations and 10 countries, were reviewed in depth. The country with the highest number of publications was China, followed by the United States. Collaboration was noted for 51 (22.0%) of the 232 authors forming five clusters. Deep learning algorithms with convolutional neural networks (CNN) were the most frequently used classifiers. The highest performance metrics were observed with CNN-cholangioscopy for diagnosis of extrahepatic CCA (accuracy 94.9%; sensitivity 94.7%; and specificity 92.1%). However, some of the values for CNN in CT imaging for diagnosis of intrahepatic CCA were low (AUC 0.72 and sensitivity 44%)., Conclusion: Our results suggest that there is increasing evidence to support the role of AI in the diagnosis of CCA. CNN-based computer vision of cholangioscopy images appears to be the most promising modality for extrahepatic CCA diagnosis. Our social network analysis highlighted an Asian and American predominance in the research relational network of AI in CCA diagnosis. This discrepancy presents an opportunity for coordination and increased collaboration, especially with institutions located in high CCA burdened countries., (© 2023 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Artificial intelligence (AI), when applied to computer vision using a convolutional neural network (CNN), is a promising tool in "difficult-to-diagnose" conditions such as malignant biliary strictures and cholangiocarcinoma (CCA). The aim of this systematic review is to summarize and review the available data on the diagnostic utility of endoscopic AI-based imaging for malignant biliary strictures and CCA., Methods: In this systematic review, PubMed, Scopus and Web of Science databases were reviewed for studies published from January 2000 to June 2022. Extracted data included type of endoscopic imaging modality, AI classifiers, and performance measures., Results: The search yielded 5 studies involving 1465 patients. Of the 5 included studies, 4 (n=934; 3,775,819 images) used CNN in combination with cholangioscopy, while one study (n=531; 13,210 images) used CNN with endoscopic ultrasound (EUS). The average image processing speed of CNN with cholangioscopy was 7-15 msec per frame while that of CNN with EUS was 200-300 msec per frame. The highest performance metrics were observed with CNN-cholangioscopy (accuracy 94.9%, sensitivity 94.7%, and specificity 92.1%). CNN-EUS was associated with the greatest clinical performance application, providing station recognition and bile duct segmentation; thus reducing procedure length and providing real-time feedback to the endoscopist., Conclusions: Our results suggest that there is increasing evidence to support a role for AI in the diagnosis of malignant biliary strictures and CCA. CNN-based machine leaning of cholangioscopy images appears to be the most promising, while CNN-EUS has the best clinical performance application., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Background and Aims: Chronic opioid effects on the esophagus are poorly understood. We investigated whether opioids were associated with increased prevalence of esophageal motility disorders., Methods: A retrospective study of all patients undergoing high-resolution manometry (HREM) at the Yale Gastrointestinal Motility Lab between January 2014 and August 2019. Data were extracted from the electronic medical record after studies were reviewed by two motility specialists using the Chicago Classification v.3.0. We compared the manometric results of patients who use opioids to those who do not and adjusted for type and dose of opioids using a 24 h Morphine Milligram Equivalents (MME) scale to compare patients taking low or high amounts of opioids., Results: Four manometric abnormalities were significantly different between the opioid and non-opioid users. Achalasia type III, esophagogastric junction outflow obstruction (EGJOO), and distal esophageal spasm (DES) (p < 0.005, p < 0.01, and p < 0.005, respectively) were common among opioid users, whereas ineffective esophageal motility (IEM) was more common among non-opioid users (p < 0.01). The incidence of EGJOO was significantly higher in opioid users compared to non-opioid users (p < 0.001). Lastly, IRP, DCI, and distal latency were significantly different between the two groups. Patients in the high MME group had significantly greater IRP, DCI, and lower distal latency than non-opioids (p < 0.001). Also, achalasia type III and DES were more common in the high but not the low MME group., Conclusions: Opioid use is associated with multiple abnormalities on esophageal motility and these effects may be dose-dependent., (© 2021 John Wiley & Sons Ltd.)

Viral hepatitis in pregnancy may be caused by many types of viruses that cause systemic infection or target hepatocytes in their pathogenesis. Because viral hepatitis during pregnancy may represent acute or chronic infection or the reactivation of a prior infection, a high clinical suspicion, medical history review, and awareness of risk factors for the acquisition of infection are important management principles. The route of infection varies widely and ranges from fecal-oral transmission for the hepatitis A and E viruses to vertical transmission for hepatitis B, blood-borne transmission for hepatitis C, and sexual transmission for the herpes simplex virus. For this reason, the exposure details about travel, food preferences, drug use, and sexual contacts are important to elicit. Although routine prenatal screening is recommended for chronic viral hepatitis caused by hepatitis B and C, most other causes of viral hepatitis in pregnancy are detected in the setting of compatible signs and symptoms (fatigue, abdominal discomfort, jaundice, scleral icterus) or incidentally noted transaminitis on routine labs. Serologic testing is helpful for diagnosis with molecular testing as indicated to guide the management of hepatitis B and C. Preventive vaccines for hepatitis A and B with established safety of use in pregnancy are recommended for women who are at risk of acquisition. Postexposure prophylaxis for hepatitis A is a single dose of immunoglobulin and vaccination can be used if immunoglobulin G is not available. Antiviral therapy with tenofovir disoproxil fumarate is recommended as prophylaxis in pregnant women with active hepatitis B and an elevated viral load (>200,000 IU/mL) during the third trimester to prevent vertical transmission. The neonate exposed to hepatitis B at birth should receive immunoglobulin G and a monovalent birth dose vaccine within 12 hours, followed by completion of the 3-dosage vaccine series. The prevalence of hepatitis C in women of reproductive age has increased in the United States, and the role of antiviral therapy during pregnancy is of great interest. Cesarean delivery is not currently recommended for the sole purpose of reducing vertical transmission risk in pregnant women with viral hepatitis. Breastfeeding is recommended in women with hepatitis A, B, and C. New and promising prevention and treatment options for hepatitis B and C are under investigation. Investigators and regulatory authorities should ensure that these clinical trials for promising antivirals and vaccines are designed to include pregnant and lactating women., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to perform a structured systematic review and meta-analysis to evaluate the effectiveness and complication rate of cholecystectomy deferral versus prophylactic cholecystectomy among patients post-endoscopic biliary sphincterotomy for common bile duct stones., Background: Although previous reports suggest a decreased risk of biliary complications with prophylactic cholecystectomy, biliary endoscopic cholangiopancreatography (ERCP) with sphincterotomy may provide a role for deferring cholecystectomy with the gallbladder left in situ., Methods: Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed through August 2019 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Measured outcomes included: mortality, recurrent biliary pain or cholecystitis, pancreatitis, cholangitis, and eventual need for cholecystectomy. Random effects models were used to determine pooled effect size and corresponding 95% confidence intervals (CIs)., Results: Nine studies (n = 1605) were included. A total of 53.8% (n = 864) patients had deferred cholecystectomy post-sphincterotomy. Deferral cholecystectomy as compared to prophylactic cholecystectomy resulted in a significant increased risk of mortality [odds raio (OR) 2.56 (95% confidence interval, CI 1.54-4.23); P < 0.0001; I2 = 18.49]. Patients who did not undergo prophylactic cholecystectomy developed more recurrent biliary pain or cholecystitis [OR 5.10 (95% CI 3.39-7.67); P < 0.0001; I2 = 0.00]. Rate of pancreatitis [OR 3.11 (95% CI 0.99-9.83); P = 0.053; I2 = 0.00] and cholangitis [OR 1.49 (95% CI 0.74-2.98); P = 0.264; I2 = 0.00] was unaffected. Overall, 26.00% (95% CI 14.00-40.00) of patients with deferred prophylactic cholecystectomy required eventual cholecystectomy., Conclusions: Prophylactic cholecystectomy remains the preferred strategy compared to a deferral approach with gallbladder in situ post-sphincterotomy for patients with bile duct stones. Future studies may highlight a subset of patients (ie, those with large balloon biliary dilation) that may not require cholecystectomy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aims: Percutaneous liver biopsy (PCLB) or transjugular liver biopsy (TJLB) have traditionally been performed to obtain a sample of hepatic tissue; however, endoscopic ultrasound-guided liver biopsy (EUSLB) has become an attractive alternative. The aim of this study was to compare the efficacy and safety of EUSLB, PCLB, and TJLB., Methods: Search strategies were developed in accordance with PRISMA and MOOSE guidelines. Major outcomes included the following: adequacy of biopsy specimens (i.e., complete portal triads [CPT], total specimen length [TSL] in mm, and length of longest piece [LLP]) in mm), and rate of adverse events. Only studies comparing all biopsy approaches (i.e., EUSLB, PCLB, and TJLB) were included., Results: Five studies (EUSLB [n=301]; PCLB [n=176]; and TJLB [n=179]) were included. Biopsy cumulative adequacy rates for EUSLB, PCLB, and TJLB were 93.51%, 98.27%, and 97.61%, respectively. Based on the subgroup analysis limited to EUS biopsy needles in current clinical practice, there was no difference in biopsy adequacy or adverse events for EUSLB compared to PCLB and TJLB (all p>0.050). A comparison of EUSLB and PCLB revealed no difference between specimens regarding both CPT (p=0.079) and LLP (p=0.085); however, a longer TSL (p<0.001) was observed. Compared to TJLB, EUSLB showed no difference in LLP (p=0.351), fewer CPT (p=0.042), and longer TSL (p=0.005)., Conclusion: EUSLB appears to be a safe, minimally invasive procedure that is comparable to PCLB and TJLB regarding biopsy specimens obtained and rate of adverse events associated with each method.

Background: Despite rising rates of obesity among human immunodeficiency virus (HIV)-positive individuals, the safety and tolerability of surgery in this population have not been established. The primary aim of this study was to examine the safety of bariatric surgery and rate of in-hospital postoperative complications in morbidly obese patients with HIV. Materials and Methods: The U.S. Nationwide Inpatient Sample database was queried between 2004 and 2014 for discharges with codiagnoses of morbid obesity and bariatric surgery. The primary outcome was in-hospital mortality. Secondary outcomes included length of stay, hospitalization costs, and multiple categories of complications, including systemic complications, surgical complications, and nutritional and behavioral complications. Results: Among 267,082 patients with discharge diagnoses of morbid obesity and bariatric surgery, 346 (0.13%) were diagnosed with HIV. On multivariable analysis, HIV did not influence in-hospital mortality ( p  = 0.530). HIV was not associated with increased risk of renal failure ( p  = 0.274), thromboembolism ( p  = 0.713), myocardial infarction ( p  = 0.635), sepsis ( p  = 0.757), hemorrhage ( p  = 0.303), or wound infection ( p  = 0.229). Other measured surgical complications were not significantly different ( p  > 0.05). Notably, HIV-positive patients had an increased risk for postoperative pneumonia ( p  = 0.002), pancreatitis ( p  = 0.049), and thiamine deficiency ( p  = 0.016). Conclusion: Bariatric surgery among HIV-positive patients appears to be acceptably safe with the risk of postoperative complications comparable with non-HIV patients., Competing Interests: No competing financial interests exist., (Copyright 2020, Mary Ann Liebert, Inc., publishers.)

Background & Aims: Female sex hormones affect several non-reproductive organs, but little is known about their effects on the liver during a normal menstrual cycle. We aimed to investigate the association between sex hormones and liver enzymes in healthy menstruating women., Methods: We performed a post-hoc analysis of data from the BioCycle study, a longitudinal cohort study designed to determine the association of sex hormones with markers of oxidative stress during the menstrual cycle. We analyzed data collected from 259 menstruating women, over 1-2 menstrual cycles, who had as many as 16 separate office visits, timed by fertility monitors. Levels of liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase, and alkaline phosphatase (ALKP), bilirubin, and lipids were measured by laboratory assays., Results: We found a natural cyclic pattern for liver enzymes, with transaminases and ALKP peaking in the mid-follicular phase and reaching a trough in the late luteal phase; the peak to trough differences were 4.0 ± 4.9 U/L for ALT and 8.8 ± 4.0 U/L for ALKP. Levels of ALT were significantly and negatively associated with levels of progesterone on the preceding visit (P = 5x10 -4 ), whereas level of ALKP was negatively associated with level of estrogen (P = .007) and progesterone (P = 1x10 -11 ). Food and alcohol intake did not modify the association. The amplitude of ALT fluctuation was greater in African Americans and decreased with age. Fluctuations in levels of ALT were smaller in women with body mass indices >30 kg/m 2 (P = .03). During menstrual fluctuation, 49% of participants had ALT values both above and below the normal cut-off value (19 U/L)., Conclusions: Levels of liver enzymes fluctuate during the normal menstrual cycle, possibly mediated by progesterone, and the fluctuation varies with age and body mass index. These findings indicate the importance of accounting for phase of menstrual cycle when interpreting liver enzyme measurements in menstruating women., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and study aims  While several interventions may decrease risk of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, it remains unclear whether one strategy is superior to others. The purpose of this study was to compare the effectiveness of pharmacologic and endoscopic interventions to prevent post-ERCP pancreatitis among high-risk patients. Methods  A systematic review was performed to identify randomized controlled trials from PubMed, Embase, Web of Science, and Cochrane database through May 2017. Interventions included: rectal non-steroidal anti-inflammatory drugs (NSAIDs), aggressive hydration with lactated ringer's (LR) solution, and pancreatic stent placement compared to placebo. Only studies with patients at high-risk for post-ERCP pancreatitis were included. Bayesian network meta-analysis was performed and relative ranking of treatments was assessed using surface under the cumulative ranking (SUCRA) probabilities. Results  We identified 29 trials, comprising 7,862 participants comparing four preventive strategies. On network meta-analysis, compared with placebo, rectal NSAIDs (B = - 0.69, 95 % CI [-1.18; - 0.21]), pancreatic stent (B = - 1.25, 95 % CI [-1.81 to -0.69]), LR (B = - 0.67, 95 % CI [-1.20 to -0.13]), and combination of LR plus rectal NSAIDs (B = - 1.58; 95 % CI [-3.0 to -0.17]), were all associated with a reduced risk of post-ERCP pancreatitis. Pancreatic stent placement had the highest SUCRA probability (0.81, 95 % CI [0.83 to 0.80]) of being ranked the best prophylactic treatment. Conclusions  Based on this network meta-analysis, pancreatic stent placement appears to be the most effective preventive strategy for post-ERCP pancreatitis in high-risk patients., Competing Interests: Competing interests Dr. Shyam Varadarajulu is a consultant for Boston Scientific and Olympus. Dr. Udayakumar Navaneethan is a consultant for Janssen, AbbVie, Pfizer and Takeda.

Background & Objectives: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca 2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca 2+ release channels in HCC., Design: Expression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice., Results: ITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca 2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis., Conclusions: These results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: With advances in disease-specific treatments and improved overall survival, obesity rates are rising among patients with sickle cell disease (SCD). The primary aim of this study was to evaluate the role of bariatric surgery on clinical outcomes among hospitalized obese patients with SCD., Methods: The United States Nationwide Inpatient Sample database was queried between 2004 and 2014 for discharges with co-diagnoses of morbid obesity and SCD. The primary outcome was in-hospital mortality. Secondary outcomes included vaso-occlusive crisis, acute chest syndrome, biliary-pancreatic complications, renal failure, urinary tract infection, malnutrition, sepsis, pneumonia, respiratory failure, thromboembolic events, strictures, wound infection, length of stay, and hospitalization costs. Using Poisson regression, adjusted incidence risk ratios (IRR) were derived for clinical outcomes in patients with prior-bariatric surgery compared to those without bariatric surgery., Results: Among 2549 patients with a discharge diagnosis of SCD and morbid obesity, only 42 patients (1.7%) had bariatric surgery. On multivariable analysis, bariatric surgery did not influence mortality (P = 0.98). Bariatric surgery was not associated with increased risk for acute chest syndrome, sepsis, multi-organ failure, biliary-pancreatic, or surgery-related complications (all P > 0.05). Interestingly, bariatric surgery decreased risk of vaso-occlusive crises (IRR 0.21; 95% CI, 0.07-0.69; P = 0.01) in these patients and was associated with a shorter length of stay (P < 0.001) but higher hospitalization costs (P < 0.001)., Conclusions: Bariatric surgery may lower rates of vaso-occlusive crises in morbidly obese sickle cell patients without significantly affecting mortality and other adverse outcomes. In spite of this, these weight loss surgeries are underutilized in this select population.

Background & Aims: Concerns related to hepatotoxicity frequently lead to discontinuation or non-initiation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase therapy in patients with cirrhosis despite data supporting statin use. We investigated the independent effects of hyperlipidemia and statin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma development in a large national cohort of patients with cirrhosis., Methods: We performed a retrospective cohort study of patients with newly diagnosed cirrhosis from January 1, 2008 through June 30, 2016 in the Veterans Health Administration. Subjects were divided into 2 cohorts: 21,921 patients with prior statin exposure (existing users) and 51,023 statin-naïve individuals, of whom 8794 subsequently initiated statin therapy (new initiators) and 44,269 did not (non-initiators). Multivariable Cox proportional hazard models with inverse probability weighting were constructed to assess the effects of time-updating lipid profiles and cumulative exposure to statins on survival and hepatic decompensation. Statin-naïve new initiators were propensity matched with non-initiators to simulate a randomized controlled trial of statin use in cirrhosis., Results: In statin-naïve subjects, every 10-mg/dL increase in baseline total cholesterol was associated with a 3.6% decrease in mortality. In existing users, each year of continued statin exposure was associated with a hazard ratio of 0.920 (95% confidence interval 0.0.897-0.943) for mortality. After risk-set matching, each year of statin exposure among new initiators was associated with a hazard ratio of 0.913 (95% confidence interval 0.890-0.937) for mortality., Conclusions: In a retrospective cohort study of veterans with a new diagnosis of cirrhosis, we associated hypercholesterolemia with well-preserved hepatic function and decreased mortality. Nonetheless, each cumulative year of statin exposure was associated with an independent 8.0%-8.7% decrease of mortality of patients with cirrhosis of Child-Turcotte-Pugh classes A and B., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Veterans with hepatitis C virus (HCV) infection may face geographic obstacles to obtaining treatment., Objective: We studied the influence of region and rural versus urban residence on receipt of direct-acting antiretroviral (DAA) medications for HCV., Subjects: Veterans receiving care within Veterans Affairs Healthcare System born between 1945 and 1965., Research Design: This is a observational study using national electronic health record data., Measures: Receipt of DAAs was defined as ≥1 filled prescription from January 1, 2014 to December 31, 2016. Region (South, Northeast, Midwest, and West) and residence (urban, rural-micropolitan, small rural towns, and isolated rural towns) variables were created using residential zone improvement plan codes and rural-urban commuting area (RUCA) codes. Multivariable models were adjusted for age, race, sex, severity of liver disease, comorbidities, and prior treatment experience., Results: Among 166,353 eligible patients 64,854 received, DAAs. Variation by rural-urban residence depended on region. In unadjusted analyses, receipt varied by rural-urban designations within Midwest, and West regions (P<0.05) but did not vary within the South (P=0.12). Southern rural small town had the lowest incidence of DAA receipt (40.1%), whereas the incidence was 52.9% in Midwestern isolated rural towns. In adjusted logistic analyses, compared with southern urban residents (the largest single group), southern rural small town residents had the lowest odds ratio, 0.85 (95% confidence interval, 0.75-0.93), and Midwestern residents from isolated and small rural towns had the highest odds (odds ratio, both 1.27) to receive treatment., Conclusions: Substantial geographic variation exists in receipt of curative HCV treatment. Efforts are needed to provide more equitable access to DAAs.

Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca 2+ release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor, Toll-like receptor 4 (TLR4), which links to activation of nuclear factor-κB (NF-κB). Analysis of the human ITPR3 promoter revealed five putative response elements to NF-κB, and promoter activity was inhibited by p65/p50. Nested 0.5- and 1.0-kilobase (kb) deletion fragments of the ITPR3 promoter were inhibited by NF-κB subunits. Chromatin immunoprecipitation (ChIP) assay showed that NF-κB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from those with severe AH. Conclusion: Stimulation of TLR4 by LPS activates NF-κB to down-regulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or AH., (© 2018 by the American Association for the Study of Liver Diseases.)

Background: While patients with celiac disease have increasingly developed an atypical pattern of weight gain and obesity, the role of bariatric surgery remains unclear. The primary aim of this study was to evaluate the effect of bariatric surgery on clinical outcomes among hospitalized patients with celiac disease., Methods: The United States Nationwide Inpatient Sample database was queried for discharges with co-diagnoses of morbid obesity and celiac disease between 2004 and 2014. The primary outcome was in-hospital mortality. Secondary outcomes included renal failure, urinary tract infection, malnutrition, sepsis, pneumonia, respiratory failure, thromboembolic events, strictures, micronutrient deficiency, length of stay, and hospitalization costs. Using Poisson regression, adjusted incidence risk ratios (IRR) were derived for clinical outcomes in patients with prior bariatric surgery compared to those without bariatric surgery., Results: Among 1499 patients with a discharge diagnosis of celiac disease and morbid obesity, 126 patients (8.4%) underwent bariatric surgery. Despite an increase in morbid obesity over the study period, the proportion of morbidly obese patients with celiac disease who had bariatric surgery declined by 18.5% (P trend <0.05). On multivariable analysis, bariatric surgery did not influence mortality (P=0.98), but was associated with a lower risk of renal failure, pneumonia, sepsis, urinary tract infection and respiratory failure (all P<0.05). Bariatric surgery increased the risk of vitamin D deficiency (IRR 3.5; 95% confidence interval [CI] 1.6-7.7; P=0.002) and post-operative strictures (IRR 3.3; 95%CI 1.5-7.5; P=0.004)., Conclusion: Despite the underutilization of bariatric surgery in morbidly obese celiac disease patients, the procedure is safe and appears to significantly reduce morbidity., Competing Interests: Conflict of Interest: None.

Background: The association between obesity and rising incidence of hepatocellular carcinoma (HCC) in the USA has been documented; however, the role of bariatric surgery remains less clear., Aim: To evaluate the cross-sectional association of prior-bariatric surgery and HCC., Methods: The United States Nationwide Inpatient Sample (NIS) database was queried from 2004 to 2014 for discharges with a diagnosis of morbid obesity. Primary outcomes of interest were HCC and in-hospital mortality rate. Secondary outcomes were length of stay and cost. Baseline characteristics were balanced using propensity score matching (PSM). Using Poisson and logistic regressions, adjusted HCC prevalence ratio (PR) and mortality odds ratio (OR) were derived in patients with prior-bariatric surgery compared to those without bariatric surgery., Results: Of the 2,881,414 patients included in our study, 267,082 (9.3%) underwent bariatric surgery. From 2004 to 2014, there was a threefold increase in age-adjusted prevalence of HCC from 27 per 100,000 to 72 per 100,000 (P Trend < 0.001). After PSM, 230,956 patients with prior-bariatric surgery were matched with 230,956 patients without bariatric surgery. Prior-bariatric surgery was associated with lower prevalence of HCC (PR 0.11; 95% CI, 0.03-0.48; P < 0.001). In-hospital mortality was also lower for patients with surgery (OR 0.22; 95% CI, 0.20-0.26; P < 0.001). The occurrence of HCC added $18,840 extra cost, increased mean length of stay by 2 (95% CI; 1-3) days, and increased risk of death by 65% (aOR 1.65; 95% CI 1.18-2.29)., Conclusion: In this nationwide study of morbidly obese patients, prior-bariatric surgery was associated with a lower prevalence of HCC and lower in-patient mortality.

Objective: The aim of this study was to investigate the impact of cannabis on post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP)., Methods: The US Nationwide Inpatient Sample was queried to identify patients who underwent endoscopic retrograde cholangiopancreatography pancreatitis from 2004 to 2014. Cannabis use was identified by International Classification of Diseases, Ninth Edition codes, and patients in remission were excluded. Poisson regression models were used to derive adjusted incidence risk ratios (IRRs) for outcomes., Results: Among 37,712 patients with PEP, 0.4% had documented cannabis use disorder. From 2004 to 2014, the rate of PEP and cannabis use increased (8.9%-11.0% [P < 0.01] and 0.20%-0.70% [P < 0.01], respectively). Univariate analysis demonstrated cannabis was associated with increased risk of PEP (IRR, 1.70; 95% confidence interval [CI], 1.50-1.90; P < 0.01). On multivariate analysis, cannabis use was an independent predictor of PEP (IRR, 1.2; 95% CI, 1.1-1.4; P = 0.004). Cannabis was not associated with in-hospital death (IRR, 0.15; 95% CI, 0.02-1.04; P = 0.06) but was associated with shorter hospital stay (IRR, 0.96; 95% CI, 0.94-0.98; P < 0.001) and lower costs (IRR, 0.91; 95% CI, 0.91-0.92; P < 0.001)., Conclusions: Cannabis use was associated with an increase in PEP without significant increase in mortality.

Objective: Despite rising rates of obesity among patients with HIV, the potential role for weight loss surgery in this population remains less clear. The primary aim of this study was to evaluate the role of bariatric surgery on relevant clinical outcomes among hospitalized obese patients with HIV., Design: Retrospective analysis using the United States Nationwide Inpatient Sample database from 2004 to 2014. Using Poisson regression, adjusted incidence risk ratios (IRR) were derived for clinical outcomes in patients with prior-bariatric surgery compared with those without bariatric surgery., Patients: Patients with discharge co-diagnoses of morbid obesity and HIV., Intervention: Bariatric surgery., Main Outcome Measures: Primary outcome was in-hospital mortality. Secondary outcomes included renal failure, urinary tract infection, malnutrition, sepsis, pneumonia, respiratory failure, thromboembolic events, gastrointestinal strictures, micronutrient deficiency, length of stay, and hospitalization costs., Results: Among 7803 patients with discharge diagnoses of HIV and morbid obesity, 346 patients (4.4%) had bariatric surgery. The proportion of bariatric surgery in obese patients with HIV initially declined by -0.10% per year from 2004 to 2009 (Ptrend < 0.05), then increased at an annual rate of +0.33% from 2012 to 2014 (Ptrend < 0.05). On multivariable analysis, bariatric surgery did not influence mortality (P = 0.98). Bariatric surgery was associated with decreased risk for renal failure, respiratory failure, and sepsis (all P < 0.001). However, bariatric surgery increased the risk for postoperative strictures (IRR 2.5; 95% CI 1.5-4.5; P = 0.001)., Conclusion: Though initially underutilized, bariatric surgery in morbidly obese HIV patients is increasing and appears to be well tolerated and effective in significantly reducing life-threatening morbidity.