Impact of HIV Infection on Liver and Cardiovascular Outcomes in Veterans With Metabolic Dysfunction-Associated Steatotic Liver Disease.

INTRODUCTION: Hepatic steatosis is highly prevalent in people living with HIV. It remains unclear whether HIV in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with greater risks of liver disease progression and cardiovascular disease (CVD). We aim to evaluate the impact of HIV infection on risks of liver and CVD outcomes among US Veterans with MASLD. METHODS: Using national Veterans Administration data from 2010 to 2022, we created a propensity score-matched cohort of MASLD patients with vs without HIV. Primary outcomes were incidence of cirrhosis and hepatocellular carcinoma (HCC) among patients with vs without HIV and patients with MASLD-HIV on antiretroviral therapy (ART) vs not on ART. Secondary outcomes included incidence of major adverse cardiovascular events and overall survival. RESULTS: The propensity-matched cohort included 920 MASLD patients with HIV and 920 MASLD patients without HIV and was similar in demographics and comorbidities. Compared with MASLD patients without HIV, incidences of cirrhosis and HCC were similar among MASLD with HIV. Compared with MASLD patients without HIV, incidence of major adverse cardiovascular event was higher among MASLD patients with HIV (5.18 vs 4.48 per 100 person-years, P = 0.03). Overall 5-year survival was significantly lower among MASLD patients with HIV and even lower among those not on ART. DISCUSSION: Among US Veterans with MASLD, concurrent HIV infection, and particularly not being on ART, is associated with greater risks of CVD and decreased overall survival. No differences in risks of cirrhosis or HCC were observed.

Impact of Longitudinal Alcohol Use Patterns on Long-Term Risk of Cirrhosis Among US Veterans With Steatotic Liver Disease.

BACKGROUND & AIMS: Conflicting data exist on the impact of alcohol use on risk of liver disease progression in patients with steatotic liver disease. We aimed to evaluate the effect of longitudinal alcohol use on risk of cirrhosis among veterans with steatotic liver disease. METHODS: US veterans with steatotic liver disease were identified from January 2010 through December 2022. Alcohol use was assessed using documented Alcohol Use Disorders Identification Test-Concise (AUDIT-C) scores and categorized as no alcohol (AUDIT-C = 0), low-risk alcohol use (AUDIT-C 1-2 for women and 1-3 for men), and high-risk alcohol (AUDIT-C ≥ 3 for women and ≥ 4 for men). Incidence of cirrhosis was evaluated with competing risks Nelson-Aalen methods. Adjusted multivariable regression models evaluated risks of cirrhosis associated with baseline alcohol use and changes in alcohol use during follow-up. RESULTS: There were 1,156,189 veterans with steatotic liver disease identified (54.2% no alcohol, 34.6% low-risk alcohol, and 11.2% high-risk alcohol). Veterans with steatotic liver disease and high-risk alcohol have a 43% higher incidence of cirrhosis compared with patients reporting no alcohol use. Compared with patients with baseline high-risk alcohol who reported no change in alcohol use, those who decreased their alcohol use during follow-up experienced a 39% reduction in long-term risk of cirrhosis (hazard ratio, 0.61; 95% CI, 0.45-0.83; P < .01). CONCLUSIONS: One in 9 veterans with steatotic liver disease report concurrent high-risk alcohol use, which is associated with 43% greater risk of cirrhosis compared with no alcohol use. However, reducing alcohol use lowers risk of cirrhosis, emphasizing the importance of timely alcohol use assessment and early interventions to address high-risk alcohol use in steatotic liver disease.

Incidence of Cirrhosis and Hepatocellular Carcinoma Among Veterans With Noncirrhotic Metabolic Dysfunction-associated Fatty Liver Disease.

BACKGROUND AND AIMS: Despite the high prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD), the long-term incidence of cirrhosis or hepatocellular carcinoma (HCC) among adults with MAFLD is not well described. Using a national cohort of United States Veterans, we evaluated the overall incidence and predictors of cirrhosis and HCC among adults with noncirrhotic MAFLD. METHODS: Data from the 2010 to 2022 Veterans Affairs database were used to identify adults with noncirrhotic MAFLD using established definitions. Five and 10-year incidence of cirrhosis and HCC were assessed and stratified by demographics and relevant clinical variables. Multivariate Cox proportional hazard models were utilized to determine predictors of cirrhosis and HCC. RESULTS: Among 969,253 patients with noncirrhotic MAFLD (94.5% males, 70.2% non-Hispanic white, mean age of 62.7 ± 12.2 y), the 10-year incidence of cirrhosis and HCC was 3.70% (95% CI: 3.66-3.74) and 0.69% (95% CI: 0.67-0.70), respectively. When stratified by race/ethnicity, the 10-year incidence of cirrhosis was lowest among Asians (2.63%, 95% CI: 2.37-2.88) and highest among Hispanics (4.60%, 95% CI: 4.45-4.75), a pattern also observed with HCC. Significant disparities in risk of cirrhosis or HCC were observed when stratified by sex, substance use, and comorbidities. Risks of cirrhosis and HCC were highest in patients with baseline fibrosis-4 >2.67. CONCLUSION: This large study provides important epidemiological data describing the natural history of adults with MAFLD. Disparities in risk of cirrhosis and HCC were observed by demographic and clinical characteristics, emphasizing the importance of early identification of MAFLD with modifiable high-risk features to implement earlier interventions to improve long-term outcomes.

Exercise Does Not Independently Improve Histological Outcomes in Biopsy-Proven Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: The independent effect of exercise on liver histology in non-alcoholic fatty liver disease (NAFLD) remains unclear. As such, we conducted a systematic review and meta-analysis of the effect of exercise alone on histological endpoints in biopsy-proven NAFLD. MATERIALS AND METHODS: A systematic literature search was conducted to include controlled clinical trials investigating the effect of exercise alone on liver histology in biopsy-proven NAFLD. Meta-analysis was conducted for histological outcomes with available data from a minimum of three studies. Pooled estimates of the effect of exercise on histological endpoints were calculated using random-effects models. RESULTS: We identified three controlled clinical trials that assessed the independent effect of exercise on histological outcomes in patients with biopsy-proven NAFLD. The studies consisted of 72 total participants, including 40 subjects in the exercise intervention and 32 individuals in the comparison group. Meta-analysis showed that exercise did not significantly improve Brunt grade, NAFLD activity score, and fibrosis in NAFLD. DISCUSSION: Exercise alone may not lead to significant histopathological improvement in NAFLD. Future well-powered randomized controlled trials are needed to better characterize the impact of exercise on histological outcomes and clinical endpoints.

Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice.

PURPOSE OF REVIEW: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease affecting 30% of the global population. In this article, we summarize current expert guidelines, review clinical practice implications, and provide insight into the utility of non-invasive tests (NITs). RECENT FINDINGS: The burden of MASLD is growing with the obesity epidemic, yet disease awareness and diagnosis is low. Patients can progress to metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), which can advance to liver fibrosis, cirrhosis, hepatic decompensation, and liver cancer. NITs help identify high-risk patients who may benefit from specialty referral and MASH-directed therapy. Global societies offer various recommendations for the screening and diagnosis of MASLD utilizing evidence-based, widely accessible methods such as serum indices, NITs, and liver biopsy. Several targeted steatotic liver disease (SLD) screening tools and novel therapies are under development.

Cardiovascular Disease Risk and Statin Use Among Adults with Metabolic Dysfunction Associated Fatty Liver Disease.

BACKGROUND: A leading cause of mortality in fatty liver disease is cardiovascular disease. Metabolic dysfunction-associated fatty liver disease (MAFLD) is new terminology that classifies fatty liver due to metabolic dysfunction attributable to obesity and associated complications. We evaluated atherosclerotic cardiovascular disease (ASCVD) risk and statin use in adults with MAFLD. METHODS: This was a retrospective study of the 2011-2018 National Health and Nutrition Examination Survey. Adults with MAFLD were identified using established criteria: presence of hepatic steatosis (US Fatty Liver Index>30) plus ≥1 of the following: 1) body mass index >25 kg/m2 in non-Asians or >23 kg/m2 in Asians, 2) diabetes mellitus, and 3) ≥2 metabolic risk factors. Cardiovascular disease risk was estimated using the validated 10-year ASCVD risk score. Statin use was assessed in intermediate and high 10-year ASCVD risk groups. RESULTS: Prevalence of MAFLD was 34.8% (95% confidence interval [CI], 33.9%-35.8%), comprising 54.4% males, 27.9% aged 65 years and older, and 38.2% non-Hispanic white. Among adults with MAFLD, 23.3% and 23.0% had intermediate and high 10-year ASCVD risk, respectively. Compared with females, males were more likely to have high 10-year ASCVD risk (28.7% vs 16.1%, adjusted odds ratio 5.24, 95% CI, 3.87-7.10, P < .01). In intermediate and high ASCVD risk groups, overall statin use was 48.3% (95% CI, 46.1-51.3). CONCLUSIONS: Over 46% of adults with MAFLD had intermediate or high 10-year ASCVD risk. Statin use was underutilized at 48.3% in those meeting statin criteria. These findings are alarming given the high cardiovascular disease risk and low statin use in this cohort.

The independent effect of exercise on biopsy-proven non-alcoholic fatty liver disease: A systematic review.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Although previous studies have demonstrated that exercise independently reduces hepatic steatosis measured by imaging modalities in NAFLD, the effect of exercise on histological endpoints remains unclear. We aimed to conduct a systematic review of the independent effect of exercise on hepatic steatosis, steatohepatitis, and liver fibrosis as measured by histological assessment or non-invasive tests (NITs) in biopsy-proven NAFLD. A systematic literature search of PubMed, Embase, and Web of Science databases was performed using keywords related to exercise, NAFLD, and biopsy. Articles were selected based on the following inclusion criteria: (1) involved human subjects with biopsy-proven NAFLD, (2) analyzed the independent effect of exercise, (3) assessed changes in hepatic steatosis, steatohepatitis, or liver fibrosis via either histological evaluation or NITs, and (4) were original research studies. We identified a total of six studies that analyzed the independent effect of exercise on histological endpoints in biopsy-proven NAFLD. Two randomized controlled trials (RCTs) did not detect significant histological improvement following exercise interventions, while other non-randomized interventional studies showed that exercise reduces hepatocyte ballooning and liver fibrosis. In addition, five studies assessed NIT outcomes, collectively demonstrating that exercise improves hepatic steatosis measured by magnetic resonance imaging-based techniques but not serum biomarkers for steatohepatitis and liver fibrosis. Additional large RCTs and meta-analyses are warranted to investigate the independent effect of exercise on histological and clinical outcome endpoints in NAFLD.

Outcomes of Patients with Opioid-Related Diagnoses in Acute Coronary Syndrome: a National Inpatient Sample-Based Analysis.

BACKGROUND: Acute coronary syndrome (ACS) and opioid use are both major causes of morbidity and mortality globally. Although epidemiological studies point to increased risk of ACS in opioid users, in-hospital management and outcomes are unknown for this population when presenting with ACS. We sought to determine whether there are differences for in-hospital outcomes and management of ACS for those with and without opioid-related diagnoses (ORD). METHODS AND RESULTS: From the National Inpatient Sample database, we extracted patients hospitalized between 2012 and 2016 for ACS. The primary independent variable was ORD by International Classification of Diseases, 9th and 10th Revision, codes. The primary outcome was in-hospital mortality; secondary outcomes were cardiac arrest, receipt of angiogram, and percutaneous coronary intervention (PCI). Statistical comparisons were performed using χ2 test and Student's t test. Multivariable logistic regression was performed to determine the independent association between ORD and outcomes of interest. Among the estimated 5.8 million admissions for ACS, the proportion of patients with ORD increased over the study period (p for trend < 0.01). Compared to patients without ORD presenting with ACS, patients with ORD were younger with fewer cardiovascular risk factors. Yet, in-hospital mortality was higher in patients with ORD presenting with ACS (AOR 1.36, 95% CI 1.26-1.48). Patients with ORD were more likely to experience in-hospital cardiac arrest (AOR 1.42, 95% CI 1.23-1.63) and less likely to undergo angiogram (AOR 0.42, 95% CI 0.38-0.45) or PCI (AOR 0.30, 95% CI 0.28-0.32). CONCLUSION: Despite evidence of increased risk of mortality and cardiac arrest, patients with ORD admitted for ACS are less likely to receive ACS management.

Concentration-dependent transcriptional switching through a collective action of cis-elements.

Gene expression specificity of homeobox transcription factors has remained paradoxical. WUSCHEL activates and represses CLAVATA3 transcription at lower and higher concentrations, respectively. We use computational modeling and experimental analysis to investigate the properties of the cis-regulatory module. We find that intrinsically each cis-element can only activate CLAVATA3 at a higher WUSCHEL concentration. However, together, they repress CLAVATA3 at higher WUSCHEL and activate only at lower WUSCHEL, showing that the concentration-dependent interactions among cis-elements regulate both activation and repression. Biochemical experiments show that two adjacent functional cis-elements bind WUSCHEL with higher affinity and dimerize at relatively lower levels. Moreover, increasing the distance between cis-elements prolongs WUSCHEL monomer binding window, resulting in higher CLAVATA3 activation. Our work showing a constellation of optimally spaced cis-elements of defined affinities determining activation and repression thresholds in regulating CLAVATA3 transcription provides a previously unknown mechanism of cofactor-independent regulation of transcription factor binding in mediating gene expression specificity.

Clinical Phenotyping and the Application of Precision Medicine in MAFLD.

Content available: Audio Recording.

Increased Mortality in Patients Undergoing Inpatient Endoscopy During the Early COVID-19 Pandemic.

BACKGROUND AND AIMS: The Coronavirus disease 2019 (COVID-19) pandemic led to the restructuring of most healthcare systems, but the impact on patients undergoing inpatient endoscopic procedures is unknown. We sought to identify factors associated with 30-day mortality among patients undergoing inpatient endoscopy before and during the first wave of the pandemic within an academic tertiary care center. METHODS: We studied patients who underwent inpatient endoscopic procedures from March 1-May 31 in 2020 (COVID-19 era), the peak of the pandemic's first wave across the care center studied, and in March 1-May 31, 2018 and 2019 (control). Patient demographics and hospitalization/procedure data were compared between groups. Cox regression analyses were conducted to identify factors associated with 30-day mortality. RESULTS: Inpatient endoscopy volume decreased in 2020 with a higher proportion of urgent procedures, increased proportion of patients receiving blood transfusions, and a 10.1% mortality rate. In 2020, male gender, further distance from hospital, need for intensive care unit (ICU) admission, and procedures conducted outside the endoscopy suite were associated with increased risk of 30-day mortality. CONCLUSIONS: Patients undergoing endoscopy during the pandemic had higher proportions of ICU admission, more urgent indications, and higher rates of 30-day mortality. Greater proportions of urgent endoscopy cases may be due to hospital restructuring or patient reluctance to seek hospital care during a pandemic. Demographic and procedural characteristics associated with higher mortality risk may be potential areas to improve outcomes during future pandemic hospital restructuring efforts.

Low real-world eligibility rates for nonalcoholic steatohepatitis patients for phase 3 clinical trial criteria application in a large academic health system.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is the most common liver disease in the USA. Clinical trials have stringent study criteria which may limit real-world generalizability. Thus, we studied whether a real-world, university-based cohort of patients could be eligible for a pivotal phase 3 NASH clinical trial. METHODS: We queried Yale-New Haven Health System electronic medical records for patients with a diagnosis of NASH from 2013 to 2017. Of those who received liver biopsy, we extracted demographic, clinical, laboratory, and biopsy data. We compared patient characteristics to enrollment criteria of the Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment. RESULTS: Of 14 403 patients with NASH, 478 (3.3%) completed liver biopsy, of whom 237 (49.6%) had histological confirmation by a gastrointestinal pathologist. Histologically-confirmed NASH patients were 51.1 ± 13.2 years old, 56.5% female, 69.6% white race, and 24.6% had cirrhosis. In this group, 68 (28.7%) patients met all inclusion criteria, 87 (36.7%) had no exclusions, and 34 (14.4%) met all enrollment criteria. Other than cirrhosis, common reasons for ineligibility were presence of medical comorbidity (n = 83) or laboratory abnormalities (n = 47). Multiple logistic regression did not reveal significant predictors of eligibility. CONCLUSION: Within a university-based cohort of NASH patients, few met phase 3 clinical trial enrollment criteria, mostly due to low rates of liver biopsy. Of those with histologic confirmation, 14.4% met enrollment criteria. Validation of generalizability for safety and efficacy of NASH investigational agents in real-world populations is needed.

Endoscopic Retrograde Cholangiopancreatography: Deciphering the Black and White.

Endoscopic Retrograde Cholangiopancreatography (ERCP) remains the conventional method of imaging the pancreatic and biliary tree and is performed by direct injection of iodinated contrast material via the major papilla. This diagnostic procedure gained popularity in the 1970s and subsequently paved way for ERCP guided interventions such as sphincterotomy, stone retrieval and stent placement. Currently, therapeutic ERCP is more widespread than diagnostic ERCP primarily due to the availability of noninvasive imaging. Nevertheless, more than half a million ERCPs are performed annually in the United States and radiologists need to be comfortable interpreting them. The following review will familiarize the reader with the imaging appearances of biliary and pancreatic disorders on conventional ERCP, and elaborate on therapeutic ERCP with illustrative examples.

Drug development of nonalcoholic fatty liver disease: challenges in research, regulatory pathways, and study endpoints.

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

Correction to: Excess Weight Gain After Cure of Hepatitis C Infection with Direct-Acting Antivirals.

JGIM published the article matched with the editorial in this issue in the July 2020 issue. Our apologies to the authors of the paper and the editorial.

Excess Weight Gain After Cure of Hepatitis C Infection with Direct-Acting Antivirals.

BACKGROUND: Cure from chronic hepatitis C virus (HCV) infection is readily achievable with direct-acting antivirals (DAA), but little is known about optimal management after treatment. Weight gained after DAA treatment may mitigate benefits or increase risk for liver disease progression. As the single largest sample of HCV-infected individuals receiving DAA treatment in the United States, the Veterans Affairs (VA) Birth Cohort is an ideal setting to assess weight gain after DAA treatment. METHODS: We performed a prospective study of patients dispensed DAA therapy from January 2014 to June 2015. Weight change was calculated as the difference in weight from sustained virologic response (SVR) determination to 2 years later. Demographic, weight, height, prescription, laboratory, and diagnosis code data were used for covariate definitions. We used multiple logistic regression to assess the association between candidate predictors and excess weight gain (≥ 10 lbs) after 2 years. RESULTS: Among 11,469 patients, 78.0% of patients were already overweight or obese at treatment initiation. Overall, SVR was achieved in 97.0% of patients. After 2 years, 52.6% of patients gained weight and 19.8% gained excess weight. In those with SVR, weight gain was as high as 38.2 lbs, with the top 10% gaining ≥ 16.5 lbs. Only 1% of those with obesity at treatment initiation normalized their weight class after 2 years. Significant predictors of post-SVR weight gain were SVR achievement, lower age, high FIB-4 score, cirrhosis, and weight class at treatment initiation. CONCLUSION: Weight gain is common after DAA treatment, even among those who are overweight or obese prior to treatment. Major predictors include age, baseline weight, alcohol, cirrhosis, and SVR. Everyone receiving DAAs should be counseled against weight gain with a particular emphasis among those at higher risk.

Chronic Viral Hepatitis: Current Management and Future Directions.

The past decade has seen transformation in the strategies for identifying and managing viral hepatitis, most dramatically the transformation of hepatitis C virus from a mostly chronic affliction to a curable disease that is accessible to wide populations through direct-acting antiviral therapies. More recently, shifting of hepatitis C virus burden to younger patients driven by intravenous drug use has shaped screening recommendations. Future work focusing on effective screening, linkage to care, treatment initiation, and post-cure management will allow countries to work toward meeting goals of eliminating viral hepatitis as a major public health threat. Concurrently, hepatitis B virus has also seen advances in management using oral nucleos(t)ide therapies with high-resistance barriers. However, virologic cure remains elusive in the setting of viral genetic persistence within the hepatocyte nucleus, even with suppressive antiviral therapy. Future directions include a refined definition of "cure," new biomarkers, and development of therapies targeting multiple pathways in the viral pathogenic and replication pathway. Progress is additionally being made on the management of hepatitis D infection. This review summarizes the recent evolution in disease characteristics, associated affected population, and changes in our understanding of management for these infections. We also discuss future directions in the management of viral hepatitis, including discussion on issues related to management before and after antiviral therapy. Conclusion: We summarize recent advances in the identification and management of viral hepatitis, which hold the potential to markedly reduce disease burden and therefore associated liver-related complications. However further work is needed to adequately identify and manage these diseases.