Spotlight on alcohol-related liver disease

Recent research identified risk factors that predict the severity of alcohol-related liver disease, distinct patterns of alcohol use that may affect survival after liver transplantation for alcoholic hepatitis, potential effects on the microbiome, and more.

Several recent studies focused on patients with alcohol-related liver disease (ALD).

First, a liver biopsy-controlled, cross-sectional study in patients with a history of excessive drinking for more than one year found that insulin resistance and genetic susceptibility predict the severity of ALD. In 325 patients (median age, 57 years; 76% men), researchers measured the homeostatic model assessment of insulin resistance (HOMA-IR), plasma triglycerides, high- and low-density lipoprotein (HDL and LDL) cholesterol, and total cholesterol, as well as genotyped four single nucleotide polymorphisms in PNPLA3, TM6SF2, MBOAT7, and HSD17B13. Patients were recruited through standard referrals to three outpatient liver clinics, from two municipal alcohol rehabilitation centers, and through a community call to screen for ALD in the region of Southern Denmark. Results were published online on Dec. 3 by Clinical Gastroenterology and Hepatology.

Overall, 82 (25%) patients had severe fibrosis or cirrhosis, and 191 (59%) had a HOMA-IR of 2.5 or greater. In multivariable regression, independent predictors of higher fibrosis stage were HOMA-IR of 2.5 or greater (odds ratio [OR], 3.04; 95% CI, 1.90 to 4.87), an LDL cholesterol level below 2.60 mmol/L (OR, 2.05; 95% CI, 1.33 to 3.16), TM6SF2 rs58542926-T (OR, 1.99; 95% CI, 1.17 to 3.37), age above 50 years (OR, 1.66; 95% CI, 1.03 to 2.70), and PNPLA3 rs738409-G (OR, 1.54; 95% CI, 1.11 to 2.12). Independent predictors of hepatic inflammatory activity were increasing HOMA-IR, active drinking, increasing age, and PNPLA3 risk variant, while active drinking, elevated triglyceride levels, and PNPLA3 risk variant predicted steatosis. Among other limitations, the study included only Danish individuals of European ancestry, the authors noted. They concluded that “[O]ur findings raise the question of whether metabolic and genetic profiling should be considered part of the clinical work-up in ALD, particularly insulin resistance. Control of metabolic disorders could be as important as lowering alcohol use in patients with alcohol-related liver disease.”

The second study looked at another emerging therapeutic target in ALD: the microbiome. Researchers assessed microbiome composition by collecting fecal samples from 24 patients with the most aggressive form of ALD, severe alcoholic hepatitis, and from 24 healthy controls at six university hospitals in South Korea. They also collected fecal samples after four weeks in eight patients with severe alcoholic hepatitis who completed rifaximin treatment to determine microbiome recovery in gut bacteria and bacteria derived-extracellular vesicles. Results were published online on Dec. 2 by Alimentary Pharmacology and Therapeutics.

Fecal microbiomes of patients with severe alcoholic hepatitis had lower alpha diversity and higher beta diversity than those of healthy controls in both gut bacteria and extracellular vesicles. In the gut bacteria of patients with severe alcoholic hepatitis, Bacilli, Lactobacillales, and Veillonella were significantly increased, whereas Eubacterium_g23, Oscillibacter, and Clostridiales were decreased. In the extracellular vesicles of patients with severe alcoholic hepatitis, Veillonella, V. parvula group, and Lactobacillales were significantly increased and Eubacterium_g23, Oscillibacter, and Christensenellaceae were decreased. After rifaximin treatment in patients with severe alcoholic hepatitis, 17 taxa in the gut bacteria and 23 taxa in extracellular vesicles were significantly restored. The study did not include active alcohol drinkers without liver disease or patients with nonsevere alcoholic hepatitis, among other limitations, the authors noted.

A third study found that patients with chronic liver disease (CLD), particularly severe ALD, who present with acute myocardial infarction (MI) are less likely to receive invasive management and may have worse clinical outcomes than those without. Researchers used the Nationwide Inpatient Sample (2004-2015) to assess in-hospital clinical outcomes of acute MI patients stratified by severity and subtypes of CLD. Of more than 7 million acute MI admissions, 54,283 (0.8%) patients had a CLD diagnosis, while the remaining patients comprised the no-CLD group. Results were published online on Nov. 21 by the International Journal of Clinical Practice.

Overall, 10,366 (0.1%) patients had alcohol-related CLD, 84.2% nonsevere and 15.8% severe. Compared to patients with no CLD, patients with alcohol-related CLD had the lowest odds of receiving coronary angiography (ORs, 0.48 [95% CI, 0.46, 0.50] for nonsevere ALD and 0.25 [95% CI, 0.23 to 0.28] for severe ALD) and percutaneous coronary intervention (ORs, 0.44 [95% CI, 0.42 to 0.46] for nonsevere ALD and 0.25 [95% CI, 0.21 to 0.28] for severe ALD), which were significantly different from the nonsevere CLD subtype, as well as the severe chronic viral hepatitis and severe “other CLD” subgroups. In addition, major adverse cardiovascular and cerebrovascular events, mortality, and bleeding were worst in patients with severe forms of ALD and other CLD. Among other limitations, data were from an administrative dataset, and, given the limited ICD codes, the specific etiologies of chronic hepatitis and other causes of CLD were unknown, the authors said.

A final study found that early patterns of alcohol use after liver transplantation for alcoholic hepatitis significantly reduce longer-term survival. Researchers retrospectively assessed data from consecutive adults who received a transplant and had the indication of severe alcoholic hepatitis at 11 ACCELERATE-AH study sites from 2006 to 2018. They identified longitudinal patterns of alcohol use after liver transplant and assessed their association with post-transplant outcomes, including overall life expectancy. They defined early-onset alcohol use as within the first 12 months after transplant and heavy use as frequent or binge use for more than one follow-up interval after transplant. Binge drinking was defined as five or more drinks in men and four or more drinks in women in one setting, and frequent drinking was defined as four or more days in the week of drinking. Results were published online on Dec. 3 by Clinical Gastroenterology and Hepatology.

Of 153 liver transplant recipients, one-, three-, and five-year survival rates were 95%, 88%, and 82%. Of 146 patients who survived to home discharge, four distinct patterns of post-transplant alcohol use were identified: 1) complete abstinence (n=103; 70.5%), 2) abstinence followed by late-onset nonheavy use (n=9; 6.2%), 3) early-onset nonheavy use (n=22; 15.1%), and 4) early-onset heavy use (n=12; 8.2%). While one-year survival was similar across the four patterns (100%), patients with early post-transplant alcohol use had lower five-year survival (62% with nonheavy use and 53% with heavy use) compared to those with abstinent and late/nonheavy patterns (95% and 100%), corresponding to a more than 10-fold higher risk of overall mortality for patients with each early drinking pattern compared to those who abstained. Younger age, history of multiple rehabilitation attempts, and overt encephalopathy were predictors of harmful post-transplant alcohol use. The study had a retrospective design and lacked granular data regarding patients with severe alcoholic hepatitis who were not selected for early liver transplant, among other limitations, the authors said.