Metabolic and Genetic Risk Factors Are the Strongest Predictors of Severity of Alcohol-Related Liver Fibrosis

Clin Gastroenterol Hepatol. 2022 Aug;20(8):1784-1794.e9. doi: 10.1016/j.cgh.2020.11.038. Epub 2020 Dec 4.


Background & aims: Individual risk for developing alcohol-related liver disease (ALD) varies greatly. We hypothesized that metabolic risk factors and genetic polymorphisms predict severity of ALD.

Methods: Biopsy-controlled, cross-sectional study in patients with a history of excessive drinking. We measured the homeostatic model assessment of insulin resistance (HOMA-IR), plasma triglycerides, high- and low-density lipoproteins (HDL, LDL), and total cholesterol. Moreover, we genotyped four single nucleotide polymorphisms in PNPLA3 (rs738409C>G), TM6SF2 (rs58542926C>T), MBOAT7 (rs641738C>T), and HSD17B13 (rs72613567T>TA). We assessed predictors of higher fibrosis stage using multivariable ordered logistic regression.

Results: Of 325 included patients, 25% had severe fibrosis or cirrhosis and 59% had HOMA-IR ≥2.5. HOMA-IR increased for each fibrosis stage, while there was a similar decrease in LDL and total cholesterol. Individuals with risk variant PNPLA3 rs738409-G or TM6SF2 rs58542926-T had higher fibrosis stage. In multivariable regression, HOMA-IR ≥2.5 (OR = 3.04, 95% CI 1.90-4.87), LDL <2.60 mmol/L (OR = 2.05, 95% CI 1.33-3.16), TM6SF2 rs58542926-T (OR = 1.99, 95% CI 1.17-3.37), age above 50 years (OR = 1.66, 95% CI 1.03-2.70), and PNPLA3 rs738409-G (OR = 1.54, 95% CI 1.11-2.12) independently predicted higher fibrosis stage. Independent predictors of hepatic inflammatory activity were HOMA-IR, active drinking, age, and PNPLA3 risk variant. Active drinking, elevated triglycerides, and PNPLA3 risk variant predicted steatosis.

Conclusions: Insulin resistance is the strongest predictor of liver fibrosis stage and hepatic inflammation in patients with alcohol-related liver disease. Genetic susceptibility further aggravates this risk. These data highlight the clinical value of detailed metabolic and genetic profiling of patients with excessive alcohol use.

Keywords: Alcoholic Liver Disease; Fatty Liver; Genetics; Insulin Resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking* / adverse effects
  • Cholesterol
  • Cross-Sectional Studies
  • Fatty Liver, Alcoholic* / genetics
  • Fatty Liver, Alcoholic* / pathology
  • Fibrosis
  • Genetic Predisposition to Disease
  • Humans
  • Insulin Resistance*
  • Lipase / genetics
  • Liver / pathology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / pathology
  • Membrane Proteins / genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Triglycerides


  • Membrane Proteins
  • Triglycerides
  • Cholesterol
  • Lipase