Increasing metabolic co-morbidities are associated with higher risk of advanced fibrosis in nonalcoholic steatohepatitis

PLoS One. 2019 Aug 1;14(8):e0220612. doi: 10.1371/journal.pone.0220612. eCollection 2019.


Hepatic fibrosis and advanced fibrosis in particular is the strongest predictor of liver-related outcomes and mortality among nonalcoholic steatohepatitis (NASH) patients. Understanding prevalence and predictors of NASH with advanced fibrosis is critical for healthcare resource planning. Using a large U.S. clinical laboratory database from 10/1/2017-9/30/2018, adults negative for hepatitis B and hepatitis C and after excluding for alcoholic liver disease and pregnancy were evaluated for prevalence of F3 and F4 fibrosis using a systematic algorithm of five fibrosis-4 (FIB-4) criteria: Criteria 1 (≥F3: >2.67), Criteria 2 (2.67<F3≤4.12 and F4>4.12), Criteria 3 (2.67<F3≤3.15, F4>3.15), Criteria 4 (3.25<F3≤3.5, F4>3.5), Criteria 5 (3.25<F3≤4.12, F4>4.12). Metabolic co-morbidities evaluated included decreased high density lipoprotein (<40 mg/dL men, <50 mg/dL women), high triglycerides (≥150 mg/dL), elevated hemoglobin A1C (≥6.5%). Parallel analyses of patients with specific NAFLD/NASH ICD-9/10 codes from 10/1/2013-9/30/2018 were performed. Multivariate logistic regression models evaluated for predictors of ≥F3 fibrosis. Among patients with NAFLD/NASH ICD-9/10 codes, ≥F3 prevalence ranged from 4.35% - 6.90%, and F4 prevalence ranged from 2.52%- 3.67%. Increasing metabolic co-morbidities was associated with higher risk of ≥F3 fibrosis. Compared to NASH patients without metabolic co-morbidities, NASH with four concurrent metabolic co-morbidities had higher risk of ≥F3 (OR 1.56, 95% CI 1.40-1.73, p<0.001). In summary, prevalence of NASH with advanced fibrosis among U.S. adults was as high as 6.90% and prevalence of NASH with cirrhosis was as high as 3.67%, representing 5.18 million and 2.75 million, respectively, when using an estimate of 75 million U.S. adults with NAFLD. Co-morbid metabolic abnormalities were associated with higher risk of advanced fibrosis among NASH patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Algorithms
  • Female
  • Glycated Hemoglobin A / analysis
  • Humans
  • Hypertriglyceridemia / complications
  • Lipoproteins, HDL / blood
  • Liver Cirrhosis / etiology*
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / complications*
  • Retrospective Studies
  • Risk Factors
  • Sex Factors
  • Triglycerides / blood
  • Young Adult


  • Glycated Hemoglobin A
  • Lipoproteins, HDL
  • Triglycerides
  • hemoglobin A1c protein, human

Grant support

This study was supported by a research grant from Gilead Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.