Nonalcoholic fatty liver disease: a systematic review

JAMA. 2015 Jun 9;313(22):2263-73. doi: 10.1001/jama.2015.5370.


Importance: Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30% and 5%, respectively, of the US population. In patients with nonalcoholic steatohepatitis, half of deaths are due to cardiovascular disease and malignancy, yet awareness of this remains low. Cirrhosis, the third leading cause of death in patients with nonalcoholic fatty liver disease, is predicted to become the most common indication for liver transplantation.

Objectives: To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease.

Evidence review: PubMed was queried for published articles through February 28, 2015, using the search terms NAFLD and cirrhosis, mortality, biomarkers, and treatment. A total of 88 references were selected, including 16 randomized clinical trials, 44 cohort or case-control studies, 6 population-based studies, and 7 meta-analyses.

Findings: Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis. Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest (<50%) and none is approved by the US Food and Drug Administration. The association between nonalcoholic steatohepatitis and cardiovascular disease is clear, though causality remains to be proven in well-controlled prospective studies. The incidence of nonalcoholic fatty liver disease-related hepatocellular carcinoma is increasing and up to 50% of cases may occur in the absence of cirrhosis.

Conclusions and relevance: Between 75 million and 100 million individuals in the United States are estimated to have nonalcoholic fatty liver disease and its potential morbidity extends beyond the liver. It is important that primary care physicians, endocrinologists, and other specialists be aware of the scope and long-term effects of the disease. Early identification of patients with nonalcoholic steatohepatitis may help improve patient outcomes through treatment intervention, including transplantation for those with decompensated cirrhosis.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Alanine Transaminase / blood
  • Biomarkers / blood
  • Biopsy
  • Diabetes Complications
  • Diet Therapy
  • Exercise
  • Fatty Liver / diagnosis
  • Humans
  • Liver / pathology*
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / diagnosis*
  • Non-alcoholic Fatty Liver Disease / therapy*
  • Obesity / complications
  • Pioglitazone
  • Risk Factors
  • Thiazolidinediones / therapeutic use
  • Vitamin E / therapeutic use


  • Biomarkers
  • Thiazolidinediones
  • Vitamin E
  • Alanine Transaminase
  • Pioglitazone