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Nonalcoholic Fatty Liver Disease A Systematic Review

Mary E. Rinella, MD1
[+] Author Affiliations
1Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
JAMA. 2015;313(22):2263-2273. doi:10.1001/jama.2015.5370.
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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 14 randomized clinical trials, 19 cohort or case-control studies, 1 population-based study, 2 practice guidelines, 7 meta-analyses, 43 classified as other, and 2 webpages.

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.

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Figure 1.
Histological Subtypes of NAFLD and Their Implications for Disease Progression

Nonalcoholic fatty liver disease is broadly divided into those with NAFL (isolated steatosis with or without nonspecific inflammation) and NASH, with varying degrees of hepatic fibrosis. A, Isolated steatosis is characterized by macrovesicular fatty change in the absence of cellular injury (ballooning) (hematoxylin-eosin, original magnification × 10). B, Steatosis with nonspecific inflammation (hematoxylin-eosin, original magnification × 20). C, NASH is characterized by the additional presence of cellular ballooning (inset) (hematoxylin-eosin, original magnification × 20). D, NASH with early fibrosis in a typical pericellular pattern (arrowhead) (Trichrome, original magnification × 20). E, NASH cirrhosis is characterized by the development of broad collagen bands that form nodules (arrowhead) (Trichrome, original magnification × 10). Other characteristic features of NASH may or may not be present once cirrhosis has developed. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; AST:ALT, ratio of AST to ALT.

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Figure 2.
Mechanisms Involved in the Pathophysiology of Nonalcoholic Fatty Liver Disease

Dashed lines indicate emerging data. FFA indicates free fatty acids.

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Figure 3.
Algorithm for the Decision to Perform Liver Biopsy in Patients With Presumed Nonalcoholic Fatty Liver Disease After Negative Serological Evaluation and Exclusion of Alcohol as a Contributing Factor

ARFI indicates acoustic radiation force impulse; CT, computed tomography; MR, magnetic resonance; MRI, magnetic resonance imaging; NASH, nonalcoholic steatohepatitis.

aIncludes the metabolic syndrome (diabetes, hypertension, central obesity, high level of triglycerides or low level of high-density lipoprotein cholesterol), older than 60 years, and family history of diabetes.

bHigher level of aspartate aminotransferase than alanine aminotransferase, low platelet count, elevated international normalized ratio, and elevated bilirubin level without alternative explanation suggest the presence of cirrhosis.

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