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Key Points

  • Disease summary:

    • Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of conditions involving excess fat accumulation in the liver. The term encompasses conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which is defined by histologic findings of steatosis, inflammation, ballooned hepatocytes, Mallory-Denk bodies, and varying degrees of fibrosis. Simple steatosis is thought to have a benign prognosis, whereas a subset of individuals with NASH progress to end-stage complications of cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD has not been clearly defined; however, there is a strong association with metabolic syndrome and insulin resistance.

  • Differential diagnosis:

    • Alcoholic liver disease, viral hepatitis, autoimmune hepatitis, hemochromatosis, Wilson disease, medication-induced fatty liver disease (amiodarone, tamoxifen, valproic acid, TPN).

  • Monogenic forms:

    • There is no single gene known to cause NAFLD. However, there are rare monogenic inherited disorders of lipid metabolism, insulin signaling, and mitochondrial function that result in hepatic steatosis. These disorders usually have other phenotypic manifestations which dominate over hepatic steatosis.

  • Family history:

    • Small studies in kindreds demonstrate a higher prevalence of NAFLD among first-degree relatives of patients. One study demonstrated a 59% prevalence of fatty liver in siblings and a 78% prevalence of fatty liver in parents of children with NAFLD. About 18% of patients with NASH have an affected first-degree relative.

  • Twin studies:

    • One study of monozygotic twins discordant for obesity demonstrated intrapair differences in liver fat that correlated with acquired obesity, suggesting the presence of strong nongenetic determinants of hepatic steatosis.

  • Environmental factors:

    • Western diets containing increased amounts of high fructose corn syrup, saturated fats, and trans fats have been implicated in rising obesity trends and increasing incidence of NAFLD.

  • Genome-wide associations:

    • The strongest association has been with a single-nucleotide polymorphism (SNP) variant in the PNPLA3 gene (also called “adiponutrin”). Other SNPs have been described in patients with NAFLD (Table 75-1). Testing for gene variants is not yet clinically validated for diagnosis or management of NAFLD.

  • Pharmacogenomics:

    • There are no known genetic predictors of response to pharmacotherapy.

Table 75-1Nonalcoholic Fatty Liver Disease Associated Susceptibility Variants

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