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Key Clinical Updates in Nonalcoholic Fatty Liver Disease

Risk factors for fibrosis in patients with fatty liver without nonalcoholic steatohepatitis are severe steatosis and the I148M variant of the PNPLA3 gene.


  • Often asymptomatic.

  • Elevated aminotransferase levels, hepatomegaly, or steatosis on ultrasonography.

  • Predominantly macrovesicular steatosis with or without inflammation and fibrosis on liver biopsy.


Nonalcoholic fatty liver disease (NAFLD) is estimated to affect 20–45% of the US population and has increased in incidence at least fivefold since the late 1990s. Even adolescents and young adults may be affected. The principal causes of NAFLD are obesity (present in 40% or more of affected patients), diabetes mellitus (in 20% or more), and hypertriglyceridemia (in 20% or more) in association with insulin resistance as part of the metabolic syndrome. The risk of NAFLD in persons with metabolic syndrome is 4 to 11 times higher than that of persons without insulin resistance. Nonobese persons (more frequently Asians) account for 3–30% of persons with NAFLD and have metabolic profiles characteristic of insulin resistance. Breastfeeding for more than 6 months and avoidance of early supplemental milk formula appears to reduce the risk of NAFLD in adolescence. Other causes of fatty liver include corticosteroids, amiodarone, diltiazem, tamoxifen, irinotecan, oxaliplatin, antiretroviral therapy, toxins (vinyl chloride, carbon tetrachloride, yellow phosphorus), endocrinopathies such as Cushing syndrome and hypopituitarism, polycystic ovary syndrome, hypothyroidism, hypobetalipoproteinemia and other metabolic disorders, obstructive sleep apnea (with chronic intermittent hypoxia), excessive dietary fructose consumption, starvation and refeeding syndrome, and total parenteral nutrition. NAFLD may be a predisposing factor in liver injury caused by some drugs. Gut dysbiosis and genetic factors, including polymorphisms of the gene that encodes apolipoprotein C3, are likely to play a role in NAFLD, and polymorphisms of the patatin-like phospholipase domain containing 3 (PNPLA3) gene modify the natural history of NAFLD and may account in part for an increased risk in Hispanics. A polymorphism of TM6SF2 is associated with advanced fibrosis and cirrhosis, and a polymorphism of HSD17B13 is associated with a reduced risk of progression of steatosis to steatohepatitis and of chronic liver disease. The risk of NAFLD is increased in persons with psoriasis and appears to correlate with the activity of psoriasis. Soft drink consumption and cholecystectomy have been reported to be associated with NAFLD. Physical activity protects against the development of NAFLD.

In addition to macrovesicular steatosis, histologic features may include focal infiltration by polymorphonuclear neutrophils and Mallory hyalin, a picture indistinguishable from that of alcohol-associated hepatitis and referred to as nonalcoholic steatohepatitis (NASH), which affects 3–5% of the US population. In patients with NAFLD, older age, obesity, and diabetes mellitus are risk factors for advanced hepatic fibrosis and cirrhosis, whereas coffee consumption reduces the risk. The frequency and severity of NAFLD is greater in men than in women during reproductive age, but after menopause the frequency is higher in women than men, suggesting that estrogen is protective. ...

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