18-10: Nonalcoholic Fatty Liver Disease

ESSENTIALS OF DIAGNOSIS

GENERAL CONSIDERATIONS

NAFLD is estimated to affect 36% of the US adult population and has increased in incidence at least fivefold since the late 1990s, with the highest rates in persons over age 60 and Latinos/Latinas. 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. Moreover, greater than 25% of patients consume moderate to excessive amounts of alcohol. In fact, the alternative designation “metabolic-associated (or metabolic dysfunction‒associated) fatty liver disease” (MAFLD) has been proposed. 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 7–20% of persons with NAFLD and have metabolic profiles characteristic of insulin resistance. Maternal obesity and higher maternal early-pregnancy glucose concentrations in mothers of European ancestry are associated with NAFLD in offspring, and breastfeeding for longer than 6 months with avoidance of early supplemental milk formula appears to reduce the risk of NAFLD in offspring during adolescence and in the mother later in life. Other causes of fatty liver include corticosteroids, amiodarone, diltiazem, methotrexate, 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, malnutrition, starvation and refeeding syndrome, and total parenteral nutrition. NAFLD may be a predisposing factor in liver injury caused by some drugs. Gut dysbiosis, altered bile acid metabolism, and genetic factors (in up to 35% or patients), including polymorphisms of the gene that encodes apolipoprotein C3, are thought to play a role in NAFLD (and likely account for NAFLD in lean persons), 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 Latinx persons. 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. Other associations include variants of MBOAT1 and GCKR and epigenetic factors. The risk of NAFLD is increased in persons with psoriasis and appears to correlate with the activity of psoriasis. Soft drink and red meat consumption, ambient air pollutants, 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, ...