Lean NAFLD: A not so benign condition?

Nonalcoholic fatty liver disease (NAFLD) is a worldwide epidemic with global prevalence estimated at 25%. Although NAFLD is usually associated with obesity, patients who are not obese can also present with NAFLD; this is known as “lean NAFLD.” Lean NAFLD is defined as NAFLD that develops in patients with a body mass index (BMI) <25 kg/m. The prevalence of lean NAFLD varies from 7% in the United States to as high as 19% in Asia. Unfortunately, being lean (not overweight) does not necessarily lead to better health. A recent large meta-analysis by Sookoian and Pirola of almost 2,000 patients with NAFLD who were lean demonstrated that patients with NAFLD who are lean or obese share a common altered metabolic and cardiovascular profile, which in turn may lead to collective risk for adverse cardiometabolic outcomes, including diabetes and ischemic heart disease. Indeed, atherosclerotic cardiovascular disease remains the most common cause of death in all weight categories. The increase in cardiometabolic risk in lean NAFLD has been attributed primarily to alterations in body fat distribution, in particular visceral adiposity as measured by waist circumference or waist-to-hip ratio. In fact, measures of abdominal adiposity may best predict development of severe liver disease in NAFLD. Severity of NAFLD is also driven, in part, by singlenucleotide polymorphisms in genes involved in lipid metabolism, oxidative stress, insulin signaling, and fibrogenesis. Genetic polymorphisms in the patatinlike phospholipase domain-containing-3 (PNPLA3) gene, which is related to lipid transformation, is now recognized as the major common genetic determinant of NAFLD and is associated with progression to nonalcoholic steatohepatitis (NASH) in both lean and obese NAFLD. In addition, alterations in the transmembrane 6 superfamily member 2 (TM6SF2) gene, which confers a susceptibility to NASH and fibrosis but protection against cardiovascular events, has been shown to be increased in lean NAFLD compared to patients with NAFLD who are overweight/ obese. However, studies to date in lean NAFLD have been severely limited by small sample size and lack of natural history data with histologic assessment of NAFLD at baseline. In the current issue, Hagstr€om et al. report retrospective findings from the largest and longest series of patients with biopsy-proven NAFLD to date (n5 646), with a mean follow-up time of 19.3 years. The lean NAFLD prevalence in this cohort was high at 19% (n5 123; Fig. 1). The cohort was derived from three large Swedish university hospitals and comprised all patients with biopsy-proven NAFLD from 1971 Abbreviations: BMI, body mass index; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.