UC San Diego

Whereas the rising prevalence of nonalcoholic fatty liver disease (NAFLD) is closely related with the global obesity epidemic, up to 10–20% of individuals with NAFLD are lean as defined by a body mass index of < 25 kg/m2, or < 23 kg/m2 in Asians. This entity designated as “lean NAFLD” is estimated to affect 8 to 10 million individuals in the United States alone. Here, we review the emerging data on the epidemiology, natural history and prognosis of lean NAFLD and put forward a diagnostic approach that combines detailed clinical phenotyping with genomic analysis. We propose two subtypes of lean NAFLD referred to as type 1: individuals with visceral adiposity and insulin resistance but normal BMI; and type 2: lean individuals with hepatic steatosis secondary to a known or unknown monogenic disease. We envision that incorporation of genomic analysis in the diagnostic algorithm of lean patients with NAFLD will elucidate the contribution of common genetic variants through the calculation of NAFLD polygenic risk score and also characterize the diverse array of rare monogenic diseases that can lead to triglyceride accumulation in the cytoplasm of hepatocytes. Collectively, the integration of a molecular diagnosis in the clinical evaluation of patients with lean NAFLD will provide an accurate diagnosis, with possible targeted therapies and may uncover novel molecular mechanisms with potential broader therapeutic implications.