NASH in lean individuals

Non alcoholic Fatty Liver Disease (NAFLD) is generally associated with obesity and the related co-morbidities but it can also develop in subjects with a BMI within the ethnic-specific cut-off of 25 kg/ m2 BMI in Caucasian and 23 kg/ m2 in Asian subjects, the so-called ‘lean’ NAFLD. This sub-phenotype of NAFLD patients has been described across populations of different ethnicity, particularly in Asia, but it can be diagnosed in 10%-20% of non-obese Americans and Caucasians. Pathophysiological mechanisms underpinning the “lean” phenotype are not completely understood, but they may include a more dysfunctional fat (visceral obesity, differences in adipocyte differentiation and altered lipid turnover), altered body composition (decreased muscle mass), a genetic background, not limited to PNPLA3 C>G polymorphisms, epigenetic changes occurring early in life and a different pattern of gut microbiota. Lean subjects with NAFLD have milder features of the metabolic syndrome when compared to obese patients. Nonetheless they have a higher prevalence of metabolic alterations (e.g. dyslipidemia, arterial hypertension, insulin resistance and diabetes) compared to healthy controls. Data on histological severity are controversial, but they can develop the full spectrum of liver disease associated with Non Alcoholic Steatohepatitis (NASH). Since ‘Lean’ NAFLD usually present with less obesity-related comorbidities, it is commonly believed that this group would follow a relatively benign clinical course but recent data challenge this concept. Here we describe the current knowledge about NAFLD in lean individuals and highlight the unanswered questions and gaps in the field.