The term metabolic dysfunction-associated fatty liver disease (MAFLD) has recently been suggested as an alternative to non-alcoholic fatty liver disease (NAFLD). Unlike NAFLD, MAFLD’s diagnosis is based on the active identification of NAFLD-associated metabolic abnormalities. While MAFLD is commonly associated with obesity, recent evidence has affirmed that a significant proportion of MAFLD patients in fact possess normal body mass indexes (BMI). These individuals suffer from what is termed lean MAFLD. Lean MAFLD’s pathophysiology remains poorly characterised, and its management in this patient population has yet to be clarified.
This review aims to assess epidemiological data associated with this patient population and explain its heterogeneity in patients of normal weight as well as those above normal weight.
There is a strong association between metabolic health and MAFLD in patients of normal weight, with the former being a major determinant for lean MAFLD development. Metabolic health is itself regulated by metabolic flexibility and adaptation.
Metabolic inflexibility has been shown to significantly contribute to insulin resistance, weight gain, MAFLD, and type 2 diabetes mellitus. In the context of lean MAFLD, metabolic inflexibility may lead to hepatic fat accumulation independently of weight gain. As such, future drug development programmes should consider metabolic flexibility as a therapeutic target for lean MAFLD management. Drugs which are known to impact metabolic flexibility include those affecting fatty acid oxidation, such as peroxisome proliferator-activated receptor agonists or AMP-activated protein kinase (AMPK) activators.
No guidelines currently exist for the treatment of lean MAFLD. However, healthcare professionals should not disregard patients of normal weight when diagnosing and managing MAFLD. Professional dietary advice and encouragement of physical activity should be provided for all patients with MAFLD, irrespective of their BMI. An early diagnosis and treatment of metabolic comorbidities should also be a priority for patients with lean MAFLD.