Non-alcoholic Fatty Liver Disease in Lean Subjects: Characteristics and Implications

Abstract

Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in obese subjects; however, it is not rare among lean individuals. Given the absence of traditional risk factors, it tends to remain under-recognised. The metabolic profiles of lean NAFLD patients are frequently comparable to those of obese NAFLD patients. Though results from several studies have been mixed, it has been generally revealed that lean subjects with NAFLD have minor insulin resistance compared to that in obese NAFLD. Several genetic variants are associated with NAFLD without insulin resistance. Some data suggest that the prevalence of steatohepatitis and advanced fibrosis do not differ significantly between lean and obese NAFLD; however, the former tend to have less severe disease at presentation. The underlying pathophysiology of lean NAFLD may be quite different. Genetic predispositions, fructose- and cholesterol-rich diet, visceral adiposity and dyslipidaemia have potential roles in the pathogenic underpinnings. Lean NAFLD may pose a risk for metabolic disturbances, cardiovascular morbidity or overall mortality. Secondary causes of hepatic steatosis are also needed to be ruled out in lean subjects with NAFLD. The effectiveness of various treatment modalities, such as exercise and pharmacotherapy, on lean NAFLD is not known. Weight loss is expected to help lean NAFLD patients who have visceral obesity. Further investigation is needed for many aspects of lean NAFLD, including mechanistic pathogenesis, risk assessment, natural history and therapeutic approach.

Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non‐Alcoholic Steatohepatitis

“…The effect of liraglutide in these animals could, in part, be ascribed to a reduction in hyperglycaemia and subsequent prevention of glucose‐induced de novo lipogenesis . The absence of glucose intolerance and obesity in the lean guinea pig NASH model is in accordance with the observation that insulin resistance is not universally present in lean NASH patients and may help account for the unaffected hepatic steatosis after liraglutide treatment. The absence of glucose intolerance also allows the current study to dissociate a hepatic effect of liraglutide from an effect promoted by liraglutide's ability to improve glucose metabolism.…”

“…Research efforts are currently engaged in developing novel intervention strategies against NASH; however, no effective pharmacological treatment option is presently available and data supporting reliable effects of lifestyle (e.g. dietary) intervention in lean NAFLD are lacking . Furthermore, much of the current clinical and pre‐clinical research largely targets obese NASH, potentially neglecting the lean NASH phenotype.…”

Non-alcoholic Fatty Liver Disease: Growing Burden, Adverse Outcomes and Associations

“…22,23 In Asia, NAFLD can occur in lean subjects with central obesity, which may be partly because of a higher metabolic activity of visceral fat and genetic predisposition, such as the patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism. 24,25 It is worth noting that a wide variation in clinical presentation and sensitivity of diagnostic tools complicate diagnosis of NAFLD, often leading to an underestimate of the actual disease burden.…”

Isocaloric Fructose Restriction Reduces Serum d-Lactate Concentration in Children With Obesity and Metabolic Syndrome

“…These are turned into fat through de novo lipogenesis (4). The process impairs FA oxidation by the mitochondria, as malonyl-CoA inhibits carnitine palmitoyl transferase-1 (CPT-1) and FA transport into mitochondria for ß-oxidation, Some of the trioses decompose into the toxic metabolite methylglyoxal (MG) (5), which can damage either proteins or DNA (6), or be detoxified to D-lactate (7,8), by the enzyme glyoxalase 1 (Glo1), which is critical for this process and dependent on hepatic supplies of glutathione (GSH) (9).…”

“…Non-alcoholic fatty liver disease (NAFLD) (2) currently exhibits a global prevalence of 24% (3), and is linked with other metabolic comorbidities such as type 2 diabetes, dyslipidemia, and cardiovascular disease. Although NAFLD is commonly associated with obesity, it also occurs in normal weight individuals (4)(5)(6), even in children (7).…”