Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?

Abstract

ObjectiveThe full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.DesignThe study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) </≥25 kg/m2). Liver/non-liver-related events and survival free of transplantation were recorded during the follow-up, compared by log-rank testing and reported by adjusted HR.ResultsLean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the PNPLA3 I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069).ConclusionsCaucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds.Lay summaryNAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.

Independent Dose–Response Associations between Fetuin-A and Lean Nonalcoholic Fatty Liver Disease

“…Experimental studies have shown that fetuin-A promotes the expression of proinflammatory cytokines at the mRNA and protein levels [ 12 , 30 ] and chronically responds to inflammatory stimuli [ 31 ], leading to the progression from steatohepatitis to NASH [ 32 , 33 ]. In a study cohort comprising 1339 Caucasian biopsy-proven NAFLD patients, it was found that both lean and non-lean NAFLD may progress to advanced liver disease, metabolic comorbidities, cardiovascular disease, and liver-related mortality, independent of the progression to obesity [ 34 ].…”

Non-alcoholic fatty liver disease: A patient guideline

“…32,73 These numbers vary across the world, being as low as 25% in South-East Asian countries, and up to 50% elsewhere, 74 depending on how obesity is defined in each country. 75 The concept of lean NAFLD is, however, somewhat misleading and simplistic. The definition of lean is based on body mass index (BMIyour weight divided by your height squared) but does not take into account how the weight is distributed in the body (fat vs. muscle, intra-abdominal fat vs. subcutaneous fat) (Box 6).…”

“…Lean people with NAFLD often have some abdominal fat accumulation or other subtle metabolic abnormalities. 75 Lean NAFLD hence refers to the presence of NAFLD in people that have few obvious metabolic risk factors. They might have some excess body fat but still be lean according to the BMI criteria.…”

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

“…Putative pathophysiological drivers in lean patients with MAFLD (-)/NAFLD (+) like gut microbiota and genetics also play a role in MAFLD (+)/NAFLD (+) (6,7). It should also be noted that patients with lean NAFLD patients are usually younger than those with the classical NAFLD phenotype who also qualify as MAFLD (8,9). In the present study too, patients with MAFLD (-)/NAFLD (+) were almost a decade younger (35.0 ± 0.9 years) than those with MAFLD (+)/NAFLD (+) (47.2 ± 0.6 years) (1).…”