Lean NAFLD is associated with adverse liver events and mortality: Moving beyond BMI

NAFLD represents a common etiology of chronic liver disease, which is associated with significant morbidity and mortality, and is characterized by significant heterogeneity in clinical phenotypes, although it is commonly viewed as a hepatic manifestation of the metabolic syndrome. Although NAFLD is typically identified in individuals with obesity and/or diabetes mellitus, up to 7%–20% are characterized as lean based on the body mass index of <25 kg/m2 (non-Asian) or <23 kg/m2 (Asian).1 The pathogenesis of lean NAFLD seems to overlap with that of overweight and obese NAFLD. However, the current data suggest that lean NAFLD may be associated with important differences in epidemiology, natural history, and clinical outcomes with regard to liver and cardiometabolic events.2,3 In this context, Nabi et al4 report the results of a population-based observational cohort analysis, which aimed to examine differences in subject characteristics and mortality between patients with lean versus nonlean NAFLD. The authors used the CONSTANCES cohort of 169,303 adult participants aged 18 years or older who were representatives of the French general population and were followed longitudinally from 2012 to 2019 of whom 137,206 individuals met study inclusion criteria after the exclusion of excessive alcohol consumption, viral hepatitis, or other liver diseases. NAFLD was diagnosed using the Fatty Liver Index, and liver fibrosis was assessed using the Forns Index. The authors reported an overall NAFLD prevalence of 5.3% in this cohort, with 16.3% of NAFLD subjects characterized as lean. Within the NAFLD population, the lean subjects were more likely than the nonlean subjects over a mean follow-up of 3.58 years to have advanced fibrosis (3.7% vs. 1.7%, p < 0.01) with OR 1.26 (95% CI, 1.20–1.65, p=0.005), as well as an increased risk for liver-related events (aHR=5.84, 95% CI, 4.03–8.46), chronic kidney disease (aHR=2.49, 95% CI, 1.49–4.16), and overall mortality (aHR=3.01, 95% CI, 2.21–4.11). These findings support a growing body of literature, which suggest that patients with lean NAFLD may have similar or higher rates of liver-related events than patients with nonlean NAFLD. Overall, this paper contributes important new data to the literature in the context of conflicting results reported in epidemiologic surveys and multicenter cohort studies from the US, Europe, and Asia. These results should be interpreted with caution considering methodologic strengths and weaknesses. Key strengths include a large study population (n=137,206 overall, including 22,089 nonlean NAFLD and 3664 lean NAFLD), unselected population-based community cohort, use of prospective observational data, adequate detail on alcohol consumption and lifestyle factors, laboratory-confirmed metabolic parameters (glucose/lipids), and liver enzymes. However, the analysis was limited by cross-sectional study design, absence of biopsy-confirmed NASH, reliance on a noninvasive fibrosis index (Forns) with limited test performance because of the absence of elastography, ELF score, or biopsy data, the study population of predominantly European origin (93.0%) with limited African or Asian representation, relatively short median follow-up of 3.58 years for assessment of outcomes, limited information on insulin resistance, which is of special relevance in lean NAFLD, and use of diagnostic ICD-10 codes without access to primary medical records, thereby creating significant risk for exposure and event misclassification. Considering these methodologic limitations, causality cannot be established between the lean NAFLD and liver fibrosis or other clinical outcomes. Many unanswered questions remain regarding the implications of lean NAFLD on natural history, histologic NASH and fibrosis, liver and cardiometabolic outcomes, and approach to management. The reported differences across studies in the relationship between lean NAFLD and these endpoints may reasonably stem from the patient, disease, and environmental variables, which likely contribute to these outcomes, such as age, ethnicity, genetic polymorphisms, dietary factors, physical inactivity, alcohol and tobacco consumption, body composition, sarcopenia, insulin resistance, dyslipidemia, alterations in bile acid metabolism, and gut microbiome dysbiosis.5 Further elucidation of the influence of these variables on NASH pathogenesis, fibrosis progression, and clinical outcomes may support future clinical and molecular phenotyping and individualized approaches to management. NAFLD-directed pharmacotherapies addressing key mechanistic targets beyond overnutrition, such as endocrinopathy, endoplasmic reticulum and mitochondrial stress, lipotoxicity and cholesterol toxicity, systemic inflammation, and hepatic fibrosis, will play a prominent role in treating those with lean NAFLD.6 Finally, the terminology of “lean NAFLD” itself may require careful reconsideration as body weight largely serves as an imperfect surrogate anthropometric biomarker for total body fat mass, which is associated with variable risk for cardiometabolic disease based on genetic, epigenetic, and environmental factors. In this context, the use of sex-specific fat mass index7 may represent a preferred tool over body mass index alone to signal the metabolic risk in patients with lean NAFLD for whom medical, pharmacologic, endoscopic, and surgical weight loss and metabolic NASH-directed therapies may mitigate cardiometabolic and liver outcomes despite normal body weight. Although differences will continue to be observed between lean versus nonlean NAFLD and clinical outcomes in cohort studies across geographical regions, this study adds important new data in support of a growing body of evidence that NAFLD of both phenotypes are associated with increased liver and nonliver morbidity and mortality.8–10 It is time to move beyond body mass index as a primary criterion for the assessment and risk stratification of NAFLD. Screening for NAFLD should include individuals with normal body weight but have other markers for cardiometabolic risk. Further characterization, phenotyping, and investigation of lean subjects with NAFLD in outcome studies and interventional trials will be essential to inform future diagnostic and management strategies for this unique and important subpopulation.