Prevalence and Profile of Nonalcoholic Fatty Liver Disease in Lean Adults: Systematic Review and Meta‐Analysis

Abstract

Data on prevalence and profile of nonalcoholic fatty liver disease (NAFLD) among individuals who are lean (normal body mass index) is unclear. Published data from studies comparing lean with obese NAFLD or with healthy subjects on prevalence, comorbidities, liver chemistry and histology, and metabolic/inflammatory markers were analyzed. Data were reported as odds ratio and 95% confidence interval for categorical variables and difference of means for continuous variables. Analysis of 53 studies on 65,029 subjects with NAFLD (38,084 lean) and 249,544 healthy subjects showed a prevalence of lean NAFLD at 11.2% in the general population. Among individuals with NAFLD, the prevalence of lean NAFLD was 25.3%. Lean NAFLD versus healthy subjects had higher odds for abnormalities on metabolic profile, including metabolic syndrome and its components, renal and liver function, and patatin-like phospholipase domain-containing protein 3 (PNPLA3) G allele; and inflammatory profile, including uric acid and C-reactive protein.The abnormalities were less severe among lean versus obese NAFLD on metabolic syndrome with its components, renal and liver chemistry, liver stiffness measurement, PNPLA3 and transmembrane 6 superfamily member 2 polymorphisms, and uric acid levels as markers of inflammation. Lean NAFLD had less severe histologic findings, including hepatocyte ballooning, lobular inflammation, NAFLD activity score, and fibrosis stage. Limited data also showed worse outcomes between obese versus lean NAFLD. Conclusion: Lean NAFLD is a distinct entity with metabolic, biochemical, and inflammatory abnormalities compared to healthy subjects and a more favorable profile, including liver histology of steatohepatitis and fibrosis stage, compared to obese NAFLD. We suggest that prospective multicenter studies examine long-term hepatic and extrahepatic outcomes in individuals with lean NAFLD. (Hepatology Communications 2020;4:953-972).N onalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the world, with a global prevalence of approximately 25% and a prevalence of 24% in North America. (1,2) The incidence is increasing, especially in the Western world, due to the rising prevalence of obesity in the general population. (3) Approximately 15% to 20% of patients with NAFLD progress to the more advanced stage of nonalcoholic steatohepatitis (NASH), with a risk to progress to advanced liver

Nonalcoholic fatty liver disease in lean subjects: is it all metabolic-associated fatty liver disease?

“…An Italian study, albeit did not find a difference between G allele frequencies in lean or obese NAFLD, found that this variant is associated with disease severity (presence of steatohepatitis and significant fibrosis) only in lean patients [118] . Two meta-analyses failed to find a difference in G allele between lean and obese patients with NAFLD [12,18] , which indicates that variants in PNPLA3 might not be a major factor in the development of lean-NAFLD. Of note, Asian studies showed higher differences in the PNPLA3 variant in lean-NAFLD as opposed to overweight/obese NAFLD [119] , suggesting interplay between racial background and PNPLA3 phenotype in the development of lean-NAFLD.…”

“…Although studies have shown a wide range of prevalence of NAFLD in lean individuals (from as low as 5% to as high as 26%), two recent meta-analysis showed that roughly 10% of lean adults have NAFLD. The prevalence rises to 16% in non-obese adults [12,18] . Interestingly, the prevalence of lean-NAFLD gradually increased from 5.6% (95%CI: 3.6-8.8) in studies before 2000 to 12.6% (95%CI: 8.8-17.9) in studies after 2011 [18] .…”

“…Roughly 20% of patients with hepatic steatosis present with normal body mass index (BMI) and 40% are not obese [12,13] . As such, lean-NAFLD represents a significant burden on the daily practice of hepatologists.…”

“…The prevalence of NAFLD is around 4 times lower in the lean population compared to the overweight/obese population [11,[19][20][21][22][23][24] . Asians seem to have a higher prevalence of lean-NAFLD, and African Americans lower [12,25] , which might be explained, at least to some extent, with different compartmentalization of fat depots and intrinsic differences in adipose tissue structure/function in individuals with different racial backgrounds [26] .…”

“…Regarding the association with metabolic features, lean patients with NAFLD seem to have an intermediate phenotype between healthy subjects and obese patients with MAFLD [12,18,27,28] , regarding glucose intolerance and insulin resistance (IR), type-2 diabetes mellitus (T2DM), hypertension, and hyperuricemia. The lipid profile, however, appears to be similar between lean and obese patients with NAFLD, with similar levels of total cholesterol and triglycerides, although lean patients tend to present higher levels of HDL cholesterol [20,27,29,30] .…”