NAFLD in lean patients

25 Mar 2021

Nonalcoholic fatty liver disease (NAFLD) is commonly associated with type 2 diabetes and metabolic syndrome [ref 1]. For this reason, it is almost automatic to think that NAFLD is closely associated with obesity. This concept is largely correct, given that the prevalence of NAFLD increases with increasing Body Mass Index (BMI) [ref 2]. However, it has been demonstrated that patients can develop NAFLD even with a normal BMI (i.e. <25 kg/m2 in Caucasian and <23 kg/m2 in Asian subjects), therefore showing clinical signs of the so-called “lean NAFLD” [ref 3]. Data on the prevalence and clinical history of lean NAFLD in Caucasian patients have only recently been acquired. Based on recent clinical studies performed in a European cohort, liver biopsies suggestive for NAFLD appear to be associated with patients with a normal BMI in 14.4% of cases [ref 4]. Lean patients with NAFLD showed less frequently central obesity and diabetes mellitus, and lower values of serum triglycerides, while no difference was found in the serum concentration of total cholesterol and HDL-cholesterol. As far as liver biopsies is concerned, lean subjects had significantly less steatosis, less lobular inflammation, less ballooning and less advanced liver fibrosis as compared with the non-lean group [ref 4]. The indirect measurement of fibrosis through hepatic stiffness obtained by transient elastography was also lower in lean patients than in obese patients in a series of Asian subjects [ref 5].

During follow up cardiovascular diseases were developed in 11.3% of non-lean patients vs 7.3% in lean patients (p=ns) [ref 4]. These data are similar with other data of American subjects, where cardiovascular events were registered in 11.2% of lean patients and 12.0% of non-lean patients (p=ns) [ref 6]. Moreover, data show no difference in the development of liver-related events (i.e. end-stage cirrhosis with MELD>15, decompensation of cirrhosis with development of ascites, hepatic encephalopathy or gastrointestinal bleeding), that seem to occur in 7.7% of non-lean patients and in 4.7% of lean patients [ref 4].  Likewise, lean and non-lean subjects with NAFLD show similar rates of HCC development (1.0% of lean patients vs 2.6% of non-lean patients, p=ns) [ref 4].

Why lean subjects develop complications of NAFLD with the same frequency of overweight and obese patients is still to be clarified. In fact, pathophysiology of lean-NAFLD is still not completely explained. Many mechanisms have been supposed, such as the presence of environmental causes (i.e. high fructose and/or high fat intake), body fat distribution (with an increase tendency towards visceral obesity), body composition (acquired or congenital lipodistrophy, sarcopenia), genetic risk factors (congenital defects of metabolism like Lysosomal Acid Lipase deficiency), early epigenetic changes, endocrine disorders (such as polycystic ovary syndrome or hypothyroidism) and alterations in gut microbiota [ref 3]. Clinicians observed that lean patients usually present an increased severity of risk factors (i.e. dyslipidemia, arterial hypertension, diabetes, and insulin resistance), that is probably related to a more dysfunctional adipose tissue. In this sense, recent studies identified different mechanisms in insulin resistance and different metabolomic profiles in lean subjects and in obese patients [ref 7-8]. However, the field of “omics” is still very large and many studies are needed before identifying directly causal relationships in this area.

Whatever the cause, these data suggest that lean patients with NAFLD should not be overlooked. In fact, lean-NAFLD constitutes almost 15% of all NAFLD cases. Furthermore, although initially it appears to be associated with a lower risk of fibrosis and lower cardiovascular risk factors, lean-NAFLD leads to development of cardiovascular events and complications of cirrhosis with similar rates than in patients with increased BMI.


  1. Mantovani A, Scorletti E, Mosca A et al. Complications, morbidity and mortality of nonalcoholic fatty liver disease. Metabolism 2020,111,154170.
  2. Lazo M, Hernaez R, Eberhardt MS, et al. Prevalence of nonal-coholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol 2013;178:38–45.
  3. Younes R, Bugianesi E. NASH in lean individuals. Semin Liver Dis 2019;39:086–95.
  4. Younes R, Govaere O, Petta S, et al. Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach? Gut 2021 Feb 4;gutjnl-2020-322564.
  5. Leung JC, Loong TC, Wei JL et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in non obese patients. Hepatology. 2017 Jan;65(1):54-64.
  6. Weinberg EM, Trinh HN, Firpi RJ et al. Lean Americans With Nonalcoholic Fatty Liver Disease Have Lower Rates of Cirrhosis and Comorbid Diseases. Clin Gastroenterol Hepatol. 2020 Jul 3:S1542-3565(20)30930-7.
  7. Albhaisi S, Chowdhury A, Sanyal AJ. Non-Alcoholic fatty liver disease in lean individuals. JHEP Rep 2019;1:329–4.
  8. Feldman A, Eder SK, Felder TK et al. Clinical and metabolic characterization of lean Caucasian subjects with non-alcoholic fatty liver. Am J Gastroenterol 2017;112:102–10.