Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects

Abstract

Background and Aims: Although non-alcoholic fatty liver disease (NAFLD) is linked to obesity, a proportion of lean subjects also have NAFLD with potentially distinct clinical features. We studied the outcome of lean NAFLD subjects.
 Methods: 299 consecutive patients (215 male, 84 female, 49.5 ± 13.5years) with biopsy-proven NAFLD and a follow-up of 8.4 years (±4.1; range: 0.9-18.0) were stratified by body mass index (BMI) at the time of liver biopsy: lean (BMI ≤25.0 kg/m, n=38), overweight (BMI 25.0-29.9 kg/m2, n=165), obese (BMI ≥30.0 kg/m2, n=93). A control group of 1,013 subjects (547 male, 52.4 ± 5.8) was used for comparison. The time to the event was recorded. Multivariable Cox regression analyses were performed to assess associations with 10-year-mortality. Hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) were calculated.
 Results: Age and gender were similar, while components of the metabolic syndrome were less frequent in lean subjects. The proportion of subjects with significant fibrosis and the number of subjects with cirrhosis was increased in lean subjects while the proportion of non-alcoholic steatohepatitis was not different. Mortality in the NAFLD groups was significantly higher than in the control group. Multivariable analysis adjusting for age, gender, and glucose confirmed lower mortality in overweight (aHR 0.21; 95% CI 0.07-0.62, p=0.005) and in obese (aHR 0.22; 95% CI 0.06-0.76, p=0.02) compared to lean subjects. Further adjustment for fibrosis weakened the difference between lean and obese (p=0.12) while the difference to overweight subjects remained intact (p=0.01).
 Conclusion: Lean subjects with NAFLD have a high risk of liver-related death. Our data support that lean NAFLD subjects deserve particular attention with regard to clinical follow-up.

Outcomes of subjects who are lean, overweight or obese with nonalcoholic fatty liver disease: A cohort study in China

“…Compared to the participants with normal BMI and non‐NAFLD, the LN group had a higher risk of death, but the ON and ONN groups (mainly overweight to class I obesity) had a lower risk. The results are consistent with other studies that individuals classified as normal weight or underweight may have higher all‐cause mortality, [ 26 , 27 ] representing a “lean paradox.” [ 8 ] In addition, the LN group in our population increased the all‐cause mortality risk by 52% and liver‐related mortality risk by 177% compared to the ON group, consistent with the results in other cohort studies that reported a positive association between LN and all‐cause mortality [ 14 , 15 , 17 ] and liver‐related mortality [ 28 , 29 ] compared with the ON group. Participants with LN may be individuals who are lean as characterized by a relatively low leg‐fat mass and high subcutaneous abdominal fat mass.…”

AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review

“…6,13 In a small longitudinal study, lean participants with biopsy-confirmed NAFLD followed for a median of 8.4 years had a higher risk of liver-related death compared with overweight or obese participants with NAFLD, although those with lean NAFLD had a higher prevalence of advanced fibrosis at baseline in this study. 18 A larger longitudinal study of more than 1300 subjects with biopsy-confirmed NAFLD from Europe and Australia found that those with lean NAFLD had less severe histologic disease compared with those with nonlean NAFLD. 19 Despite these differences, over about 7.5 years of follow-up, nearly 5% of those with lean NAFLD reported liver-related events, even though the vast majority maintained a lean BMI.…”

Age and the relative importance of liver‐related deaths in nonalcoholic fatty liver disease

“…First, liver-related disease ranked as the leading or top three causes of death in biopsy-based studies. [12][13][14] This likely represents selection bias, with overrepresentation of patients with more advanced disease. Likewise, some studies included patients with cryptogenic cirrhosis and other chronic liver diseases in the cohort and might have introduced bias.…”

“…However, the incidence and ranking of liver‐related deaths depended on a number of factors (Table S11). First, liver‐related disease ranked as the leading or top three causes of death in biopsy‐based studies 12–14. This likely represents selection bias, with overrepresentation of patients with more advanced disease.…”