Metabolically Healthy Versus Unhealthy Obesity and Risk of Fibrosis Progression in Non-alcoholic Fatty Liver Disease

Yejin Kim; Yoosoo Chang; Yong Kyun Cho; Jiin Ahn; Hocheol Shin; Seungho Ryu


Liver International. 2019;39(10):1884-1894. 

In This Article

Abstract and Introduction


Background & Aims: Little is known about the impact of metabolically healthy obesity on fibrosis progression in non-alcoholic fatty liver disease (NAFLD). We investigated the association of body mass index (BMI) category, body fat percentage and waist circumference with worsening of noninvasive fibrosis markers in metabolically healthy and unhealthy individuals with NAFLD.

Methods: A cohort study was performed on 59 957 Korean adults with NAFLD (13 285 metabolically healthy and 46 672 metabolically unhealthy individuals) who were followed for a median of 7.7 years. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homoeostasis model assessment of insulin resistance <2.5. Progression from low to intermediate or high probability of advanced fibrosis was assessed using the NAFLD fibrosis score (NFS).

Results: During 339 253.1 person-years of follow-up, 9857 subjects with low NFS at baseline progressed to intermediate or high NFS. Among metabolically healthy individuals, the multivariable-adjusted HRs (95% CI) for NFS worsening comparing BMIs 23-24.9, 25-29.9 and ≥30 with a BMI of 18.5-22.9 kg/m2 were 1.19 (1.00-1.42), 1.79 (1.52-2.10) and 3.52 (2.64-4.69), respectively, whereas the corresponding HRs (95% CI) in metabolically unhealthy individuals were 1.37 (1.24-1.52), 2.18 (1.99-2.39) and 4.26 (3.83-4.75). A similar trend was observed in the analyses using body fat and waist circumference.

Conclusion: In the large-scale cohort of young and middle-aged individuals with NAFLD, BMI was positively associated with worsening of noninvasive fibrosis marker regardless of metabolic health status. Excess adiposity per se, even without accompanying metabolic health status, may contribute to fibrosis progression in NAFLD.


With rising prevalence of obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease worldwide.[1] NAFLD ranges from simple benign steatosis to non-alcoholic steatohepatitis (NASH), in which a subset of patients may progress to fibrosis, cirrhosis, hepatocellular carcinoma and liver failure.[1] Accumulating evidence suggests that liver fibrosis, rather than other histologic features such as NASH per se, is the most important predictor of liver-related and overall mortality in patients with NAFLD.[1,2] Several studies have identified risk factors adversely affecting the histological severity of NAFLD and fibrosis progression, such as obesity, type 2 diabetes, hypertension and polymorphism in the PNPLA3 and TM6SF2 genes.[3,4] However, the risk factors for liver fibrosis progression are not yet fully understood.

Obesity is a chronic condition often accompanied by obesity-related metabolic disturbances, and evidence suggests a positive association of obesity with the development of NAFLD and liver fibrosis.[5–7] Recently, growing attention has been given to a subgroup of obese individuals, referred to as having metabolically healthy obesity (MHO), who exhibit normal metabolic profiles despite having excessive body fat.[8] This concept of metabolically healthy versus metabolically unhealthy obesity phenotypes may help understand whether obesity per se versus metabolic health affects health outcomes. While MHO is fairly common, comprising approximately 10%-35% of obese adults,[8] the effect of this phenotype on liver health is not well understood. Several studies have demonstrated that MHO is also associated with incident NAFLD,[9,10] but scarce evidence exists with regard to the impact of MHO on NAFLD fibrosis progression. Furthermore, it is not yet clear whether obesity per se or its associated metabolic abnormalities affect fibrosis progression in NAFLD, and, to the best of our knowledge, the longitudinal relationship between MHO phenotype and fibrosis progression in NAFLD has not been evaluated in cohort studies.

We performed a longitudinal cohort study to evaluate the association of body mass index (BMI), body fat percentage and waist circumference with fibrosis progression using noninvasive fibrosis markers in metabolically healthy and unhealthy adults with NAFLD.