In this study, we retrospectively assessed the histological severity of NAFLD in lean and obese patients. In summary, lean NAFLD occurred in approximately 14.81% (n = 12) of the total patients. Lean NAFLD/NASH patients were older age and had a less severe degree of activity and fibrosis and therefore a lower proportion of NASH but no difference in advanced fibrosis (Tables 1–3). Furthermore, the proportion of lean NAFLD/NASH increased with increasing age (Fig. 1). Compared with obese NAFLD, lean NAFLD was accounted with less severe activity (LI and ballooning) in patients aged < 45 years and less severe fibrosis in those aged ≥ 45 years (Table 4). However, no difference in steatosis/activity/fibrosis was observed between different age groups (< 45 years and ≥ 45 years) in lean NAFLD patients, whereas obese NAFLD patients tended to have severe fibrosis (Table 5).
The prevalence of lean NAFLD in the NAFLD population differs among different regions. The proportion of lean NAFLD were 51.3% in Europe, 37.8% in Eastern Asia, 12.9% in Southeast Asia, and 44.3% in mainland China. In our study, lean NAFLD accounted for 14.81% of NAFLD cases, which was lower than that reported in a previous study. Ultrasound was commonly used to diagnose NAFLD and evaluate the prevalence of non-obesity in previous studies, and it may misdiagnose mild NAFLD. In this study, we used liver biopsy as the diagnostic method, and patients selected for liver biopsy are more likely to have elevated enzyme levels. The diagnostic sensitivity and selection bias may partially explain the different prevalence of lean NAFLD observed in China.
In our study, the proportions of NASH were 58.33% and 97.10% in lean and obese NAFLD patients, respectively, which was higher than that reported in previous studies. NASH was observed in 43.5% and 51.9% of lean and obese NAFLD cases, respectively, in Hong Kong China, 28%, 47%, and 38% of lean, overweight, and obese NAFLD cases, respectively, in India, and 54.1% and 71.2% of lean and obese NAFLD cases, respectively, among Caucasians. The high prevalence of NASH in our study may be due to a large proportion of patients who underwent biopsy had elevated ALT/AST levels: 82.72% (n = 67) with ALT ≥ 40 U/L and 54.32% (n = 44) with AST ≥ 40 U/L. On the other hand, many studies have defined lean and overweight/obesity according to BMI. But some studies have found that central obesity may pose a greater threat than general obesity, and waist circumstance is a simple and accessible index to diagnose NAFLD. It is common for Asians to have normal BMI and increased abdominal adiposity. Although waist circumference was not recorded in our study, increased abdominal adiposity in Asians have led to a high prevalence of NASH.
We found that the age difference was significantly higher in the lean NAFLD/NASH groups. This was consistent with findings of a recent meta-analysis that involved 7752 Japanese NAFLD patients and a retrospective study from the US. However, in these two studies, lean NAFLD was reported to have higher all-cause mortality. Liver fibrosis drives the progress of NAFLD. Increased mortality of lean NAFLD patients as reported in different studies suggests that lean NAFLD may have more serious pathological progression. However, a few published histological studies on NAFLD have reported conflicting conclusions. Two studies from Australia by Feldman et al. and Denkmayr et al. reported that pathological changes were more severe in lean NAFLD, while Kumar et al., Younes et al., Chen et al., and Leung et al. reported the opposite. Interestingly, some patients in the study by Younes et al. and all patients in the study by Chen et al. were from Australia. In our study, lean patients with NAFLD had less severe hepatic inflammation and fibrosis. There was no difference in histology in older patients with lean NAFLD, but more severe fibrosis was observed in older patients with obese NAFLD. This phenomenon indicated that the progression of lean NAFLD was slower than that of obese NAFLD. The reasons why pathological changes differ in lean NAFLD patients are unclear. This may be related to environmental or genetic factors. Patients with lean NAFLD have been reported to have a distinct gut macrobiotic profile[17, 28], which may be because of different dietary habits and environments. Patatin-like phospholipase domain-containing protein (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genetic polymorphisms are the best-effective determinants of NASH and severe fibrosis. The PNPLA3 (G) allele was reported to have a higher prevalence in lean individuals according to some studies[30, 31], and it had a greater effect on Asian lean individuals than overweight individuals. The TM6SF2 variant (decreased expression of TM6SF2) increases triglyceride levels and therefore increases the risk of NAFLD and NASH. These environmental and genetic differences may partly explain the contradictory results of different studies.
Our study provided histological data regarding lean NAFLD in mainland China where such histological information was limited. This study had some limitations. First, this was a retrospective cross-sectional study conducted at a single centre with a small population. Second, although we enrolled all biopsy-proven cases within a specific period, selection bias was inevitable. The major reason for liver biopsy was the elevated transaminase levels. Third, no long-term outcomes were observed in these patients.