Non‐alcoholic fatty liver disease in Asia: How is it different from the West? (2019)

Non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease worldwide.1 In the past, NAFLD was believed to be a condition found mostly in the West.2 In fact, the prevalence of NAFLD in Asia can be as high as 40–50% in some parts of the region exceeding figures in the West.3 Non-alcoholic steatohepatitis (NASH), the more active form of NAFLD with hepatic necroinflammation and accelerated fibrosis,4 has already become the second leading indication for liver transplantation and the third leading cause of liver cancer in the United States.5 In Asia where chronic hepatitis B and C virus infections remain the predominant causes of liver cancer and cirrhosis, NASH-related hepatocellular carcinoma (HCC) is not as common as it is in the West.6 So how different is NAFLD in Asia compare with NAFLD in the West? In recent issues of Journal of Gastroenterology and Hepatology, four publications from Asia—three from Japan and one from Malaysia—investigated the screening and risk factors of liver fibrosis in NAFLD patients. Fujii and colleagues in the Japan Study Group of NAFLD reported that insulin resistance (IR), reflected by the homeostasis model assessment parameter of IR (HOMA-IR), was an independent predictor of advanced liver fibrosis in Japanese NAFLD patients without diabetes mellitus (DM).7 The group proposed that it would be important to improve IR in these non-diabetic NAFLD patients in order to reduce liver fibrosis.7 IR has been reported previously as an important predictor for NAFLD in European patients.8 Yet this Japanese study was one of the first describing the independent role of IR in non-diabetic NAFLD patients. The beauty of this study is the potential therapeutic approach for NASH fibrosis by improving IR, even in the absence of DM; nonetheless, this hypothesis should be tested in randomized trials in the near future. The second and third studies involved non-invasive tests for liver fibrosis and fat. Lai et al. adopted a widely used non-invasive tool for liver fibrosis and fat, transient elastography, to screen DM patients for NAFLD. With this targeted screening approach, the authors reported a very high prevalence of NAFLD (72.4%) and advanced fibrosis (21.0%) based on transient elastography. This echoes the findings of another screening study for 1918 Chinese DM patients, among whom the prevalence of NAFLD (72.8%) and advanced fibrosis (17.7%) were also very high.9 These consistent findings support targeted screening for NAFLD in high-risk patients, which has been recently recommended in the United States.10 The question remained unanswered by this, as well as the previous study, is whether it is cost-effective to screening all DM patients, in particular in some resource-limited regions in Asia. With the risk factors for liver fibrosis identified in both studies, we may first screen subjects who are at risk of advanced fibrosis. Tomeno et al. evaluated the predictive ability of the fibrosis-4 index (FIB-4 index), a widely adopted serum-based formula for liver fibrosis,11 for significant liver fibrosis (F ≥ 2) in Japanese NAFLD patients.12 FIB-4 index may act as the first step to screen NAFLD patients with significant fibrosis with a positive predictive value of 36.6%.12 Patients with abnormal FIB-4 index may benefit from liver stiffness measurement or other more accurate non-invasive tests of fibrosis. Non-invasive markers for liver fibrosis are pivotal for the clinical management and risk stratification for NAFLD patients.13 However, we should bear in mind that there might be differences in the cutoff values for some important parameters between patients from the East vs the West. The absolute value of body mass index (BMI) is used in the formula of NAFLD fibrosis score,14 yet normal BMI is defined differently in the East (23 kg/m2) and the West (25 kg/m2).15 Such differences may lead to suboptimal performance of some of the scores derived in the West in Asian patients.16 Hence, some adjustment may be needed for the fibrosis scores if ethnic-specific parameters are involved. The last study by Liu is a very hot topic—lean NAFLD.17 In this large Japanese cohort of biopsy-proven NASH patients, more than 25% male and around 40% female NASH patients were non-obese. In contrast, most of them had visceral fat obesity and/or insulin resistance.18 More importantly, histological features were not milder in non-obese NAFLD patients than their obese counterparts.18 This leads to the concept of “metabolically obese,” which refers to subjects with body mass index within the normal range, yet they have various metabolic risk factors.19 This study adds fuel to the heated debate: Is lean NAFLD a more benign form of the disease comparing with the obese NAFLD? A Chinese cohort of histologically proven NAFLD patients showed that non-obese NAFLD patients had less severe disease and may have a better prognosis than obese patients.20 On the other hand, a recent European study demonstrated that non-obese NAFLD patients had a severe histological picture similar to obese patients but were even more progressive (with a higher rate of cirrhosis) compared with overweight patients who had NAFLD.21 The different observations in the above studies may be partly explained by selection bias. The threshold to perform liver biopsy examination may be different in obese and non-obese NAFLD patients in some centers—non-obese group was older than the obese group (49.9 vs 40.5 years; P < 0.01).18 A systematic review with meta-analysis using patient-level data would be helpful to evaluate with lean NAFLD patients really have worse outcomes. In any case, healthcare practitioners should not just focus on diagnosing NAFLD and the subsequent liver fibrosis assessment in obese subjects. In non-obese subjects, NAFLD and its complications are not insignificant and should not be ignored. NAFLD patients in Asia share many similarities in terms of pathophysiology and diagnostic approaches compared with the West. Yet the pandemics of obesity in the East may come a bit later than the West,22 such that the liver complications such as HCC and cirrhosis would remain in an increasing trend in the coming years. Furthermore, given the large population and endemics of chronic viral hepatitis in Asia, NAFLD would be even more impactful in terms of liver complications in the East than in the West. The latest Asia–Pacific guidelines highlight the fact that Asian people are particularly susceptible to lean NAFLD, partly because of body composition differences in fat and muscle, and genetic susceptibility via predisposition to T2DM, PNPLA3 SNPs, and polymorphisms in apolipoprotein 3.1 The new findings from the Asian latest studies would be important to bring forward the diagnostic and therapeutic development in the region.