Changing NAFLD Epidemiology in China

Supported by the General Research Fund of the Research Grants Council, Hong Kong SAR Government (14108916). Potential conflict of interest: Dr. Wong consults, is on the speakers’ bureau, and received grants from Echosens and Gilead. He consults for 3V Bio, AbbVie, Allergan, Boehringer Ingelheim, Janssen, Novartis, Novo Nordisk, Pfizer, and Terns. He is on the speakers’ bureau for Bristol‐Myers Squibb and Merck. See Article on Page 1119. In Factfulness, the late Dr. Hans Rosling illustrated how most people grossly underestimated education, income, life expectancy, and vaccination rates in low‐income countries.1 It is natural human psychology to have fixed images about the developing world. Nonetheless, the world is changing. According to the latest World Bank figures, 184 of 218 (84%) countries or regions are now classified as middle‐income or high‐income economies.2 Many countries previously labeled as developing countries (such as Armenia, Colombia, Malaysia, and Serbia) are now classified as upper‐middle‐income economies. Although many problems remain and deserve our attention, Dr. Rosling emphasized that it is equally important to recognize that there is progress and many policies do work. Otherwise, we risk dismissing useful strategies and impeding their implementation. Nevertheless, with economic growth comes overnutrition and obesity‐related disorders. A meta‐analysis by Younossi et al. reported a global prevalence of nonalcoholic fatty liver disease (NAFLD) of 25%, with similarly high prevalence in North America (24%), Europe (24%), and Asia (27%).3 An updated meta‐analysis focusing on Asian epidemiological studies reported an NAFLD prevalence of 30% and an incidence of 50.9 cases per 1,000 person‐years.4 However, the included studies differ by study period, setting, and method of diagnosis. If we agree that NAFLD is becoming more common, a crude prevalence figure based on combined data from old and recent studies may not mean much. Data that are more granular are required. In this issue of Hepatology, Zhou et al. report a new systematic review and meta‐analysis on the epidemiology of NAFLD in China.5 They reviewed 392 studies representing more than 2 million subjects. With this wealth of data, the authors made a number of important observations. First, although the pooled nationwide prevalence of NAFLD was 29.2%, it increased from 25.4% in 2008‐2010 to 32.3% in 2015‐2018. There were significant differences in the prevalence of NAFLD in subgroups stratified by age, sex, obesity, ethnicity, geographical region, and income. In the past, we tended to think that urbanization was the main reason for the obesity problem, but we now know it is not the entire picture. In the current meta‐analysis, regions with a per capita gross domestic product of less than US $7,200 had higher NAFLD prevalence (29.7%) than many other regions. Another meta‐analysis of 2,009 population‐based studies also showed that the rise in body mass index (BMI) in rural areas has been the main driver behind the global obesity epidemic.6 When energy‐rich food becomes available and affordable, poorer people are often affected more because they are less likely to have the resource and knowledge to select healthier options. Because most liver‐related morbidity and mortality only occur in patients with cirrhosis, it is important to look at not only the prevalence of NAFLD but also its severity. In the current meta‐analysis, 14%‐25% of Chinese NAFLD patients had advanced fibrosis.5 However, patients undergoing liver biopsy are highly selected and usually have more severe disease. Using transient elastography as a noninvasive test of liver fibrosis, a population‐based study in Hong Kong showed that 4% of the NAFLD patients in the community had advanced fibrosis.7 Although it is tempting to conclude that NAFLD is less severe in Asia than in the West, one must remember that duration matters in the development of liver‐related complications. It takes several decades before a patient with a chronic liver disease can progress to cirrhosis. Because economic growth is a recent event in many Asian countries, most current Asian NAFLD patients only become overweight or obese when they reach middle age. As a result, they do not have sufficient disease duration to develop advanced liver disease. However, if we remember that nonalcoholic steatohepatitis has just become a leading indication for liver transplantation in recent years even in the United States, it should not surprise us to see major changes in epidemiology and liver‐related outcomes in Asia in the years to come. Indeed, a recent modeling study suggests that China already harbors the largest number of NAFLD patients today because of its huge population.8 Although the proportion of patients with steatohepatitis and advanced fibrosis in China remains lower than that in Western countries, it is projected to have the largest number of liver‐related deaths from NAFLD by 2030. Similar to reports from Western countries, older age, male sex, and metabolic conditions are strong risk factors for the development of NAFLD in China. Zhou et al. further highlighted a number of gene polymorphisms associated with NAFLD.5 In particular, the single nucleotide polymorphism of the patatin‐like phospholipase domain‐containing protein 3 (PNPLA3 rs738409) gene has been consistently shown to increase the risk of NAFLD and its histological severity across different countries and ethnic groups. The genotype distribution partly explains why the prevalence of NAFLD is higher in Hispanics and lower in African Americans in the United States. Interestingly, the at‐risk PNPLA3 allele is more common among East Asians than Caucasians. This may be the reason behind the high NAFLD prevalence in East Asia despite a lower metabolic burden. In terms of phenotype, NAFLD among individuals with BMI less than 25 kg/m2 is a well‐reported phenomenon (often described as lean or nonobese NAFLD). The prevalence of nonobese NAFLD in Asia ranges from 7%‐20%.4 In the study by Zhou et al., the pooled prevalence of NAFLD was 10.8% among people with BMI less than 25 kg/m2.5 When compared with obese patients, nonobese patients with NAFLD are younger and have a lower prevalence of the metabolic syndrome. On the other hand, these patients may be more insulin‐resistant and have higher triglyceride levels when compared with matched controls without NAFLD. The PNPLA3 gene polymorphism is more common among nonobese NAFLD patients, suggesting that genetic effects may be more important in patients with less severe metabolic factors.9 What do all of these findings mean to clinicians taking care of Asian patients? Above all, we should recognize that NAFLD is increasingly common in Asia. Lifestyle intervention is effective and should be recommended to all patients with NAFLD and metabolic risk factors. Nevertheless, lifestyle advice and therapeutic advances would mean very little if we fail to identify patients. There are already reasonable noninvasive tests for the detection of NAFLD and advanced fibrosis. According to the United Kingdom experience, it is possible to use simple blood tests followed by specific fibrosis biomarkers to increase the detection of advanced fibrosis by 5‐fold at primary care settings and reduce inappropriate referrals.10 Further studies should define the optimal pathways for patient identification at different settings. In summary, the study by Zhou et al. provides a comprehensive overview on the NAFLD situation in China and demonstrates a rapid increase in NAFLD prevalence over a short period. Although we agree with Dr. Rosling that the world is improving, we should be alert to new challenges and work together to combat this new epidemic (Fig. 1).Figure 1: China in the 1980s and today. Since the 1980s, the total population of China has grown from 0.98 billion to 1.42 billion. The combination of the increase in life expectancy and the one‐child policy has led to rapid changes in the population composition. During the same period, the prevalence of obesity and nonalcoholic fatty liver disease has increased several fold. Abbreviation: HBsAg, hepatitis B surface antigen.