Epidemiological Features of NAFLD From 1999 to 2018 in China : Hepatology (original) (raw)

Supported by grants from the National Key R&D Program of China (2016YFF0101504 to Z. S.), the Key Project of the National Natural Science Foundation (81630011 to H. L.), the National Science Fund for Distinguished Young Scholars (81425005 to H. L.), the Major Research Plan of the National Natural Science Foundation of China (91639304 and 91729303 to H. L.), the Creative Group Project of Hubei Province (2016CFA010 to H. L.), the Hubei Science and Technology Support Project (2018BEC473 to H. L.), the National Science Foundation of China (81870171 and 81570271 to J. C.), the Hunan Distinguished Young Scholars (2017RS3015 to J. C.), and the National Science Foundation of China (81570412 to L. Z.).

Potential conflict of interest: Nothing to report.

Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease, affecting approximately 1.7 billion individuals worldwide. The spectrum of the disease extends from liver steatosis to nonalcoholic steatohepatitis (NASH); the latter may progress to advanced liver fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). In addition, a large proportion of patients with NAFLD have metabolic comorbidities, which increases the risk of cardiovascular disease (CVD) and extrahepatic cancers to a great extent.1 NAFLD and its complications pose a tremendous health burden not only in Western countries but also increasingly in Asia. A recent meta‐analysis found the prevalence of NAFLD in Asian countries to be similar to, and in some cases higher than, the West. Notably, in Asia, China had the highest prevalence, incidence, and annual NAFLD‐related mortality rate. If such a pandemic continues, China is predicted to have the largest number of patients with NAFLD and liver‐related deaths worldwide.3 Therefore, control of this disease in China will have a major impact on the global burden of liver disease.

NAFLD until recently was not considered a serious public health issue in China. Although the prevalence of viral hepatitis has decreased substantially because of the implementation of effective vaccines and potent antiviral therapies,4 the prevalence and incidence of end‐stage liver diseases (ESLDs; e.g., cirrhosis and HCC) continue to soar.5 Our recent meta‐analysis revealed an alarming national prevalence of NAFLD in China (29.2%),6 which suggested that NAFLD may contribute significantly to the prevalent of ESLDs.

A deeper understanding of the epidemiological features of NAFLD in China has therefore become imperative and will benefit health decision‐making processes and guide actions to control NAFLD and its complications. However, because of insufficient awareness of NAFLD, large‐scale longitudinal studies describing the features of NAFLD in China are scarce, but systematic evaluation of data from previous publications can potentially delineate its general features of NAFLD. Our previous systematic review and meta‐analysis provided information on overall prevalence and incidence and an overview of risk factors, complications, and disease management in the past decade. In this article, we highlight eight dominant features of NAFLD in China based on a comprehensive search of the literature from 1999 to 2018 and undertake a meta‐analysis of the data. The features cover the detailed temporal changes and age patterns of the epidemiology of NAFLD, the frequencies of NAFLD susceptibility genes, the dynamic changes in the distribution of major liver diseases in China, the awareness of NAFLD in the public and scientific arena, and the status of diagnosis and treatment of NAFLD in China. The results have important implications to address the burden of NAFLD in China.

Materials and Methods

Data Sources and Search Strategy

Potential studies from January 1999 to March 2019 were searched in five English‐language (PubMed, Medline/OvidSP, Embase/OvidSP, Web of Science, and Cochrane Central) and three Chinese‐language databases (China National Knowledge Infrastructure, Wanfang, and Weipu). We conducted 14 systematic searches of these databases for NAFLD prevalence, incidence, NAFLD‐related CVD, diagnosis and pharmacological treatments, prevalence of other liver diseases (hepatitis B virus [HBV], hepatitis C virus [HCV], alcoholic liver disease [ALD], drug‐induced hepatic injury, HBV complicated with NAFLD, HCV complicated with NAFLD), and NAFLD‐related susceptibility genes (patatin‐like phospholipase domain containing protein 3 [_PLPLA3_], adiponectin, lysophospholipase‐like 1 [_LYPLAL1_], superoxide dismutase 2 [_SOD2_], peroxisome proliferator‐activated receptor gamma [_PPARγ_], glucokinase regulator [_GCKR_], transmembrane 6 superfamily member 2 [_TM6SF2_], microsomal triglyceride transfer protein [_MTTP_]). Detailed search strategies for each issue are shown in the Supporting Information. Regarding registered clinical trials for NAFLD, we systematically retrieved primary registries from the World Health Organization (WHO) registry network. To obtain data about the National Natural Science Foundation of China from 1999 to 2018 for NAFLD, HBV, and HCV, we conducted our search on Letpub (http://www.letpub.com.cn). In addition, we completed the search strategy in the Web of Science and Chinese databases (China National Knowledge Infrastructure, Wanfang) to retrieve the numbers of published papers and conference publications on the topics of NAFLD, HBV, and HCV.

Eligibility Criteria

We included the original study of clearly defined recruited liver diseases (e.g., NAFLD and HBV). Only studies in humans were included. Animal and cellular experiment studies, reviews, and letters were excluded. Detailed eligibility criteria for NAFLD as described in the literature are shown in literature criteria from I to VIIII in the Supporting Information.

Quality Assessment, Data Extraction, and Statistical Analysis

The quality of the studies included in this systematic review and meta‐analysis was assessed using the Agency for Healthcare Research & Quality scale, Newcastle‐Ottawa Scale,Quality Assessment of Diagnostic Accuracy Studies 2 tool, and Jadas scale for cross‐sectional studies, case‐control/cohort studies, diagnostic studies, and randomized controlled trials (RCTs), respectively. Information was extracted from each article. Any discrepancies in study eligibility or data extraction were resolved through investigator discussion until consensus. All statistical analyses were performed using RevMan 5.0.2 (Cochrane Collaboration, Oxford, England) and R, version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria). More details are provided in Supporting Tables S1‐S15.

Results

Increasing Burden and Onset of NAFLD at Lower BMI

During the past two decades, the burden of NAFLD has increased substantially with radical modifications in lifestyle in China. In the early 2000s, the prevalence of NAFLD in China was estimated to be 23.8% (95% confidence interval [CI], 16.4%‐31.2%). The increasing trajectory on the burden of NAFLD began in the mid‐2000s and accelerated in 2010. In 2018, the prevalence reached 32.9% (95% CI, 28.9%‐36.8%). The overall prevalence of NAFLD over the past two decades is 29.6% (95% CI, 28.2%‐31.0%; Fig. 1A; Supporting Tables S1 and S8). The prevalence of NAFLD is parallel with the rising trend of obesity in China (the prevalence from approximately 2% in 2000 to 7% in 2014), but it is noteworthy that Chinese people have substantially higher risks of NAFLD even at much lower BMI levels compared with the US population (Fig. 1B).7 This indicates a strong ethnic difference in BMI and its association with NAFLD.

Figure 1:

Increasing burden and onset of NAFLD at lower BMI. (A) The prevalence of NAFLD and obesity and GDP per capita in China from 2001 to 2018, from 2000 to 2014, and from 1999 to 2018, respectively. (B) The prevalence of NAFLD and obesity and GDP per capita in the United States from 2000 to 2018. (C) The incident of NAFLD during 2007‐2010, 2011‐2013, and 2014‐2018. (D) The cardiovascular comorbidities in the NAFLD population. The data of GDP per capita is from the National Bureau of Statistics and the World Bank. Abbreviations: AF, atrial fibrillation; CAD, coronary artery disease; Car‐AS, carotid artery atherosclerosis.

The incidence of NAFLD in China rose substantially over time, from 4.2% (95% CI, 2.3%‐6.0%) between 2007 and 2010 to 4.6% (95% CI, 3.3%–6.0%) between 2011 and 2013 and to 5.2% (95% CI, 3.9%‐6.5%) between 2014 and 2016, surpassing the incidence rates in the US (2.32% to 4.26%) and among European countries (1.85%; Fig. 1C; Supporting Tables S3 and S9). By 2030, the total NAFLD population is projected to increase to 314.58 million cases in China, the greatest increase in NAFLD prevalence globally.3

Global epidemiology studies have suggested that NAFLD can progress to liver cirrhosis (LC) or HCC, although the exact burden of NAFLD‐related LC and HCC remains uncertain. A study based on the US population revealed that NAFLD is one of the most common etiologies (59%) for HCC, and data from the Scientific Registry of Transplant Recipients for 2002 to 2017 demonstrate that the prevalence of HCC in NASH increased 11.5‐fold and that liver transplant that was due to HCC increased 8.5‐fold in the United States.10 NASH has also become the fastest growing cause of advanced liver complications.10 Studies on NAFLD related cirrhosis and HCC in China are limited. Sporadic studies have reported NASH‐related LC over the past two decades, with an average proportion of NASH‐related LC in China of 1.9% in the early 2000s that increased to 3.2%‐5% in the 2010s.16 There are no data regarding the contribution of NAFLD to HCC or liver transplantation. Furthermore, NAFLD is not even reported as a major cause for liver transplant in the 2016 Annual Report of China Liver Transplant.

The burden of NAFLD is not confined to liver‐related consequences. Accumulating evidence has demonstrated that CVD is the leading cause of death in individuals with NAFLD. Globally, 25%‐40% of patients with NAFLD have CVD. In the Chinese population, the prevalence of CVD is reported to be higher than 55% in patients with NAFLD. Carotid atherosclerosis (55.5% [95% CI, 35.4%‐75.7%]), hypertension (47.1% [95% CI, 42.7%‐51.6%]), coronary heart disease (40.9% [95% CI, 30.2%‐51.5%]), ischemic and hemorrhagic stroke (13.1% [95% CI, 6.1%‐20.1%]), and atrial fibrillation (2.7% [95% CI, 0.1%‐4.4%]) are major coexisting cardiovascular comorbidities of NAFLD in China (Fig. 1D; Supporting Tables S4 and S10).

The economic burden of NAFLD will increase enormously because of the large expansion in the population in China. The estimated annual medical costs directly attributable to NAFLD already exceed $103 billion in the United States and €35 billion in four European countries (Germany, France, Italy, and the United Kingdom).18 The economic burden of NAFLD in China is unknown. With the rising prevalence of NAFLD in China, it is imperative that studies examine the economic implications of NAFLD.

Greater Predisposition Toward NAFLD in China

Although the Chinese population has much lower rates of overweight and obesity, China has a higher prevalence and incidence of NAFLD than Western countries. A meta‐analysis showed a higher NAFLD risk associated with obesity or increased BMI in Asian populations (3.74 [95% CI, 2.51‐5.55]) compared with that in the Caucasian populations (2.67 [95% CI, 1.58‐4.52]).20 This predisposition toward NAFLD and metabolic diseases suggests hereditary factors might contribute to the initiation and progression of the disease in Chinese populations. Indeed, genetic polymorphisms in genes involved in lipid and glucose metabolism (PNPLA3, adiponectin, TM6SF2, MTTP, LYPLAL1, PPARγ, and GCKR) and redox reactions (SOD2) have been reported to contribute to individual susceptibility to NAFLD in gene association studies. The pooled frequencies of at‐risk alleles in Chinese/Asian populations and Caucasian counterparts are listed in Supporting Tables S7 and S12. Our meta‐analysis showed that the frequencies of rs738409:G in PNPLA3, rs1501299:T in adiponectin, rs12137855:T in LYPLAL1, rs4880:C in SOD2, rs1801282:T in PPARγ, and rs780094:T in GCKR are higher, but the frequencies of rs58542926:T in TM6SF2 and rs3816873:C in MTTP are lower in the Chinese population than the Caucasian population (Fig. 2 and Supporting Table S7). In short, these mutations may increase the risks of metabolic disorders and NAFLD more frequently in Chinese populations compared with Caucasian populations, whereas the alleles associated with NAFLD risk reduction were less frequent in China. However, other gene polymorphisms, such as membrane‐bound O‐acyltransferase domain containing 7, phosphatidylethanolamine N‐methyltransferase, and hydroxysteroid 17‐beta dehydrogenase 13, involved in the susceptibility to NAFLD in Western populations have not been reported in Chinese populations. Here, we reported the pooled frequencies of individual risk alleles of NAFLD; it would be valuable to conduct a nationwide whole‐genome sequencing study calculating the frequencies of multiple risk alleles and the polygenic risk score of NAFLD, which would provide more insight for the NAFLD predisposition in Chinese populations.

Figure 2:

The alleles increase or decrease the risk of NAFLD and their frequencies in Chinese and Caucasian NAFLD populations. The results show that the frequencies of rs738409:G in PNPLA3, rs1501299:T in adiponectin, rs12137855:T in LYPLAL1, rs4880:C in SOD2, rs1801282:T in PPARγ, and rs780094:T in GCKR are higher but the frequencies of rs58542926:T in TM6SF2 and rs3816873:C in MTTP are lower in the Chinese population than in the Caucasian population. Abbreviations: PPARG, peroxisome proliferator‐activated receptor gamma.

Changes in the Distribution of Liver Disease and Viral Hepatitis Coexisting With NAFLD

Currently, China harbors the world’s largest number of liver cancer cases. Data from the Global Burden of Disease study revealed that age‐adjusted prevalence of liver cancer increased substantially from 29.55/100,000 cases in 1999 to 60.04/100,000 in 2016. HCC is the most common type of liver cancer5 (Fig. 3). If public health strategies remain the same, China is estimated to carry the greatest prevalence and incidence of HCC cases by 2030.3 Viral hepatitis and nonalcoholic liver diseases and ALDs are the major factors leading to chronic liver injury and end‐stage liver pathology in China.4

Figure 3:

Changes in the distribution of liver disease and viral hepatitis coexisting with NAFLD. The annual prevalence of NAFLD, HBV, HCV, ALD, and DILI was calculated. The prevalence of NAFLD, ALD, and DILI increases and the prevalence of HBV and HCV decreases.

Because of the success of universal hepatitis vaccination programs and the rise in metabolic diseases after 2000, the patterns of liver diseases and major factors contributing to ESLD have changed dramatically. For example, China has experienced a substantial decline in viral hepatitis incidence between 1999 and 2018 but a rapid increase in the incidence of NAFLD and its concomitant metabolic disorders. The prevalence of HBV (hepatitis B surface antigen [HBsAg] carrier rates) in the general population decreased from 9% (95% CI, 3.4%‐14.6%) to 10.5% (95% CI, 3.9%‐17.1%) in the early 2000s to 5% (95% CI, 0%‐11.4%) in recent years (Fig. 3; Supporting Tables S1 and S11). In particular, HBsAg carrier rates among children (<10 years old) fell to 1.5% in 2018.21 After the strengthening of blood donation and transfusion regulations, the anti‐HCV seroprevalence has declined from 4.7% (95% CI, 2.8%‐6.7%) in 1999 to 0.8% (95% CI, 0.1%‐1.6%) in 2018 (Fig. 3).

Notably, the rate of NAFLD prevalence has increased robustly with the introduction of a Westernized lifestyle in China. In fact, the increase in the prevalence of NAFLD from 23.8% in 2001 to 32.9% in 2018 indicates that NAFLD is replacing hepatitis B as the leading cause of chronic liver disease in China. Of note, according to the pooled analysis, there are 35% (95% CI, 22.9%‐47.4%) of patients with HBV concomitant with NAFLD, which further accelerated the progression of liver damage.

The overall prevalence of ALD has also increased among the Chinese population during the last two decades. It is noteworthy that there is a pronounced difference in the prevalence between sexes. Alcohol abuse and ALD are more prevalent among male than female populations. Nonetheless, the ALD population increased significantly in both sexes: the pooled prevalence of ALD increased from 5.1% (95% CI, 2.4%‐7.7%) and 0.2% (95% CI, 0%‐0.6%) to 12.9% (95% CI, 7.4%‐18.5%) and 2.9% (95% CI, 0%‐6.2%) in male and female populations, respectively, from the early 2000s to the mid‐2010s (Fig. 3; Supporting Tables S2 and S11).

A large number of Chinese individuals believe that traditional Chinese medicine (TCM) and herbal and dietary supplements (HDS) have no side effects, and they accordingly consume these reagents without medical consultation. Thus, there is a higher incidence of drug‐induced liver injury (DILI) in China than in Western countries, and TCM, HDS, and antituberculosis drugs are the leading categories of agents causing DILI.22 The prevalence of DILI in the general population was reported at 4% (95% CI, 3.2%‐4.8%) to 7.7% (95% CI, 0%‐17.7%; Fig. 3; Supporting Tables S2 and S11).

Regional Variations in NAFLD

NAFLD prevalence is parallel with urbanization and industrialization. According to the statistics from the World Bank, the relative increases of national gross domestic product (GDP) per capita (compared with GDP per capita in 1999) were in line with the pooled annual prevalence of NAFLD (Fig. 4A). Meanwhile, there was a noticeable increase of studies with regard to the prevalence of the disease in recent decades, but the studies were mainly within the region with higher GDP per capita. The limited number of studies in less developed areas may attribute to larger bias and thus warrant more research attention. Linear regression analysis revealed the GDP rank was negatively associated with the prevalence of NAFLD in the past 20 years (_r_2 = 0.036; P = 0.0317). This result suggested that the local epidemic of NAFLD is associated with its economic growth (Fig. 4B).

Figure 4:

The association between GDP per capita and prevalence of NAFLD. (A) Annual GDP per capita obtained from the National Bureau of Statistics. The relative increases of national GDP per capita were calculated as [GDP per capita in the indicated year] ‐ [GDP per capita in 1999] and are indicated as the gray shading. The annual national prevalence of NAFLD is indicated as the pink dotted line; (B) the annual prevalence of NAFLD in a negative association with regional GDP per capita rank. The district with the highest GDP per capita ranks the lowest and the district with the highest GDP per capita ranks highest.

Outbreak in Younger Generations

Improvements in health care quality and the single‐child policy have led to a dramatic increase in the aging population in China. The aging population comprises over 100 million and is expected to exceed 220 million by 2030. The burden of NAFLD and its related comorbidities constantly accumulate in an aging population. More alarmingly, our analysis revealed that the prevalence of NAFLD rose from 17.8% (95% CI, 12.4%‐23.3%) among those younger than 60 years during 2007‐2010 to 28.7% (95% CI, 24.3%‐33.2%) during 2015‐2018, and the rates of increase were higher compared with those among populations older than 60 years of age (increased from 23.9% [95% CI, 16.8%‐31.1%] to 30.9% [95% CI, 26.4%‐35.5%]; Fig. 5A; Supporting Table S6). Studies on the incidence of NAFLD are consistent, with the annual incidences of NAFLD being higher (4.7% [95% CI, 4.0%‐5.5%]) in the population below age 60 than in the population above age 60 (2.4% [95% CI, 2.1%‐2.8%]) from 2010 to 2018. The trend indicates a heavier disease burden in the coming decades (Fig. 5B; Supporting Table S3).

Figure 5:

The prevalence and incidence of NAFLD in the age groups <60 and ≥60. (A) The prevalence of NAFLD in the age groups <60 (blue line) and ≥60 (red line) from 2007 to 2018; (B) the incidence of NAFLD in the age groups <60 (blue bar) and ≥60 (red bar) from 2010 to 2018.

Poor Awareness and Lack of Research Attention in China

The current awareness and perception of NAFLD as a chronic disease with severe consequences remain inadequate among public and policy decision makers and even among doctors. Surveys from the 2000s report that awareness of NAFLD in China was only 17% in the general population and that the rate increased to only 31% in 2018. In addition, only 1.55%‐1.87% of the general population had sufficient knowledge of NAFLD.23 Such poor awareness can be partly explained by the relatively short period of time since the sharp growth in the NAFLD population in China. Regardless, the majority of the populations in Western countries with a substantially longer history of the NAFLD pandemic also have little awareness of NAFLD. For instance, there are surveys revealing that public awareness of NAFLD was only 2.4%‐3.1% in the United States.25 Likewise, a most recent study among 29 European countries also revealed a general lack of national policies, awareness, civil societies, and organization for NAFLD.27

In addition, there are great disparities between research attention and the disease burden of NAFLD. We evaluated research focus on NAFLD compared with viral hepatitis B and C in China using parameters that included research opportunities offered by the National Science Foundation of China, registered clinical trials, and the number of scientific publications between 1999 and 2018. Taken together, the number of scientific publications and registered clinic trials on the topic of viral hepatitis was 5 times higher than that on NAFLD, according to data from the Web of Science and clinical trial registry, respectively (Fig. 6A,B). Similarly, viral hepatitis also received 1.86‐fold higher funding opportunities and 1.45‐fold of funds than did NAFLD (Fig. 6C,D). Fortunately, in recent decades, the number of funded research studies on NAFLD have increased significantly. However, increased research attention on NAFLD still lags far behind the growth of the disease, and an effective mechanism to increase awareness and attention of NAFLD in both the general population and the scientific community is required and must be initiated.

Figure 6:

Research attention to NAFLD, HBV, and HCV from 1999 to 2018. The research attention to NAFLD, HBV, and HCV was evaluated from four aspects: (A) scientific publications (the Web of Science), (B) registered clinical trials (Chinese Clinical Trial Registry and ClinicalTrials.gov), (C) research opportunities offered by the National Science Foundation of China (http://www.letpub.com.cn), and (D) funds offered by the National Science Foundation of China.

Inadequate Tools for Diagnosis and Follow‐Up NAFLD

Given the rapid expansion and growth in the NAFLD population, the development of cost‐effective tools for diagnosis, staging, and monitoring of NAFLD has become essential.8 Liver biopsy remains the gold standard for the diagnosis of NAFLD and to distinguish steatosis from NASH; however, its expense, potential complications, and sampling error limit its utility for large‐scale population‐based screening. Many noninvasive approaches for diagnosing NAFLD are being developed, and different modalities have strengths and limitations for diagnosing NAFLD.

In China, ultrasonography is the predominant modality for NAFLD diagnosis (>99% of cases; Supporting Table S8); however, it is limited when used in patients with steatosis less than 20%‐30% and does not provide information about inflammation or fibrosis. The state‐of‐the‐art modality for detecting liver fat by magnetic resonance spectroscopy (MRS)/proton density fat fraction (PDFF) is able to distinguish 5% fat accumulation in the liver irrespective of the patient’s body mass (Supporting Table S8). However, only three studies applied MRS to detect NAFLD in our included studies, which may be explained by the fact that MRS is time‐consuming, requires specialized expertise in device operation and data analysis, and is not readily availability in clinical practice.

To assess the severity of liver fibrosis, noninvasive imaging tools for detecting organ stiffness, including transient elastography (TE), magnetic resonance elastography (MRE), shear wave elastography (SWE), and acoustic radial force imaging (ARFI), have been developed and are constantly evolving. A recent meta‐analysis and other studies have revealed that TE, MRE, SWE, and ARFI have good performance for the detection of fibrosis, with areas under the curve above 0.8 for significant fibrosis, advanced fibrosis, and cirrhosis.28 However, these procedures are rarely conducted in China, and authorized data on the performance of these tools in the Chinese population are scant.

Using either serum biomarkers or imaging tools, identifying patients with NASH without significant fibrosis has always been a challenge. To achieve better diagnostic accuracy for NASH, many serum biomarker panels and risk stratification algorithms have been developed and actively tested in China; the accuracy of these tests is listed in Table 1 and Supporting Table S13. Nonetheless, these studies were conducted using small sample sizes without external validation. Further validation of these noninvasive tests on a larger‐scale population is required before they can be recommended for clinical use.

Table 1 - NASH Biomarker Panels in China

Abbreviations: AFABP, adipocyte fatty acid‐binding protein; ALT, alanine aminotransferase; ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; APRI, aspartate aminotransferase‐to‐platelet ratio index; AST, aspartate aminotransferase; AUROC, area under the receiver operating characteristic curve; CK‐18, cytokeratin 18; CK‐18‐M30, cytokeratin‐18 M30 fragment; CRP, C‐reactive protein; FGF21, fibroblast growth factor 21; FIB‐4, fibrosis‐4; IL‐1Ra, interleukin‐1 receptor antagonist; NPV, negative predictive value; OPG, osteoprotegerin; PEDF, pigment epithelium‐derived factor; PLT, platelets; PPV, positive predictive value; TG, triglyceride.

Absence of Effective Drug Therapy

Because of its complex pathogeneses and large individual heterogeneity in disease, there is no specific medication for the treatment of NASH. Globally, more than 400 registered trials have explored potential treatments for NAFLD. The proportion of world patients enrolled in NAFLD and NASH trials are plotted in Fig. 7A (Supporting Table S14). In China, over 200 million people may have NAFLD, and among them, 40 to 120 million might have NASH.4 However, the majority of clinical trials have focused on investigating the effects of TCM, herbal extracts,31 antidiabetic agents,10 and probiotics34 for the treatment of NAFLD.

Figure 7:

The number of registered clinical trials worldwide and in China from 1999 to 2018. (A) The number of registered clinical trials for NAFLD/NASH worldwide from 1999 to 2018 (the WHO registry network); the map gradient color indicates the prevalence of NAFLD in continents. The pie chart indicates the proportion of trials of NAFLD or NASH in indicated countries, and the size of the charts shows the total number and weight of trials of indicated countries in the world. (B) Total number of TCM clinical trials and enrolled patients in China from 1999 to 2018.

Several potent reagents have entered phase III clinical trials, such as the farnesoid X receptor agonist obeticholic acid, the peroxisome proliferator‐activated receptor alpha/delta agonist elafibranor, the ASK1 inhibitor selonsertib, and the chemokine (C‐C motif) receptor (CCR) 2/CCR5 inhibitor cenicriviroc; none of these have been sufficiently evaluated in the Chinese population. The surge in the prevalence of NAFLD among Asian and Western populations as well as the genetic and socioeconomic differences have prompted attention from pharmaceutical companies. TCM originated in ancient China, and it is commonly used in the treatment of NAFLD. Patients with NAFLD receive TCM as auxiliary treatment. The use of TCM is usually based on experience without clinical trial–proven evidence and thus is not well acknowledged in Western countries. Currently, clinical trials are being conducted in China to evaluate the effectiveness of TCM. According to data from Chinese‐language and English‐language literature databases, there were 438 trials with 39,971 enrolled patients during the period 1999‐2018. However, only eight studies followed RCT criteria (Fig. 7B; Supporting Table S15). Therefore, the quality of TCM trials must be improved for evidence‐based decision‐making in TCM.

Discussion

There are currently more than 240 million individuals with NAFLD in China, accounting for more than one fifth of the global NAFLD population and the majority of Asian patients with NAFLD.3 Therefore, because of the impact on global health burden, it is imperative to address the epidemiological features of NAFLD in China. This systematic review highlights eight important issues about NAFLD in the Chinese population over the past 20 years. These issues have strong implications for policy making and the control of NAFLD.

From 1999 to 2018, the prevalence of NAFLD increased by 8%‐9% corresponding with the economic boom, with the current overall prevalence reaching 29.1%. Recent data from Li J et al. has also revealed a similar overall prevalence of NAFLD in the Asian population.3 The similarity of the situation in China and Asia may be due to the large Chinese population contributing a larger weight when calculating the prevalence of NAFLD. We also found Chinese people with substantially higher risks of NAFLD even at much lower BMI levels compared with the US population. With recognition of this characteristic of NAFLD in the Chinese population, there is mounting evidence demonstrating a genetic predisposition toward NAFLD among Chinese.8 Based on published literature, the mutant alleles that increase the risk of NAFLD are 2.9%‐30% more frequent in the Chinese NAFLD population compared with that in Caucasians with NAFLD, whereas alleles that decrease the risk are 1%‐3% less frequent. However, because of the limited sample size, this conclusion should be replicated in larger population studies by whole‐genome sequencing. Meanwhile, these discovered genetic variants may only account for a small fraction of gene variations in the regulation of liver steatosis, inflammation, and fibrosis. Further studies will be required to identify additional variants that change the predisposition to metabolic disorders. Moreover, NAFLD and NASH development involves complex gene‐environment interactions, which deserve more investigation of their epigenetic regulation.

Few studies have reported on natural history (e.g., NASH, LC, and HCC), liver transplant, and long‐term death rates in patients with NAFLD in China. As there is an increasing number of patients suffering from fatty liver disease‐related complications according to data from Western countries, NAFLD is gaining increasing recognition as an etiology of ESLD in China.36 Moreover, patients with NAFLD die of CVD more frequently than of liver disease per se.38 Our study has also revealed that there is a higher proportion of the NAFLD population with CVD complications compared with the general population in China. Among all CVDs, atherosclerotic disease (such as carotid and coronary artery disease) is the most common comorbidity.

Our study reveals a more rapid growth in the number of young people with NAFLD compared with that in older age groups. The estimated prevalence of NAFLD in the younger population rose from 17.8% in the period between 2007 and 2010 to 28.7% between 2015 and 2018. Worryingly, these patients are usually asymptomatic until late stages, and thus, the increasing rates of NAFLD in younger populations will create a heavy disease burden in coming decades.3

Chronic viral hepatitis has long been considered a major etiology for liver cancer in China.4 Even if the implementation of effective vaccines helps to control the prevalence of viral hepatitis, the number of liver cancer cases remain the largest in the world and is still climbing. The rapid growth in NAFLD may contribute to the rising prevalence of ESLDs. Although NAFLD is a growing health problem because of the epidemic of obesity and metabolic disorders, awareness did not increase simultaneously among either clinicians or the general population.24 Overall, enhancement of public awareness and education on NAFLD and its impacts is essential for the control of the disease and its complications.

Unfortunately, a cost‐effective and reliable diagnostic approach for NAFLD is lacking, especially for NASH, resulting in a large number of patients who are undiagnosed and untreated. If NAFLD is suspected, a patient is most likely to receive personal history collection followed by ultrasonography in China. These patients are less likely to be referred to a specialist who is well‐equipped with NAFLD knowledge to provide appropriate assessment and guidance. Advanced diagnostic approaches, such as MRS‐PDFF, TE, MRE, SWE, and liver biopsy, are not applied adequately because of their expense, specialized technology, and potential risks. Emerging serum biomarkers could be an auxiliary diagnostic approach for NASH, but the majority of these require further investigation. Because of larger heterogeneity and few studies using liver biopsy as a reference, we were not able to perform meta‐analysis comparing the accuracy of each diagnostic method.

Lifestyle modification is beneficial for treating NAFLD and should be considered as the cornerstone of long‐term management.40 However, poor adherence to lifestyle modification makes NAFLD management a difficult task. Pharmaceutical treatment is an essential component for the treatment of NAFLD and NASH, yet no drugs to date have been specifically approved.42 Moreover, several promising therapeutic agents developed by pharmaceutical companies, such as Gilead, Merck, and Pfizer, have not been sufficiently evaluated in the Chinese population. Because of the large genetic variations and predisposition to NAFLD as we discussed earlier, ethnic difference needs to be addressed during drug development. Treatment of liver disease with TCM has a long history in China but is not well accepted in the West because prescriptions are usually based on heritage experience rather than on clinical trial evidence. In the past 20 years, increasing numbers of TCM clinical trials have been conducted in China, although the quality of these trials must be improved.

Given the enormous NAFLD population burden in China, health policies should be developed to control and prevent the disease. Recognition of the epidemiological features of NAFLD is the first step in identifying issues and guiding effective decision‐making. To achieve control of NAFLD, public health initiatives to raise awareness should be expanded to diverse populations nationwide. Developing a strong research program at a national level to support both clinic and basic research on NAFLD will deepen our understanding of the disease and accelerate the development of new therapeutic strategies to cure or prevent the disease.

Author Contributions

H.L., J.C., and L.Z. conceived the ideas, designed and supervise the project, and interpretation of data; J.Z., F.Z., and W.W. contributed to collection of literature, acquisition, analysis and management of data; X.‐J.Z., Y.‐X.J., P.Z. and Z.‐G.S. contributed to drafting the article and revised it critically for important intellectual content; JC and JZ conducted the visualization and data presentation; All authors approved the final submitted version.

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Author names in bold designate shared co‐first authorship.

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