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Journal of Gastroenterology

, Volume 52, Issue 2, pp 164–174 | Cite as

Nonalcoholic fatty liver disease in Asia: emerging perspectives

  • Wai-Kay Seto
  • Man-Fung Yuen
Review

Abstract

As in the West, nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease in Asia, with a prevalence higher than 40 % in some countries. The risk factors for NAFLD development are similar to those in Western countries, including increased body mass index, diabetes, insulin resistance, and metabolic syndrome. NAFLD in Asians is associated with different extrahepatic manifestations involving the cardiovascular, gastrointestinal, and renal systems. A considerable proportion of Asians with NAFLD are described as having “lean” NAFLD. Present in approximately 20 % of the Asian population, lean NAFLD is closely linked with insulin resistance, diabetes, and other metabolic complications, but its association with disease progression to nonalcoholic steatohepatitis and cirrhosis remains to be defined. There is emerging evidence of the interactions of NAFLD with hepatitis B virus and hepatitis C virus infection in Asia. Unlike in Western countries, NAFLD constitutes only a minority of cirrhosis and hepatocellular carcinoma cases in Asia. Possible explanations are the lower prevalence of obesity and the overwhelming problem of viral hepatitis in Asia. With aging of the obesity cohort in Asia, NAFLD-related liver complications are expected to increase.

Keywords

Nonalcoholic fatty liver disease Steatosis Obesity Metabolic Nonalcoholic steatohepatitis Hepatitis B virus Hepatitis C virus Cirrhosis Asian 

Abbreviations

BMI

Body mass index

DAA

Direct-acting antiviral

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

NAFLD

Nonalcoholic fatty liver disease

NASH

Nonalcoholic steatohepatitis

Introduction

Nonalcoholic fatty liver disease (NAFLD) comprises a wide disease spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) and NASH-related cirrhosis [1]. The prevalence of NAFLD in Asia is increasing and this can be attributed to the increased prevalence of associated metabolic risk factors, including obesity, diabetes, and metabolic syndrome. Despite the emerging importance of NAFLD in Asia, most of the medical literature on NAFLD is based on patients of European descent. Asian NAFLD patients share some risk factors with their non-Asian counterparts, but with slightly different clinical profiles and disease outcomes. There is also increasing interest in nonobese or “lean” NAFLD, which is commonly found in Asia, as well as interactions with viral hepatitis. This review highlights different clinical aspects of NAFLD in Asia and discusses relevant perspectives of their importance.

Epidemiology of NAFLD in Asia

The prevalence of NAFLD in Western countries, as defined by typical ultrasonographic features, ranges from 24 to 46 % [2, 3, 4]. The Asian prevalence of NAFLD is widely variable [5] and has been described in recent population-based studies as depicted in Fig. 1 [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18], ranging from 7.9 % in Indonesia to 54.0 % among the elderly female population in Taiwan.
Fig. 1

Population-based prevalence of nonalcoholic fatty liver disease in different regions of Asia

An important factor influencing the variability in NAFLD prevalence is age. Increased age is a significant risk factor for NAFLD [19], as illustrated by the more than 50 % prevalence in elderly Taiwanese (mean age 70.3 years) [13] and the more than 60 % prevalence in certain populations aged 45 years or older in Malaysia [14]. A second important factor is sex, with NAFLD significantly commoner among Asian males than among Asian females [20]. Studies showing a high NAFLD prevalence had a relatively higher proportion of male participants [8, 11, 15]. As in Western populations [2], ethnic differences could play a role, as demonstrated by the significantly higher prevalence of NAFLD in Malays and Indians than in Chinese in Malaysia [14].

Although the prevalence of NAFLD is increasing with time as highlighted by the 18 % increase in Japan in 10 years [21], whether the prevalence of NAFLD is associated with increased urbanization is debatable. The pooled analysis of Chinese NAFLD by Li et al. [9] failed to find a significant difference in NAFLD prevalence between urban and rural areas, although this might be due to the heterogeneous population mixture of the studies included. The relatively high prevalence of NAFLD in urbanized areas such as Beijing, Shanghai, and Hong Kong (39.5, 43.5, and 42.0 % respectively) [8, 10, 11] when compared with the whole of China (20.1 %) supports this hypothesis [9]. Moreover, NAFLD prevalence in Asia has been shown to correlate strongly with economic prosperity [22]. Urbanization brings about a change in dietary and lifestyle habits [23]: an unhealthy dietary pattern and a sedentary lifestyle can increase the risk of NAFLD [24].

In contrast, there are scanty data on the incidence of new-onset NAFLD in Asia. A recent study investigated the population incidence of NAFLD using paired proton magnetic resonance spectroscopy for measurements of intrahepatic triglyceride content. Among 565 individuals without NAFLD at the baseline, the incidence of new NAFLD was 13.5 % after 3–5 years [25]. Although NAFLD in Asia emerges at an increased rate compared with that in Western populations [26], its impact on disease prevalence and clinical outcomes remains debatable, especially since remission of NAFLD over time is also common [27].

Established and emerging risk factors for NAFLD in Asia

The clinical parameters associated with an increased risk of NAFLD in Asia are listed in Fig. 2. In general, the risk factors for NAFLD are similar for Asians and non-Asians. Besides the traditional risk factors of increased age, male sex, and certain ethnicities, there are also emerging Asia data on other risk factors, including hypothyroidism [28] and obstructive sleep apnea [29].
Fig. 2

Risk factors for the development of nonalcoholic fatty liver disease (NAFLD) and extrahepatic manifestations of NAFLD in Asians

Genetic variation of PNPLA3 (which encodes patatin-like phospholipase domain containing protein 3) is a well-established susceptibility factor for NAFLD, although the original genome-wide association study did not include participants of Asian descent [30]. Subsequent studies from China [31], Japan [32], and India [33] and among different ethnic groups in Malaysia [34] showed PNPLA3 also predisposes Asians to develop NAFLD. Although PNPLA3 is not associated with metabolic syndrome component traits [35], it can still increase the risk of fibrosis progression and hepatocellular carcinoma (HCC) [36], including in patients with underlying cirrhosis of other etiologies [37]. Supportive Asian data on PNPLA3 can be found in Japanese [38] and Malaysian [34] studies, although confirmatory studies in Asian patients for other genetic phenotypes identified by genome-wide association studies that increase susceptibility to NAFLD are lacking [39]. Genetic alteration related to NAFLD is also found at the microRNA level, as shown by a histology-based study demonstrating altered microRNA expression among NAFLD patients [40].

Metabolic risk factors for Asian NAFLD include diabetes, insulin resistance, obesity, and different components of metabolic syndrome [1, 6, 41, 42, 43, 44], with poor glycemic control in diabetes, in addition to age, associated with NAFLD disease progression and fibrosis severity [45]. Obesity remains an important determinant of NAFLD even when different ethnic-specific body mass index (BMI) cutoffs are used for Asians [46]. Nonetheless, a considerable proportion of NAFLD develops in nonobese Asians [47, 48], a clinical entity commonly described as “lean” NAFLD, which will be described in more detail later. Unhealthy dietary patterns and a sedentary lifestyle also play a role in NAFLD development. A community-based study from Japan showed regular exercise to be protective against NAFLD, with an increased prevalence of NAFLD in patients with unhealthy eating habits [49]. A Japanese study showed modest intake of alcohol to be protective against fatty liver development in certain patient subgroups; this finding needs further validation among other cohorts [50].

Low vitamin D levels are also associated with NAFLD in men, as determined by a large population-based study in East China involving 5066 participants. Decreased vitamin D levels, when compared with normal vitamin D levels, had an odds ratio of 1.54 (95 % confidence interval 1.26–1.88) of predisposing to NAFLD. Participants with the lowest quartile of vitamin D levels had a very high NAFLD prevalence of 62.2 %. However, low vitamin D levels in women did not predispose to NAFLD [11]. The significance of this finding needs further evaluation, especially since vitamin D levels differ among ethnicities, with lower levels generally found in Asians [51].

NAFLD and extrahepatic manifestations

The interplay between NAFLD and different metabolic parameters can be bidirectional (Fig. 2), with NAFLD increasing the risk of developing different disease entities, including diabetes, metabolic syndrome, hypertension, and hypertriglyceridemia [52, 53, 54]. Cardiovascular disease is a major extrahepatic association. A Hong Kong study showed NAFLD to be associated with coronary artery disease as diagnosed by coronary angiogram, with the association independent of other metabolic factors [55], although a follow-up study showed no association with cardiovascular complications or mortality [56]. A study from Korea showed NAFLD to be associated with coronary artery calcifications as detected by computed tomography coronary angiogram [57]. NAFLD is associated with early alterations in the cardiovascular system as detected by echocardiography [58], increased arterial stiffness [59], and increased carotid intima–media thickness among patients with coexisting metabolic syndrome [60]. A high prevalence of microvascular retinopathy was also noted among biopsy-proven NAFLD patients [61].

The risk of colonic adenomas and colorectal cancer is increased in NAFLD patients, with a Hong Kong study showing NASH to be independently associated with the development of both colonic adenomas and advanced neoplasms [62]. Similar findings were also observed in China, Taiwan, and Korea [63, 64, 65]. The risk of other premalignant gastrointestinal conditions (e.g., Barrett’s esophagus) is also increased in obese NAFLD patients [66].

NAFLD is also linked to the development of chronic kidney disease. A community-based Korean study in 8329 nondiabetic, nonhypertensive men found NAFLD to be an independent risk factor for the development of chronic kidney disease [67]. A subsequent Japanese study also revealed similar findings [68]. As chronic kidney disease has multiple causes, studies are needed to categorize the types of renal injury manifestations that are specifically associated with NAFLD.

Lean NAFLD: a distinctive Asian entity?

Despite the strong association with obesity, NAFLD can occur in nonobese individuals. A population-based study from the United States found lean NAFLD (BMI < 25 kg/m2) accounted for 17.3 % of the total NAFLD cohort [69]. In Asia, a Hong Kong study found that lean NAFLD accounted for 41.5 % of the NAFLD cohort; 15.5 % had a BMI below the stricter Asian-specific cutoff of less than 23 kg/m2 [8]. In Japan and India, lean NAFLD accounts for 50 and 75 % respectively of the total NAFLD cohort [21, 47]. General population prevalence studies in Asia found lean NAFLD to be present in 15.2 to 27.4 % of the nonobese populations (Table 1) [44, 70, 71, 72].
Table 1

Prevalence of nonalcoholic fatty liver disease in nonobese populations

Region

Study

Number of participants

Prevalence (%)

Asian countries

 Japan

Nishioji et al. [44]

3271

15.2

 Korea

Sinn et al. [70]

5878

27.4

 Hong Kong

Wei et al. [71]

701a

19.3

 Hangzhou, China

Xu et al. [72]

6905

16.15

Western countries

 USA

Younossi et al. [69]

4457

7.39

aProton magnetic resonance spectroscopy performed for the detection of nonalcoholic fatty liver disease

A comparison of the clinical and metabolic profiles of lean and classic NAFLD is depicted in Fig. 3. Genetic variation of PNPLA3 remained predictive of NAFLD in the nonobese population, particularly the CG and GG genotypes [73]. Metabolic factors also continue to play a role. Specifically, a central or visceral distribution of body fat as indicated by an increased waist circumference, a key component of metabolic syndrome, was an important determinant [44]. Increased waist circumference reflects an increased amount of visceral fat, leading to increased production of proinflammatory cytokines and adipokines, resulting in disease progression of NAFLD [74]. As in the obese population, insulin resistance, hyperglycemia, and dyslipidemia are important risk factors for the development of lean NAFLD [42, 44, 47, 70]. A recent study showed lean NAFLD to display a metabolomic profile distinctly different from that of NAFLD in obese individuals, with different amino acid and acylcarnitine concentrations noted during serum metabolomic analysis [73].
Fig. 3

Comparison between clinical presentation and mechanisms of “classic” and “lean” nonalcoholic fatty liver disease (NAFLD). HCC hepatocellular carcinoma, NASH nonalcoholic steatohepatitis

Lean NAFLD was also similarly associated with an increased risk of metabolic-related complications, including the development of diabetes, hypertension, and metabolic syndrome [75]. A Korean study involving 30,172 nonobese individuals found that the risk of cardiovascular risk factors, including diabetes and hypertension, was increased in NAFLD patients with increased serum aminotransferase levels when compared with nonsteatotic healthy controls [76].

Currently, the key question is whether lean NAFLD has a different disease course from that of NAFLD in the obese population, especially since ethnic-specific cutoffs for BMI are arbitrary in nature [8]. A study published in abstract form found that lean NAFLD, when compared with NAFLD in obese individuals, was associated with a lower cumulative survival rate [77]. A study in India found that the prevalence of NASH and cirrhosis in nonobese NAFLD individuals was 31 and 2.4 % respectively [47]. Both studies are selectively biased as only patients with liver biopsy were analyzed, and the results might not be representative of the general population. To date, there are no published data demonstrating a difference in the natural history of lean NAFLD and obesity-related NAFLD.

The increased prevalence of lean NAFLD in Asia implies weight reduction may not be the backbone of therapy, but should instead be supplementary to other management strategies. At this stage, it is still best not to regard lean NAFLD and classic NAFLD as two distinct entities, and to acknowledge that even in the absence of obesity, NAFLD-related complications can still occur.

Interactions between NAFLD and viral hepatitis in Asia

Interactions between hepatic steatosis and chronic hepatitis C virus (HCV) infection are well established (Fig. 4). Steatosis in HCV-infected patients is an independent predictor of fibrosis progression [78] and is a negative predictor of response to pegylated interferon and ribavirin therapy [79], especially in genotype 3 patients [80]. Steatosis increases the risk of HCC in HCV-infected patients [81]. These findings have been validated in Asian populations. HCV-infected Taiwanese with coexisting steatosis have an increased risk of disease progression [82]. Steatosis predicts both a poor response to interferon-based therapy and the development of HCV-related HCC in Japan [83, 84].
Fig. 4

Interactions between nonalcoholic fatty liver disease (NAFLD) and viral hepatitis. DAA direct-acting antiviral, HBV hepatitis B virus, HCC hepatocellular carcinoma, HCV hepatitis C virus

In the current era of interferon-free direct-acting antivirals (DAAs) that achieve high rates of treatment response [85, 86], coexisting NAFLD can still influence the disease course of chronic HCV infection. A recent study demonstrated DAA treatment was associated with rapid changes in cholesterol homeostasis and an increase in serum low-density lipoprotein levels [87]. Another study investigating lipid metabolism in HCV genotype 3 patients treated with DAAs found HCV to be associated with relative hypocholesterolemia and reduced lipid circulation; subsequent HCV eradication increased serum cholesterol levels [88]. Both studies imply HCV patients with coexisting NAFLD need tight monitoring of serum lipid profiles after DAA treatment. Confirmatory studies of this change in lipid homeostasis are needed in Asia, especially since DAAs have similarly excellent treatment responses in HCV-infected Asian patients [89].

Paradoxically, chronic hepatitis B virus (HBV) infection appears to be associated with a reduced risk of NAFLD (Fig. 4). A cross-sectional population study among Hong Kong Chinese found HBV infection to be associated with a lower risk of NAFLD (adjusted odds ratio 0.42), although this study included only a minority of HBV-infected patients (8.9 % of the total cohort) [90]. Likewise, HBV-infected patients seemed to have fewer metabolic risk factors, including lower levels of serum triglyceride [91] and a reduced risk of metabolic syndrome [92]. A meta-analysis involving 17 studies and 4100 HBV-infected patients concluded hepatic steatosis was associated with lower levels of serum HBV DNA [93]. These results seem to be contradictory to the finding that metabolic syndrome increases the risk of cirrhosis development among Chinese HBV-infected patients [94], or that the expression of HBV-related genome proteins promotes hepatic lipid accumulation [95]. There is also evidence suggesting coexisting NAFLD itself has no relationship at all with the severity of liver disease in HBV-infected patients [96].

Further research is needed to elucidate if there is any interaction between HBV and NAFLD. With the cohort of HBV-infected patients receiving nucleoside analogue therapy increasing in Asia, a possible area of research is whether NAFLD affects HBV-related treatment response, especially when an increased BMI is associated with reduced fibrosis regression rates during nucleoside analogue therapy [97].

NAFLD in Asia: an indolent disease course?

NAFLD is emerging as an important cause of end-stage liver disease in Western countries. Between 2001 and 2009, NASH was the third commonest reason for liver transplant in the United States, after HCV infection and alcoholic cirrhosis, and is the only disease entity that increased in frequency [98]. NASH among Western populations, after a mean follow-up duration of 13.7 years, is associated with a 41 % risk of fibrosis progression, and NASH patients when compared with controls have a significantly reduced survival rate [99]. Although the association between NASH and HCC is only modest and usually occurs only in underlying cirrhosis [100], diabetes and obesity are the two most dominant risk factors for HCC in the USA [101].

However, NAFLD currently contributes to only a small proportion of liver-related complications in Asia. Among all histological features of NASH, only fibrosis was associated with a worsened clinical outcome [102]. Yet a population-based study in Hong Kong found advanced fibrosis or cirrhosis, as indicated by liver stiffness measurements using transient elastography, to be present in only 3.7 % of NAFLD patients [19]. According to a nationwide survey in Japan, NASH remained an uncommon cause of cirrhosis (2.1 %); HCV infection (60.9 %) and HBV infection (13.9 %) were far commoner [103]. Histological features of advanced liver disease were rarely found in liver biopsy samples from China [54]. A study from India found the prevalence of cirrhosis among biopsied NAFLD patients to be only 2 % [104]. A Malaysian study demonstrated the prevalence of cryptogenic HCC in different Asian ethnic groups to range from 13.8 to 29.0 % [105]. However, a considerable portion of cryptogenic HCC in Asia could be due to underlying occult HBV infection [106], and hence the true prevalence of NAFLD-related HCC remains uncertain.

A possible reason for this difference is the currently wide disparity in the prevalence of obesity (BMI ≥ 30 kg/m2) between Asia and Western countries (1.3–12.0 % and 18.4–33.9 % respectively) [107]. Obesity, similarly to NAFLD, might have ethnic-specific manifestations [108, 109], and to understand its exact role in hepatocarcinogenesis in Asia will require evaluation in different ethnicities. One population-based Korean study demonstrated obesity to be a key determinant of HCC, but the relative risk increased dramatically only in individuals with a BMI of at least 30 kg/m2, which constituted only 0.8 % of the whole study population cohort in terms of person-years [110]. Indeed, the current impact of diabetes and obesity on HCC development in the USA is mainly due its high prevalence; in terms of the subsequent relative risk of HCC, both had much lower impact than either HBV infection or HCV infection [101].

Despite the above-mentioned findings, it is inappropriate to assume NAFLD has a milder disease course in Asians. A Hong Kong study involving paired liver biopsies found that 27 % of Asian NAFLD patients developed histological progression over a 3-year period [111]. A study in Japan found the 5-year survival rates of patients NASH-related cirrhosis and patients with HCV-related cirrhosis to be similar [112]. It is worth noting that the prevalence of obesity among individuals younger than 20 years in Asia is now comparable to that in Western countries. For example, in China, Taiwan, and Malaysia, the male prevalence of obesity in this age group is 6.9, 7.7 and 8.8 % respectively; in the UK, France, and Spain, it is 7.4, 5.8, and 8.4 % respectively [107]. By 2030, the prevalence of obesity in China and other Asia–Pacific countries is expected to reach 12.6 and 14.5 % respectively [113].

The importance of NAFLD in contributing to liver cirrhosis and HCC in Asia will increase in the future. Male NAFLD patients might be particularly at risk, with a histology-based study suggesting HCC develops at an earlier stage of liver fibrosis [114]. However, HCC is diagnosed at an average age of 60 years or more [115], with a recent Japanese study showing NAFLD-related HCC to be diagnosed at a median age of 72 years [114]. Hence, it might take decades before the relatively younger Asian obesity cohort reaches the age of developing liver-related complications.

Conclusion

Our knowledge of NAFLD especially from an Asian perspective is constantly evolving. NAFLD in Asian and Western populations shows differences in risk factor prevalence, genetic susceptibility, and environmental interactions. The disparity in disease outcomes might be narrowed in the future with the increasing rise in obesity prevalence in Asia. Nonetheless, further research is needed, especially on the long-term outcomes of lean NAFLD and on the interactions between NAFLD and viral hepatitis in patient populations receiving or not receiving antiviral therapy. The increasing availability of novel noninvasive tools, including controlled attenuation parameter measurements via transient elastography [116], multiparametric magnetic resonance imaging [117], and novel serum-based markers of NASH [118], will offer an accurate quantification of the severity of NAFLD and may help in the prognostication of both hepatic and extrahepatic disease outcomes. As Asia moves further into the twenty-first century, the importance of NAFLD will only increase.

Notes

Compliance with ethical standards

Conflict of interest

The authors declares no conflicts of interest.

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Copyright information

© Japanese Society of Gastroenterology 2016

Authors and Affiliations

  1. 1.Department of Medicine, Queen Mary HospitalThe University of Hong KongPok Fu LamHong Kong
  2. 2.State Key Laboratory for Liver ResearchThe University of Hong KongPok Fu LamHong Kong

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