NAFLD in Asia—as common and important as in the West

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 10 | MAY 2013 | 307

ANU Medical School, Australian National University and Gastroenterology and Hepatology Unit, The Canberra Hospital, Yamba Drive, Garran, ACT 2605, Australia (G. C. Farrell, S. Chitturi). Department of Medicine and Therapeutics, Clinical Sciences Building, The Chinese University of Hong Kong, Shatin, Hong Kong (V. W.–S. Wong).

Correspondence to: G. C. Farrell [email protected]

NAFLD in Asia—as common and important as in the WestGeoffrey C. Farrell, Vincent Wai-Sun Wong and Shiv Chitturi

Abstract | NAFLD—regarded as a consequence of the modern sedentary, food-abundant lifestyle prevalent in the West—was recorded in Japan nearly 50 years ago and its changing epidemiology during the past three decades is well-documented. NAFLD, and its pathologically more severe form NASH, occur in genetically susceptible people who are over-nourished. Asian people are particularly susceptible, partly owing to body composition differences in fat and muscle. Community prevalence ranges between 20% (China), 27% (Hong Kong), and 15–45% (South Asia, South-East Asia, Korea, Japan and Taiwan). This Review presents emerging data on genetic polymorphisms that predispose Asian people to NAFLD, NASH and cirrhosis, and discusses the clinical and pathological outcomes of these disorders. NAFLD is unlikely to be less severe in Asians than in other populations, but the associated obesity and diabetes pandemics have occurred more recently in Asia than in Europe and the USA, and occur with reduced degrees of adiposity. Cases of cryptogenic cirrhosis and hepatocellular carcinoma have also been attributed to NAFLD. Public health efforts to curb over-nutrition and insulin resistance are needed to prevent and/or reverse NAFLD, as well as its adverse health outcomes of type 2 diabetes, cardiovascular events, cirrhosis and liver cancer.

Farrell, G. C. et al. Nat. Rev. Gastroenterol. Hepatol. 10, 307–318 (2013); published online 5 March 2013; doi:10.1038/nrgastro.2013.34

IntroductionNAFLD embraces the full pathological spectrum of conditions from simple steatosis to NASH and cirrhosis. Ludwig (1980)1 from the Mayo Clinic coined the term NASH for severer forms of fatty liver disease associated with obesity, type 2 diabetes mellitus and dyslipidaemia in the absence of excessive alcohol intake. This condi-tion, however, had already been recognized by Japanese physicians for more than two decades.2,3 NAFLD has never been a ‘Western disease’, although it is indisput-able that the worldwide trend of postindustrialized economies to nonagrarian, urban and inactive lifestyles, which enable the unprecedented access of individuals to cheap ‘processed’ foods, is the reason why NAFLD has had a major increase in prevalence (estimated ~20-fold) since 1983. Interest in NAFLD in Asia has been highlighted over the past decade in several excellent reviews.4–8 The first Asia–Pacific Consensus report on NAFLD was published in 20079–13 (several years before equivalent reports from Europe and the USA14,15) and discussed multiple aspects of the disease including epi-demiology,11 risk factors,12 pathology9 and patient man-agement,13 which we update in this Review. However, a seminal contribution from this consensus report was a suggested operational definition of NAFLD,9,10 a condi-tion that is more often defined by what it is not, rather than what it is.16,17

What is NAFLD? NAFLD can be attributed to over-nutrition and its c omplications, such as weight gain, central obesity, insulin resistance, glucose intolerance, atherogenic dyslipi daemia and arterial hypertension. This ‘positive’ definition of NAFLD is not generally accepted by clinicians;9,10,14–17 instead, a complete definition of NAFLD also has negative implications that are stipulated by the term nonalcoholic. In light of new information about the likely beneficial effects of mild–moderate levels of alcohol intake (dis-cussed below), our view is that the positive aetiopatho-genic factors that direct management strat egies need greater emphasis in the definition, as too much emphasis is placed on the ‘nonalcoholic’ label. It should be noted that no informative data about the safe levels of alcohol intake for Asians are available, as in many countries and population subgroups, social taboos and patterns of drinking alcohol make it difficult to obtain an accurate, semiquantitative alcohol history. Emerging data indicate that low levels of alcoholic intake have putative beneficial effects in patients with NAFLD, including reduced likeli-hood of NASH and reduced frequency of hepatic fibrosis (Box 1).18–23 The management implications for patients with NAFLD are that those who drink 1–2 standard drinks a day, with a minimum of two alcohol -free days per week, might be better advised to continue this habit than to become totally abstinent.

NAFLD is not the only cause of steatosis: HCV i nfection; drug therapy with tamoxifen, corticosteroids and some antiretroviral drugs; toxins from industrial solvents and some environmental contaminants; and

Competing interestsThe authors declare no competing interests.

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Wilson disease and other inherited enzymopathies or mitochondrial disorders can also lead to steatosis and these patients should not be diagnosed with NAFLD. In Asian patients with HBV infection, steatosis can occur, but it is actually less common (about half) the prevalence of the general population24 and is attributable to the same metabolic factors as NAFLD, not HBV infection.9,24,25 However, when individuals have both hepatitis B and metabolic syndrome, the risk of cirrhosis is greater than in lean patients with hepatitis B.26

What is NASH? Liver pathology of NAFLD NAFLD can be diagnosed by the presence of steatosis on hepatic imaging.27–29 Establishing the nature of the liver disease, however, requires either liver pathology,14,15,17,30–32 or the finding of advanced liver fibrosis and/or cirrhosis (as determined by clinicopathological criteria) and/or a physical modality (such as transient elastography).33,34 The pathology of NAFLD and NASH have been reviewed extensively elsewhere,30–32 including a perspective from Asia.35 The diagnosis of NASH requires steatosis (stain-able fat in >5% of hepatocytes) and two additional cri-teria: substantial lobular inflammation and hepatocyte

Key points

■ NAFLD prevalence in most regions of Asia is similar to that in the USA, Australia and New Zealand, and Europe

■ For equivalent levels of over-nutrition, Asian people are more prone to metabolic syndrome, type 2 diabetes and NAFLD than Europeans because of differences in body composition, particularly adiposity and muscle bulk

■ Lifestyle changes are likely to account for the pandemics of fatty liver, obesity and type 2 diabetes in Asia; more detail is required about the relative importance of physical activity and dietary constituents

■ The genetic predisposition to NAFLD and NASH shows similarities (particularly PNPLA3 polymorphisms) and possible differences (APOC3, PPARA polymorphisms) between Asian and non-Asian people

■ The course of fatty liver disease is unlikely to differ between Asian and other populations, but the obesity epidemic is more recent in Asia than elsewhere in the world

■ NAFLD as a cause of cryptogenic cirrhosis and hepatocellular carcinoma (including a high proportion of cases in noncirrhotic liver) is now readily apparent throughout Asia

ballooning. Some portal tract inflammation might also be observed, but it is not usually prominent; NASH with prominent portal tract inflammation is associated with a worse prognosis.30,35 Severity of steatosis in NAFLD cor-relates with likelihood of NASH, but not with features of hepatocellular injury or with advanced fibrosis.36 The indications for liver biopsy in NAFLD are controver-sial,9,14,15 owing to the invasive nature of the pro cedure and the lack of specific pharmacological therapy for NASH (discussed later). However, liver biopsy is the only approach that currently provides reliable criteria for establishing the presence of NASH and/or liver fibro-sis in NAFLD—the important factors for predicting the outcome of liver disease.

Hepatocyte ballooning Ballooning is a characteristic form of hepatocyte injury in which cells are swollen and lose their normal struc-ture of lipid droplets and cell membranes.30 Ballooned hepato cytes often contain Mallory hyaline (Mallory–Denk bodies), comprising clumps of degraded interme-diate (keratin) filaments that are ubiquitin positive and lack the hepatocyte-specific markers cytokeratin-8 and cytokeratin-18.37 Livers that show steatosis without ballooning and with minimal or no inflammation are termed simple steatosis or non-NASH NAFLD.16,17 The pathology of NASH changes clinical outcomes: non-NASH pathology is associated with a very low risk of c irrhosis and its complications, whereas NASH pathol-ogy carries a risk of developing cirrhosis in the next 10 years that approaches 10%.17,32,38–40

Liver fibrosis in NAFLD and NASH The single most important determinant of liver o utcomes in NAFLD is the presence of hepatic fibro-sis,17,32 which is usually, but not always, associated with NASH pathology. This finding is not surprising, given that follow-up studies,17,32,38–40 including one from Hong Kong,41 demonstrate that steatohepatitis comes and goes with changes in body weight; sampling error is another issue.42 Fibrosis usually starts around the central hepatic venule (zone 3) and extends around sinusoids before the collagen strands thicken and extend to portal tracts, creating bridges of dense hepatic fibrosis. Multiple cri-teria have been developed for the grading of fibrotic severity using liver biopsy, including the system devised by Brunt (the most commonly used grading system in c linical practice.30,32,35,36

End-stage liver pathology in NAFLDA diagnosis of cryptogenic cirrhosis is made when few diagnostic features can be recognized, and hepatitis viral infections, haemochromatosis and specific meta-bolic, cholestatic and autoimmune liver diseases have been excluded. In NAFLD, the development of cirrhosis can be associated with resolution of liver inflammation, even steatosis.43,44 Occasional ballooned hepatocytes (a nonspecific finding in cirrhosis) and the detection of Mallory hyaline might be the only clues to previous steato hepatitis.44 Such cases of cryptogenic cirrhosis

Box 1 | Beneficial effects of low–moderate* alcohol intake

■ Fasting serum insulin and blood glucose concentrations show improved insulin sensitivity in postmenopausal women21

■ Cardiovascular events are reduced, particularly in patients with diabetes; overall mortality is also reduced19,22

■ Elevation of serum aminotransferase levels (strict criteria for lean men and women) in National Health and Nutrition Examination Survey show reduced prevalence of NAFLD18

■ Blinded assessment of NAFLD pathology by experienced liver pathologists show reduced proportion of cases of NASH19,20,23

■ Blinded assessment of NAFLD pathology show less liver fibrosis19

*Non-toxic level.

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often occur in patients with type 2 diabetes or obesity,43,44 or the patient’s medical history might reveal earlier long-standing obesity has resolved with increasing age and increasing severity of cirrhosis.

Epidemiology of NAFLD in Asia Community surveys employing ultrasonography or proton NMR spectroscopy have measured the preva-lence of NAFLD in several parts of Asia. In Japan, the community prevalence of NAFLD increased from 13% before 1990, to 30% by 1998, and ~32% in men and 17% in women by 2008.6 Data from Korea,45,46 China47,48 and Taiwan49,50 also indicate a similar high prevalence of NAFLD (11–45%) in northern Asian populations during the past decade, including a high prevalence (>50%) in obese children and adolescents.51,52 A study in 2012 from Hong Kong using proton NMR spectroscopy provides reliable evidence that the prevalence of NAFLD in Chinese people living with a ‘westernized’ sedentary lifestyle exceeds 25% (Figure 1).29 In Shanghai, a community-based survey from 2005 of 3,175 individuals found that ~20% had fatty liver by ultrasonography; in the vast majority of individuals, steatosis was attributable to metabolic causes rather than alcohol intake.53 Clinical experience and smaller surveys from India,54,55 Sri Lanka,56,57 Malaysia,58,59 Singapore60 and Indonesia have led authors to conclude that the prevalence of NAFLD in South Asia and South-East Asia varies from 9–45%. The lowest estimates (8.7–18%) are generally from rural (physically active, poorer) areas with a lean population.55,57,61

Risk factors for NAFLD and NASH in Asia Generally the risk factors for NAFLD and NASH are the same in Asians as in non-Asians.4–7,12,45–64 Multiple studies in the USA in different ethnic groups have confirmed this observation.65,66

Age and genderNAFLD prevalence increases with age, being <30% in those aged less than 40 years, and >50% in those older than 60 years (Figure 1).12,29 On the basis of the known age-dependent decrease in insulin sensitivity, this trend is likely to be a result of a biological difference, but the age distribution of NAFLD might change in the future as rates of obesity in young people continue to increase in most countries. Indeed, NAFLD is now common among older children and adolescents in Asian countries, as well as Australia and the USA,51,52 with a prevalence (10–15%), similar to that of obesity.62 The increase in obesity in Asian children62,67 has implications for age-specific prevalence, severity and long-term outcomes of NAFLD. Likewise, the prevalence of type 2 diabetes in Japanese children was 0.2% in the 1970s but now exceeds 7%;67 similar changes have been recorded in other Asian countries.62

In early reports, NASH was regarded as a disease of middle-aged to older women,1–4 but the gender-specifi c incidence depends on age.12,29,48 Before 50 years of age, NAFLD prevalence is nearly twice as high in men as women;29,48 thereafter, the gender ratio gradu-ally changes and women most often develop NAFLD as

shown in data from Hong Kong (Figure 1). In South-Western USA, 10–25% of patients with evidence of stea-tosis from ultrasonography had histological NASH,68 but no Asian studies have been conducted and so whether the proportion of NAFLD cases showing NASH increases with age is currently unknown.

BMI and central obesityAlthough being overweight or obese are strong risk factors for NAFLD, early Asian studies often failed to apply ethnic-specific indices for measuring central obesity. The International Diabetes Federation criteria for measuring central obesity are currently favoured by the Asia–Pacific Working Party on NAFLD.9,10 Both the percentage of fat for a given body mass and its distribu-tion between subcutaneous and visceral compartments differ between Asian and European people. The implica-tion for NAFLD is that a person who is not overweight or centrally obese by European criteria, such as the Third National Health and Nutrition Examination Survey (NHANES III), might still have excessive amounts of adipose tissue (defined as >15% of total tissue), par-ticularly visceral adiposity.52,61,62 In our opinion, this mis interpretation contributes to a frequently voiced comment that NAFLD often occurs in lean Asians. In reality, a small proportion (~15%) of Asians who have NAFLD conform to ethnic-specific anthropometric indices of leanness.55,61,64 In addition to the problems of defining ‘normal’ anthropometrics for multiethnic populations in Asia, such individuals have usually gained some weight over their ideal body mass, as has been documented in ‘lean’ Korean men with NAFLD.63 Such individuals usually exhibit insulin resistance and can be termed lean, but metabolically obese;16,69 this phenom-enon seems to be more common in Asians than other ethnic groups.60–63,65,66 A Japanese study showed a clear relationship between BMI and development or resolution

<30 30–39 40–49Age (years)

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Figure 1 | Prevalence of NAFLD in the Hong Kong community increases with age (purple bars). The prevalence increases in men throughout life (pink bars), but in women (green bars) the prevalence does not increase until the fifth decade, after which it rises steeply. Steatosis was detected by proton NMR spectroscopy. Permission obtained from BMJ Publishing Group Ltd © Wong et al. Gut 61, 409–415 (2012).

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of NAFLD over time,70 providing strong evidence that over-nutrition causes NAFLD, and that this disease can be reversed during its early stages.

Insulin resistance and type 2 diabetes Among patients with NAFLD, 25–40% have established diabetes.16,31,70 In Australia and Asian populations, an additional 15–25% have been reported to have previ-ously undiagnosed diabetes by oral glucose tolerance testing,71–73 whereas others often have a family history of type 2 diabetes.74–76 Furthermore, Japanese, Korean, Chinese and Sri Lankan studies have shown that the risk of developing diabetes within 3 years of NAFLD diagno-sis increases 3–4-fold, even among lean individuals.77–82 Conversely, insulin resistance (the pathophysiological precursor of type 2 diabetes) and glucose intolerance (one of its consequences) are both associated with an increased risk of fibrotic progression in NAFLD.16,39,64,83,84

From the strong associations between NAFLD and diabetes, genetic predisposition to diabetes might also predispose to NASH and fibrotic progression in NAFLD. Support for this genetic association has now been provided by a study from the USA,76 but it has not been studied extensively in Asia; strong links between NAFLD and diabetes have, however, been stressed in Japan, Korea, China and South Asia (sum-marized in Supplementary Table 1). A systematic review of Japanese studies investigating the clinical outcomes of patients with type 2 diabetes found that cirrhosis is a common cause of death, most likely attributable to the liver damage that occurs during NAFLD progression.6 However, an even more common cause of pre mature mortality is cancer, especially primary liver cancer (hepatocellular carcinoma, HCC). In one systematic review, 11% of Japanese patients with type 2 diabetes died from HCC, making it the single most common cause of death from diabetes;85 similar data are available from Taiwan.86 Further studies are required to establish whether a similar trend is observed in other Asian or non-Asian countries (in the latter, cardiovascular disease

[CVD] is the most common cause of death from type 2 diabetes, albeit cancer is also common87). Alternatively, genetic and/or environmental factors might have a role in Japanese populations that predispose them to this form of cirrhosis and liver cancer.

Metabolic syndrome Approximately two-thirds of patients with NAFLD are associated with insulin resistance, and this figure rises to >98% among those with NASH.4,14–16,31,69 A strong rela-tionship exists between the number of components of metabolic syndrome and prevalence of NAFLD, as well as the severity of NAFLD and NASH.20,39,83 In Japan, devel-opment and resolution of NAFLD over time were both closely related to metabolic syndrome.70 In Australian and European studies, at least 85% of patients with NASH have at least three components of the metabolic syn-drome;14,69,74 moreover, hypertension and other features of metabolic syndrome have often been included among clinico pathological criteria and independently predict progression to cirrhosis.20,83 Similar relationships seem to be evident in Asia,29,48,50 but further studies are required.

Pathogenesis of NAFLD in Asians NAFLD as a lifestyle disease Overeating and dietary factors NAFLD is attributable to overeating, consumption of energy-dense (high saturated fat content), nutrition-ally imbalanced and appetite dysregulating (sucrose, fructose-containing soft drinks) food, and under-activity.16,31,69,88–92 Most or all of these factors operate in Asian populations with NAFLD.4–12,45–64,70 The tradi-tional Asian lifestyle largely consists of the following: self-productio n of food; a diet containing relatively low levels of fat and meat with high levels of vegetables and rice as staple carbo hydrate; manual labour (often as farm workers); and other forms of sustained physical activity. During the past 50 years (longer in Japan),6 numerous social changes have occurred that might have resulted in over-nutrition and a predisposition to NAFLD and related metabolic disorders in Asian populations (Box 2).

Studies of childhood obesity in Singapore and China indicate the roles of physical inactivity and over-eating –poor food choices are the same in Asia as else-where,51,52,60,62 but the particular factors that pre dispose these children to NAFLD or NASH are currently unclear. Similar studies from the USA and Europe have not always provided a clear picture of the most important risk factors, which need to be identified so that they can be targeted in public health programmes. Diet is an important example. Some, but not all, studies have shown that a diet high in saturated fat content or exces-sive fructose intake increases the risk and severity of NAFLD.88–91 In a large transectional study conducted by the NIH NASH Clinical Research Network (CRN), fructose intake was a risk factor for fibrotic severity in NAFLD,90 but the variance was small and confined to men. Although Asians consume less fructose in the form of high-fructose corn syrup than Americans (as the dietary source in this region is cane sugar and fruit),

Box 2 | Social changes in Asia since 1945*

■ Fat intake (Japan: fourfold increase 1945–1985) ■ Protein intake (increase ~25%) ■ Total calorie intake (less change 1945–1985) ■ Number of registered motor vehicles (Japan: fivefold

increase same interval) ■ Increasing urbanization, less village life ■ General access to internet, since mid-1980s ■ Increase in gross domestic product (timing varied

between Japan, Korea, South-East Asia, China and South Asia)

■ Growth of international trade from higher sales and market penetration of soft drinks from outside Asia

■ Similarly for processed foods ■ Lower prices, ready availability and increasing use of

‘fast food’ ■ Less consumption of ‘slow foods’ (homegrown

vegetables, eggs, livestock)*Changes with potential to affect over-nutrition and predisposition to NAFLD, diabetes, cardiovascular disease and common cancers.6,35,142

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one Japanese study found that dietary excess of simple carbohydrates was associated with NASH among patients with a fatty liver.91

Among the few dietary studies conducted in Asia, Japanese workers found a marked link between choles-terol intake and NAFLD in lean (but not obese) men.92 A study from the USA of 9,221 individuals found a posi-tive association between consumption of cholesterol and risk of all-cause cirrhosis and HCC.93 Furthermore, current research is aimed at trying to elucidate the mech-anistic role of hepatic cholesterol in NASH, which seems to involve lipotoxicity.69,94,95 More detailed dietary studies are required in other Asian populations to provide a basis for simple dietary guidelines to prevent NAFLD and its liver complications of NASH, cirrhosis and HCC. One of the most commonly identified dietary factors is the micronutrient deficiency caused by low intake of vita-mins and minerals (such as zinc).91,92 By contrast, this deficiency was not observed in studies of some very old (>100 years) populations, such as the Okanawa people, among whom regular consumption of a large number of different foods, including homegrown vegetables, are reproducible behaviours. As vitamin E is one of few pharmacological therapies shown to influence NASH,96,97 albeit with fairly limited efficacy and with unresolved safety issues for all-cause mortality, further studies of micronutrient intake in Asian populations with NAFLD could be informative.

Physical activity Among 813 biopsy samples of NAFLD in the NIH NASH CRN, regular physical activity (defined as at least 150 min of aerobic exercise each week) was associated with a reduced rate of NASH, and a minimum of two episodes of moderately vigorous exercise (for at least 30 min each session) was associated with reduced levels of fibrosis.98 Indeed, lifestyle intervention as a treatment approach for NAFLD and NASH is gaining increasing support from research studies.99 A Korean study evaluated the effects of exercise and diet modification on histological severity of steatosis in 120 living liver donors, only 59% of whom were overweight or obese.100 Lifestyle modification for 12 weeks achieved weight reduction in 77% of patients and steatosis improvement in 86%; reduction of serum total cholesterol >10% and weight >10% were strongly related to major improvements in steatosis.100

NAFLD as an inherited disease In Asia, a proportion of patients with NAFLD are not overweight,61–63,100 although these individuals often give a history of weight gain during the previous 12 months,63 or a family history of type 2 diabetes.74–76 Family studies, comparisons of NAFLD frequency between ethnic groups,65,66 and genome-wide association studies indi-cate that genetic predisposition contributes to individual susceptibility to NAFLD, and also to its severity.16,69,101 At least 12 genetic polymorphisms have so far been linked with NAFLD101–118 with reported similarities and differences between Asian and non-Asian populations (Supplementary Table 2).

Some genetic polymorphisms influence lipid p artitioning from adipose to liver (such as PPARA and PPARG polymorphisms)102,105,106,108 and/or pathways of lipo lysis or lipogenesis (patatin-like phospholipase domain -containing protein 3 [PNPLA3],101,103,110–114 apolipo protein C-III [APOC3]113,115 and adiponecti n116,117) and cholesterol turnover.107 Other polymorphisms could influence the pathogenesis of NASH by exerting effects on redox pathways, inflammatory recruitment and fibro-genesis.104,113 Among Asians, PPARG polymorphisms have been associated with obesity,109 and a PPARG single nucleotide polymorphism has been associated with NAFLD,108 possibly via low serum adiponectin levels and insulin resistance. Conversely, the Val227Ala PPARA polymorphism, which is fairly common in Asians, might protect against NASH;105 the same polymorphism is asso-ciated with low levels of serum cholesterol and protection from CVD.106

Variation in APOC3 was initially described in lean Asian Indians in association with delayed postprandial clearance of low-density lipoproteins, a key feature of NASH;88,95 this polymorphism was then linked to NAFLD.113,115 Although a landmark article suggested that the gene frequency was the same in European and Indian individuals,115 this asso-ciation has not been confirmed.113 By contrast, numerous studies have confirmed a strong relationship between a common polymorphism in PNPLA3, and both preva-lence and severity of NAFLD.101,103,110–114,116,118 The resultant Ile148Met substitution accounts for all of the ethnic dif-ferences in steatosis prevalence between Hispanic people (~40%), white people (~30%) and African Americans (~24%) in south-western USA.101 This polymorphism is a determinant of raised serum alanine aminotransferase (ALT) levels,118 including in childhood,103 reflecting liver injury as well as fatty liver. PNPLA3 has now been linked with the histological severity of NAFLD,104,111,112 and also alcoholic liver disease and hepatitis C.119,120

PNPLA3 is a triacylglycerol hydrolase in both adipose and liver; the Ile148Met substitution decreases the affin-ity of substrates to PNPLA3.121 Mice with hepatic over-expression of mutant Pnpla3 have increased formation of fatty acids and triacylglycerol, impaired hydrolysis of triacylglycerol, and relative depletion of triacyl glycerol long-chain polyunsaturated fatty acids.122 Humans car-rying this gene variant also have lower secretion of large, triglyceride-rich very low density lipoproteins,123 and decreased serum adiponectin levels; adiponectin is an anti-inflammatory adipokine associated with insulin sensitivity, polymorphisms of which have also been implicated in predisposition to NASH.16,116,117

Course of NAFLD in Asia Originally, NAFLD was thought to be less severe in Asians than in other ethnicities.7,11 However, NAFLD is a more recent problem in Asia than in North America and, as persistence of NAFLD over several decades is required for the development of cirrhosis, the propor-tion of such cases in Asia is expected to be relatively small. The younger age distribution in clinical series of NAFLD cases from Asia compared with the West

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provides support for this prediction. On the other hand, evidence now suggests that liver pathology is not always benign. In a prospective serial biopsy study of 52 patients, Hong Kong investigators found progression of liver fibrosis in 14 (27%) patients during 3 years.124 Furthermore, of the 13 patients who presented with simple steatosis at baseline, eight exhibited features of NASH at follow up. This observation from Asia is one of the few reliable pieces of evidence for a dynamic inter-change between simple steatosis and NASH in response to metabolic conditions, and a potential explanation of why patients with NAFLD and fibrosis do not always show NASH at the time of liver biopsy.17,32

In Asia, cryptogenic cirrhosis attributable to metabolic liver disease is less common than in Western countries, but nevertheless has been well-documented.7,125 A report from India of 47 patients with NAFLD-related cirrho-sis, including eight with HCC,125 provides evidence that awareness of this condition (and possibly its incidence) is increasing in South Asia. Progression to HCC is an important outcome of NAFLD in Asia, as it is world-wide.125–128 A study from South Korea of 329 patients reported that the proportion of patients with HCC asso-ciated with NAFLD increased from 3.8% in 2001–2005 to 12.2% in 2006–2010; by contrast, HBV-related HCC declined from 86.6% to 67.4%.129 In Japan, 6,508 patients with NAFLD were followed up at a median of 5.6 years; 16 patients with HCC were identified, an annual rate of 0.043%.130 Older age and raised aspartate amino-transferase (AST) levels and/or low platelet count were independent risk factors. NAFLD now accounts for 2% of all HCC in Japan; the median age of patients is 72 years, and 62% are male.6,126

Although studies from Europe and the USA have shown that NAFLD increases standardized mortality, liver disease is only the third most common cause of death after cardiovascular events and common cancers (albeit 13th in people without NAFLD).14,15,131 As dis-cussed earlier, NAFLD is a risk factor for development of type 2 diabetes in Asia,77–82 as elsewhere in the world.16,69

Relationship of NAFLD to other diseases CVD Strong evidence indicates that NAFLD is associated with increased prevalence and incidence of CVD, not only via shared metabolic risk factors, but also independently.132–138 Community surveys from Taiwan134 and Shanghai48,53,81 have found strong relationships between the presence of fatty liver (and its severity) by ultrasonography53 and hypertension. Other Asian studies have found a relation-ship between serum aminotransferase elevations and risk of carotid atherosclerosis,135 which provides evidence that NASH is strongly associated with CVD.132 Korean studies have further highlighted the relationship between NAFLD and coronary artery disease.136,137 Even in non diabetic, nonhypertensive individuals, NAFLD is associated with arterial stiffness.136 In 612 patients undergoing coronary angiography in Hong Kong, coronary artery disease occurred in 85% of those with NAFLD compared with ~64% in those without a fatty liver.138

Cancers Obesity-associated cancersObesity139 and type 2 diabetes85–87 increase the risk of all malignancies ~twofold, in particular those malignan-cies related to insulin resistance such as breast, prostate, colorectal, pancreatic and oesophageal adenocarcinoma. The risk is greatest for HCC (~3.4) and endometrium.85 In Japan, cancer is now the most common cause of death from type 2 diabetes (34%), compared with 27% from CVD.6,85 Among these cancers, liver cancer (8.6%) was the most common, followed by lung (5.3%), pancreas (4.8%) and stomach (3.5%).85 Studies from Korea and Hong Kong have shown that NAFLD is associated with a 2–3-fold increased risk of adenomatous polyps and colorectal carcinoma,140–142 which will also influence patient management.

Liver cancer in NASH Data from Japan indicate how important HCC has become as a cause of death from type 2 diabetes,6,85 which is a probably a consequence of associated NAFLD.126,130,143 In the USA and Australia, the inci-dence of HCC has doubled since 1985, and some of this increase is not attributable to known aetiologies (HCV, HBV, alcohol).143 In New Zealand and north-ern UK, obesity and/or NAFLD as a cause of HCC has increased over the past decade. The same trend was evident in Japan at an earlier time, with the incidence of HCC attributable to no known cause in 1993 being 6%, rising to ~15% by 2003; over the same interval, HBV remained a constant aetiological factor (~10%) and HCV, by far the most important aetiology of HCC in Japan since 1980 (~90% cases), fell slightly.6 In Japan, longitudinal studies have confirmed development of HCC in patients with NAFLD,129 and HCC has been noted in those with advanced NAFLD in India.124 More data are needed from other Asian countries, but, given the relatively recent pheno menon of obesity–NAFLD, it might be another decade before HCC related to NAFLD and NASH becomes an important public health issue in this region.

Obesity and type 2 diabetes synergistically increase the risk of HCC on their own,86,144 and in those with other risk factors (chronic hepatitis B or hepatitis C),145 but these data do not necessarily prove that NAFLD causes HCC. However, the strong association between metabolic syndrome and HCC is persuasive,146 as is the increasing number of cases of HCC that seem to develop in livers showing cirrhosis attributable to NAFLD.125–127,143 In general, at least 85% of HCCs occur in a liver showing cirrhosis. However, a growing number of case series emphasize that HCC related to NAFLD or NAFLD risk factors might occur in noncirrhotic liver,143 as has been reported in 10–75% of cases in Japan.126 If this relationship is confirmed by prospective studies, the findings have challenging implications for HCC surveillance as part of individual patient care for NAFLD. Alcohol increases the risk of HCC in patients with NASH in the USA,127 and so needs to be considered in public health recommendations.

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Public health implications for prevention WHO has identified global obesity as the most important health challenge of the 21st century. Liver disease is an important adverse outcome; cirrhosis and HCC are high among potential causes of premature death. Furthermore, NAFLD is likely to have an aetiopathogenic role in type 2 diabetes, metabolic syndrome and CVD;16,69,132,133 under-standing who is at disproportionately high risk, and the environmental, socioeconomic, early developmental and behavioural factors that interact to cause this dis-order would enable targeted interventions to prevent NAFLD. Identification of NAFLD is relatively easy using simple, inexpensive and widely available hepatic ultra-sonography and liver tests (such as measuring ALT or AST levels), which could be an excellent strategy to find those at highest risk of metabolic disease and its vascular and cancer outcomes. Use of genetic tests might similarly achieve this goal, but it is not likely to be as cost-effective. Strategies to reduce food intake, alter food choices and improve physical activity will test the political willpower of all countries during the next few decades; details have been reviewed elsewhere.69,88,89,95,99,147 An approach tar-geted at those at highest risk could prove cost-effective, particularly programmes similar to the diabetes interven-tion studies of a decade ago in which beneficial health effects are still evident.148 However, the “stop for futil-ity” of the Look Ahead NIH study reflects the challenge of ever proving this approach.

Patient management Lifestyle intervention In NAFLD, weight loss of at least 3–5% is associated with improvement in serum ALT levels as well as metabolic indices, such as waist circumference, blood pressure, fasting blood glucose, serum insulin and blood choles-terol.69,99,134,147 Histological improvement might require further (7–10%) weight reduction.147 Although such weight loss could be achieved by dietary restriction, increasing evidence indicates that programmes that combine dietary advice with enhanced physical activity are more success-ful.99,149 As mentioned earlier, moderately vigorous exer-cise performed regularly seems to protect against liver fibrosis in NAFLD.98 Studies into possible effects of weight reduction and physical activity on reversal of liver fibrosis related to NAFLD are needed, including outcomes among younger patients (<50 years), before fibrotic liver disease has progressed to the stage of cirrhosis. A key aspect of lifestyle intervention programmes is that successful outcome depends on a behavioural change that needs to be embraced by the patient, and implemented on a long-term basis. Involvement of a trained ‘lifestyle intervention leader’ might be of importance, as has been the model used in suc-cessful diabetes intervention programmes.148 More research in this area in the Asian context would be informative. The Asia–Pacific NAFLD Consensus,13 leading authorities,16,69,88 and European and American guidelines all recommend lifestyle intervention as an essential and first-line approach to managing people with NAFLD.14,15 The reality, however, is that few patients adhere to such advice, the availability of suitable programmes is limited (particularly without

financial support) and available data often show short-term gains followed by high rates of recidivism.

SurgeryIndividuals who are very obese (BMI >35 kg/m2 for an Asian person) have usually tried numerous dietary approaches to weight reduction without permanent success. For these patients, bariatric surgery can cure diabetes in ~66%, and reverse NASH in ~80% of cases; effects on fibrosis are less clear.149,150 Again, the major issues concerning bariatric surgery are logistic: in most Asian countries and elsewhere in the world, demand greatly exceeds available services, most of which are not available outside of the private healthcare sector.

Pharmacological treatmentPharmacological therapy for NASH is greatly needed,88,96 and, at least in France, it is widely used, although without good evidence of efficacy.151 An often neglected aspect is the need for drug therapy to abrogate other adverse health outcomes for people with NAFLD. For instance, the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study showed that the greatest efficacy of statins against cardiovascular events was achieved in those with raised ALT levels,152 suggest-ing superior efficacy in the presence of NAFLD. Statins are safe to use in people with NAFLD who have raised serum ALT levels, and to withhold them on the basis of concerns about drug-induced liver injury (a very rare complication of statins) is inappropriate.95 Whether statins can actually improve liver disease, particularly given current evidence of increased hepatic cholesterol accumulation in NASH,69,94,95 requires further study. Available data are few, but one study indicated that patients treated with a statin were less likely to develop worsening of liver fibrosis than those not so treated.38 Experimental evidence also suggests that statins par-tially abrogate hepato carcinogenesis; a review in 2012 called for a trial of statins as chemopreventive agents against HCC,153 and Danish population data indicate that statin use reduces cancer-related mortality.154 In relation to other cholesterol-lowering drugs, data from Japan have been the first to indicate possible benefits of ezetimibe against NASH.95,155 Future studies of more intense cholesterol-lowering therapy in NASH will now be of interest.94,95

Agents used to target NASH include those directed at insulin sensitization and lipid partitioning, agents to counter oxidative stress and cytokine release, and puta-tive hepatoprotectants (Table 1). Several meta-analyses and systematic reviews have summarized the results of clinical trials of drugs used specifically to treat NASH.96 Metformin is ineffective over the long-term, but it sub-stantially reduces the risk of HCC in patients with type 2 diabetes.86,87 The implication of this approach for long-term management of patients with both type 2 diabetes and NAFLD requires exploration.

The group of drugs of greatest interest against NASH has been the thiazolidinedione (‘glitazones’), among which pioglitazone is the only agent not yet withdrawn

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in most countries. Meta-analyses have shown that p ioglitazone has modest efficacy for NASH, improv-ing liver pathology in ~40% of patients (versus ~15% in patients given placebo).96 The most impressive effect is on steat osis (which has no prognostic importance), with lesser effects on ballooning and necroinflamma-tory change (NASH) and no effects on fibrosis. In the largest study to date of pioglitazone, the PIVEN study, the marginal effect of pioglitazone was not statistically significant (the study was probably under-powered), whereas the equally marginal effect of vitamin E just achieved statistical significance.97 However, vitamin E cannot yet be recommended as first-line therapy for NASH as concerns about its unopposed use for all-cause mortality remain unresolved.

Other agents studied in Asia include fish oil (to stim-ulate PPAR-α-mediated suppression of lipo genesis and fatty acid β-oxidation),156 pentoxifylline (an antioxidant

which blocks TNF elaboration),157,158 vitamin E,159–161 pioglitazone,162 atorvastatin,163 sitagliptin164 and angiotensin -receptor blockers;165 these agents, however, have been used in the context of under-powere d pre-liminary studies. The results give few insights into mechanism-based or effective therapy for NASH. In our opinion, a more complete understanding of the pathogenesis of NASH is needed.16,69,122,123

Conclusions Well-conducted studies of NAFLD in Asian people are important because they could elucidate the inter actions between environmental factors and a genetically sus-ceptible host that determine the unwanted outcome of metabolic disease. From existing data, the causes of being overweight or obese are likely to differ between Asians and other ethnic groups (including genetic sus-ceptibility genes and the relative importance of physical

Table 1 | Asian studies of pharmacotherapy for liver disease in patients with NASH, with comments on broader literature

Study Agent or group of drugs

Location Study findings Comment

Multiple13,88,96 Metformin Worldwide Minimal if any effect on liver histology Important for glycaemic control, reduces serum insulin; associated with substantial reduction in risk of HCC in patients with type 2 diabetes85–87

Iwasaki et al. (2011)164

Sitaglipin Japan Open-label study of 30 patients with diabetes Improved liver biochemistry-associated glycaemic control

Await histological evaluation of agents that enhance the enteroglucagon–pancreatic axis to improve diabetes glycaemic control

Ono et al. (2005)162

Pioglitazone Japan Improves biochemical indices of liver disease in diabetics

Inadequate evidence of efficacy against NASH (see below97)

PIVEN97 Pioglitazone USA (similar in Europe)

~40% improvement in NAS (not statistically significant), mainly in steatosis, none in fibrosis

Under-powered study; meta-analyses of 5 RCTs suggest a real, but marginal, effect, associated with weight gain, not sustained after drug discontinuation14,96

PIVEN97 Vitamin E USA As above, but statistically significant See below97

Madan et al. (2005)159

Vitamin E India Lowers serum ALT in patients with NAFLD Poor study: ALT not a valid reflection of liver injury in NASH14,96

Hasega et al. (2001)160

Vitamin E Japan Open-label study of 12 patients with NASH; 10 with non-NASH NAFLD found a histological benefit

No control group

Wang et al. (2008)161

Vitamin E (lifestyle intervention)

China (Zhejiang)

Improved ALT levels in small number of children

Consistent with wider data96

Park et al. (2011)155

Ezetimibe Japan Open-label study showed improvement in metabolic indices and liver disease

Other small studies also show fibrosis improvement95,155

Hyogo et al. (2012)163

Atorvastatin Japan Open-label study of 42 biopsy-proven cases of NASH found improved biochemical tests, serum TNF and NAS

Requires RCT

Ekstedt et al. (2006)38

Statins (various) Europe Prospective open, observational study found less fibrosis progression

Few studies on statins for liver disease in NASH; they are poorly controlled, small164 Requires further study and possible use in combination cholesterol-lowering therapy95

Tanaka et al. (2008)156

Fish oil (eicosa-pentanoic acid)

Japan Open study of only 7 follow-up biopsies showed improvement in NASH and fibrosis

PPAR-α agonist, need further controlled study in larger cohorts

Satapathy et al. (2007)157

Pentoxifylline India 9 patients with NASH treated for 12 months had histological improvement, including fibrosis

Poorly controlled and under-powered155 Only adequately powered study had difficulty recruiting, but found statistically significant benefit166

Enjoji et al. (2008)165

Angiotensin receptor blockers

Japan Pilot study found improved liver biochemistry and insulin sensitivity

Need histological assessment of possible benefits on fibrosis

Abbreviations: ALT, alanine aminotransferase; HCC, hepatocellular carcinoma; NAS, NAFLD activity score; PPAR, peroxisomal proliferation-activator receptor; RCT, randomized controlled trial; TNF, tumour necrosis factor.

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inactivity and diet). Understanding such associations could give insights that enable those individuals who are at risk to be identified before they are affected or at early stages when judicious (and targeted) lifestyle interventions can be highly effective and sustained. Meanwhile, liver disease should not be ignored when the health detriments of metabolic syndrome and type 2 diabetes are considered in relation to the obesity epi-demic. Primary liver cancer is predicted to be one of the most important causes of premature death, particularly for Asian people, in this 21st century pandemic, and measures to prevent it or to improve clinical outcomes are greatly needed.

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Review criteria

A search for original articles on NAFLD in Asia, China, Japan, Korea, Taiwan, India, Sri Lanka, Singapore, Philippines, Malaysia was performed in PubMed, for years 2000 to 2012 inclusive. Separate searches were conducted for “genetic polymorphisms and NAFLD”, “diet and NAFLD”, “lifestyle and NAFLD”, “physical activity and NAFLD”, “diabetes and fatty liver”, “cardiovascular disease and fatty liver”, “cryptogenic cirrhosis and Asia”, “HCC and NAFLD”, “diabetes and HCC”. For these searches, most attention was given to full-length articles in English published from Asian centres. We also searched the reference lists for further relevant articles.

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Author contributionsAll authors contributed to researching data for the article and writing the article. G. C. Farrell also substantially contributed to the discussion of content and reviewed and edited the manuscript before submission.

Supplementary information is linked to the online version of the paper at www.nature.com/nrgastro.

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NAFLD in Asia—as common and important as in the West

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