Introduction

Non-alcoholic fatty liver disease (NAFLD), as conventionally recognized, is a metabolic disorder largely confined to residents of affluent industrialized Western countries. However, obesity and insulin resistance, the common substrates of NAFLD, are not restricted to the West, as witnessed by their increasingly universal distribution.^[1] In particular, there has been an upsurge in obesity-related metabolic syndrome in the Asia-Pacific region, although there are critical differences in the extent of adiposity between Eastern and Western populations.^[1-3] In light of this, we provide a regional perspective on obesity-related metabolic syndrome and NAFLD, reviewing existing data and recommending new revised definitions for future Asian studies.

Definitions and controversies concerning metabolic syndrome

The term "metabolic syndrome" refers to a cluster of metabolic derangements that cause affected subjects to have an increased risk for the development of diabetes and cardiovascular diseases associated with insulin resistance, which has numerous names including the Deadly Quartet, Syndrome X, Dysmetabolic Syndrome and Insulin Resistance Syndrome. During the past decade, there have been various attempts to standardize the definition of the metabolic syndrome as a diagnostic category, with various criteria proposed by the following institutions: the World Health Organization (WHO, 1998), the European Group for Study of Insulin Resistance (EGIR, 1999), the National Cholesterol Education Program's Adult Treatment Panel Ⅲ (ATP Ⅲ, 2001), the American Association of Clinical Endocrinologists (AACE, 2003), the Chinese Diabetes Society (CDS, 2004) and the International Diabetes Federation proposal (IDF, 2005).^[4-8] All of them agree on the core components of the syndrome: obesity, insulin resistance, dyslipidaemia and hypertension; however, they provide different clinical criteria.

Clearly, the development of these definitions over the years has led to considerable confusion. Each definition uses differing sets of criteria, which reflect contrasting views on the pathogenic mechanisms and the need for clinical usefulness. The use of these definitions to conduct research into the metabolic syndrome in diverse populations has resulted in wide-ranging prevalence rates, inconsistencies and confusion, and spurred on a vigorous debate regarding how metabolic syndrome should be defined.^[3]

Critics of the WHO definition identify several limitations, of which the most important is related to the use of the euglycaemic clamp to measure insulin sensitivity, making the definition virtually impossible to use in either clinical practice or epidemiological studies. Similarly, the EGIR definition retains insulin resistance as an essential component, but this restricts the use of the definition to those in whom insulin resistance can be easily and reliably measured. However, it is not always possible to estimate fasting serum insulin level and microalbuminuria in a resource-constrained population. There is a lack of standardization, and the assays for insulin and microalbuminuria are not readily accessible in Asia.^[3]

Designed to have clinical utility, the ATP Ⅲ definition does not include a specific measure of insulin sensitivity, and adopts a less 'glucose-centric' approach by treating all components with equal importance. However, the cut-off point for waist circumference (as a measure of central obesity) is higher than EGIR, there is no consideration of ethnic group differences, and, importantly, patients receiving treatment for metabolic syndrome components are not explicitly considered to meet the respective criteria. In addition, unlike the WHO definition, the ATP Ⅲ  definition does not incorporate inflammatory and hemostatic variables as part of an extended definition. Although the ATP Ⅲ definition was modified by AACE, the AACE definition is not clearly described and is just a guideline for physicians to identify subjects with increased risk for type 2 diabetes and cardiovascular disease (CVD). Moreover, the omission of central obesity as an identifying component in the AACE definition has evoked much criticism, because there is a strong association between waist circumference, CVD and other components of metabolic syndrome.^[3]

Although the new IDF proposal has now established a worldwide consensus definition of metabolic syndrome, it might increase the prevalence in Europeans and decrease the prevalence in Asians,^[9] and decrease the risk of vascular events and type 2 diabetes more than the ATP Ⅲ definition.^{[10, 11]} In addition, agreement between the ATP Ⅲ and IDF definitions may be lower for men than for women in all populations and might be relatively poorer in men from Mexico City.^[12] There are two important differences between the ATP Ⅲ and IDF definitions that may explain the phenomenon. First, the lowering of the cut-off values for waist circumference and fasting glucose leads to the inclusion of patients with relatively lower levels of these risk factors in the IDF category of metabolic syndrome. Second, the mandatory status of the waist circumference criterion in the new definition results in a relatively lower prevalence of other (potentially stronger) metabolic syndrome risk factors in patients with the syndrome. Indeed, 8% of the population have multiple risk factors despite a waist circumference less than 94 cm. However, the predictive ability of the IDF and ATP Ⅲ definitions for mortality might be similar.^[13]

In light of the controversy over the various limitations in the current definitions of the metabolic syndrome, we recommend applying modified ATP Ⅲ criteria for Asians. That is, the ATP Ⅲ definition is revised by lowering the threshold for blood glucose to correspond to the impaired fasting glucose cut-off of the American Diabetes Association,^[7] and the Asian-Pacific criteria are adopted for obesity and central obesity.^[14] Therefore, according to the definition recommended by the Asia Pacific Working Party on NAFLD 2006,^[15] for a person to be defined as having metabolic syndrome they must have any three or more of the following:

[1] Central obesity: waist circumference >90 cm (M), >80 cm (F), and/or body mass index (BMI) >25 kg/m² in both sexes.

[2] Hypertriglyceridaemia: triglycerides ≥1.7 mmol/L.

[3] Low HDL-C: high-density-lipoprtein cholesterol (HDL-C) <1.03 mmol/L (M) and <1.29 mmol/L (F).

[4] Elevated blood pressure: blood pressure ≥130/85 mmHg. 

[5] Elevated fasting glucose: fasting plasma glucose (FPG) ≥5.6 mmol/L or previously diagnosed type 2 diabetes.

In addition, patients receiving treatment for metabolic syndrome components are considered to meet the respective criteria. If FPG is above 5.6 mmol/L, the oral glucose tolerance test is strongly recommended but is not necessary to define the presence of the syndrome.

The primary aim of the Asia-Pacific Working Party on NAFLD is to develop a new operational definition which will be clinically useful, facilitate comparative research into the syndrome across countries and populations in the Asia-Pacific region, and highlight areas where more research is needed. This revised definition might help to identify those at increased risk, particularly those who may not have been previously identified. Still, the newly proposed definition of the metabolic syndrome for Asians needs larger-scale epidemiological studies for confirmation, and further research may stimulate modifications.

Prevalence of metabolic syndrome in Asians

What is needed is a definition that is useful for clinicians to identify which persons are at risk of diabetes and CVD, and facilitates epidemiological and clinical research into the metabolic syndrome. Whether any current definition of the metabolic syndrome components can outperform the others as a marker for increased risk of CVD and diabetes is unresolved. This question is at the focus of current controversies, but requires prospective data.

Although BMI and waist circumference can predict some metabolic disorders, only 2%-3% of Asians are classified as obese by current Western criteria (BMI of more than 30 kg/m²). It is recognized that obesity-related metabolic disorders commence at much lower levels of BMI in Asians. Studies on body fat have shown that Asians have a higher percentage adiposity at a lower BMI than Caucasians. Data from Singapore demonstrated that for any given percentage of body fat, the BMI of Singaporeans is 3 kg/m² lower than that in Caucasians. Studies of Hong Kong Chinese and Asian Indians showed that the odds ratio of clustering risk factors started to increase at a BMI of about 23 kg/m². Therefore, the recommended BMI cut-off values of overweight and obesity for Asians vary from 23 to 25 kg/m² and more than 25 kg/m², respectively, according to the new BMI criteria for Asians by the regional office for the Western Pacific Region of WHO.^[14] The use of these new criteria presents a very different picture of the prevalence of obesity in Asia: mainland China (12% in men, 14% in women); Japan (24%, 20%); Malaysia (24%, 18%); Philippines (13%, 15%); Taiwan, China (18%, 16%); and Thailand (17%, 20%).^[14] But these numbers will only worsen with the increasing adoption of a Western lifestyle. Indeed, in China the number of obese subjects has doubled in 10 years. In 2004 the first comprehensive national survey on diet, nutrition and disease found that an estimated 200 million of the Chinese population of around 1.3 billion are overweight/obese. Twenty million have diabetes and 160 million have hypertension.^[16]

Although central obesity is an important determinant of the metabolic syndrome, the optimal waist circumference threshold value for predicting mortality within the context of the syndrome needs to be determined in the Asia-Pacific region. The prevalence of the syndrome vary markedly owing to the differences in definitions used and populations studied. The ATP Ⅲ criteria, applied to an Asian population, underestimate the population at risk.^[17] With a lower waist circumference cut-off (90 cm for men and 80 cm for women), the prevalence rates of metabolic syndrome in adult Singaporeans, Chinese, Indians, and Koreans, are comparable to those in Western populations according to the ATP Ⅲ criteria.^[18-23] Therefore, the cut-off points for central obesity based on waist circumference recommended by the IDF definition are applicable to individual ethnic groups, although ethnic differences are likely to exist between populations across Asia.^[8] Among 4723 subjects aged 18-69 years in Singapore, the decreased waist circumference (>90 cm in men and 80 cm in women) increases the crude prevalence of metabolic syndrome from 12.2% to 17.9%. It is more common in men (prevalence 20.9% in men versus 15.5% in women) and Asian Indians (prevalence 28.8% in Asian Indians, 24.2% in Malays, and 14.8% in Chinese).^[18] In a Asian Indians study showed that the highest prevalence (29.9%) of the metabolic syndrome was observed by the inclusion of modified cut-offs of waist circumference (>90 cm in men and 80 cm in women), BMI (≥23 kg/m²) and subscapular skinfold thickness (>18 mm) in place of the existing cut-offs of waist circumference in the ATP  Ⅲ  criteria (prevalence 9.2%).^[19] The age- and sex-adjusted prevalence of metabolic syndrome in Shanghai adults by the ATP  Ⅲ definition with modified waist circumference (>90 cm in men and 80 cm in women), was significantly higher than that by the ATP Ⅲ  definition (15.3% versus 9.2%).^[20] Similarly, the rates of metabolic syndrome in an urban Korean population (206 men and 449 women, aged 30-80 years) were 16.0% in men and 10.7% in women according to the ATP Ⅲ definition; when waist circumference was reduced to 90 cm in men and 80 cm in women, the prevalence increased to 29.0% and 16.8%, respectively.^[21] Recently, the age-adjusted prevalence of metabolic syndrome among 8465 Korean adults, according to the criteria of the IDF (waist circumference ≥90 cm for men and ≥85 cm for women), was reported to be 13.5% in men and 15.0% in women. The age-adjusted prevalence of central obesity was 19.4% in men and 22.5% in women.^[22] However, the cut-offs of the components of metabolic syndrome from these studies were not evaluated by measuring the insulin resistance directly. The relationships between insulin resistance (using the insulin suppression test) and components of metabolic syndrome in Taiwan Chinese showed that the mean values of FPG and HDL-C in the insulin-resistant group were consistent with the cut-offs of WHO-defined criteria for metabolic syndrome, but the mean values of blood pressure (125/80 mmHg) and triglycerides (>1.6 mmol/L for males and 1.4 mmol/L for females) were lower than all available criteria of metabolic syndrome, and the threshold of obesity happened to be BMI ≥27 kg/m² or waist circumference >90 cm for men and >80 cm for women.^[24]

Fatty liver and insulin resistance

Insulin resistance can be classified as peripheral insulin resistance and/or hepatic insulin resistance. The former primarily refers to diminished insulin-mediated uptake of glucose in skeletal muscle and adipocytes, while the latter refers to the inability of insulin to decrease hepatic glucose production. It is recognized that insulin resistance is important in the pathophysiology of NAFLD, and fatty liver itself is an insulin-resistant state, not only in subjects with additional metabolic disorders, but also in lean subjects with normal glucose tolerance.^[25-28] Hepatic fat accumulation can lead specifically to hepatic insulin resistance through a block in the insulin signaling cascade at the level of insulin receptor substrate-2-associated phosphatidylinositol-3 kinase activity. Although the initial site and cause of insulin resistance is unknown, a large number of studies indicate that fatty liver is the hepatic component of metabolic syndrome. NAFLD mostly seen in patients with obesity (60%-95%), type 2 diabetes mellitus (28%-55%) and hyperlipidemia (27%-92%).^[25-28] The risk of hepatic steatosis increases exponentially with addition of the components of metabolic syndrome, and the presence of the syndrome is associated with non-alcoholic steatohepatitis (NASH) and advanced fibrosis in NAFLD patients after correction for sex, age and BMI.^[25] Thus, in the appropriate setting, a primary diagnosis of NAFLD can be made easily, and NAFLD patients with metabolic syndrome are more likely to have NASH rather than pure fatty liver. On the other hand, in persons with liver disease from other causes, the presence of insulin resistance may adversely influence the progression of liver injury.

NAFLD affects 17%-33% of the general population in Western countries. It is not associated with suspected liver disease, but with many features of metabolic syndrome. The prevalence increases to 57.5% to 74% in obese persons.^{[12, 29-31]} In the general population of China and Japan, the incidence of NAFLD is as lower as 15% and 14% respectively.^{[1, 30, 31]} Racial and ethnic distributions of NAFLD patients might reflect differences in genetic susceptibility to visceral adiposity, including hepatic involvement.^[32] A large longitudinal study from BaoSteel Group Inc. (Shanghai, China) revealed that the prevalence of ultrasonographic fatty liver increased rapidly over the past decade, concurrent with the pandemic of obesity and metabolic disorders.^[33] NAFLD is now recognized as one of the most prevalent manifestations of obesity-related metabolic syndrome. A population-based survey from Shanghai showed that among the 661 patients with fatty liver, 611 (92.43%) had NAFLD. It is clear that fatty liver is more strongly associated with obesity than heavy alcohol use. The risk for fatty liver is 3.6-fold higher in heavy drinkers, 11.6-fold higher in obese persons, and 17.1-fold higher in obese drinkers, compared with the controls. Indeed, obesity increases the risk for fatty liver by 4.8-fold (95% confidence interval [CI], 1.4-16.6), in heavy drinkers, although heavy drinking does not significantly increase the risk for fatty liver in obese subjects (odds ratio, 1.50, 95% CI, 0.9-2.6).^[30] These findings are consistent with those of Bellentani et al.^[34] Therefore, NAFLD should be regarded as a global problem, with Asian countries likely to harbor a significant reservoir of the disease.

In those patients with abnormal liver biochemistry or imaging suggestive of fatty liver disease, certain clues in medical record and physical examination should be suspected of NAFLD, for example, weight gain, expanding waistline, change of lifestyle, features of metabolic syndrome or its complications, and family history of diabetes or NAFLD. The clinical and metabolic profile of NAFLD in Asia is broadly similar to that in Western countries, although the cut-off BMI for obesity and waist circumference for central obesity is lower than that in Western populations. In addition to hepatic histology (the presence or absence of NASH), a number of risk factors have been identified as predictors for the development of progressive fibrosis and cirrhosis: obesity, diabetes, age, arterial hypertension, AST∶ALT ratio, triglycerides, high insulin resistance index, elevated ALT, extent of steatosis and the grade of hepatic inflammation. Among these facors, the presence of either obesity and/or diabetes is the most robust predictor for advanced fibrosis in NASH. In Asia severe hepatic fibrosis and also cirrhosis have been observed in patients with NAFLD, but natural history studies are not available. The existence of established metabolic disorders has been found in the diagnosis of NAFLD, and NAFLD does not always appear in patients with obese and metabolic disorders at the initial diagnosis.^[28] Therefore, the sequence of development of metabolic syndrome and liver steatosis and the metabolic significance of NAFLD in nonobese, nondiabetic adults worth studing. A recent study has shown that a significant proportion of patients with NAFLD have metabolic problems.^[35]

NAFLD is found to be closely related to increased new metabolic disorders, even in previously nonobese subjects.^[36] A cross-sectional survey showed that there is a high prevalence of metabolic syndrome and fatty liver in Shanghai adults and that fatty liver appears to be a good predictor for the clustering of risk factors. Compared with obesity and central obesity, NAFLD has the highest clustering rate, specificity, positive predictive value and attributable risk percentage in detecting risk factors clustering in both sexes.^[20] Which are consistent with the results reported by Kim et al. Hence, NAFLD is closely associated with metabolic disorders, even in nonobese and nondiabetic subjects, and NAFLD can be considered an early predictor for metabolic disorders, particularly in the normal-weight population.^[37] In addition, the development of CVD in persons with NAFLD is potentially important, given that 10 to 20 times as many persons die from CVD as liver disease.^{[1, 2, 38]} Therefore, NAFLD patients could be at an increased risk of CVD besides the well-known liver-related morbidity and mortality. Regular screening for metabolic disorders and related complications in patients with NAFLD is therefore important, and assessment of central adiposity and carotid atherosclerosis are critical even in so-called 'lean' patients.^{[35, 39-43]}

In conclusion, the worldwide epidemic of obesity has taken center stage as a clinical, scientific, and public health issue within the past decade, even in the once lean giant of China.^{[16, 44]} Obesity contributes to the development of more than 50 distinct medical disorders, and NAFLD is now recognized as one of the most prevalent manifestations of the obesity-related metabolic syndrome. The epidemiological transition being witnessed in the Asia-Pacific region offers a unique opportunity to study the evolution of a previously described 'First World' disease. Thus, future studies should continue to focus both on the similarities and highlight the differences in the regional presentation of NAFLD. A perspective of NAFLD beyond its hepatic consequences is also needed. Because the importance of metabolic syndrome is primarily due to a high risk of CVD among those with the syndrome, NAFLD should only be considered a constituent of the syndrome if it increases risk of CVD, for which there is limited evidence.^[44-49] Further studies are needed to evaluate the impact of NAFLD on the well established obesity- and diabetes-related risks of CVD and malignancy.^{[44, 50]} Public health initiatives are imperative to halt or reverse the 'diabesity' epidemic, the underlying basis of NAFLD.

Funding: None.

Ethical approval: Not needed.

Contributors: FJG wrote the main body of the article. PYD provided advice on endocrinological aspects. FJG is the guarantor.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received August 17, 2007

Accepted after revision October 30, 2007