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Keywords:

  • alcoholic liver disease;
  • diabetes mellitus;
  • fatty liver;
  • metabolic syndrome;
  • obesity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References
Thumbnail image of graphical abstract

The prevalence of patients presenting with fatty liver disease (FLD) in China has approximately doubled over the past two decades. At present, FLD, which is typically diagnosed by imaging, is highly prevalent (∼27% urban population) in China and is mainly related to obesity and metabolic syndrome (MetS). However, the percentage of alcoholic liver disease (ALD) among patients with chronic liver diseases in clinic is increasing as well, and a synergetic effect exists between heavy alcohol drinking and obesity in ALD. Prevalence figures reveal regional variations, with a median prevalence of ALD and nonalcoholic FLD (NAFLD) of 4.5% and 15.0%, respectively. The prevalence of NAFLD in children is 2.1%, although the prevalence increases to 68.2% among obese children. With the increasing pandemic of obesity and MetS in the general population, China is likely to harbor an increasing reservoir of patients with FLD. The risk factors for FLD resemble to those of Caucasian counterparts, but the ethnic-specific definitions of obesity and MetS are more useful in assessment of Chinese people. Therefore, FLD/NAFLD has become a most common chronic liver disease in China. Public health interventions are needed to halt the worldwide trend of obesity and alcohol abuse to ameliorate liver injury and to improve metabolic health.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References

Although viral hepatitis, especially chronic hepatitis B (CHB), remains a major cause of liver-related morbidity and mortality in China, the prevalence of CHB infection in mainland China has decreased from 10% to 7% between 1992 and 2006.[1] On the other hand, fatty liver disease (FLD) is emerging as a leading cause of chronic liver disease in China as a result of the aging population, the improved control of viral hepatitis, and the obesity and alcoholism epidemics.[2-4] FLD refers to a wide clinical and histological spectrum from simple hepatic steatosis to steatohepatitis to cirrhosis, and FLD has been classified as nonalcoholic FLD (NAFLD) and alcoholic liver disease (ALD) according to etiology.[5, 6] In addition, steatosis can occur in other chronic liver diseases with deleterious effects on the treatment and prognosis.[2, 3, 5] Beyond damage to the liver, steatosis can also worsen and/or induce insulin resistance, and is correlated with the incident of the metabolic syndrome (MetS), type 2 diabetes (T2D), and atherosclerosis.[2, 3, 5] Therefore, the Chinese Fatty Liver and ALD Study Group established in 2001 have issued a series of consensus guidelines for the diagnosis and management of NAFLD and ALD (Table 1).[7-12] Increased epidemiological studies have revealed that FLD is highly prevalent and more often linked to obesity than to alcoholism in China.[3, 13]

Table 1. Threshold of alcohol consumption for the criteria of alcoholic and nonalcoholic fatty liver disease in China
 AlcoholicNonalcoholic
Past[7, 8]Excessive alcohol consumption ≥ 40 g/day, usually > 5 years, and/or ongoing daily alcohol consumption > 80 g in 5 daysNo history of alcohol consumption or alcohol intake less than 40 g on average per week
Current[9-12]Excessive alcohol consumption ≥ 40 g/day in men (≥ 20 g/day in women), usually > 5 years, and/or ongoing daily alcohol consumption > 80 g in 2 weeksNo history of alcohol consumption or alcohol intake less than 140 g in men (70 g in women) on average per week in the past 12 months

Prevalence of FLD in China

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References

Imaging surveys for FLD, typically based on ultrasound, have been underway in China since the 1990s.[3, 13] The reported point prevalence of FLD varies widely (1% to more than 50%) mainly based on the information available in a given population (age, gender, occupation, geographic locality), the diagnostic criteria used, and the time of the study.[3, 13, 14] Of particular interest, the prevalence of FLD in China has approximately doubled over the past decades, increasing from 3.9% to 14.0% in Shanghai BaoSteel Group employees between 1995 and 2002, and from 12.5% to 24.5% in Wuhan city administrative staff (Central China) between 1995 and 2004.[15, 16] The prevalence of FLD in participants with elevated serum alanine aminotransferase (ALT) levels (> 40 U/L) increased as well (Fig. 1).[15] Elevated ALT, which is fairly common in the general population, is typically due to NAFLD and MetS.[17] Although CHB remains the most common reason for referral to a liver clinic, the ratio of FLD to outpatients with chronic liver diseases has gradually increased over the past decade.[18] The main etiology of outpatients with FLD in Shanghai was NAFLD (78.1% cases), followed by ALD (7.2%) and chronic hepatitis C (CHC), and/or CHB infection-related steatosis (6.4%).[19] There is strong evidence that the substantially increased prevalence of FLD in China parallels regional trends in age, overnutrition, obesity, T2D, and dyslipidemia. Conversely, the prevalence of habitual alcohol use did not consistently increase over the study period in the study regions (Fig. 1).[3, 14]

figure

Figure 1. The incidence of fatty liver disease increased with metabolic disorders in Shanghai. Habitual drinking, alcohol consumption equal to or over twice per mouth over 2 years. Data from Fan et al.[15] (image) Fatty liver; (image) habitual drinking; (image)prevalence of fatty liver in patients with elevation of alanine aminotransferase (FL/abnormal ALT); (image) obesity; (image) diabetes; (image) hypertension; (image) hypertriglyceridemia (Hyper-TG); (image) increased serum level of total cholesterol (Hyper-TC).

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Recent population-based epidemiological studies indicate that the median prevalence of FLD in China is 17% (12.5∼27.3%), and approximately 90% of FLD cases appeared to be nonalcoholic (Table 2).[20-24] FLD is more strongly associated with obesity than with excessive alcohol drinking in these surveys.[20-24] Although steatosis is common in patients with CHC, the prevalence of hepatitis C virus (HCV) infection in the Chinese urban population is low and has remained stable over the past decade.[3, 13] Unlike CHC, steatosis is less common in CHB; steatosis is not directly related to the viral infection and can be caused by the same metabolic factors that cause NAFLD.[25, 26] The present upward trends in the obesity and T2D pandemic in China led us to forecast a further increase in the prevalence of NAFLD in the near future.

Table 2. Population-based epidemiologic studies of fatty liver disease in China
Reference, yearRegionnDiagnosis criteriaPrevalence of FLD (%)Prevalence of AFLD (%)Prevalence of suspected AFLD (%)Prevalence of NAFLD (%)Risk factors for FLD
  1. AFLD, alcoholic fatty liver disease; ALT, alanine aminotransferase; BMI, body mass index; FLD, fatty liver disease; FPG, fasting plasma glucose; HBV, hepatitis B virus; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome; MRS magnetic resonance spectroscopy; NAFLD, nonalcoholic fatty liver disease; T2D, type 2 diabetes; —, not available.

Fan et al., 2005[20]Shanghai, East China3175Ultrasound17.3 (males 19.3, females 15.1)0.791.1515.3Male, low education, waist circumference, BMI, HDL-C, triglyceride, FPG, diabetes, hypertension
Zhou et al., 2007[21]Guangzhou, South China3543Ultrasound17.2 (males 18.0, females 16.7)0.41.815.0Male, urban residency, low education, hypertension, BMI, waist circumference, serum triglyceride and glucose levels
Li et al., 2009[22]Chengdu, Southwest China9094Ultrasound12.5 (18.9 in men, 5.7 in women)2.63.66.3Male, age, BMI, FPG, hypertension, triglyceride, total cholesterol, HDL-C, LDL-C, ALT
Shi et al., 2011[23]Jilin, Northeast China6043Ultrasound19.243.7415.5Obesity, hypertension, dyslipidemia, T2D, central obesity, MetS
Wong et al., 2011[24]Hong Kong, South China1013Proton-MRS27.340.3927.0MetS, HBV infection (protective factor)

Prevalence of ALD in China

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References

ALD has long been one of the most prevalent and devastating conditions caused by excessive alcohol drinking and is one of the leading causes of alcohol-related death in developed countries.[6] The national production and consumption of alcoholic beverages in China have significantly increased in recent years.[12] Unfortunately, data on nationwide large-scale epidemiological ALD surveys are unavailable in China. The point prevalence of habitual alcohol drinking and ALD in some Chinese studies ranges from 14.8% to 56.3% and from 2.3% to 6.1% (median prevalence was 4.5% in Chinese people), respectively (Table 3).[27-30] Both prevalence rates in men were significantly higher than the respective rates in women in these surveys, and the prevalence of ALD in Chinese Han people was lower than that in other ethnic people in Yuanjiang, Yunnan Province.[27-30] The prevalence of different stages of ALD was also reported in some surveys; the incidence of alcoholic steatosis, alcoholic hepatitis, and alcoholic cirrhosis was found to be at least 50%, 10%, and 10% among heavy alcohol drinkers with ≥ 5-year drinking history, respectively.[27, 29]

Table 3. Population-based epidemiological studies of alcoholic liver disease in China
Reference, yearRegionnAge (years)Habitual drinking (%)MALD (%)AFL (%)AH (%)Alcoholic cirrhosis (%)Overall of ALD (%)
  1. a

    Risk drinking, habitual alcohol consumption over 40 g/day for more than 5 years.

  2. b

    Sex- and age-adjusted prevalence.

  3. AFL, alcoholic fatty liver; AH, alcoholic hepatitis; ALD, alcoholic liver disease; MALD, mild ALD; —, not available.

Li et al., 2003[27]Zhejiang, East China18 237 (male 12 042)38.3 ± 12.314.8a0.63b0.51b0.76b0.40b2.31b (male 3.26b, female 0.30b)
Lu et al., 2003[28]Xi'an, Northwest China3613 (male 2191)36.0 ± 13.035.2 (male 52.2, female 8.9)78 (2.16)4 (0.11)2.27 (only one was female)
Chen et al., 2010[29]Liaoning, Northeast China6598 (male 4101)39.3 ± 11.127.0% (male 38.3, female 5.6)3.86b1.9b0.32b6.10b (male 9.7, female 2.0)
Yao et al., 2011[30]Yuanjiang, Yunnan, Southeast China1690 (male 1140)47.9 ± 16.156.3% (male 82.6, female 1.8)4.97 (4.48 in Chinese people)

From a multicenter study of ALD in China, the incidence of ALD among hospitalized patients with liver diseases each year from 2000 to 2004 were 2.7%, 2.9%, 3.0%, 3.6%, and 4.4%, respectively. Among 902 patients with ALD, 11.2% exhibited mild ALD, 22.6% exhibited a fatty liver, 28.8% suffered from hepatitis, and 37.4% were classified as having cirrhosis. The severity of liver damage correlates with the amount and duration of alcohol use.[31] There has been a gradual increase in the number of patients with end-stage ALD undergoing liver transplantation in mainland China in the past 10 years.[32] Therefore, alcohol-induced liver injury has become an important issue in China, which cannot be neglected.

Prevalence of NAFLD in China

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References

The prevalence of NAFLD among adults in the general population in China is approximately 15% (6.3–27.0%), depending on the population studied, and has paralleled the increase in both obesity and T2D observed in these regions (Table 2).[20-24] NAFLD is found in over a quarter of the general adult Chinese population in Hong Kong, but the proportion of patients with advanced fibrosis in NAFLD patients is low (3.7%).[24] Based on liver ultrasound, the prevalence of NAFLD is 2.1% among the 1180 surveyed schoolchildren age 6–14 years. The prevalence of NAFLD was higher in overweight and obese students than in students with a normal body mass index (BMI). Male students were more likely to have NAFLD than female students.[33] In addition, compared with the nonobese controls, mixed obesity had the strongest association with NAFLD and dyslipidemia, followed by abdominal obesity and peripheral obesity in Chinese school-aged children.[34] The prevalence of NAFLD among 861 obese children (6–16 years old) was 68.2%, and the prevalence increased to 84.6% (187/222) in obese patients with MetS.[35]

In contrast with the vast epidemiological data on the prevalence of NAFLD, there is minimal data available on the incidence of this disease in China. Fan et al. studied the incidence of ultrasound-defined NAFLD in 5402 nonalcoholic healthy subjects (4633 men, mean age 37 years) after a 2-year follow-up and observed 327 subjects (6.1%) with new cases of NAFLD.[36] The incidence of NAFLD increased significantly with the changes in BMI at baseline: 1.4% in subjects with normal weight, 6.4% in overweight patients, 16.8% in obese patients, and 24.5% in patients with severe obesity. Logistic regression analysis revealed a significant interaction between the incidence of NAFLD and age, BMI and serum triglycerides at baseline, and the subtle gain in BMI and triglycerides during follow-up. The other study by Zhou et al. revealed that the annual incidence of NAFLD is 9.1%, and the MetS components represent risk factors for the development and progression of NAFLD.[37] With the Westernization of lifestyles and the rising prevalence of obesity and T2D, NAFLD represents an emerging health problem in China. In addition, NAFLD combined with ALT levels may be used to stratify individuals at different risk levels for metabolic disorders.[38] However, there is an inadequate knowledge of NAFLD among the general population in Hong Kong.[39]

Although NAFLD appears to be the most common cause of elevated ALT and liver injury in healthy Chinese adults, it currently comprises a low proportion of cases of chronic liver disease in both inpatient and outpatient series from tertiary referral hospitals in China.[13, 15, 17, 18] Among cases of chronic hepatitis of unknown etiology, the prevalence of biopsy-verified nonalcoholic steatohepatitis (NASH) is found to be 16% (15/97); in patients with morbid obesity, the prevalence is 34% (54/160).[40] In 110 biopsy-verified NAFLD patients, simple fatty liver, NASH, and cirrhosis were diagnosed in 45 (40.9%), 63 (57.3%), and 2 (1.8%) cases, respectively. Both elevated serum levels of ALT and MetS are independent predictors of steatohepatitis with fibrosis in these patients.[41] However, Wong et al. found that metabolic factors, but not ALT, are associated with the histological severity of NAFLD.[42] Patients with normal ALT levels may still have NASH and significant fibrosis. But, the proportion of NAFLD patients with advanced fibrosis is low.[24] Modest alcohol consumption does not increase the risk of fatty liver or liver fibrosis.[24]

The natural history of NAFLD globally is currently difficult to assess, but there is mounting evidence that some patients may eventually develop cirrhosis and hepatocellular carcinoma (HCC).[3, 5, 43] At present, the full range of histological manifestations of NAFLD has been demonstrated in Chinese patients.[3, 5, 43] As an indolent form of chronic liver disease, NAFLD may be even less important than primary biliary cirrhosis in China, and it should be noted that NAFLD patients are not expected to develop complications of cirrhosis until late in life.[3, 5, 43] To date, prospective studies in Chinese patients are too short in duration to exclude the late liver complications of NAFLD. On the other hand, although serum ALT levels often decrease over time in NAFLD patients at 6-year follow-up, a significant proportion develop dyslipidemia, T2D, and hypertension soon after the diagnosis of NAFLD, even in once nonobese individuals.[44] Recently, NAFLD was found to be independently associated with coronary artery disease, colorectal neoplasm, osteoporotic fracture, and impairment of kidney function in Chinese subjects.[45-49] Thus, the importance of NAFLD may not be limited to liver disease but may apply to its role as a predictor or even an early mediator of MetS and its related complications.

Risk factors for FLD in China

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References

A detailed analysis of the available epidemiological data shows that risk factors for FLD in China resemble those in the West and in other regions of Asia.[3, 50] The major risk factors include central obesity, obesity, dyslipidemia, prediabetes, T2D, arterial hypertension, insulin resistance, and MetS. Even the use of the ethnic-specific obesity and central obesity criteria reveals a relatively high proportion of Chinese FLD patients with normal BMIs and waist circumferences. On one hand, MetS is a strong predictor of FLD, especially NAFLD and NASH. On the other hand, NAFLD is a good predictor for the clustering of components of MetS.[51] In addition, a number of other risk factors for FLD have been identified in Chinese studies. These risk factors include advancing age, male gender, lower education, physical inactivity, daytime somnolence, high-fat intake, overeating, recent slight weight gain, expanding waist circumference, and family history of MetS components and cardiovascular disease.[3, 13, 50] Conditions with an emerging association with NAFLD in Chinese patients include low docosahexaenoic acid content in plasma phospholipids, high plasma reactive carbonyl species levels, increased serum uric acid levels, elevated hematocrit, polycystic ovary syndrome, and overt thyroid dysfunction.[52-57] In addition, chronic hepatitis B virus (HBV) infection in Chinese patients is a protective factor for hepatic steatosis and MetS. Steatosis in patients with CHB is mainly related to host metabolic disorders, but viral impacts are also observed.

Heavy alcohol drinking or at-risk drinking, defined as ≥ 280 g/week in men and 140 g/week in women, is a risk factor for ALD in Chinese patients.[58, 59] The risk factors for ALD that have been identified in Chinese studies include cumulative alcohol consumption, years of drinking, the type of alcoholic beverages consumed, the pattern of drinking, female gender, nutritional status, obesity, concomitant viral hepatitis, exposure to drugs or toxins, ethnicity, genetic factors, and more.[12, 13, 27, 30, 58, 59] Alcohol-related hepatotoxicity is dose-dependent; the threshold dose is 20 g of alcohol per day for more than 5 years.[58, 59] The risk for ALD increases gradually with increased daily alcohol intake and drinking duration. However, several cross-sectional studies in China suggest that light alcohol consumption appears to protect against MetS and fatty liver, and modest alcohol consumption does not increase the risk of liver fibrosis in NAFLD patients.[3, 13, 24, 58, 60] Moreover, diets rich in polyunsaturated fatty acids, being overweight, and obesity can facilitate the development and progression of ALD.[13, 27-29] The risk confer by alcohol consumption and obesity in inducing liver injury is far greater than the risk of a single factor inducing liver injury (Table 4).[20-22, 61] However, the effects of malnutrition on the presence and severity of FLD, including ALD, have not been investigated in China.

Table 4. Interaction of obesity and alcoholism in fatty liver disease[20]
GroupFLD (%)OR (95% CI)
ControlObesitySignificant alcohol consumption
  1. CI, confidence interval; FLD, fatty liver disease; OR, odds-ratio.

Control35/1049 (3.3)
Significant alcohol consumption without obesity3/25 (8)3.6 (1.1–11.7)
Obesity without significant alcohol consumption484/1252 (38.7)11.6 (8.2–16.5)3.2 (1.1–10.1)
Significant alcohol consumption with obesity20/35 (57.1)17.1 (9.1–32.4)4.8 (1.4–16.6)1.5 (0.9–2.6)

Genetic polymorphisms of FLD in China

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References

Data are increasingly available in China to support the role of genetic factors in the development of NAFLD and ALD. Recently, the association of genetic polymorphisms and the susceptibility to FLD has been confirmed by candidate gene approaches and genome-wide association studies. Single nucleotide polymorphisms within patatin-like phospholipase domain-containing 3 protein; apolipoprotein 3, tumor necrosis factor alpha, apoptosis-inducing ligand; leptin; adiponectin; peroxisome proliferator activated receptors; angiotensin receptors; farnesyl diphosphate farnesyltransferase; liver fatty acid-binding protein; and glucokinase regulatory protein have been reported to contribute to insulin resistance, hepatic steatosis, inflammation, and fibrosis in the Chinese population.[62-70] In addition, genetic polymorphisms of alcohol dehydrogenase, acetaldehyde dehydrogenase, cytochrome P 450 II E1, glutathione S-transferase P1, and interleukin-1 receptor antagonist have also been identified for their associations with alcohol abuse and the development of ALD in Chinese patients.[71-73] However, most of these studies included a small number of patients, and the findings are inconsistent.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References

Hepatic steatosis (∼27% urban population) in China is largely related to obesity and MetS, not alcohol use. However, the percentage of ALD among inpatients with liver diseases is gradually increasing. The median prevalence of ALD and NAFLD in China is 4.5% and 15.0%, respectively. The prevalence of NAFLD in children is 2.1%, although the prevalence increases to 68.2% among obese children. Neither alcohol abuse nor chronic viral infection (HBV, HCV) accounts for the rapidly increased prevalence of FLD in China. With the increasing pandemic of obesity and MetS in Chinese patients, China is likely to harbor an increasing reservoir of patients with FLD. The risk factors for alcoholic and NAFLD resemble to those of Caucasian counterparts, and a synergetic effect exists between heavy alcohol consumption and obesity in FLD. NAFLD appears to be associated with insulin resistance and represents the hepatic manifestation of MetS. Patients with NAFLD are thus at high risk for developing metabolic complications, perhaps much higher than their risk of cirrhosis and HCC. Therefore, public health interventions are required to stop the worldwide trend of obesity and alcohol consumption to prevent FLD and improve metabolic health.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References

Funding was provided by the State Key Development Program for Basic Research of China (2012CB517501), the National Natural Science Foundation of China (81070322 & 81270491), the 100 Talents Program of the Shanghai Board of Health, and the Experimental Animal Program of the Shanghai Committee of Science and Technology (09140903500 & 10411956300).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prevalence of FLD in China
  5. Prevalence of ALD in China
  6. Prevalence of NAFLD in China
  7. Risk factors for FLD in China
  8. Genetic polymorphisms of FLD in China
  9. Conclusion
  10. Acknowledgements
  11. Conflict of interest
  12. References
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