Zhe Shen, You-Ming Li, Chao-Hui Yu, Lei Xu, Cheng-Fu Xu, Jin-Jin Chen, Hua Ye, Department of Gastroenterology, The First Affiliated Hospital, Medicine School, Zhejiang University, Hangzhou 310003, Zhejiang Province, China

Yi Shen, Department of Statistics, Medicine School, Zhejiang University, Hangzhou 310000, Zhejiang Province, China

Gen-Yun Xu, Department of Clinical Laboratory, The First Affiliated Hospital, Medicine School, Zhejiang University, Hangzhou 310003, Zhejiang Province, China

Author contributions: Shen Z, Li YM and Yu CH designed the research; Shen Z, Li YM, Yu CH, Shen Y, Xu L, Xu CF, Chen JJ and Ye H performed the research; Xu GY contributed to the new reagents; Shen Z and Shen Y analyzed the data; Shen Z, Li YM and Yu CH wrote the paper.

Correspondence to: Professor You-Ming Li, Department of Gastroenterology, The First Affiliated Hospital, Medicine School, Zhejiang University, Hangzhou 310003, Zhejiang Province, China. zlym@zju.edu.cn

Telephone: +86-571-87236603  Fax: +86-571-87236611

Received: October 25, 2007      Revised: December 3, 2007

Abstract

AIM: To investigate the association of alcohol dose, duration of drinking and obesity with abnormal alcohol-related liver injury indicators, the prevalence of alcohol-related liver injury in the island population of China.

METHODS: Randomized multistage stratified cluster sampling from the island population of China was used in the population-based case-control study. Then interview, physical examination, laboratory assessments and ultrasonography were done.

RESULTS: Daily alcohol intake ≥ 20 g, duration of drinking ≥ 5 years and obesity were closely related to alcohol-related liver injury (P < 0.05). The odds-ratio (OR) (95% CI) was 1.965 (1.122-3.442), 3.412 (1.789-6.507) and 1.887 (1.261-2.824), respectively. The prevalence rate of alcohol-related liver injury in ≥ 20 g daily alcohol intake group and < 20 g daily alcohol intake group was 37.14% and 12.06%, respectively. The prevalence rate of alcohol-related liver injury in ≥ 5 years drinking group and < 5 years drinking group was 34.44% and 8.53%, respectively. No significant dose-response relation was found between daily alcohol intake and abnormal alcohol-related liver injury indicators as well as between duration of drinking and abnormal alcohol-related liver injury indicators. There was no significant difference in the prevalence of alcohol-related liver injury between beer drinking group and yellow rice wine drinking group, hard liquor drinking group, multiple drinking group.

CONCLUSION: The risk threshold of daily alcohol intake is 20 g and duration of drinking inducing alcohol-related liver injury 5 years in the island population of China. Liver injury induced by obesity should be concerned.

© 2008 WJG. All rights reserved.

Key words: Alcohol; Liver injury; Prevalence; Case-control study; Epidemiology

Peer reviewers: James Neuberger, Professor, Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom; Giovanni Addolorato, MD, Institute of Internal Medicine, L.go Gemelli 8, Rome 00168, Italy

Shen Z, Li YM, Yu CH, Shen Y, Xu L, Xu CF, Chen JJ, Ye H, Xu GY. Risk factors for alcohol-related liver injury in the island population of China: A population-based case-control study. World J Gastroenterol 2008; 14(14): 2255-2261  Available from: URL: http://www.wjgnet.com/1007-9327/14/2255.asp  DOI: http://dx.doi.org/10.3748/wjg.14.2255

INTRODUCTION

Alcohol-induced liver disease remains one of the most common causes of chronic liver diseases^[1]. Studies on alcoholic liver disease (ALD) have drawn wide attention in the Western world^[2-5]. It was reported that ALD should be defined as an alcohol-associated lifestyle disease^[6]. The predisposition to ALD is largely governed by gene-environment interactions. In recent years, along with the improved living standard and increased alcohol consumption, several epidemiological surveys showed that it has become a serious public health problem in China^[7-10]. The island population in East China is a specific cluster of population. They feed themselves mainly on fishing, spend most of their time on sea-going ships, and consume a large amount of alcohol compared to the inland population. However, few population-based ALD studies are available from islands in China. Therefore, it is currently difficult to evaluate alcohol-related liver injury in the island population. Certainly, it is extremely important to select a sensitive and specific indicator in epidemiological survey. ALD is characterized by elevated serum gamma-glutamyltranspeptidase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT)^[11-13]. According to the Practical Guidelines for Alcoholic Liver Disease published by the American College of Gastroenterology in 1998^[14], GGT, AST and ALT were used as indicators of alcohol-related liver injury in this survey. We conducted a population-based case-control study to investigate the association of alcohol dose, duration of drinking and obesity with alcohol-related liver injury in East China.

MATERIALS AND METHODS

Study design and sample selection

We assigned a number to each of the counties is located along the coast of Zhejiang Province, and randomly selected one county (Xiangshan County). We randomly selected two islands (Hepu and Dongmen) of the 5 islands in the Xiangshan County and 9 villages of the 12 villages in the Hepu and Dongmen islands from August 2006 to September 2006. All individuals investigated in this study were at the age of over 18 years. All procedures were approved by the Ethics Committee of Zhejiang University School of Medicine. Each method and potential risks were explained in detail to the participants who gave their written informed consent before the survey.

Through a stratified multistage probability cluster sampling method, we acquired a representative sample from the island population in Zhejiang Province. We investigated 814 individuals aged 18 years or more in this survey, and obtained the complete data on 782 individuals. However, 129 individuals reporting clinical diagnosis of chronic viral hepatitis, schistosomiasis japonica (according to their epidemiological history, enzyme-linked immunosorbent assay results), cirrhosis (according to their medical history and ultrasonography results), or other severe diseases (mainly including drug-induced liver disease, cancer, pancreatitis, kidney disease, etc, based on their medical history) were excluded. Therefore, complete data were collected from 653 individuals. Their HBsAg and anti-HCV were negative. All individuals had no history of drug-induced liver disease and other severe diseases. There was no significant difference in the mean age between males and females. The mean age of males and females was 50.11 ± 13.48 years and 50.56 ± 11.72 years, respectively. There was also no significant difference in the mean BMI between males and females. The mean BMI of males and female was 24.60 ± 3.83 kg/m² and 24.54 ± 3.58 kg/m², respectively.

Interview

A face-to-face interview was conducted by trained physicians using a standardized questionnaire at the local community hospital. Data on demographic variables, alcohol drinking status, medical history and health behavior were collected from the questionnaire. Educational attainment of the followed up individuals was categorized into 5 groups according to the years of education (0, 1-6, 7-9, 10-12, ≥ 12 years). Based on smoking habit grading^[15], the followed up individuals were categorized into non-smoker group (never and cessation of smoking for more than 6 mo), smoking addict group (daily smoking for more than 6 mo), and smoking non-addict group (cessation of smoking or daily smoking for less than 6 mo). A series of questions of alcohol use included quantity of alcohol intake each time, times of alcohol intake each day, months of alcohol intake each year, years of alcohol intake, types and alcoholicity of alcoholic beverage, drinking and dietary habits. From the above data, we calculated the average daily alcohol intake (g), total alcohol intake (kg), and duration of drinking (years) by alcohol dose convert formula^[16].

Physical examination

All followed up individuals were invited to have a physical examination at the local community hospital after the face-to-face interview. The followed up individuals were required to fast overnight. Body measurements were performed by a trained medical professional using a standardized protocol. Body weight and standing height were measured in light indoor clothing without shoes. Body mass index (BMI) was then calculated as mass (kg)/height (m)². The followed up individuals were divided into non-obese (BMI < 25 kg/m²) group or obese (BMI ≥ 25 kg/m²) group as previously described^[17]. Blood pressure was measured with an electronic blood pressure monitor (Omron HEM-746C, Omron Healthcare Inc., Bannockburn, Illinois, USA) on the right arm of the followed up individuals at a comfortable sitting position after a 5-min rest. Three measurements were taken. The second and third pressure readings were averaged and used for analysis. Diagnosis of hypertension was based on The JNC 7 Report^[18] or on the current use of anti-hypertensive medications.

Laboratory assessments

Peripheral venous blood samples were collected after physical examination and centrifuged at 3000 r/min for
15 min at 4℃. After being frozen, the samples were shipped on dry ice to Department of Clinical Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University, and stored at -80℃. Blood samples were taken to check alcohol-related liver injury indicators which reflect the changes in the alcohol-related liver injury^[14,16], including ALT, AST, GGT. Also, HBsAg, anti-HCV and enzyme-linked immunosorbent assay (ELISA) for schistosomiasis japonica were detected. All serum biochemistries were measured with a Hitachi 7600-110 automatic analyzer (Hitachi co., Tokyo, Japan). Reference value ranges of all indexes were based on the biochemistry criteria of Department of Clinical Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University. According to the Practical Guidelines for Alcoholic Liver Disease published by the American College of Gastroenterology in 1998^[14], abnormal alcohol-related liver injury indicators were defined based upon AST > ALT (ALT or AST exceeding the upper normal level) or GGT exceeding the upper normal level.

Ultrasonographic examination

Hepatic ultrasonography for all individuals was performed by the same experienced ultrasonographist using a GE Logic Book XP portable ultrasound with a 3.5 MHz probe. Ultrasonographic diagnosis of cirrhosis followed the ultrasonographic criteria^[19].

Statistical analysis

We established a database using Epi Data 3.0 software (The EpiData Association, Odense, Denmark). Two typists recorded the data respectively and checked each other, corrected errors until two pieces of data were consistent. Statistical analysis was performed with SPSS 13.0 statistical package (SPSS Inc., Chicago, Illinois, USA). The mean value for different groups was compared using Student t-test. Chi-square (c²) test was used for comparing group ratios. We carried out univariate and multivariate stepwise logistic regression analyses. P < 0.05 was considered statistically significant.

RESULTS

Risk factors for abnormal alcohol-related liver injury indicators

Of the 653 individuals, 149 were diagnosed having abnormal alcohol-related liver injury indicators in this study. Univariate logistic-regression analysis showed that male gender, smoking, ≥ 20 g daily alcohol intake, ≥ 5 years drinking, ≥ 36.5 kg total alcohol intake, hypertension, obesity were closely related to abnormal alcohol-related liver injury indicators, while age, education level, unmarried state were not significantly related to abnormal alcohol-related liver injury indicators (Table 1).

Multivariate stepwise logistic-regression analysis showed that ≥ 20 g daily alcohol intake, ≥ 5 years drinking and obesity were closely related to abnormal alcohol-related liver injury indicators (Table 2). Compared to the < 20 g daily alcohol intake group, the odds-ratio (OR, 95% CI) of abnormal alcohol-related liver injury indicators in the ≥ 20 g daily alcohol intake group was 1.965 (1.122-3.442). Compared to the < 5 years drinking group, the OR (95% CI) of abnormal alcohol-related liver injury indicators in the ≥ 5 years drinking group was 3.412 (1.789-6.507).

Prevalence of alcohol-related liver injury

Based on the daily alcohol intake and BMI, 216 subjects were assigned to control group (daily alcohol intake < 20 g and BMI < 25 kg/m²), 161 to excessive drinking group (daily alcohol intake ≥ 20 g and BMI < 25 kg/m²), 157 to obese group (daily alcohol intake < 20 g and BMI ≥ 25 kg/m²), 119 to excessive drinking and obese group (daily alcohol intake ≥ 20 g and BMI ≥ 25 kg/m²). The prevalence rate of abnormal alcohol-related liver injury indicators in the four groups was 10.7%, 27.3%, 14.0% and 50.4%, respectively (Table 3). Compared to the control group, the OR (95% CI) of abnormal alcohol-related liver injury indicators in the other groups was 3.156 (1.813-5.492, P = 0.000), 1.367 (0.732-2.553, P = 0.325), 8.534 (4.864-14.972, P = 0.000), respectively (Table 4).

Based on the duration of drinking and BMI, 175 subjects were assigned to control group (duration of drinking < 5 years and BMI < 25 kg/m²), 202 subjects to long-term drinking group (duration of drinking ≥ 5 years and BMI < 25 kg/m²), 118 to obese group (duration of drinking < 5 years and BMI ≥ 25 kg/m²), 158 to long-term drinking and obese group (duration of drinking ≥ 5 years and BMI ≥ 25 kg/m²). The prevalence rate of abnormal alcohol-related liver injury indicators in the four groups was 7.4%, 26.7%, 10.2% and 44.3%, respectively (Table 3). Compared to the control group, the OR (95% CI) of abnormal alcohol-related liver injury indicators in the other groups was 4.547 (2.385-8.668, P = 0.000), 1.411 (0.620-3.209, P = 0.410), 9.913(5.194-18.918, P = 0.000), respectively (Table 4).

Dose-response relation of alcohol intake with alcohol-related liver injury

Compared to the < 20 g daily alcohol intake group, the OR of abnormal alcohol-related liver injury indicators in the other groups ( daily alcohol intake was 20-40 g, 40-80 g, 80-160 g, ≥ 160 g, respectively) was 3.573 (P = 0.000), 4.278 (P = 0.000), 4.267 (P = 0.000), 5.371 (P = 0.000), respectively (Table 5). The prevalence rate of abnormal alcohol-related liver injury indicators in the other groups was 12.1%, 32.9%, 37.0%, 36.9%, 42.4%, respectively. Compared to the < 20 g daily alcohol intake group, the prevalence rate in the other groups was 2.73, 3.07, 3.06 and 3.52, respectively. Compared to the < 5 years drinking group, the OR of abnormal alcohol-related liver injury indicators in the other groups (drinking duration was 5-10 years, 10-20 years, 20-40 years, ≥ 40 years ) was 2.382 (P = 0.131), 6.551 (P = 0.000), 6.267 (P = 0.000), 4.535 (P = 0.000), respectively (Table 5). The prevalence rate of abnormal alcohol-related liver injury indicators in the other groups was 8.5%, 18.2%, 37.9%, 36.9%, 29.7%, respectively. Compared to the < 5 years drinking group, the prevalence ratio in the other groups was 2.13, 4.45, 4.32 and 3.49, respectively.

Different types of alcoholic beverage and alcohol-related liver injury

Of the 313 drinkers, 126 were beer drinkers, 36 yellow rice wine drinkers, 41 hard liquor drinkers and 110 multiple drinkers. The prevalence rate of abnormal alcohol-related liver injury indicators in these four kinds of drinkers was 30.2%%, 38.9%, 39.0% and 40.0%, respectively. Compared to the beer drinkers, no significant difference was found in the prevalence rate of abnormal alcohol-related liver injury indicators among the other groups (Table 6).

Analysis of obesity

Obesity (BMI ≥ 25 kg/m²) was also found to be an important risk factor for liver injury (Tables 1 and 2). Multivariate stepwise logistic-regression analysis showed that the OR (95% CI) of abnormal alcohol-related liver injury indicators was 1.887 (1.261-2.824) in the BMI ≥ 25 kg/m² group compared to the BMI < 25 kg/m² group (Table 2).

DISCUSSION

Liver is the major alcohol processing organ. Chronic heavy drinking induces liver injury and results in alcoholic liver disease, even irreversible alcoholic liver cirrhosis^[20]. Since ALD has no specific clinical features^[21] and no specific laboratory tests^[14] are available for it, its diagnosis is currently based on drinking history, related laboratory assessments and imaging^[16,22,23]. Certainly, liver biopsy is the gold standard for diagnosis of ALD^[24], but it is hard to use this invasive examination in population-based epidemiological surveys. Irie et al^[11] found that GGT synthesis and protein expression are increased in ALD, leading to elevated serum levels of GGT that are commonly noted in patients with the disease. Elevated GGT is somewhat more sensitive at 69%-73% with a specificity of 65%-80% for excessive alcohol consumption^[25,26]. An elevated serum AST in relation to serum ALT has been proposed as an indicator of alcohol-induced organ damage^[27]. It was reported that most patients with high alcohol consumption but without severe liver disease do not have an AST/ALT ratio above one. A high AST/ALT ratio suggests advanced alcoholic liver disease^[13]. Therefore, we chose the GGT and AST/ALT ratio as the indicators of alcohol-related liver injury in this epidemiological survey.

In the present study, logistic-regression analysis demonstrated that daily alcohol intake ≥ 20 g, drinking time ≥ 5 years and obesity were important risks for abnormal alcohol-related liver injury indicators. The risk for abnormal alcohol-related liver injury indicators was 1.965-fold higher in the ≥ 20 g daily alcohol intake group than in the < 20 g daily alcohol intake group, while the risk for abnormal alcohol-related liver injury indicators was 3.412-fold higher in the ≥ 5 years drinking group than in the < 5 years drinking group. However, the risk thresholds of alcohol intake-induced alcoholic liver injury were different in different areas. No uniformed conclusion has been achieved in alcohol intake- induced alcoholic liver injury^[28-32]. It was reported that even low alcohol level is a significant risk of developing liver disease^[33]. Therefore, significant differences exist among different racial and ethnic groups and even in different individuals^[34,35]. It has been shown that genotype of ethanol metabolizing enzyme genes in the Chinese population is different from Western population^[36]. Therefore, genetic factors in the island population from East China need to be further studied.

As to the dose-response relation of alcohol intake and abnormal alcohol-related liver injury indicators, our results demonstrate that there was no significant dose-response relation between daily alcohol intake, drinking time and abnormal alcohol-related liver injury indicators. Kamper-Jorgensen et al^[37] showed that alcoholic threshold has a greater effect on the mortality of alcoholic cirrhosis.

Obesity is also an important risk factor for liver injury. In this study, logistic-regression analysis showed that the risk of obesity for abnormal alcohol-related liver injury indicators was 1.887. Some studies found that obesity is an independent risk factor for liver injury in alcohol drinkers^[38-40]. In our study, the prevalence rate of alcohol-related liver injury in the non-obese group, non-excessive drinking or no long-term drinking group was lower than that in the obese group, excessive drinking group or long-term drinking group. The highest prevalence rate of alcohol-related liver injury was found in the obese and excessive drinking/long-term drinking group. There was a difference in the odds-ratio of abnormal alcohol-related liver injury indicators between the non-obese and excessive drinking/long-term drinking group, the obese and excessive drinking/long-term drinking group and control group (P < 0.05), while was no difference in the odds-ratio of abnormal alcohol-related liver injury indicators between the obese and non-excessive drinking group and no long-term drinking group, suggesting that the specificity of GGT and AST/ALT ratio can be sued as the indicators of alcohol-related liver injury.

However, hepatotoxic consequences of obesity and ethanol ingestion have important prognostic implications and might be useful to formulate body mass index-based guidelines for “safe” alcohol consumption^[41].

No significant difference was found in the morbidity of abnormal alcohol-related liver injury indicators between the beer and other groups, suggesting that the types of alcoholic beverage are not closely related with abnormal alcohol-related liver injury indicators. Therefore, we believe that alcohol intake plays a more significant role in liver injury than the type of alcoholic beverage.

The island population from East China is a specific cluster of population. They feed themselves mainly on fishing and spend most of their time on sea-going ships. Although they consume a large amount of alcohol every day, their alcohol-related liver injury is not very severe. Most individuals in this area are alcohol drinkers. It was reported that treatment modalities aiming at reducing alcohol intake in alcohol-dependent patients include psychological, pharmacological and psychological therapies, but many patients benefit more from pharmacological therapy^[42]. We believe that epidemiology study of the island population from East China is more important than that of the inland population. Certainly, it is more useful to analyze the differences in island and inland populations, including drinking habit, diet habit, living and working pressure, genotype, etc. ALD is governed by gene, environmental and psychological factors. We will continue to pay close attention to the island population from East China.

ACKNOWLEDGMENTS

The authors thank Drs. Guo-Liang Ye and Hong-Tan Chen for their excellent assistance in this survey.

COMMENTS

Background

The island population from East China is a specific cluster of population. They consume a large amount of alcohol compared to the inland population. However, few population-based studies on alcoholic liver disease (ALD) are available from islands in China. We conducted a population-based case-control study to investigate the association of alcohol consumption, drinking time and obesity with liver injury in the island population from East China.

Research frontiers

The association of alcohol consumption and drinking time with alcohol-related liver injury in the island population from East China was studied.

Innovations and breakthroughs

The risk threshold of daily alcohol intake is 20 g and the drinking time that induces alcohol-related liver injury is 5 years in the island population from East China. Obesity-induced liver injury should also be concerned. Whether hepatotoxic consequences of obesity and alcohol ingestion are additive or synergistic is worthy to be further studied.

Applications

The results are useful to analyze the differences in the island and inland population, including drinking habit, diet habit, living and working pressure, genotype.

Terminology

Gamma-glutamyltranspeptidase (GGT) and aspartate aminotransferase/ alanine aminotransferase (AST/ALT) ratio are the characteristics of alcoholic liver disease (ALD). Abnormal alcohol-related liver injury indicators are defined based upon the condition that aspartate aminotransferase / alanine aminotransferase (AST>ALT) (ALT or AST exceeding the upper normal level) or GGT exceeding the upper normal level.

Peer review

The paper describes the association of alcohol consumption and drinking time with alcohol-related liver injury in the island population from East China. The topic is highly interesting. The island population should be concerned in the follow-up research in future.

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S- Editor  Ma L    L- Editor  Wang XL    E- Editor  Ma WH

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