Lin YC, Hsiao ST, Chen JD. Sonographic fatty liver and hepatitis B virus carrier status: Synergistic effect on liver damage in Taiwanese adults. World J Gastroenterol 2007; 13(12): 1805-1810 [PMID: 17465470 DOI: 10.3748/wjg.v13.i12.1805]
Corresponding Author of This Article
Dr. Jong-Dar Chen, Department of Family Medicine and Center for Environmental and Occupational Medicine, Shin Kong Wu Ho-Su Memorial Hospital, 95, Wen Chang Road, Shih Lin, Taipei 111, Taiwan, China. jdarchen@ms28.hinet.net
Article-Type of This Article
Clinical Research
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Yu-Cheng Lin, Jong-Dar Chen, Department of Family Medicine and Center for Environmental and Occupational Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, China
Shu-Tin Hsiao, Institute of Occupational Medicine Industrial Hygiene, National Taiwan University, Taipei, Taiwan, China
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed equally to the work.
Correspondence to: Dr. Jong-Dar Chen, Department of Family Medicine and Center for Environmental and Occupational Medicine, Shin Kong Wu Ho-Su Memorial Hospital, 95, Wen Chang Road, Shih Lin, Taipei 111, Taiwan, China. jdarchen@ms28.hinet.net
Received: December 8, 2006 Revised: December 13, 2006 Accepted: January 17, 2007 Published online: March 28, 2007
Abstract
AIM: To examine the epidemiology of hepatitis B virus carrier status (HBVC) and sonographic fatty liver (SFL) in Taiwanese adults, and to evaluate their possible interaction in inducing liver damage (LD). From an epidemiological viewpoint, we analyzed previous studies which indicated that fatty liver sensitizes host immune response to HBV infection and enhances liver damage.
METHODS: A cross-sectional retrospective analysis of health records including medical history, physical examination, abdominal sonogram, blood biochemistry and hepatic virological tests. We utilized the Student’s t-test, chi-square, multivariate logistic regression and synergy index to assess risks for LD.
RESULTS: Among a total of 5406 Taiwanese adults (mean age 46.2 years, 51.5% males), the prevalence of LD, HBVC and SFL were 12.3%, 15.1% and 33.4%, respectively; 5.1% of participants had SFL plus HBVC. Multivariate logistic regression analysis demonstrated that male gender (odds ratio (OR) = 2.8, 95% confidence interval (CI): 2.3-3.5), overweight state (OR = 1.6, 95% CI: 1.3-2.0), HBVC (OR = 2.5, 95% CI: 2.0-3.1) and SFL (OR = 4.2, 95% CI: 2.2-5.3) were independently associated with LD. Synergism analysis showed that the adjusted OR for LD in adults with HBVC-alone was 3.3 (95% CI: 2.4-4.6), SFL-alone, 4.7 (95% CI: 3.7-6.1) and combined HBVC and SFL, 9.5 (95% CI: 6.8-13.3); the synergy index was 1.4 (95% CI: 1.001-2.0).
CONCLUSION: In Taiwanese adults, SFL plus HBVC have a significant synergistic association with LD.
Citation: Lin YC, Hsiao ST, Chen JD. Sonographic fatty liver and hepatitis B virus carrier status: Synergistic effect on liver damage in Taiwanese adults. World J Gastroenterol 2007; 13(12): 1805-1810
Fatty liver and hepatitis B virus (HBV) infection are important causes of liver damage (LD)[1-3]. However, only limited data is available on the interaction of these two risk factors in inducing liver damage.
Fatty liver, termed histologically as hepatosteatosis, refers to an accumulation of fat in the hepatocytes. Fatty liver can be detected non-invasively by sonogram[4]. Several epidemiological studies have shown that sonographic fatty liver (SFL) has a strong positive association with the metabolic syndrome[2,5]. SFL may progress to fibrosis or cirrhosis and is a growing health problem in many developing as well as developed countries[2,5,6]. HBV infection is usually transmitted through blood or sexual contact with an infected person. Chronic HBV infection also results in serious sequelae including hepatocellular carcinoma, and continues to be an important public health problem in hyperendemic areas including several Asian countries[3].
Both SFL and HBV carrier status (HBVC) are commonly encountered by primary health care doctors in Taiwan[4,7]. According to previous epidemiological studies, coexistence of SFL and HBVC is not uncommon in clinical practice[8]. The findings that fatty liver sensitizes the host immune response to the HBV infection had been reported in some studies[9,10]; however, little is known as to whether the damaging effects of SFL and HBVC are enhanced by the co-existence of the two diseases.
We examined the epidemiology of SFL and HBVC in Taiwanese adults by analyzing retrospectively the database of a health care center in Taipei. We focused on whether a combination of these two liver disorders has a deleterious effect on the serum alanine aminotransferase levels, which is a conventional marker of liver damage and is a predictor of advanced liver disease[11,12].
MATERIALS AND METHODS
Subjects
The records of 5899 adult subjects, 18 to 65 years in age who had visited the Shin Kong Wu Ho-Su Memorial Hospital health center between January 2004 and December 2005 for routine periodic checkups, were collected anonymously.
Methods
A questionnaire on personal medical history, including alcohol consumption (usage more than once a week in the recent past 3 mo: yes vs no; yes defined as a habitual drinker), medication usage and major operations, was filled out by the examinees. A total of 493 participants were excluded from the final analysis for following reasons: habitual drinking, history of major abdominal surgery, diabetes and long-term use of corticosteroids, hormone replacement therapy, insulin replacement therapy and oral antidiabetic agents.
The physical examination data included anthropometrical evaluation and measurements of systolic and diastolic blood pressure. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). Waist circumference was measured midway between the lowest rib and the iliac crest. Definition of overweight was BMI > 24 kg/m2, and that of central obesity was waist circumference > 90 cm for men and > 80 cm for women, based on Taiwanese criteria[13].
The biochemical blood tests were obtained using the Hitachi/Roche auto analyzer model 7600 PPEE (Hitachi Corp, Tokyo, Japan). The tests included aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting plasma glucose, serum triglycerides, and total and high-density lipoprotein (HDL) cholesterol. The results of tests for metabolic syndrome (blood glucose and lipids) are not shown in the tables but were adjusted for the multivariate analysis. HBV surface antigen (HBsAg), anti-HBV surface antibody (HBsAb) and anti-HCV antibody were measured by the microparticle enzyme immunoassay (MEIA) using the Abbott Axsym System instrument (Abbott Laboratories Services Corporation, Taipei, Taiwan). LD was defined by cutoff > 40 U/L for ALT[14].
Abdominal sonographic examinations were performed using convex-type real-time electronic scanners (Toshiba SSA-340 with 3.75 MHz convex-type transducer) by four gastrointestinal specialists who were blind to the examinees’ medical history and blood test results. The definition of SLF was based on a comparative assessment of image brightness relative to the kidneys, as described previously[4,15-17].
SAS software was used for statistical analysis (Version 8.0; SAS Institute, Cary, NC, USA). Student’s t and chi-square tests were used for analyzing continuous variables and categorical variables, respectively. Multivariate logistic regression was utilized to evaluate the relationship between salient risk factors. A program developed in the SAS computer package for the calculation of synergy index (SI) was used[18]. ASI value of > 1.0 indicates that the interaction is more than an additive interaction, i.e. is a synergism.
RESULTS
The records of a total of 5406 Taiwanese adults (2760 males, 2646 females; aged from 18 to 65 years) were used for the analysis.
Table 1 summarizes the findings in the total study population. The mean ± standard deviation of the different characteristics were: age, 46.2 ± 9.4 years; BMI, 23.5 ± 3.3 kg/m2; waist circumference, 82.6 ± 9.2 cm; AST, 22.8 ± 9.6 U/L and ALT, 25.8 ± 19.9 U/L. Central obesity was seen in 19.2% individuals while 41.15% were overweight. The prevalence rates of LD, HBVC and SFL were 12.3%, 15.1% and 33.4%, respectively; 5.1% of participants (277 in 5406) were HBV carriers with SFL.
Table 1 Demographic data of the total study population and the subgroups defined by HBVC1 and SFL2 positive or negative status mean ± SD.
The results obtained in the subgroups categorized by HBVC and SFL are shown in Table 1. HBV carriers had significantly higher levels of AST (26.9 ± 14.0 vs 22.1 ± 8.3 U/L, P < 0.001) and ALT (34.0 ± 30.4 vs 24.3 ± 17.0 U/L, P < 0.001) compared to non-carriers. There were no significant differences between HBV carriers and non-carriers with respect to age, BMI, and waist circumference. The proportion of males was higher in HBV carriers compared to non carriers (59.9% vs 49.5%). Liver function tests were abnormal significantly more frequently in HBV carriers compared to non-carriers (21.3% vs 10.7%). No significant differences were observed between carriers and non-carries with respect to SFL (33.3% vs 33.9%), overweight status (41% vs 43.3%) and central obesity (19.2% vs 19%). The proportion of subjects who were HBsAb negative was 36.7% in the total population and 26.4% in non-HBV carriers.
The results of different parameters based on whether the subjects were positive or negative for SFL are shown in Table 1. The results showed significant (P < 0.001) differences between subjects with SFL compared to those without SFL for all the characteristics: age 45.3 ± 9.6 vs 48 ± 8.7 years, BMI 22.3 ± 2.7 vs 25.9 ± 3.1 kg/m2, waist circumference 79.9 ± 8.5 vs 87.8 ± 8.3 cm, AST 21.6 ± 9.1 vs 25.3 ± 10.1 U/L, ALT 21.6 ± 16.5 vs 34 ± 23.3 U/L, overweight status 25.5% vs 73%, obesity 15.1% vs 27.3% and liver damage, 5.6% vs 25.9%. There were significantly more males in the subgroup with sonographic fatty liver compared to those without SFL (64.5% vs 44.4%; P < 0.001). The only exceptions were HBVC (15.0% vs 15.4%, P = 0.72) and HBsAb-negative rates (36.4% vs 37.2%, P = 0.61), which were similar in the subgroups without or with SFL.
The results of the following physical findings and metabolic tests have not been shown in the tables but were used as potential confounding factors in the multivariate analysis: systolic blood pressure 15.5 ± 2.4 kPa, diastolic pressure 9.4 ± 1.5 kPa, fasting sugar 4.9 ± 0.5 mmol/L, triglycerides 3.2 ± 2.0 mmol/L and HDL-C 1.4 ± 0.4 mmol/L. The prevalence of elevated blood pressure was 23.6%, hyperglycemia 2.7%, hypertriglyceridemia 24.8%, and hypo-HDL-cholesterolemia 21.1%.
The results of multivariate analysis and adjusted odds ratios for LD of the total population are summarized in Table 2. According to the multiple logistic regression analysis, risks factors such as male gender (OR = 2.8, 95% confidence interval (CI): 2.3-3.5), overweight state (OR = 1.6, 95% CI: 1.3-2.0), SFL (OR = 4.2, 95% CI: 2.2-5.3) and HBVC (OR = 2.5, 95% CI: 2.0-3.1) were independently associated with LD in total study population.
Table 2 Results of logistic multivariate regression analysis1 of LD2 and tested variables.
Risk factors
All cases
OR
95%CL
Gender(male vs female)
2.8
2.3-3.5
Overweight(yes vs no)
1.6
1.3-2.0
Central obesity(yes vs no)
1.0
0.8-1.3
SEL(yes vs no)
4.2
3.3-5.3
HBVC(yes vs no)
2.5
2.0-3.1
Table 3 displays the results obtained in the four subgroups: SFL plus HBVC, SFL-alone, HBVC-alone and the reference group which consisted of non-carriers without SFL. Adults in the SFL plus HBVC group had significantly (P < 0.001) higher values of the following characteristics: age 48.2 ± 8.3 vs 45.4 ± 9.7 years, BMI 26.1 ± 3.2 vs 22.3 ± 2.7 kg/m2, waist circumference 88.9 ± 9.4 vs 79.9 ± 8.5 cm, AST 29.6 ± 16.4 vs 20.9 ± 8.1 U/L, ALT 43.3 ± 39.4 vs 20.3 ± 14.6 U/L, overweight state 73.3% vs 25.1%, central obesity 31.1% vs 15.5% and abnormal liver function 37.2% vs 4.2%. Likewise, the SFL-alone subjects, had significantly higher values compared to the reference group with respect to: age 47.9 ± 8.8 years, BMI 25.9 ± 3.0 kg/m2, waist circumference 87.5 ± 8.0 cm, AST 24.5 ± 8.3 U/L, ALT 32.3 ± 18.5 U/L, overweight state 73.0%, central obesity 26.7% and liver damage 23.8%. Unlike the SFL-alone and SLF plus HBVC groups, the HBVC-alone subjects had significantly higher levels than the reference group only with respect to AST 25.6 ± 12.5 U/L, ALT 29.2 ± 23.3 U/L and liver damage 13.2%, whereas age, BMI, waist circumference, rates of overweight or central obesity were not significant (Table 3). There were significantly more males in the SFL-alone, HBVC-alone and SFL plus HBVC groups: 63.0%, 53.3% and 72.6% respectively, compared to the reference group, 42.8%. The proportion of HBsAb-negative subjects was similar in non-carriers with or without SFL, 26.0% vs 27.1%.
Table 3 Characteristics of four subgroups classified by HBVC and SFL positive or negative status mean ± SD.
Table 4 shows the risk of LD in subjects with SFL or HBVC alone and those with SFL plus HBVC compared to the reference group. The multivariate-adjusted odds ratios of liver damage for adults with HBVC-alone, SFL-alone and combined SFL plus HBVC were 3.3 (95% CI: 2.4-4.6), 4.7 (95% CI: 3.7-6.1) and 9.5 (95% CI: 6.8-13.3) respectively, the synergy index of HBV plus SFL for elevated AST levels was 1.4 (95% CI: 1.006-2.0), indicating a synergist effect[18].
Table 4 Prevalence and odds ratio of LD for single or combined states of HBVC and SFL.
In the present study carried out on a Taiwanese adult population, the prevalence rates of HBVC and SFL were 15.1% and 33.4% respectively, which are similar to those reported from other hyperendemic developing and developed Asian countries[3,5,19].
Male gender and an overweight state were independently associated with liver damage as non-modifiable and theoretically modifiable risk factors. Although several workers have shown that males are vulnerable to HBV infection, hepatosteatosis and liver damage[20-24], studies on overweight subjects also show that weight reduction brings about significant improvement in the liver function tests[6]. The importance of weight control in the management of liver damage should be emphasized in Taiwanese adults, especially males.
Our findings support previous observations that both SFL and HBVC have a strong association with liver damage[6,25]. In addition, our study shows that SFL and HBVC produce liver injury by different mechanisms. In hepatosteatosis, the severity of liver injury is closely related to the amount of lipid accumulation in the hepatocytes[15,16]. Fat accumulation can be semi-quantitatively estimated by sonograms[5,16,26,27], thus analysis of hepatosteatosis on sonogram can determine the potential for liver injury[15,16,27-29]. By contrast, the severity of liver injury in HBV carriers depends on several viral factors including virus type and viral load[30-33]. Thus, knowledge of HBsAg carrier status alone, without information on the viral type and number viral copies, provides only limited information on the severity of liver injury[34,35]. In the present multivariable analysis (Tables 2 and 4), HBVC exhibited a significant but weaker association with liver injury than SFL, nevertheless, in future studies the impact of these risk factors on liver damage should be assessed by analysis adjusted for virus type and viral copies.
Our study provides an epidemiological analysis on the influence of combined HBVC and SFL on liver damage, and indicates a synergistic effect (Table 4). According to the widely accepted “two-hit theory” of steatohepatitis, the “first hit” is excess lipid accumulation in hepatocytes; lipids in the liver cells are sensitive to the “second hit” involving factors such as oxidative stress, oxygen-radicals, cytokines, lipid-peroxidation, which result in steatohepatitis[36-40]. It is possible that the two hits can exist simultaneously in lipid-containing hepatocytes infected with HBV.
In the present study, the “first hit”, lipid accumulation detected by sonogram, showed no significant difference between HBV carriers and non-carriers (Table 3). These findings are in agreement with previous observations[41] that HBVC prevalence is not influenced by the presence of SFL, and vice versa (Table 1). Despite the insignificant association of the “first hit” regarding the coexistence of HBVC and SFL, the “second hit” should be considered as the candidate causing significant liver injury. Several studies on HBV infection and fatty liver have reported oxidative stress-related events such as the assembly of HBV viral particles[42], the HBV altered lipid peroxidation pathway and hepatocyte electron transport system by charged HBV[43-45]. It is reasonable to theorize that these oxidative stress-related events act together in inducing additional and potent oxidative stress in the hepatocytes, thus enhancing the “second hit”, which promotes injury to the vulnerable lipid-containing hepatocytes, resulting in hepatitis.
In addition, from the view point of molecular biology, both hepatosteatosis and HBV infection are associated with dysfunction of the mitochondria, which are the producers of metabolic energy, biosensor for oxidative stress, and effector for liver cell death through the process of apoptosis[46,47]. Previous studies on hepatitis B virus have shown that a viral protein, HBx protein, is found in the mitochondrion and targets mitochondrial calcium regulation, which results in mitochondrial dysfunction[48,49]. On the other hand, investigations on hepatosteatosis demonstrate that excess lipid peroxidation plays a role in triggering mitochondrial membrane permeabilization and apoptosis[50-53]. Mitochondrial dysfunction caused simultaneously by HVB infection and hepatosteatosis should be considered as an important cause of hepato-cellular injury, represented by a significant increase in the frequency of abnormal liver function tests in SFL-affected HBV carriers.
Although our study shows a statistical association between HBVC, SFL and LD, a direct biochemical and biomolecular evidence for the causality and synergism awaits further investigations.
To date, besides weight reduction and physical exercise, there are few recommendations for the management of fatty liver[6,36,39]. At the same time, the use of hepatitis B vaccine has been shown to effectively reduce the incidence of new infections, and vaccination is recommended for at-risk, sexually active adult individuals[54]. In our study, 27.1% of fatty liver-affected non-HBV carriers were HBsAb-negative (Table 1). As SFL is one of the major causes of liver damage, and is an independent risk factor predicting advanced liver disease for HBV carriers[3,7], expanding vaccination recommendations to fatty liver-affected subjects could be an effective preventive strategy against advanced liver disease.
To sum up, sonographic fatty liver and HBV carrier status are the most prevalent liver problems in Taiwanese adults, with male subjects being more vulnerable to fatty liver, HBV infection and liver damage than females. Health promotion strategies such as weight control and use of HBV vaccination should be emphasized in Taiwanese adults, especially males. Since HBVC combined with SFL has a synergistic effect on liver injury, we recommend HBV vaccination for Taiwanese adults with fatty liver who do not have adequate protective antibodies.
ACKNOWLEDGMENTS
The authors would like to acknowledge the personnel of the Department of Family Medicine and Health Center, Shin Kong Wu Ho-Su Memorial Hospital for their full support and generous assistance.
Footnotes
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