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doi:10.1111/jgh.12700

REVIEW

Hepatitis B virus infection and metabolic syndrome: Fact or fiction? Chia-Chi Wang,*,† Tai-Chung Tseng*,† and Jia-Horng Kao‡ *Department of Gastroenterology and Hepatology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and †School of Medicine, Tzu Chi University, Hualien, Taiwan; ‡Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan

Key words arteriosclerosis, fatty liver, hepatitis B virus, insulin resistance, lipid, metabolic syndrome. Accepted for publication 12 July 2014. Correspondence Professor Jia-Horng Kao, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei 10002, Taiwan. Email: [email protected] Author contributions: Chia-Chi Wang: writing the paper. Tai-Chung Tseng: perform meta-analysis. Jia-Horng Kao: revise the paper.

Abstract Although hepatitis C virus infection is known to be linked with insulin resistance, dyslipidemia, and hepatic steatosis, the relationship between hepatitis B virus (HBV) infection and metabolic factors remains unclear. HBV infection is a health problem worldwide, especially in endemic regions such as Asia and Africa. It induces liver decompensation, cirrhosis, hepatocellualr carcinoma, and premature mortality. The prevalence of metabolic syndrome continues to increase in parallel with the epidemic of obesity, which is closely associated with the development of diabetes, cardiovascular disease, or even cancer. The systemic review shows that chronic HBV infection protects against instead of promotes fatty liver. The mechanism is possibly due to a lower frequency of dyslipidemia profile in patients with chronic HBV infection. The association of HBV with metabolic syndrome, insulin resistance, and the risk of arteriosclerosis is still inconclusive. In addition, obesity, diabetes, and metabolic syndrome may accelerate the progression of liver disease in patients with chronic HBV infection and synergistically induce cirrhosis or even hepatocellualr carcinoma development.

Conflict of interest: The authors declare no conflict of interest.

Introduction Hepatitis B virus (HBV) infection affects 350 million people in the world.1 If the infected patient fails to develop immunity against the virus after acute infection, they become chronic HBV carrier. Chronic HBV infection could complicate with chronic hepatitis, cirrhosis, hepatic decompensation, or hepatocellular carcinoma (HCC).2 Although the incidence of new HBV infection has decreased since the implementation of universal hepatitis B vaccination, chronic HBV infection still contributes a considerable disease burden to the world.3 Metabolic syndrome is composed of central obesity, hypertension, glucose abnormality, and dyslipidemia.4 It correlates with an increased risk of cardiovascular diseases, diabetes, or the development of cancer.5,6 Although the pathogenesis of metabolic syndrome remains unclear, insulin resistance has been recognized as an essential mechanism.7 Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome and considered as hepatic manifestation of metabolic syndrome. The histological spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which has necroinflammation or fibrosis on top of hepatic steatosis.8 It is generally believed that up to 20% 14

of patients with NASH may progress to cirrhosis or even HCC over time.9,10 Taken together, both chronic HBV infection and metabolic syndrome are important health problems across the world. As we know, hepatitis C virus (HCV) infection can affect glucose homeostasis and lead to insulin resistance.11 Furthermore, chronic hepatitis C (CHC) patients have an increased risk of fatty liver, especially in those with HCV genotype 3 infection. Rebound of hyperlipidemia has been reported in CHC patients who achieve sustained virologic response after combination therapy of pegylated interferon plus ribavirin.12 Although hepatitis B X protein expression is found to induce hepatic steatosis in transgenic mouse and cell line models, whether HBV infection can affect their metabolism in hepatitis B carriers remains unclear.13 Thus, systemic review is performed to realize the relationship among chronic HBV infection and metabolic factors as well as metabolic syndrome.

HBV infection and metabolic syndrome The presence of chronic HBV infection and metabolic syndrome at the same time further increases the risk of cirrhosis and HCC. The

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Hepatitis B virus and metabolic syndrome

prevalence of combined metabolic syndrome and chronic HBV infection in the general population is around 0.99–1.74%,14–16 but it varies in different areas depending on whether the area is endemic for HBV infection or metabolic syndrome. The association between HBV infection and metabolic syndrome is still inconclusive in literature (Table 1). For example, one cross-sectional study found no association between metabolic syndrome and HBV infection after stratification by gender and age.14 In another study of 138 HBV patients, they were divided into two groups with or without metabolic syndrome. Metabolic syndrome was found to be highly correlated with insulin resistance but less correlated with viral factors.15 In two cross-sectional and two large sample-sized population-based studies, metabolic syndrome was inversely associated with chronic HBV infection.16,18–20 In contrast, a recent study showed higher viral load in patients of chronic HBV infection with metabolic syndrome compared with those without.17 Because of these inconsistent results, a meta-analysis was performed to clarify this important issue. First, PubMed search identified 191 papers. Studies not having the data of the prevalence or without using non-HBV subjects as control group in study popu-

Table 1

lation were excluded. A total of four studies were thus retrieved for further meta-analysis to realize the relationship between chronic HBV infection and metabolic syndrome. The results showed that the prevalence of metabolic syndrome tended to be lower in patients with HBV infection than those without, but the difference was statistically insignificant (odds ratio [OR], 0.82; 95% confidence interval 0.66–1.02 by random effect model; heterogeneity: I-squared 84.8%) (Fig. 1). Therefore, we conclude that the relationship between HBV infection and metabolic syndrome is still inconclusive and awaits further studies to confirm.

HBV and fatty liver Histologically, fatty liver is defined as intrahepatic fat content more than 5% of liver weight.21 In clinical practice, although fatty liver is usually diagnosed by ultrasound examination, proton magnetic resonance spectroscopy (MRS) has been used to non-invasively quantify the intrahepatic fatty content.22 Several reasons including alcohol, obesity, HCV infection, diabetes, or

A summary of studies on the association of hepatitis B virus infection with metabolic syndrome

Author (year)

Study design

Subjects

Jarcˇuška P (2014)

Cross-section

855

Chung TH (2014)

Cross-section

9 474

Jinjuvadia R (2014)

Large population database

Chronic HBV: past exposure to HBV = 593 594:7 280 620

Li WC (2013)

Case series

26 305

Li X (2012)

Case series

138 HBV-infected patients

Wong VW (2012)

Case series

1 013

Jan CF (2006)

Population-based cross-sectional study

53 528

Background or aim Explore the relationship between metabolic syndrome and HBV infection Investigate the relationship between HBV infection and metabolic syndrome Determine the association between HBV and metabolic syndrome Evaluate the association between hepatitis B/C infection and metabolic syndrome Investigate the role of adiponectin in chronic HBV infection and metabolic syndrome Study the prevalence of fatty liver in people with HBV or without HBV infection Assess the association between metabolic syndrome and hepatitis B/C virus infection

Findings

Reference

A higher viral load in patient of chronic HBV infection with metabolic syndrome than those without. HBV infection was negatively associated with metabolic syndrome in men. Chronic HBV infection was inversely associated with metabolic syndrome The prevalence of metabolic syndrome was not different between HBV and non-HBV patients (13.41% vs 13.96%). Metabolic syndrome in HBV patients correlated with insulin resistance and less effect of virus. HBV infection is associated with lower prevalence of metabolic syndrome than controls (11% vs 20.2%; P = 0.034). There was an inverse association between metabolic syndrome and HBV infection. The prevalence of metabolic syndrome was lower in HBV patients than non-HBV subjects. (8% vs 10.9%; adjusted OR 0.84 [0.76–0.93]).

17

18

19

14

15

16

20

HBV, hepatitis B virus.

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Hepatitis B virus and metabolic syndrome

Figure 1

C-C Wang et al.

Meta-analysis about the relationship between chronic hepatitis B infection and metabolic syndrome.

dyslipidemia could lead to the development of fatty liver. NAFLD is known to be one of common liver diseases with increased risk of cirrhosis or even HCC development.23 Several studies have investigated the relationship between chronic HBV infection and fatty liver (Table 2). In studies focused on general population, the prevalence of fatty liver determined by using ultrasound examination was comparable between patients with chronic HBV infection and healthy controls. For example, a retrospective study of 4365 subjects from a health examination center found that the prevalence of fatty liver was not different between HBV-infected group and non-HBV-infected group (16.7% vs 18.3%).27 Further analysis showed that fatty liver correlated with age and hyperlipidemia but not with HBV infection. Our own study using a cohort from the health examination center had consistent results. Furthermore, the data of insulin resistance were available, and those with anti-HCV positivity or alcohol consumption > 140 gm/week were excluded in our study. We concluded that chronic HBV infection was not associated with insulin resistance or hepatic steatosis.29 Nevertheless, a recent large study (33 439 subjects) from Taiwan demonstrated that HBV-infected patients had a lower prevalence of fatty liver disease than the general population, especially in older and obese patients.24 Wong et al. from Hong Kong performed proton MRS to define the status of fatty liver. They found that chronic HBV infection was an independent factor associated with lower risk of fatty liver after adjustment for demographic and metabolic factors.16 These results imply that chronic HBV infection may have a minor effect on the decreased risk of fatty liver. By using cohort from patients with chronic HBV infection having histology data, several studies revealed hepatic steatosis was associated with metabolic factors such as body mass index (BMI) and serum triglyceride (TG) level but not related to HBV itself.28,30–32 There was no association of hepatic steatosis with HBV viral load or Hepatitis B e antigen (HBeAg) status. An Indian study on 350 patients with chronic HBV infection also found hepatic steatosis was associated with metabolic factors but had a negative association with serum HBV-DNA level.25 A recent metaanalysis using 17 studies with 4100 HBV-infected patients showed a strong negative association between HBV viral load and hepatic steatosis, suggesting that HBV may paradoxically have a protective effect on the development of hepatic steatosis.26 In brief summary, chronic HBV infection protects against instead of promotes the development of fatty liver proved in a 16

meta-analysis and several studies with a large sample-sized cohort or using more sensitive diagnostic tools such as proton MRS or histology.

HBV infection and lipid profiles Dyslipidemia including hypercholesterolemia or hypertriglyceridemia is a risk factor of atherosclerosis, which can lead to cardiovascular and cerebral vascular diseases.33 Furthermore, elevated serum TG level and reduced serum high-density lipoprotein cholesterol (HDL-C) level are included in the components of metabolic syndrome.34 Accumulating evidence suggests that chronic HBV infection has an inverse association with all lipid profiles including cholesterol, TG, HDL-C and low-density lipoprotein cholesterol (LDL-C). For example, a large-scale community-based cohort study involving 56 336 residents found that seropositivity of HBV had a lower prevalence of both hypertriglyceridemia and hypercholesterolemia.35 A study on the basis of health examination population also showed patients with chronic HBV infection had a lower OR of hypertriglyceridemia, hyperecholesterolemia, and higher LDL-C levels.36 Furthermore, a study using clinical data of 1330 medical center employees demonstrated lower serum levels of total cholesterol and HDL-C in the patients with chronic HBV infection.37 Our previous case–control study showed that patients with chronic HBV infection had significantly lower serum TG and HDL levels compared with healthy controls. The relationships remained unchanged for middle-aged patients after modification with serum alanine aminotransferase (ALT) levels. Another cohort of 122 patients with chronic HBV infection having data of serum HBVDNA level and insulin resistance further confirmed an inverse association of serum HBV-DNA levels with serum TG levels.38 In brief summary, chronic HBV infection has an inverse association with all lipid profiles.

HBV, insulin resistance and diabetes mellitus Insulin resistance is a key contributing factor of metabolic syndrome and diabetes mellitus. Chronic HCV infection is known to link with insulin resistance and an increased risk of diabetes mellitus. In contrast, chronic HBV infection has different behavior from chronic HCV infection. Our previous studies showed that the

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Table 2

Hepatitis B virus and metabolic syndrome

A summary of studies on the association of hepatitis B virus infection with fatty liver

Author (year)

Study design

Subjects

Background or aim

Cheng YL (2013)

Case series

33 439

Clarify the relationship of HBV and fatty liver regarding different demographics of age and body mass index

Wong VW (2012)

Case series

1 013 (91 HBV patients)

Study the prevalence of fatty liver in people with HBV or without HBV infection

Rastogi A (2011)

Case series

350 HBV patients with liver biopsy

Limited data on hepatic steatosis in patients with chronic HBV infection.

Machado MV (2011)

Meta-analysis

The association of hepatic steatosis with HBV is controversial.

Xu QH (2009)

Case series

17 studies, 4 100 HBV-infected patients with histology 4365

Minakari M (2009)

Case series

132 HBV patients with liver biopsy

Wang CC (2008)

Case series

507 subjects (50 HBV carriers)

Peng D (2008)

Case series

153 HBV patients with liver biopsy

Shi JP (2008)

Case series

1915 HBV patients with liver biopsy

Altlparmak E (2005)

Case series

164 HBV patients with liver biopsy

To investigate the relationship among fatty liver, HBV infection and hyperlipidemia

Association of chronic HBV infection and liver steatosis has not been extensively studied. The association of chronic HBV infection with insulin resistance and hepatic steatosis is unclear. The relationship between hepatic steatosis and chronic HBV infection is unclear. To investigate the prevalence and risk factors of hepatic steatosis in patients with biopsy-proven chronic hepatitis B. To investigate the viral and host causes of fatty liver in patients with chronic HBV infection.

Findings

Reference

Patients with HBV infection were inversely associated with fatty liver disease than the general population, especially in older and obese patients (prevalence of fatty liver; HBV : non-HBV = 38.9% : 44.5%). HBV infection is associated with lower prevalence of fatty liver (prevalence of fatty liver; HBV : non-HBV = 13.5% : 20.6%). Hepatic steatosis is associated with host metabolic factors, but negatively correlated with HBV-DNA level. A puzzling strong negative association between viral load and hepatic steatosis.

24

Fatty liver was not related with HBV infection but closely related with age and hyperlipidemia (prevalence of fatty liver; HBV : non-HBV = 16.7% : 18.3%). Only the serum triglyceride level was significantly correlated with steatosis.

27

Chronic HBV infection seems not to be associated with insulin resistance or hepatic steatosis (frequency of fatty liver; HBV : non-HBV = 56% : 50.1%) Steatosis correlates with BMI and ALT levels.

29

Steatosis is associated with metabolic factors of the hosts and not related to the virus itself.

31

Steatosis in chronic hepatitis B appears to be a result of metabolic factors of the host rather than the effect of viruses.

32

16

25

26

28

30

ALT, alanine aminotransferase; BMI, body mass index; HBV, hepatitis B virus.

insulin resistance was not different between patients with chronic HBV infection and healthy controls.29 Serum HBV-DNA levels were also not associated with homeostatic model assessmentinsulin resistance (HOMA-IR) index in patients with chronic HBV infection. In addition, our previous longitudinal study of 1233 adults from a health examination center found that asymptomatic chronic HBV infection did not correlate with the presence of diabetes mellitus after adjustment for age, gender, and BMI. In 296 non-diabetic subjects at the first health examination, the 10-year

incidence of diabetes or glucose intolerance was similar between HBV carriers and non-HBV controls, suggesting that asymptomatic chronic HBV infection did not increase the risk of diabetes.39 In contrast, a study from Korea showed that chronic HBV infection was associated with insulin resistance. They suggested that the patients with chronic HBV infection might need to monitor the occurrence of insulin resistance and diabetes.40 Taken together, the relationship between HBV and insulin resistance remains inconclusive and awaits further studies to clarify.

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The literature review indeed shows a close association between cirrhosis and poor glycemic control.41 In a prospective cohort study with 52 histologically confirmed cirrhotic patients with a follow-up duration of up to 6 years, up to 96% of cirrhotic subjects had impaired glucose tolerance or diabetes.42 Several reasons could contribute to the development of diabetes in cirrhotic subjects such as reduced insulin clearance with peripheral hyperinsulinemia and subsequent increase of insulin resistance.43 However, the interplay among the causes of cirrhosis such as chronic HBV infection, cirrhosis itself, or the inherent risk of diabetes needs further examinations.

HBV and arteriosclerosis Chronic HBV infection appears not to be associated with carotid or coronary arteriosclerosis. Four cross-sectional studies investigated the association between chronic HBV infection and arteriosclerosis.44–47 By using carotid duplex or pulse wave velocity to determine the presence of arteriosclerosis, two studies found that patients with chronic HBV infection were not associated with an increased risk of arteriosclerosis compared with healthy controls. Another two studies enrolling subjects receiving coronary angiography found that the prevalence of HBV seropositivity was similar between patients with and without coronary arterial disease.46,47 In contrast, a relative small sample-sized case–control study using the parameter of carotid intima-media thickness, an early index of atherosclerosis, showed that NASH, HBV, and HCV were associated with early arteriosclerosis, independent of potential confounders.48 However, it is needed to be confirmed in further large-scale studies.

Impact of metabolic syndrome on the progression of liver disease in chronic hepatitis B patients Metabolic syndrome is closely associated with NAFLD, obesity, and the future development of diabetes mellitus.49 NAFLD already becomes the most common liver disease in the United States and can be expected to increase parallel with the epidemics of obesity and type 2 diabetes mellitus.50 It refers to a spectrum of disorders from simple steatosis to more severe manifestations including steatohepatitis, fibrosis, and cirrhosis.8 In the population without HBV infection, metabolic factors were proved to increase the risk of HCC development.51–53 A Chinese study suggested that HCC patients had higher BMI and insulin resistance than healthy controls.52 A large longitudinal cohort study with more than 14-year follow-up confirmed that obesity and diabetes were associated with HCC development. In addition, both obesity and diabetes could increase more than 100fold risk of HCC, suggesting a synergistic effect of metabolic factors.53 In patients with chronic HBV infection, metabolic syndrome could increase the risk of liver fibrosis progression, cirrhosis, and the development of HCC in patients with chronic HBV infection.54–57 For example, a cross-sectional study of 1466 patients using liver stiffness measurement to decide the status of cirrhosis found that metabolic syndrome increased the risk of cirrhosis in patients with chronic HBV infection.56 In addition, metabolic factors such as diabetes mellitus or obesity can also 18

increase the risk of liver damage, hepatic fibrosis, cirrhosis, and HCC. In our previous nationwide longitudinal study using the Taiwanese Health Insurance Research Database from > 99% of entire population, a total of 14 523 patients with chronic HBV infection were identified and received about 9 years of follow-up. The cumulative incidence of cirrhosis or decompensated cirrhosis was significantly higher in patients with newly developed diabetes than those without. Diabetes was confirmed to be an independent factor associated with cirrhosis and its decompensation in patients with chronic HBV infection.58 Fatty liver was reported to have a synergistic effect with chronic HBV infection on liver damage defined as elevated serum ALT levels.59 Obesity is the major component of metabolic syndrome. In a recent case–control study of three groups (HBV-related HCC, HBV carriers, and controls), BMI and insulin resistance were higher in HCC patients.60 Using liver histology, abdominal obesity was associated with hepatic fibrosis independent of other host and viral factors in patients of chronic HBV infection. Taking these findings together, metabolic syndrome and its components may accelerate the progression of liver disease in patients of chronic HBV infection. Thus, the metabolic derangements should be actively managed to slow down its progression especially in patients with chronic HBV infection who have metabolic syndrome.

Conclusions Chronic HBV infection protects against instead of promotes fatty liver. The mechanism is possibly due a lower frequency of dyslipidemia profile in patients with chronic HBV infection (Fig. 2). The association of HBV with metabolic syndrome, insulin resistance, and the risk of arteriosclerosis is inconclusive and awaits further studies to confirm. Metabolic syndrome, obesity, and diabetes have a synergistic effect to induce liver injury, fibrosis, or even the development of HCC in patients with chronic HBV infection. Therefore, lifestyle modification and aggressive treat-

Figure 2 The association of chronic hepatitis B infection with metabolic syndrome and its component. CI, confidence interval; OR, odds ratio.

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ment for metabolic derangements should be done to reduce the disease progression in patients with chronic HBV infection.

Acknowledgments Thanks for the support from the Research Department of Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation.

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Journal of Gastroenterology and Hepatology 30 (2015) 14–20 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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Hepatitis B virus infection and metabolic syndrome: fact or fiction?

Although hepatitis C virus infection is known to be linked with insulin resistance, dyslipidemia, and hepatic steatosis, the relationship between hepa...
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