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Impact of Metabolic Syndrome on Fibrosis Progression in Chronic Viral Hepatitis B Infection | OMICS International
ISSN: 2167-0943
Journal of Metabolic Syndrome
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Impact of Metabolic Syndrome on Fibrosis Progression in Chronic Viral Hepatitis B Infection

Cem Aygun*
Department of Gastroenterology and Hepatology, Istanbul Medipol University, Istanbul, Turkey
Corresponding Author : Cem Aygun
Department of Gastroenterology and Hepatology
Istanbul Medipol University,School of Medicine
Istanbul, Turkey,
Tel: +90 5327130491
E-mail: [email protected]
Received March 30, 2015; Accepted April 27, 2015; Published April 29, 2015
Citation: Aygun C (2015) Impact of Metabolic Syndrome on Fibrosis Progression in Chronic Viral Hepatitis B Infection. J Metabolic Synd 4:175. doi:10.4172/2167-0943.1000175
Copyright: © 2015 Cem Aygun, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Many factors may increase the risk of fibrosis development in chronic viral hepatitis infections. As the burden of obesity and metabolic syndrome has been increasing in recent years, there is growing concern regarding the association between metabolic factors and chronic viral hepatitis cases. However data regarding the influence of metabolic syndrome on progression of fibrosis in chronic hepatitis B virus (HBV) infection is limited. Metabolic syndrome is a constellation of problems that includes insulin resistance, obesity, hypertension, and hyperlipidemia. Initially, epidemiologic data demonstrated that HBsAg-positive serostatus was positively correlated with a high risk of metabolic syndrome; later on, HBV was considered as a “metabolovirus” because the gene expression of HBV and key metabolic genes in hepatocytes was found to be similarly regulated. Metabolic syndrome is not only found to accelerate the progression of liver disease in patients with chronic HBV infection but also found to induce cirrhosis or even hepatocellular carcinoma development. This review article it is aimed to highlight the association of metabolic syndrome with chronic HBV infection.

Chronic hepatitis B virus (HBV) infection is well-known as a major risk factor for liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [1-4]. Liver fibrosis may be represented by variable clinical manifestations, which are determined by the type and extent of liver damage, the underlying liver disease and the capacity of the whole body to respond. Cirrhosis is the end stage of liver fibrosis which is characterized by architectural disruption, aberrant hepatocyte regeneration, nodule formation and vascular changes [2]. It is important to accurately predict the rate of liver fibrosis progression in patients with chronic viral hepatitis, which has important clinical significance in terms of prognostic and treatment implications [5].
Metabolic syndrome (MS) is defined as a syndrome that involves three of the following characteristics: dyslipidemia (high levels of apoB lipoproteins and triglycerides, and/or low high density lipoprotein cholesterol), an impaired fasting glucose metabolism, hypertension or central obesity [5-6]. Metabolic syndrome is directly involved in the increased prevalence of coronary heart disease, atherosclerotic diseases, and diabetes mellitus type 2 [6-8]. Other metabolic abnormalities such as liver disease, proinflammatory and prothrombotic states and sleep apnea have also been frequently reported in patients with metabolic syndrome [6-8]. The data about the influence of MS on the prognosis of patients with HBV infection remains limited. Here we tried to investigate the impact of MS on the prognosis of this special patient group.
Epidemiologic link between metabolic syndrome and chronic hepatitis B infection
The association between hepatitis C virus (HCV) infection with lipid and glucose metabolism was demonstrated in many studies [9-10]. Similarly, in time HBV infection was suspected to be related to dyslipidemia and metabolic syndrome. A study by Su et al. reported an association between asymptomatic chronic HBV infection and lower serum levels of total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) [11]. In another campus-based study and with a transcriptional animal model, androgen production in HBV carriers with a low BMI (< 23 kg/m2) was found to be more triggered and upregulated HBV replication [12,13]. Several other studies reported a positive association between HBV infection and development of dyslipidemia and MS [14-16]. MS was also shown to cause worsening of cirrhosis in chronic HBV patients, suggesting a relationship between MS and progression of HBV infection. In a population based study chronic HBV patients diagnosed with MS had a higher HBV DNA load than patients without MS [17,18].
Hyperglycemia, insulin resistance and the consequent cellular shift to an increased oxidative stress carry a higher risk of progression in chronic liver diseases. Glycated Albumin (GA) is a marker of the glycemic control during the past three weeks which is the turnover time of albumin. The GA/HbA1c ratio is predicted to be high in patients with chronic liver diseases. Indeed, the GA/HbA1c ratio has been reported to be associated with the histological stage of liver fibrosis and portal hypertension in HCV-positive patients and nonalcoholic steatohepatitis. The GA/HbA1c ratio is also found to be increased in association with the stage of liver fibrosis in HBV-positive patients. However, the differences among the fibrosis stages were found to be relatively small [19].
The potential link between diabetes mellitus and metabolic factors with HBV-related HCC has also aroused increasing concern. A longterm community-based cohort revealed that diabetes mellitus was associated with HBV-related HCC. Extreme obesity (body mass index >or=30 kg/m2) was independently associated with a 4-fold risk of HCC and there was more than 100-fold increased risk in HBV or HCV carriers with both obesity and diabetes, indicating synergistic effects of metabolic factors and chronic hepatitis [20].
This evidence suggested metabolic profiles and subsequent development of MS might be associated with chronic HBV infection. It seems vital to explore the relationship between chronic HBV and MS to inform better prevention and control strategies.
Mechanisms of metabolic syndrome in chronic hepatitis B infection
In the liver glucose, lipid and energy homeostasis is mainly regulated by peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1α). The elevated expression of PGC-1α may alter the metabolic properties of tissues and lead to various diseases with an underlying dysregulation of metabolism, such as obesity, diabetes, neurodegeneration, and cardiomyopathy [21-24]. Several reports have suggested that HBV adopts a mode of regulation similar to major gluconeogenesis genes in the liver, such as gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6- phosphatase (G6Pase), which are co-regulated by PGC-1α, HNF4α and FOXO1 [25,26]. Interestingly, PGC-1α induces oxidative phosphorylation, and the expression of tricarboxylic acid cycle genes —such as SLC25A1 and ACLY—also increases the expression of the de novo fatty acid synthesis enzymes, acetyl CoA carboxylase (ACC) and fatty acid synthase (FASN) [27]. The genes involved in the biosynthesis of lipids, such as FASN and SREBP-2, are up-regulated in HBV-transgenic mouse liver [28]. In HCC, the extent of aberrant lipogenesis correlates with clinical aggressiveness, activation of the AKT-mTOR signaling pathway, and suppression of Adenosine 5'- monophosphate-activated protein kinase (AMPK). In addition, the protein expression of FASN, a key enzyme of lipogenesis that is overexpressed in HCC, is known to be negatively regulated by AMPK [29]. These findings imply that aberrations of glucose and lipid metabolism are closely associated with chronic HBV infection.
Effects of metabolic syndrome on fibrosis in chronic viral hepatitis B
The total prognosis of HBV infected patients is directly dependent on the extent and rate of progression of fibrosis. Therefore prediction of liver fibrosis progression has a key role in the management of chronic viral hepatitis, as it will be translated into the future risk of cirrhosis and its various complications including hepatocellular carcinoma. Both hepatitis B and C viruses mainly lead to fibrogenesis induced by chronic inflammation and a continuous wound healing response. At the same time direct and indirect profibrogenic responses are also elicited by the viral infection. There are a handful of wellestablished risk factors for fibrosis progression including older age, male gender, alcohol use, high viral load and co-infection with other viruses. Metabolic syndrome is an evolving important risk factor of fibrosis progression (Table-1) [30]. In a study including 850 HBV patients, the prevalance of MS was found to be 5%. Among the components of metabolic syndrome, fasting glucose >100 mg/dL was more frequent and MS was related to older age and higher BMI. The extent of liver fibrosis was found more serious in patients accompanying metabolic syndrome. In the study group, old age, body mass index (BMI), increased aspartate aminotransferase/alanin aminotransferase (AST/ALT), and metabolic syndrome showed association with advanced fibrosis (fibrosis stages 3 to 4). In multivariate analysis metabolic syndrome was found to be independently associated with liver fibrosis [31].
Another study including 179 cases of HBV-related HCC, who were surgically treated and pathologically confirmed, showed that the higher the BMI, the higher level of insulin and homeostasis model assessment for insulin resistance (HOMA-IR) were significant risk factors for HCC development. Authors concluded that metabolic abnormalities were closely associated with the occurrence and development of HBV-related HCC [32].
A large population based study in the United States investigated the association between metabolic syndrome and risk for both primary liver cancers, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The results indicated that pre-existing metabolic syndrome, as defined by the 2001 US NCEP-ATP III criteria, confered a statistically significant 2.13 and 1.56 fold increased risk for terminal liver diseases as HCC and ICC which was independent of other risk factors [33]. Recent data from Chinese and Korean cohorts established that MS is a risk factor of advanced liver fibrosis and cirrhosis independent of viral factors in chronic HBV infection [34,35]. In a recent prospective cohort study of 663 CHB patients, new-onset metabolic syndrome and some of its components (namely central obesity and low high-density lipoprotein cholesterol) were found associated with liver fibrosis progression (Figure-1) [36,37]. Even the effect of such coincident metabolic syndrome was most apparent in the immune tolerant phase; its effect was independent of change in viral load and ALT level [36]. This is supported by the observation from a survey in general population that CHB is associated with a lower prevalence of fatty liver, hypertriglyceridemia and metabolic syndrome [37].
Obesity and the metabolic syndrome are growing epidemics worldwide. These diseases are associated with both increased risk for, and worsened outcomes of many types liver diseases as well as chronic HBV. In the liver, inflammatory and fibrogenic and angiogenic changes due to underlying insulin resistance and fatty liver disease will likely lead to increased numbers of HBV patients with cirrhosis and HCC in the near future. Much work needs to be done to define more clearly the risks for development of terminal liver disease in those with underlying metabolic syndrome. Screening those at risk, and ultimately, the suitable treatments targeting the underlying mechanisms of pathogenesis would be beneficial.

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