Metabolic syndrome and hepatitis C infection – brothers in arms

Metabolic syndrome (MS) is a complex disorder of overlapping clinical features including visceral obesity, dyslipidaemia, increased blood pressure and elevated blood glucose 1. Its increasing prevalence in general population and undoubtful burden on mortality are the emerging health problems in recent years. Data from large general adult population survey in United States showed that prevalence of MS reaches nearly 25% and demonstrates increasing trend from 6.7% in young adults to 43.5% in participants aged 60–69 years 2. In Europe, the overall prevalence of MS in non-diabetics was shown to be 15% 3. Chronic hepatitis C (CHC) affects estimated 160 million individuals worldwide, which is 2.3% of the world population 4. An overlap between MS and CHC is natural and gains more interest in the latest years. Despite extensive basic and clinical research, the nature of their mutual association is not yet clear. The association between MS and CHC can be addressed on at least three levels of evidence: epide-miological prevalence, pathophysiological link, as well data on long-term clinical outcomes (cirrhosis, hepatocellular carcinoma, diabetes and cardiovascular disease). Currently, there is no convincing evidence that CHC can cause or increase the frequency of metabolic syndrome. On the other hand, HCV infection is well linked to insulin resistance (IR) and type 2 diabetes, while lipid profile seems to be beneficial (lower levels of cholesterol) in CHC. Therefore, it may be necessary to distinguish between classical MS and HCV-associated insulin resistance with its consequences, while both phenomena may impact outcomes and efficacy of CHC treatment 5. Epidemiological studies show that different components of MS occur with various frequencies in chronic hepatitis C. The strongest evidence links HCV infection with altered glucose metabolism, insulin resistance and type 2 diabetes. In their classical paper, Mehta et al. 6, utilizing large cohort of US III National Survey, clearly showed that HCV-infected persons, aged 40 and older were 3 times more likely to develop type 2 diabetes than respective group of HCV-uninfected. Interestingly, HCV was the second strong predictor of type 2 diabetes after obesity. In patients with HCV-infection, diabetes occurred in more than 10 years younger population than in HCV-seronegative group. Further analyses showed that HCV-infected patients who displayed any other risk factor for type 2 diabetes developed this condition 11-times more likely compared with HCV-negative group 7. This observation underlines the relevance of HCV as trigger of diabetes in previously predisposed individuals. Important evidence of direct implication of HCV in diabetes comes from therapeutic observations. It was shown that HCV eradication (SVR – sustained virologic response) by interferon alpha plus ribavirin therapy causes a two-thirds reduction in the risk of type 2 diabetes development, while patients with advanced liver disease (hazard ratio, HR 3.3), who did not achieve SVR (HR 2.73) and aged over 50 (HR 2.1), had continuously high risk of diabetes 8. Despite strong association between HCV-infection and glucose metabolism, the link with other features of MS is not clear and sometimes, counterintuitive. While MS is associated with high triglycerides and low HDL-cholesterol, in chronic hepatitis C, decreased levels of cholesterol and LDL are observed. Moreover, achieving viral clearance is associated with an increase in LDL and cholesterol, which requires use of lipid lowering therapies in up to 1/3 of individuals 9. Until recently, robust data on cardiovascular diseases prevalence in chronic hepatitis C were lacking. Recent analysis of National Health and Nutrition surveys (1999–2010) including over 19,000 participants showed that chronic hepatitis C was independently associated not only with insulin resistance and diabetes but also with hypertension and congestive heart failure in United States 10. An article by Li et al. 11 published in the current issue of Liver International brings additional piece of evidence on the prevalence of MS components in chronic hepatitis C in Taiwanese population. This retrospective, multicentre study included 26 305 subjects of whom 13% (3408) were positive for HBsAg and 4.2% (1098) had detectable anti-HCV antibodies. Details concerning smoking, alcohol consumption, medical history and concurrent therapies were collected; unfortunately, information on physical activity or dietary habits was not recorded. The only groups that showed higher prevalence of MS were males and females aged over 45 with anti-HCV antibodies vs HCV-seronegative population. The prevalence of MS in HCV-infected women aged over 45 was 33% vs 21.3% among anti-HCV-negative and prevalence 33.8% vs 25.3% respectively was observed in the same age category in men. Interestingly, statistically significant differences were found with respect to majority of MS criteria, including waist circumference, fasting blood glucose and blood pressure, but not with lipid profiles with lower serum LDL and triglycerides in patients with HCV infection. On average, anti-HCV-positive males aged over 45 years had higher mean waist circumference by more than 2 cm, fasting glucose by 3 mg/dl and systolic pressure by 8 mmHg as compared with anti-HCV-negative males. No differences were observed in HBsAg-positive individuals. This study, although retrospective and lacking long-term follow-up, included large number of subjects which should reduce the likelihood of potential bias selection and brings another body of evidence that MS is more prevalent in HCV-infected individuals by approximately 10% also in Asia. Irrespective of epidemiological link, pathophysiological explanations of possible interactions between chronic HCV-infection and metabolic syndrome are necessary to fully understand its nature and potential causative effect. Unfortunately, although the evidence is accumulating, the complexity of metabolic disorders and the extent of potential confounding factors (especially coexistence of non-alcoholic fatty liver disease) hinder current knowledge. Among the best described are mechanisms of HCV-induced insulin resistance. Interestingly, HCV-induced insulin resistance differs from classical one. HCV-related IR originates in glucose homoeostasis disturbances in both liver and muscles, but not in adipose tissue. In hyperinsulinaemic clamp study including CHC patients without any features of MS, the ability of insulin to suppress endogenous glucose was reduced 3.5-fold, but also glucose uptake by striated muscles was diminished while suppression of lipolysis was not affected 12. Pathophysiological studies point towards interaction of HCV proteins on insulin signalling pathway mainly by inhibition of IRS-1 function together with its increased degradation mediated by members of cytokine signalling proteins (SOC) family. Among other potential mechanisms of direct interference include proteasome activator 28γ, protein phosphatase 2A (PP2A); also, indirect mechanisms (pro-inflammatory cytokines, IL-18, TNFα) are most likely implicated in pathogenesis of HCV-induced IR. Details of these interactions are reviewed by Bugianesi et al. 13. Another question of upmost importance is to what extent IR and MS may affect chronic hepatitis C. The answer to this question is as well largely speculative. Release of free fatty acids from adipose tissue in MS may stimulate HCV replication, but also increased levels of cytokines and adipokines observed in MS may yield anti-inflammatory and immune suppressive activities beneficial for HCV. Irrespective of the nature of mutual association between MS and CHC, both may affect outcomes in afflicted patients. It is especially valid for the risk of fibrosis progression, hepatocellular carcinoma (HCC) prevalence and liver mortality. In meta-analysis of 11 cohort studies, overweight and obesity were independently associated with risk of liver cancer with RR of 1.17 and 1.89 respectively 14. More recently, investigators from Italy showed that odds ratio for HCC was 4.33 in patients with diabetes and 1.97 in obese 15. Moreover, subjects in this study presenting simultaneously two and more MS components held almost four-fold excess risk for HCC in subjects not chronically infected with hepatothropic viruses. The most striking data were presented in the study from Taiwan including long-term follow-up of almost 24,000 subjects 16. Authors found that in HBV- or HCV-infected individuals with both obesity and diabetes, risk of HCC was increased 100-fold (!). Insulin resistance, expressed by HOMA index, was also found to be a predictor of liver-related death or transplantation in HCV-patients with compensated cirrhosis 17. Another important issue is an effect of insulin resistance on response to PEG-IFN+RBV therapy. In recent meta-analysis from France 18 including 14 studies and 2732 patients, baseline HOMA index was a major determinant of sustained virological response (SVR) and patients with IR had response rates 20%, although not all studies included in the meta-analysis showed consistent data. Some discrepancies between studies might result from including different proportion of patients with metabolic risk factors, therefore showing different origins of IR (metabolic-IR vs HCV-related IR). It is speculated that HOMA-IR index is predictive of SVR only in patients with metabolic-IR, while HCV-related IR might be improved by therapy and thus has no impact on response rate 19. Last but not least, increasing, although not univocal, evidence suggests increased risk of cardiovascular disorders and events in chronic hepatitis C patients with MS, among them atherosclerosis 20, congestive heart failure 10 or stroke 21. In conclusion, despite the strong association of MS with chronic hepatitis C, a causal relationship has not been proven. Regardless of the reciprocal nature of an overlap, chronic hepatitis C and some elements of metabolic syndrome may synergistically worsen prognosis, increase mortality and decrease response to anti-HCV therapies. Given significant proportion of patients with intersecting CHC and MS, attention must be paid not only to optimizing anti-HCV therapies but also to screening and treating of the metabolic syndrome. Further prospective, long-term epidemiological and pathophysiological studies on the association between HCV and MS are necessary to reduce significant burden of both disorders in the future.