Chronic hepatitis C infection and insulin resistance: two best friends

August 2011, Vol. 9, No. 8, Pages 555-558 , DOI 10.1586/eri.11.72
(doi:10.1586/eri.11.72)

Chronic hepatitis C infection and insulin resistance: two best friends

Ludovico Abenavoli† & Piero L Almasio
† Author for correspondence

Approximately 170 million people worldwide are chronically infected by HCV, which can result in progressive hepatic injury and fibrosis, culminating in cirrhosis and end-stage liver disease. Among adults in the Western world, chronic hepatitis C (CHC) is the major cause of cirrhosis and the principal indication for liver transplantation [1]. The main treatment goal in patients with chronic HCV infection is sustained virological response (SVR) after treatment schedule. The ‘gold standard’ of therapeutic approach is the combination of pegylated IFN-α (PEG-IFN) with ribavirin (RBV) [2]. This association is highly successful in patients with genotype 2 and 3 infection, with SVR rate ranging between of 76 and 82% [3].

Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disorder in the Western world. It is now recognized that patients with NAFLD have a multitude of severe comorbidities (e.g., diabetes, hypothyroidism and metabolic syndrome) [4]. NAFLD incidence in adults and children is rapidly rising because of the ongoing obesity epidemic and Type 2 diabetes. NAFLD is an umbrella term that includes steatosis, nonalcoholic steatohepatitis (NASH) and advanced fibrosis or cirrhosis related to this pathological entity.

Currently the biological mechanism of the underlying steatosis and the progression of liver disease is not entirely understood; it is probably due to the expression of a number of factors. Previously, a two-step hypothesis was proposed to explain this mechanism: initially the ‘first hit’ induces liver fat accumulation prior to the ‘second hit’, which prompts steatosis progression to NASH [5]. At present, obesity, insulin resistance (IR), oxidative stress and cytokine/adipokine are identified as the major factors involved in the NAFLD pathogenesis.

These factors can promote and boost inflammation, cell injury, apoptosis, fibrogenesis and carcinogenesis, leading to fat accumulation, a development and progression of the disease. Currently, the therapeutic approach to NAFLD involves a lifestyle intervention (e.g., weight reduction and regular physical activity) and the use of insulin-sensitizing drugs. Other treatment approaches have included the consumption of special diets and antioxidant and cytoprotective therapies [6].

Numerous observations suggest that liver steatosis is a common histological feature of CHC infection ranging from 40 to 86% [7]. The majority of patients have mild steatosis affecting less than 30% of hepatocytes. Thus, steatosis occurs more frequently in patients with CHC (55%) than in the general population (20–30%) of adults in the Western world [8]. Macrovesicular steatosis is found in the periportal region of the liver, different from the centrilobular distribution characteristic of NASH patients.

Genotypes

Moderate or severe steatosis is significantly less frequent in HCV genotype 4 than 3 and similar between genotype 4 and 1. In nondiabetic, overweight patients, moderate or severe steatosis is only present in 10–15% of genotype 4 or 1, compared with 40% of genotype 3 patients. In those with genotype 3 infection, the prevalence of steatosis is much higher, and is directly linked to HCV-mediated alterations in hepatic lipid metabolism. In contrast to genotype 1 infection, the presence of hepatic steatosis is a sign of underlying IR and features of the metabolic syndrome [9]. It is believed that steatosis enhances the progression of HCV infection to liver fibrosis and decreases the response to antiviral therapy. The pathogenic association between HCV infection and hepatic steatosis is multifactorial.

Pathogenesis & correlation

Insulin resistance is defined as an impaired ability to clear glucose from the circulation at a given level of circulating insulin. Both NAFLD and HCV are associated with increased gluconeogenic drive and IR as shown by the impaired suppression of hepatic glucose output by insulin [10]. Literature has reported that HCV core protein may block assembly of apolipoprotein A1-A2 with triglycerides. The result is a decreased export of triglycerides bound to apolipoprotein-β as very low density lipoproteins out of hepatocytes [11]. Okuda et al. have proposed that the core protein induces oxidative stress within the mitochondria that contributes to lipid accumulation [12], in particular in genotype 3 patients by the cytopathic effect of high titer of intracytoplasmic negative strand HCV-RNA [13].

It has been reported that IR plays a central role in the pathogenesis of NAFLD [5]. However, the mechanisms of the biological mechanism underlying liver steatosis in HCV patients, is not definitively understood. IR causes impaired metabolic clearance of glucose, compensatory hyperinsulinemia, and increased lipolysis. In fact, during exposure to insulin, subjects with NAFLD have impaired suppression of circulating free fatty acids and glycerol. These products of lipolysis mark the effects of insulin on peripheral lipolysis [8].

By contrast, subjects with HCV infection do not show any significant changes in peripheral levels of free fatty acids and glycerol.

Insulin resistance has also been associated with fibrosis progression in CHC patients [9,10]. This link is complex and genotype specific. In CHC due to genotype 1 and 4, IR is associated with hepatic steatosis and is either virus-mediated or due to host metabolic factors, such as visceral obesity [14,15]. Conversely, liver steatosis in HCV genotype 3 infection is predominantly a direct effect of the virus, occurring in the absence of other metabolic risk factors [16]. Genotype 3 is the only subtype that has been shown to be correlated to a higher grade of steatosis independent of other host-related factors, such as the presence of NAFLD. The severity of steatosis in these patients is directly related to the HCV-RNA viral load. Indeed, steatosis often resolves with the loss of viremia after antiviral treatment [17].

Liver steatosis & interferon nonresponse in HCV patients

Insulin resistance is associated with a poor response to antiviral treatment in patients with HCV genotype 1, 2 and 3 [18]. While the mechanisms underlying the failure of IFN therapy are not well understood, evidence indicates that several host factors are involved in addition to viral factors [15]. Among them, IR has been found to reduce the chances of achieving an SVR. Both impaired fasting glucose and Type 2 diabetes are associated with lower rates of SVR in patients treated with PEG-IFN and RBV. Multivariate analysis of the Virahep-C cohort showed that the homeostasis model assessment (HOMA) index, a measure of IR, was an independent predictor of SVR [19]. Although IR was more prevalent among African–American populations compared with Caucasian–American populations, this clinical feature, and nothing else, can explain the SVR differences between the two groups. A previous study of genotype 1-infected patients treated with PEG-IFN and RBV, demonstrated that the HOMA index is correlated with treatment response [20]. In this study, patients who had a normal HOMA (<2) presented an SVR of 60.5%, compared with 40% in patients with moderate IR (HOMA 2–4), and only 20% in patients with severe IR (HOMA >4). Literature supports a connection between HCV replication and IR. In fact, HOMA decreases when the virus is eradicated [21].

One mechanism by which IR and obesity may contribute to IFN nonresponse is through upregulation of suppressor of cytokine signaling 3 (SOCS3) [22]. SOCS3 blocks IFN signaling and may also exacerbate IR by promoting ubiquitin-mediated degradation of insulin receptor substrate 1 and 2 [23]. SOCS3 seems to be a key molecule for a cross-talk between IR and therapy nonresponse. In fact, hepatic expression of SOCS3 has a predictive value for the outcome of antiviral therapy in patients with HCV infection [24]. It is well known that IR increases hepatic lipid synthesis [25]. For HCV replication, lipid droplets play a central role. In fact, the accumulation of hepatic lipid droplets can increase HCV replication, and, as a consequence of this, poor responses to antiviral treatment are observed, even in patients with HCV genotypes 2 and 3 [25].

It has been demonstrated that the use of insulin-sensitizing agents, such as thiazolidinediones, in HCV treatment increases both SVR and rapid virological response rates. In particular, the use of pioglitazone (30 mg/day) concomitantly with the standard antiviral therapy in the treatment of naive, nondiabetic patients with genotype 4 HCV infection with IR (HOMA >2) increased SVR rates compared with standard of care (60.4 vs 38.7%, respectively; p = 0.04) [26].

Conclusion & future perspective

Steatosis development and CHC infection are clearly linked. It is well known that the accumulation of lipids in the infected hepatocyte could be a determinant for virus assembly. In fact, steatosis is an efficient mechanism for promotion of HCV replication. In addition, HCV induces IR by several pathogenetic mechanisms that are also implicated in treatment resistance and an increase of fibrosis progression. In this way, antiviral responsiveness remains a major clinical problem in the eradication of HCV, even with the use of new drugs. It is now clear that NAFLD is a frequent challenge in the clinical and histological management of patients with HCV, as well as for treatment efficacy. The use of pioglitazone as an adjuvant therapy appears to be promising in the treatment of CHC patients with IR. However, the optimal dose and treatment schedule is still debatable. In order to ameliorate the response to antiviral therapy, by a rational and targeted therapeutic approach, new research to define the underlying mechanisms of HCV-associated IR, is needed.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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