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Friday, January 20, 2012

Steatosis and insulin resistance in response to treatment of chronic hepatitis C

Steatosis and insulin resistance in response to treatment of chronic hepatitis C
  1. F. Negro
Article first published online: 10 JAN 2012
DOI: 10.1111/j.1365-2893.2011.01523.x

Journal of Viral Hepatitis
Special Issue: How to Optimize Treatment of Hepatitis C
Volume 19, Issue Supplement s1, pages 42–47, January 2012

Abstract

Summary. This review will focus on the impact of steatosis and insulin resistance on the response to antiviral therapy for chronic hepatitis C. Hepatitis C virus (HCV) infection is known to have direct and/or indirect effects on lipid and glucose metabolism, leading to, among other disturbances, steatosis and insulin resistance, respectively. Some of these disturbances have a marked HCV genotype distribution. For example, on average, patients with HCV genotype 3 have the highest prevalence and severity of viral fatty liver. On the other hand, the current global spread of the metabolic syndrome represents a formidable cofactor of morbidity in HCV-related chronic liver disease. Thus, the pathogenesis of steatosis and insulin resistance in patients with chronic hepatitis C may often be dual, i.e. viral and metabolic. This distinction is relevant because the effect (if any) of steatosis or insulin resistance on the response to antiviral agents seems to depend on their pathogenesis. Accumulating data suggest that viral fatty liver may not impact on response to therapy, while metabolic steatosis does. Similarly, viral insulin resistance may not reduce the rate of response to therapy to the same extent that metabolic insulin resistance does. Some implications for patient management are discussed.
Abbreviations:
HCV
Hepatitis C virus
IRS
insulin receptor substrate
PPAR-[gamma]
peroxisome proliferator-activated receptor-[gamma]
SOCS
suppressor of cytokine signalling
SVR
sustained virological response
TNF-[alpha]
tumour necrosis factor-alpha

 

Introduction

Hepatitis C virus (HCV) infection is a major cause of acute and chronic liver disease, including their long-term sequelae, cirrhosis and hepatocellular carcinoma [1]. The spectrum of severity of HCV-associated liver disease and its rate of progression are influenced by several cofactors. These include age, gender, host genetic variability, exposure to alcohol and other toxins, immune status, coinfections and the metabolic syndrome [2]. Interestingly, HCV infection shares two pathological features with the metabolic syndrome: steatosis and insulin resistance [3,4]. This is owing to direct and indirect effects of HCV on lipid and the glucose metabolism, respectively [3,4]. These effects may lead to clinically relevant synergisms between HCV infection and the metabolic syndrome, for example affecting both liver disease progression and response to antiviral therapy [4,5]. In this article, I will analyse separately the effects of steatosis and insulin resistance on the response to antiviral therapy for chronic hepatitis C.

Steatosis and treatment response

Steatosis is a morphologically evident accumulation of neutral fats in the cytoplasm of hepatocytes. The prevalence of steatosis in patients with chronic hepatitis C varies between 40% and 80%, depending on the level of alcohol consumption, prevalence of overweight/obesity, type 2 diabetes and other causes of fatty liver [3]. When patients are selected so to rule out all these common causes of steatosis, the prevalence of fatty liver in chronic hepatitis C remains substantial (∼40%), that is, about twice as high as with chronic hepatitis B [3]. The direct steatogenic effect of HCV is supported by the strong association between steatosis and viral genotype 3: in patients infected with this particular genotype, (i) steatosis is more frequent and severe, (ii) its severity correlates with the level of viral replication and (iii) it disappears after successful antiviral therapy. The mechanisms leading to fat accumulation in HCV infection are numerous and include increased lipogenesis, decreased degradation and impaired lipoprotein secretion: their detailed description has been the subject of previous review articles and will not be discussed here [3].
The clinical consequences of viral steatosis are debated. Steatosis does not appear to predict the occurrence of fibrosis in patients with genotype 3 infections [6]. Similarly, a cohort study analysing the fibrosis progression rate in 1189 patients with known date of infection failed to identify steatosis as an independent factor for accelerated fibrogenesis in genotype 3 [7]. This suggests that viral steatosis does not contribute to fibrogenesis. If an association exists, this seems to occur in patients with metabolic steatosis, i.e. steatosis associated with insulin resistance and the metabolic syndrome [3,6].
Concerning the effect on response to antiviral therapy, again, a distinction must be made between viral and metabolic steatosis. Large clinical trials have shown that steatosis is associated with a reduced response to antivirals [8–10]. However, when results were stratified according to viral genotype, sustained virological response (SVR) rates were reduced only in patients with steatosis and non-genotype 3 infections [8]. Pretreatment steatosis was associated with lower SVR rates, except in patients with genotype 3, in whom patients with steatosis had the same chances (possibly slightly higher) of attaining an SVR than those without (85%vs 76%, P = 0.34). Similar results were reported for the DITTO trial [10]. In another study, patients with genotype 1 infections who achieved an SVR had less severe pretreatment steatosis compared to nonresponders (P = 0.02) [9]. In addition, genotype 1 infected patients with an early virological response were more likely to lack steatosis compared to those without an early response (71%vs 42%; P = 0.003) [9]. The mechanism underlying this negative effect is unclear, but it may be related to insulin resistance and/or other disturbances that correlate with steatosis and occur in the metabolic syndrome. A better knowledge of the mechanisms accounting for the poor response to antivirals in patients with steatosis may help in designing appropriate therapeutic schedules. However, the results of recent clinical trials have failed to provide useful insights.

Insulin resistance in HCV infection

Insulin resistance and diabetes are common complications of all chronic liver diseases. However, several epidemiological, clinical and experimental data show that HCV plays a direct role in perturbing glucose metabolism, leading to both insulin resistance and diabetes. Most cross-sectional studies comparing the prevalence of diabetes in patients with chronic hepatitis C with that of a comparator group have shown that patients infected with HCV present with diabetes more often than patients with chronic liver diseases of other aetiologies, even at a precirrhotic stage [10]. This observation was confirmed by a vast general population-based survey [11] and by several longitudinal studies [4,12]. Most of the risk affects patients with other cofactors of diabetes, suggesting that HCV infection may significantly increase the rate of developing glucose metabolism alterations in predisposed individuals. The association between HCV infection and glucose abnormalities holds true also when looking at the occurrence of prediabetes conditions, such as insulin resistance [13,14]. Curing HCV results in the amelioration of insulin resistance and decreased incidence of diabetes after the end of therapy [15–18]. These premises are important, also because of the current worldwide epidemic of the metabolic syndrome. As a result, insulin resistance and/or diabetes in patients with chronic hepatitis C may have a dual pathogenesis, i.e. due both to the direct and/or indirect action of the virus and to host factors.
Experimental data suggest a direct interference of HCV with insulin signalling. In a first study, liver specimens obtained from 42 nonobese, nondiabetic HCV-infected individuals and 10 non-HCV-infected subjects, matched for age and BMI, were incubated ex vivo with insulin and examined for integrity of the insulin signalling pathway [19]. This study showed that HCV directly interferes with this pathway, an observation extensively confirmed by subsequent studies. Increased proteasomal degradation of insulin receptor substrate-1 (IRS-1) and IRS-2 via activation of the suppressor of cytokine signalling-3 (SOCS-3) was reported in an in vitro expression system [20]. HCV genotype–specific interference mechanisms were suggested in another study [21], where downregulation of peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]) and upregulation of SOCS-7 were observed upon expression of the HCV genotype 3 core protein, whereas the core protein of genotype 1 activated the mammalian target of rapamycin. Interestingly, subsequent work suggested that PPAR-[gamma] may directly control SOCS-7 levels in cells transfected with HCV genotype 3 core constructs [22]. Other molecular mechanisms triggered by HCV may include increased endoplasmic reticulum stress [23] and activation of the c-Jun N-terminal kinase [24]. In a transgenic mouse model [25], the core-encoding region of HCV is sufficient to induce insulin resistance, an effect almost totally reversed by treatment with antitumour necrosis factor-alpha (TNF-[alpha]) antibodies, suggesting an increased level of serine phosphorylation of IRS-1 induced by TNF-[alpha]. Thus, in this model, HCV causes insulin resistance by stimulating TNF-[alpha] secretion.
Studies in patients with chronic hepatitis C have suggested that HCV may induce insulin resistance via increased oxidative stress [26] and intrahepatic inflammation, leading to an increased intrahepatic TNF-[alpha] response [27,28]. However, recent evidence obtained by combining use of the euglycemic hyperinsulinemic clamp, infusion of labelled glucose and glycerol, and indirect calorimetry shows that HCV infection is associated with both hepatic and peripheral insulin resistance even in patients without the metabolic syndrome [29], despite the fact that HCV infects essentially the liver. A significant extrahepatic component of HCV-induced insulin resistance has been confirmed by at least one independent study [30].

Insulin resistance and response to treatment

The clinical consequences of insulin resistance and diabetes on chronic hepatitis C are (i) accelerated fibrogenesis [13,14,31–35], (ii) increased risk of hepatocellular carcinoma [36–38] and (iii) reduced rate of virological response to IFN-[alpha]-based therapy [17,39–42], although recent data seem to contradict these latter findings [43]. This section will discuss the evidence concerning the third point only. Increasing levels of insulin resistance have been associated with reduced rates of virological response to pegylated IFN-[alpha]/ribavirin [44–48]. Increased levels of SOCS-3 in liver and/or in the peripheral blood mononuclear cells have been tentatively implicated as a potential molecular link between insulin resistance and lack of responsiveness to IFN-[alpha] in patients who respond poorly to therapy [49–53], although this observation has not been unequivocally confirmed [54]. SOCS-3 not only promotes the proteasomal degradation of IRS-1, as discussed in the previous paragraph, thus leading to impaired insulin signalling, but, like other members of the SOCS family, it is also a negative regulator of IFN-[alpha] signalling [55]. However, specific inhibitors of SOCS-3, which may become useful to correct resistance to both insulin and IFN-[alpha], are not available for clinical use. Alternatively, one may envision inhibiting TNF-[alpha] by administering infliximab or similar agents; however, while the data on the effects of infliximab and/or etanercept on insulin resistance levels in patients with the metabolic syndrome or rheumatoid arthritis are encouraging, they are not conclusive [56–59]. Thus, the only approach used so far to correct insulin resistance in chronic hepatitis C is the use of insulin sensitizers in association with the standard of care.
The data reported in four independent studies using different schedules containing the antiglycaemic PPAR-[gamma] agonist pioglitazone [60–63] are discouraging. In a first prospective study aimed at investigating the efficacy and safety of pioglitazone, 15 mg QD, administered together with the standard of care for chronic hepatitis C to patients who were prior nonresponders, failed to improve the rate of early virological response [60]. Data from three additional trials have so far been presented only in abstract form at international conferences. An interim analysis of one study showed that pioglitazone 30 mg QD, given as monotherapy for 4 weeks before the standard therapy of treatment-naïve, nondiabetic chronic hepatitis C patients, significantly increased the rate of virological response to therapy after 4 weeks, compared to pegylated IFN-[alpha]/ribavirin combination alone [61]. However, no long-term data are available from this trial. In a randomized, double-blind, placebo-controlled study, the administration of pioglitazone 30 mg QD together with the standard of care increased early and end-of-treatment virological response but failed to increase SVR [62]. Finally, in the large SENSITIZE trial [63], 155 patients were randomized to receive pioglitazone for 16 weeks (30 mg QD for 8 weeks followed by 45 mg QD for the remaining 8 weeks) prior to the standard of care or placebo. At a 12-week interim analysis, pioglitazone improved insulin and glucose concentrations and the insulin resistance score, but these changes were not paralleled by improved virological responses [63]. Long-term data are awaited, but it is unlikely that the SVR rate will be increased by pioglitazone, unless it significantly reduces the relapse rate.
In the only trial that used the antidiabetic metformin [64], only a marginal, nonsignificant increase of the SVR rate was observed, despite an increased virological response after 4 weeks of triple therapy. These data have not been independently confirmed.
Overall, the administration of insulin sensitizers together with the standard of care has not only failed to improve the virological response to therapy, but has also fallen short of providing any useful insight into the mechanisms linking reduced response to insulin resistance. Clearly, further data are warranted before insulin sensitizers can be added to the drugs to treat hepatitis C. However, the advent of direct-acting antivirals may render this issue obsolete. Preliminary data suggest that the baseline insulin resistance level does not affect the response to monotherapy with the protease inhibitor danoprevir [65]. In addition, the results of a recent trial seem to point out that viral insulin resistance may not affect the response to therapy to the same extent as metabolic insulin resistance does [43]. Thus, the future management of glucose metabolism disturbances in patients with chronic hepatitis C should focus on those lifestyle changes that are already the mainstay of treatment for patients with the metabolic syndrome and/or diabetes, with the aim of reducing the clinical and histological progression of HCV-associated


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