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Insulin resistance and HCV: Will new knowledge modify clinical management?
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Journal of Hepatology
Volume 45, Issue 4, Pages 514-519 (October 2006)
Francesco Negro
Divisions of Gastroenterology and Hepatology and of Clinical Pathology, University Hospital, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland
- 1. Introduction
- 2. The metabolic syndrome and insulin resistance
- 3. HCV infection and insulin resistance
- 4. HCV infection and steatosis
- 5. Consequences of insulin resistance and steatosis on fibrosis progression and response to antiviral therapy
- 6. What are the implications for patients' management?
"....the correct management of the metabolic syndrome should be undertaken in all affected patients and this independently of the existence of liver disease.... Control of excess body weight and increased physical exercise constitute the mainstays of any therapeutical intervention.... trials will explore whether specific therapeutic interventions aimed at decreasing insulin resistance, such as metformin and the thiazolidinediones, may modify the rate of response to interferon-α-based therapy....
... By sensitizing the liver to insulin, metformin may reduce fatty liver in leptin-deficient ob/ob mice [59], and in patients with non-alcoholic fatty liver disease [60], [61]. Glitazones, on the other hand, are known to shift the fat distribution from visceral to subcutaneous depots, which would in turn ameliorate insulin sensitivity of the liver. These compounds are also capable of stimulating adiponectin synthesis by adipocytes and opposing the effects of some pro-inflammatory adipokines...
.... the introduction of insulin sensitizers should be - for the time being - confined to randomized clinical trials. Interestingly, some moderate physical exercise and weight loss may not only reduce the insulin resistance state, but also improve the fatigue that so often accompany chronic hepatitis C, via the antagonization of leptin and pro-inflammatory adipokines...."
1. Introduction
Insulin resistance and, more generally, the metabolic syndrome are currently the focus of major research. The epidemic of obesity and related conditions, affecting the Western world and increasing portions of the Southern hemisphere, has far-reaching medical, social and economic implications [1]. The liver morphological expression of the metabolic syndrome is fatty liver, a lesion that the hepatologists have known for decades as being the most common histological picture associated with elevated liver enzymes. Among the consequences of the metabolic syndrome, one must consider the effect that it may exert on a co-existing liver disease, such as chronic hepatitis C. This dangerous interaction is further complicated by the fact that the hepatitis C virus (HCV) may directly interfere with the insulin signalling cascade, on the one hand, and cause liver steatosis, on the other. The scope of this brief review is to summarize the current knowledge on the relationship between the metabolic syndrome and chronic hepatitis C, and to assess whether this has already translated into a modification of patient management.
2. The metabolic syndrome and insulin resistance
The metabolic syndrome is defined by a cluster of metabolic risk factors of cardiovascular morbidity and mortality. Although its definitions have varied in the past, a recently convened panel promoted by the International Diabetes Federation has managed to issue a comprehensive and rational definition [2]. The clinical features that have been variably included in the definition of the metabolic syndrome span an abnormal body fat distribution, an insulin resistance state, a dyslipidemia (raised triglycerides and low concentrations of HDL-cholesterol in serum) and blood pressure, together with a pro-inflammatory and a pro-thrombotic state (blood clot formation in arteries). Insulin resistance is widely considered to be a central feature of the metabolic syndrome, even though the pathogenetic association between insulin resistance and some components of the metabolic syndrome, like arterial hypertension and the prothrombotic state, is not fully understood and warrants further investigation. For example, it is not clear to what extent insulin resistance is an independent risk factor of cardiovascular mortality, as currently evaluated by a prospective study [3].
Insulin resistance is defined as a condition in which higher-than-normal insulin concentrations are needed to achieve normal metabolic responses or, alternatively, normal insulin concentrations are unable to achieve normal metabolic responses [4]. A major issue concerning the definition of insulin resistance consists in the choice of the metabolic function that should provide its quantitative measurement. For historical reasons, glucose metabolism is usually considered. Although the glucose clamp technique remains the gold standard, other, simpler indices based on the measurement of glucose and insulin, like the homeostasis model assessment (HOMA) score, are preferred to assess the level of insulin resistance for the purpose of most clinical investigations [5].
3. HCV infection and insulin resistance
Diabetes is a known complication of all liver diseases, especially at the advanced stage. However, clinical and experimental work suggests a direct role of HCV in the derangement of glucose metabolism. The first observation that HCV-infected cirrhotic patients may present with type 2 diabetes more frequently than patients with cirrhosis of other origins came from Allison et al. in 1994 [6]. Later, a retrospective analysis of 1117 patients with chronic viral hepatitis [7] reported that diabetes occurred in 21% of HCV-infected patients but only in 12% of HBV-infected subjects. Multivariate analysis showed that HCV infection and age were independent predictors of diabetes. In a further case-control study conducted by the same authors in a cohort of 594 diabetics and 377 patients assessed for thyroid disease, 4.2% of diabetic patients were found to be infected with HCV compared with 1.6% of controls [7]. These data made a strong case in favour of an association between HCV and diabetes. The fact that HCV genotype 2a was found in 29% of HCV-infected diabetic patients but only in 3% of controls further added to the evidence, since it suggested the existence of diabetogenic sequences across HCV genome, particularly among patients infected with genotype 2a, an observation reported also by others [8]. These data on prevalence of HCV in diabetic persons have since been confirmed by several studies, including in the liver transplantation setting [9], [10], [11], [12].
The study conducted within the Third National Health and Nutrition Examination Survey (NANHES-III) pinpointed a significant association with age, i.e. persons 40 years of age or older with HCV infection were more than three times more likely than those without HCV infection to have type 2 diabetes [13]. This raised the suspicion that diabetes may be due to the stage of advancement of liver disease rather than to the viral infection per se, and that the higher prevalence among HCV-infected persons may - at least in part - depend on the higher risk of exposure to HCV through invasive procedures undergone by diabetic patients in the long term. To address this issue, the glucose metabolism had to be evaluated in the early stages of chronic hepatitis C [14], [15], [16]. Hui et al. [16] found that 121 HCV-infected patients with stage 0 or 1 hepatic fibrosis had higher levels of HOMA scores compared with 137 healthy volunteers matched by sex, body mass index, and waist-to-hip ratio. This work proved that HCV may induce insulin resistance at the early stage of liver disease, and provided some evidence that this effect may be driven by genotype-specific sequences.
The relationship between the severity of insulin resistance and the HCV replicative levels has been so far very difficult to prove. A recent work seems to suggest so [17], but it is still not clear whether HCV replication directly increases insulin resistance, or whether hyperinsulinemia stimulates viral replication, as suggested by in vitro data [18]. This lack of correlation may be due to the fact that the global level of insulin resistance is likely to depend on the contribution from the adipose tissue and the muscle, two extrahepatic compartments that are not infected by HCV.
The effect of antiviral therapy is another classical way to prove or disprove an association between infection and pathology. Romero-Gomez et al. [19] have shown that insulin sensitivity may improve in patients who achieve HCV RNA clearance, while it does not improve in non-responders, despite a decrease in BMI. An improved glucose tolerance has been reported to follow successful antiviral treatment in at least another study [20]. Further, independent confirmation of these observations is warranted.
Experimental data suggest a direct interference of HCV with the insulin cascade via proteasomal degradation of the insulin receptor substrate-1 and -2 [21] and their functional impairment through increased levels of pro-inflammatory cytokines such as TNF-α [22] or another post-receptor defect [23]. Knobler has suggested that HCV patients with more severe liver disease may have an exaggerated intrahepatic TNF-α response, resulting in insulin resistance and a higher risk of developing diabetes [24]. In patients with genotype 3a, HCV may alter the intrahepatic insulin signalling through a downregulation of peroxisome proliferator-activated receptor-ϒ [25]. Although the interference with the insulin effects shows some HCV genotype-specificity, as discussed above, insulin resistance has been reported to occur in all HCV genotypes, although to a different extent [26]. This is interesting, because it raises the issue of a potential evolutionary advantage to induce an insulin resistant state during the course of viral infection (see below).
4. HCV infection and steatosis
A direct relationship between HCV replication and steatosis has been extensively documented by both clinical and experimental data [27], [28]. Models exist that allow to study in detail the fine mechanisms underlying the triglyceride accumulation in hepatocytes [29], [30], [31]. This is mostly associated with HCV genotype 3a and seems to be mediated by an impaired VLDL secretion, most likely via an impaired activity of the liver microsomal triglyceride transfer protein [30], [32]. In addition, HCV may upregulate the sterol regulatory element binding protein signalling pathway (SREBP-1c) [33]. SREBP-1c is a protein central to insulin signalling, also involved in up-regulation of de novo lipogenesis and inhibition of fatty acid β-oxidation, two events that can favour intracellular accumulation of triglycerides. Stimulation of SREBP-1c may also activate HCV replication in vitro, underscoring the intricate relationship between glucose metabolism, fatty acids and HCV replication [33].
A virally induced steatosis may co-exist with a fatty liver due to other causes. In chronic hepatitis C patients who do not drink alcohol and are infected with non-3a genotypes, the most likely cause of steatosis is the insulin resistance that accompanies overweight [34]. This steatosis is not or very little modified by successful antiviral therapy [35], [36], and correlates with the BMI [34]. However, as many as 30% of patients with fatty liver infected with genotypes other than 3a have normal BMI and HOMA score [26], suggesting that other causes of fatty liver exist in hepatitis C. Among these, genetic polymorphisms, e.g. resulting in hyperhomocysteinemia, may play a role [37].
5. Consequences of insulin resistance and steatosis on fibrosis progression and response to antiviral therapy
Steatosis in chronic hepatitis C has been repeatedly associated with increased fibrosis stage [27], [34], [38], [39]. Some work has suggested a genotype-specific association between steatosis and fibrosis, but results are not univocal [40], [41], [42], [43]. Insulin resistance is also known to be an important pathogenic factor for fibrosis, but the relative contribution of steatosis and insulin resistance to fibrosis has not been determined in most studies. A recent meta-analysis using individual data from 3068 patients recruited at 10 centers in 5 countries suggests that steatosis and diabetes are both independent factors of fibrogenesis in patients with genotype 1 infection [44]. However, when insulin resistance, an earlier and more sensitive parameter of glucose metabolism derangement, is added to a logistic regression analysis, the association between steatosis and fibrosis disappears [16]. A body of recent epidemiologic work suggests that the presence of diabetes and insulin resistance per se are risk factors of severe fibrosis and more rapid fibrosis progression in chronic hepatitis C [16], [45], [46].
It has been contended that the association between insulin resistance and fibrosis stage may not necessarily be direct: factors promoting insulin resistance (and/or steatosis) may also be responsible for causing progressive fibrosis, and the role of intrahepatic inflammation has been advocated [44], [47] (Fig. 1).
Furthermore, the role of other circulating cytokines remains to be established. The metabolic syndrome is a chronic inflammatory state, where the liver is exposed to pro-inflammatory cytokines released into circulation by adipocytes. Among these cytokines, leptin is prominent example, and it may even be the cytokine responsible - at least in part - for the fatigue frequently reported in chronic hepatitis C [48], [49]. Recent work suggests that leptin, rather than hyperinsulinemia/hyperglycemia, may also stimulate hepatic stellate cells to produce connective tissue growth factor [50]. On the other hand, decreased serum levels of adiponectin may fail to protect the liver from a wide array of fibrogenic stimuli [51], and hypoadiponectinemia has been reported in chronic hepatitis C, especially in patients with steatosis [52].
As far as the response to antiviral therapy is concerned, steatosis has been recognized as a negative factor since 1996 [53]. This observation has been repeatedly confirmed by data coming from large clinical trials [36]. The effect seems significant for the steatosis observed in patients with non-3a genotype infection, against hinting at the insulin resistance as the real factor affecting responsiveness to interferon-α. This assumption has been nicely confirmed in a recent study [19], where the sustained virological response rate was inversely correlated with the baseline HOMA score. Indirect evidence in favour of this negative association comes also from the reduced response to antiviral seen in African Americans, reportedly due to their high rate of visceral obesity and insulin resistance [54], and from the correlation between high levels of circulating TNF-α, typically observed in insulin resistant states, and poor response to interferon therapy [55].
The molecular reasons for the correlation existing between insulin resistance and interferon-α resistance are currently the object of intense research. Patients failing to respond to interferon-α may have increased levels of SOCS-3 in their livers, a factor promoting the proteasomal degradation of IRS-1 [56]. Interestingly, members of the SOCS family are the physiological negative regulators of STAT-1, a key factor involved in the transduction of the interferon-α signal [57]. Should this occur also in HCV infection, a fascinating, unifying hypothesis may envisage a primary activation brought about by HCV on members of the SOCS family in order to inhibit the interferon-alpha signalling, with the simultaneous impairment of the insulin signalling (Fig. 2).
6. What are the implications for patients' management?
How can we transfer the current knowledge outlined above in the routine clinical practice? It should be said that the correct management of the metabolic syndrome should be undertaken in all affected patients and this independently of the existence of liver disease. What may be the optimal intervention in any given patient, i.e. taking into consideration his/her individual features in terms of BMI, age and so on, is matter of debate. Control of excess body weight and increased physical exercise constitute the mainstays of any therapeutical intervention. Paradoxically, why should physical exercise increase the level of insulin sensitivity of target organs like muscle is at present unclear.
What should be done in patients with the metabolic syndrome and chronic hepatitis C? Should the effect of insulin resistance on liver fibrosis and on response to antivirals dictate the routine management of chronic hepatitis C? It has been reported that weight loss can improve liver fibrosis in HCV-infected persons [58], most likely as a consequence of the improved insulin resistance associated with weight loss. The results of the study of Hickman and collaborators need however to be independently confirmed by prospective studies enrolling more patients followed for longer periods of time. But would the reduction of insulin resistance level be accompanied by an increased sensitivity to interferon-alpha? This is a very tricky question for which there is no clear answer at the present time. Several clinical trials are currently being set up in various countries to address this issue. These trials will explore whether specific therapeutic interventions aimed at decreasing insulin resistance, such as metformin and the thiazolidinediones, may modify the rate of response to interferon-α-based therapy.
By sensitizing the liver to insulin, metformin may reduce fatty liver in leptin-deficient ob/ob mice [59], and in patients with non-alcoholic fatty liver disease [60], [61]. Glitazones, on the other hand, are known to shift the fat distribution from visceral to subcutaneous depots, which would in turn ameliorate insulin sensitivity of the liver. These compounds are also capable of stimulating adiponectin synthesis by adipocytes and opposing the effects of some pro-inflammatory adipokines [62]. Whether all these effects will positively influence the response to interferon remains to be proven. A paradoxical effect consisting in the improved insulin sensitivity without effects on the interferon-alpha signalling cannot be excluded. It is of utter importance to assess these effects in vivo, and, as said, appropriate clinical trials are being launched to verify this working hypothesis.
Undoubtedly today we have one more reason to investigate the presence of the metabolic syndrome in chronic hepatitis C patients, especially those more at risk like the aged and the obese. The role of lifestyle changes in increasing insulin sensitivity will never be emphasized enough, but the introduction of insulin sensitizers should be - for the time being - confined to randomized clinical trials. Interestingly, some moderate physical exercise and weight loss may not only reduce the insulin resistance state, but also improve the fatigue that so often accompany chronic hepatitis C, via the antagonization of leptin and pro-inflammatory adipokines.
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