QJM vol. 98 no. 1 © Association of Physicians 2005; all rights reserved.
Review |
TNF-
, chronic hepatitis C and diabetes: a novel triad
From the Metabolic Unit and 1Department of Medicine, Kaplan Medical Centre, Rehovot, Hebrew University Hadassah Medical School, Jerusalem, Israel
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Summary |
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 Top Summary IntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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Patients with chronic hepatitis C virus (HCV) infection have a significantly increased prevalence of type 2 DM compared to controls or HBV-infected patients, independent of the presence of cirrhosis. Moreover, antecedent HCV infection markedly increases the risk of developing DM in susceptible subjects. Even non-diabetic HCV patients have insulin resistance and specific defects in the insulin-signalling pathway. Activation of the tumour necrosis factor (TNF)-
system has a pivotal role in the inflammatory process of chronic hepatitis C, and TNF- levels correlate with the degree of inflammation. TNF- is known to cause insulin resistance, with similar defects in the insulin signalling pathway to those described in HCV infection. A model of mice transgenic for the HCV core protein demonstrated insulin resistance, glucose intolerance, and elevated intrahepatic TNF- mRNA; all of which were ameliorated by anti-TNF- antibodies. In addition, diabetic HCV patients have significantly higher levels of soluble TNF- receptors, compared to non-diabetic HCV patients and controls. TNF- may be the link between HCV infection and diabetes, suggesting an additional mechanism of diabetes with important implications for prognosis and therapy. |
Introduction |
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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Infection with hepatitis C virus (HCV) is a common problem worldwide, affecting millions of people across all populations. Most acutely infected patients develop chronic hepatitis and become a potential source of virus transmission, and as many as 1 in 5 will develop cirrhosis and its complications.1,2 In addition, HCV is increasingly recognized as an important cause of extrahepatic manifestations. These are mostly immune-mediated, such as mixed cryoglobulinaemia, reported in up to half of patients with chronic hepatitis C,3 although clinically important disease is far less common. Recent data shows that HCV infection is also a significant risk factor for the development of type 2 diabetes mellitus (DM).4–10 The association may be second in prevalence only to cryoglobulinaemia, with intriguing pathogenesis and implications, but it is poorly recognized.
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Diabetes in HCV-infected patients without cirrhosis |
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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Glucose intolerance is very common in liver cirrhosis of whatever aetiology, and
20% of patients have overt diabetes.11 When cirrhosis is HCV-related, the risk of diabetes is higher4,5 and post-transplantation diabetes is also significantly more common in patients whose liver failure was due to HCV.6,7
The large ongoing National Health and Nutrition Examination Survey (NHANES III) evaluated 9841 community-living subjects and showed that people aged 
40 years who were anti-HCV-positive had an odds ratio of 3.77 (95%CI 1.8–7.87) for type 2 DM.8 This finding was adjusted for possible confounding factors such as sex, body mass index (BMI), ethnicity, poverty index, and previous drug or alcohol use, and was not found in hepatitis B infection. The HCV-positive group had no clinical stigma of chronic liver disease, although no liver biopsy data were available. In our case-control study of patients with no cirrhosis on liver biopsies, a third of HCV-infected patients had type 2 DM, a remarkable increased prevalence not found in patients with chronic hepatitis B or matched controls.9 Recently, in a large cohort of patients, a three-fold increase in the prevalence of glucose abnormalities was observed in non-cirrhotic HCV-positive subjects compared with HCV-negative subjects.12 Moreover, under multivariate analysis of patients with chronic hepatitis without cirrhosis, HCV infection was an independent predictor of glucose abnormalities, with an OR of 4.26 (95%CI 2.03–8.93).12 Thus, chronic hepatitis C is specifically and frequently associated with diabetes, regardless of the presence of liver cirrhosis.
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Risk factors for the HCV-DM association |
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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In the Atherosclerosis Risk in Communities Study, a 9-year follow-up showed that antecedent HCV infection was a significant risk factor for developing diabetes in patients with advanced age or high BMI, with a relative hazard of 11.58 (95%CI 1.39–96.6).10 Other risk factors for developing diabetes in HCV patients include positive family history of diabetes and Black ethnicity, but not auto-antibodies characteristic of type 1 DM.4,8–10,13,14 Thus HCV leads to type 2 DM in susceptible hosts.
Additional risk factors have been recently identified that may prove important in deciphering the pathogenesis of this association. HCV patients who develop diabetes had more severe liver disease according to both their liver enzymes and biopsy findings.9,13,15 Furthermore, insulin sensitivity in non-diabetic HCV patients showed significant correlation with serum aspartate aminotransferase, histological activity index and the degree of fibrosis.15 A recent study of 260 HCV-infected patients confirmed that insulin resistance was an independent predictor of the degree of fibrosis.16 Interferon therapy is often implicated in the literature as having a role in the development of diabetes in HCV patients. However, this association is rare, and the few cases of DM developing during interferon therapy had type 1 DM, in line with other autoimmune manifestations induced by interferon.17,18
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TNF- and insulin resistance
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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It has recently been suggested that chronic sub-clinical inflammation is associated with insulin resistance, and precedes the development of type 2 DM.19 Data from the large Women's Health study showed that elevated serum C-reactive protein (CRP) levels were associated with a four-fold increase in risk for future diabetes.20 Moreover, in cross-sectional studies, levels of inflammatory bio-markers such as CRP and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor
(TNF-), correlated with insulin sensitivity and with features of the insulin resistance syndrome.19
TNF- has been shown by several studies to link obesity, a known major risk factor for type 2 DM, and insulin resistance.21–24 Expression of TNF- mRNA was increased, and was strongly correlated to the degree of obesity and the level of insulin resistance in obese animal models and humans.21,22 Long-term exposure of animals to TNF- induced insulin resistance, whereas neutralization of TNF- increased insulin sensitivity.23,25 TNF- can induce insulin resistance by diverse mechanisms, both direct and indirect (Table 1). TNF- interferes with the insulin signalling pathway, particularly by inhibiting the tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1) in adipocytes.24 The lipolysis-stimulating effect of TNF- leads to increased serum levels of free fatty acids, reducing insulin sensitivity, and TNF also has a direct inhibitory effect on insulin action in the liver.22,26 These effects of TNF- lead to reduced glucose uptake in muscle, and to increased hepatic glucose production.22,26 Recent data suggest that TNF- also regulates expression of several adipocyte genes known to modulate insulin sensitivity/resistance (Table 1).27 TNF may even reduce ß-cell function by direct effects, further contributing to its role in the development of diabetes.21 These observations are already supported by significant findings in vivo. For example, obese mice with no functional genes for TNF- or with mutant TNF receptors, remained insulin-sensitive despite marked weight gain.28 Thus, interfering with the TNF signalling pathway protects from obesity-induced insulin resistance.
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TNF in chronic hepatitis C |
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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Inflammatory cytokines, including TNF-
, are an integral part of inflammation in chronic hepatitis C infection. TNF- mediates its effects by binding to two distinct cell surface receptors, TNFR-1 and TNFR-2. Subsequently, proteolytic cleavage of the extracellular parts of these receptors elicits the soluble receptors sTNFR1 (-p55) and sTNFR (-p75). Therefore, sTNFR levels are considered sensitive and reliable indicators of the activation of TNF- system, preferable to TNF- itself.29 These insights heralded important findings: serum levels of TNF- and both types of circulating soluble TNF receptors (sTNFR) were not only increased in HCV-infected patients compared with controls, but sTNFR showed significant correlation with aminotransferase levels and the histological severity of inflammation.30,31 In the liver too, TNF--producing cells (mainly of the macrophage/Kupfer cells lineage) and the expression of TNF and sTNFR were increased in HCV patients.31Intriguingly, compared with to non-diabetic patients with HCV infection, HCV patients with diabetes had increased serum and liver markers of increased inflammation and fibrosis.9,13 Thus, given the correlation between the activity of the liver disease and insulin resistance,15 a link between chronic HCV infection, TNF- and type 2 DM is an attractive hypothesis. |
TNF as a possible link between HCV and diabetes |
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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Recent research provides ample support for this hypothesis. A study of liver biopsy specimens from non-diabetic HCV patients revealed significant impairments in the insulin signaling pathway,33 which are strikingly similar to the known effects of TNF-
and can lead to insulin resistance.21,22,34 In an elegant study by Shintani et al., a transgenic mouse model that specifically expressed the HCV core protein in hepatocytes was studied.35 These animals had insulin resistance at an early age, and when challenged by a high-fat diet, they developed glucose intolerance. Further characterization of the metabolic defects in these animals revealed that insulin resistance was caused mainly by failure of insulin to suppress hepatic glucose production. The role of TNF- in the pathogenesis of this HCV-associated insulin resistance state was strongly suggested by finding elevated intrahepatic TNF- and particularly by the amelioration of the metabolic abnormalities when anti-TNF- antibodies were administered.35 Our own results provide further support to this hypothesis. Serum sTNFR levels were measured in non-cirrhotic HCV patients with and without DM, type 2 DM patients and healthy controls. Marked increases in both sTNFR1 and sTNFR2 were demonstrated only in HCV-DM patients and not in any of the other groups.36 In another recent study of non-cirrhotic non-diabetic HCV patients, insulin resistance correlated with serum TNF- levels, and also with liver fibrosis and serum aspartate aminotransferase.37 These two studies suggest that in humans, TNF- has systemic effects that result in insulin resistance and type 2 DM. The site of action by which TNF- exerts its metabolic effects in humans is still undetermined. The transgenic mice model data,35 and the findings of impairments in the insulin signalling pathway in liver biopsy specimens from non-diabetic HCV patients,33 suggest that the liver is the main site of TNF- action. Notably, in rats, the concentrations of TNF protein in tissues such as the liver are several orders of magnitude higher than in the circulation,38 supporting a local (paracrine) effect. However, considering the multiple known effects of TNF- in tissues such as adipose, muscle and pancreas, further studies are needed to elucidate various possible tissue defects and also the route of action, i.e. endocrine, autocrine or paracrine.21 Increased levels of TNF- are also known to occur in other chronic liver diseases, including chronic hepatitis B infection. Possible explanations for the unique association between insulin resistance and HCV infection may relate to differences in the clinical course of liver inflammation and fibrosis, or in the mode of TNF-receptor activation or cleavage.
We suggest the following scheme (Figure 1). HCV patients with more severe liver disease may have an exaggerated intrahepatic TNF- response, resulting in insulin resistance and a higher risk of developing type 2 diabetes. An interrelationship between HCV and other predisposing conditions can also partly be mediated by TNF-, as most of the established risk factors for type 2 diabetes also cause increased TNF- system activation. For example, in obesity there is ample evidence that increased TNF- secretion by adipose tissue is a major mediator of insulin resistance.22,38 Ageing, Black ethnicity and a family history of type 2 diabetes have also been associated with increased TNF-.39,40 Thus, African-Americans infected with HCV have higher TNF- levels compared with HCV-positive Caucasians,40 and non-diabetic lean offspring of type 2 DM patients, have significantly higher levels of sTNFR2, compared with subjects with no such family history.41 Other (‘dnon-TNF’-mediated) mechanisms may also operate, and add to the state of insulin resistance (Figure 1). However, the data discussed support the notion that activation of TNF- has a pivotal role in the pathogenesis of the HCV-DM association.
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Implications |
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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The HCV-diabetes association represents a major public health problem. Hundreds of thousands of patients in the USA alone are probably affected, and many more may have impaired glucose tolerance. Diabetes-related microvascular and macrovascular complications are likely, and the ongoing hepatic inflammatory response may contribute to atherogenesis. Furthermore, a putative bi-directional relationship between HCV-induced liver disease and diabetes may occur (Figure 1). Both insulin resistance and diabetes can adversely affect the course of chronic hepatitis C, and lead to enhanced steatosis, steatohepatitis and liver fibrosis.42,43 Moreover, recent evidence strongly suggests that steatosis and diabetes may also significantly enhance the risk of hepatocellular cancer.44,45
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Future directions |
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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Developing safe and effective interventions that block the TNF response in patients with chronic hepatitis C and studying their effect on insulin resistance seems a tangible goal. This approach has been used successfully in diverse conditions in which a deleterious role of TNF has been demonstrated, such as rheumatoid arthritis and inflammatory bowel disease.46 TNF inhibition has already been shown to be beneficial in an animal model of steatohepatitis,47 and initial data indicate its safety in chronic hepatitis C.48 Once developed, a favourable effect on insulin sensitivity and glucose tolerance in HCV patients would strongly support the role of TNF-
in the HCV-DM association and establish a novel pathogenesis and treatment for type 2 DM. Meanwhile, HCV patients who have one or more risk factors for developing DM (older age, obesity, positive family history, Black ethnicity, high degree of liver inflammation/fibrosis) should be screened for glucose intolerance. In high-risk patients, a comprehensive treatment including lifestyle modifications can be recommended. The effect of these measures, as well as the possible role of the anti-diabetic drugs thiazolidinediones,38 known to modulate TNF-, on the progression of the liver disease, remain intriguing questions. |
Footnotes |
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Address correspondence to Professor A. Schattner, Department of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge CB2 2QQ. e-mail: as655{at}medschl.cam.ac.uk or Dr H. Knobler, e-mail: knobler{at}inter.net.il
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TopSummaryIntroductionDiabetes in HCV-infected...Risk factors for the...TNF-{alpha} and insulin...TNF in chronic hepatitis...TNF as a possible...ImplicationsFuture directionsReferences |
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