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Keywords:

  • diabetes;
  • hepatocellular carcinoma;
  • hepatitis C;
  • insulin resistance;
  • liver transplant;
  • metabolic syndrome;
  • pegylated interferon;
  • ribavirin;
  • sustained virological response

Abstract

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References

Epidemiological data clearly indicate a link between chronic hepatitis C (CHC) and disturbed glucose homeostasis. The prevalences of both type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are higher among those chronically infected with hepatitis C when compared with the general population and those with other causes of chronic liver disease. Both IR and diabetes are associated with adverse outcomes across all stages of CHC including the liver transplant population. The adverse effects that directly influence patient outcome are reduced responsiveness to antiviral therapy, more rapid progression of fibrosis to cirrhosis and a higher incidence of hepatocellular carcinoma. Although both viral and host factors are known to contribute to IR (and therefore the risk of T2DM), there is a paucity of evidence to support interventions targeting IR with pharmacotherapy or lifestyle intervention. The purpose of this review is to examine the impact of abnormalities of glucose homeostasis in CHC, and in so doing, to raise a number of questions. How do we identify those at risk of diabetes in CHC? Can we reduce the incidence of hepatoma and reduce transplant-related morbidity and mortality by preventing or treating diabetes? Can we improve the response to antiviral therapy by pretreating IR and T2DM in treatment candidates? Ultimately, can we cure two diseases, diabetes and CHC, with one treatment?

Chronic infection with the hepatitis C virus (HCV) affects an estimated 170 million worldwide (1). Liver disease in those infected as adults may progress to cirrhosis and its complications in up to 25% over 25–30 years, contributing to significant morbidity and mortality (2, 3). Disease progression is much slower when infection is acquired in childhood (4).

In addition to these significant hepatic complications, a clear association has been observed between chronic hepatitis C (CHC) infection and disturbances of glucose metabolism. The prevalence of both insulin resistance (IR) and type 2 diabetes mellitus (T2DM) is significantly higher in patients with CHC when compared with other chronic liver diseases (5–11). Consequently, it has become increasingly apparent that IR with or without concomitant T2DM influences long-term outcomes in CHC. Both reduce responsiveness to antiviral therapy (12, 13) and promote more rapid progression of liver disease to cirrhosis and hepatocellular carcinoma (HCC) (14–18). In the setting of advanced liver disease, T2DM is present in 40% of patients with CHC just before liver transplantation, develops de novo in 64% post-transplant, and is thereafter associated with poor outcomes (19–21). In liver transplant candidates without T2DM, post-transplant diabetes mellitus (PTDM) is more likely to develop in those with cirrhosis because of CHC than in those with cirrhosis secondary to other causes (22). The recognition of the associations between CHC, IR and T2DM raises many questions about the pathophysiology of these disturbances of glucose metabolism, and how best to manage them.

Hepatitis C virus and diabetes

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References

Epidemiology

The association between diabetes and CHC was first reported by Allison et al. (5), who observed that diabetes was significantly more prevalent in those with hepatitis C-related cirrhosis than those with cirrhosis resulting from conditions other than CHC (50 vs 9%). Since then, a number of studies have re-affirmed this association. The reported prevalence of T2DM in CHC ranges from 7.6 to 50%; confounding factors known to influence IR such as age, body mass index (BMI), viral load, viral genotype, advanced fibrosis and steatosis likely influence the variation in the prevalence reported (6–8, 11).

Role of viral factors

The underlying mechanism for T2DM is IR. Cirrhosis itself (independent of the underlying aetiology) is associated with reduced insulin sensitivity (23), but we now know that IR is present in 30–70% of individuals with CHC, its presence independent of BMI, viral load and the severity of liver disease (9, 10). A population-based study of those at a high risk for diabetes (older age, high BMI) indicated that persons with CHC are more than 11 times as likely as the uninfected to develop diabetes (24). Conversely, it has also been observed that among patients with T2DM, the prevalence of CHC is higher than that in the general population (8, 25–28).

The mechanisms of IR in CHC are an area of intense study, and numerous molecular pathways have been implicated. In brief, IR in CHC arises both as a direct consequence of the virus and indirectly as a consequence of lipid accumulation and/or inflammation. The HCV core protein is proposed to cause IR in hepatocytes by reducing the level or the activity of molecules involved in the insulin signalling cascade (29, 30). Additionally, the HCV non-structural protein 5A mediates oxidative stress and inflammation (31), indirectly contributing to IR in CHC.

There are conflicting reports regarding virus-induced mediators of inflammation and their role in the development of IR in CHC. A cohort of 28 non-diabetic patients with CHC had significantly higher tumour necrosis factor (TNF)-α levels and soluble TNF receptor (sTNFR) and IL-6 levels when compared with 14 patients with non-HCV chronic hepatitis (32). In that study, a direct correlation was observed between sTNFR levels and HOMA-IR. TNF-α and IL-6 also induce suppression of cytokine signalling (SOCS) protein expression (33); in a mouse model, SOCS-3 has been shown to reduce insulin-induced tyrosine phosphorylation of IRS-1 (34). In contrast, a large prospective study found that virus-specific IR in CHC may be a cytokine-independent effect of the virus to modulate insulin sensitivity (35).

The molecular mechanisms of IR and the development of T2DM were recently reviewed in detail by Serfaty and Capeau in this journal (36).

Role of host factors

While CHC is independently associated with IR and T2DM, the presence of concomitant host-specific risk factors also contributes to both the prevalence and the degree of disturbance of glucose homeostasis. Figure 1 illustrates the complex interrelationship between these factors in CHC. Metabolic syndrome, as defined by the National Cholesterol Education Program – Adult Treatment Panel III criteria (37), is present in up to 26% patients with CHC, of whom 69.5% have glucose intolerance and/or overt T2DM (38). Obesity was present in 28.8% of patients with CHC referred to a Canadian hepatology centre, significantly higher than the national prevalence of obesity in Canada at that time (39).

image

Figure 1.  Relationship between hepatitis C virus (HCV) and metabolic abnormalities (5–8, 11, 24, 39–41, 82).

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These observations are important as there is clear evidence that the incidence of T2DM increases with BMI and/or the presence of the metabolic syndrome (40). The incidence of T2DM in the general population with normal body weight (BMI<25) is reported to be 1.2%, but the relative risk is over five-fold among the obese and over 10-fold in the obese with concomitant MetS or IR (40). In a cohort of 118 non-cirrhotic, non-diabetic patients with CHC, the prevalence of IR was reported to be 38% (41); in those who were obese (mean BMI 34.2±3.9 kg/m2), the rate of IR was 72%. Clearly, the coexistence of obesity and/or metabolic syndrome is an additional risk for the development of disturbed glucose homeostasis among patients with CHC.

In addition to these potentially modifiable host-specific risk factors, host genetics may play a role in the development of T2DM in CHC. Patients with chronic liver disease appear to have an immunogenetic risk for diabetes characterized by the presence of specific human leucocyte antigen alleles, higher frequencies of which have been observed in patients with CHC when compared with those with non-HCV chronic liver disease (42).

It is likely that both viral- and host-related factors combined promote IR and T2DM in individuals with CHC. Vigilance to these host risk factors is essential so as to diagnose disturbances of glucose metabolism early, and then to consider potential preventative measures.

Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References

Measuring insulin resistance

Insulin resistance is a state in which higher levels of insulin are required to achieve a normal metabolic function. IR represents a spectrum of abnormal glucose metabolism that may lead to overt hyperglycaemia, defining T2DM. Although IR may develop simultaneously in the liver and in the periphery (skeletal muscle and adipose tissue), the degree of IR may differ at these sites. The gold standard for measuring IR is the glucose clamp technique (43), but this test is cumbersome and impractical for routine clinical use. The homeostasis model for assessment of IR (HOMA-IR) may be used as an alternative measure. The HOMA-IR correlates well with the hyperinsulinaemic euglycaemic clamp method for measuring hepatic IR and is calculated with the equation (43):

  • image

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The World Health Organisation defines IR as a HOMA-IR score of the highest quartile of the non-diabetic population, as this is the cut-off value above which healthy patients are discriminated from those at risk of diabetes (44). This cut-off value may vary from population to population (45), which in part accounts for the heterogeneity in the cut-off values cited and the prevalence and outcomes reported in studies of IR in CHC. It is also important to note that IR (as measured by the HOMA-IR) may be present in the setting of a normal fasting plasma glucose, and hence may be truly ‘sub-clinical’ and thus only identified if it is considered and tested for.

The role of fasting plasma glucose and oral glucose tolerance testing

Insulin resistance represents a spectrum of diseases with varying degrees of glucose dysregulation. The use of a single fasting blood sample to diagnose impaired glucose regulation in CHC, although convenient, potentially underestimates the prevalence and degree of this disturbance. Casual (random) or fasting plasma glucose samples or a 2-h oral glucose tolerance test may be used to diagnose T2DM and lesser degrees of disturbed glucose homeostasis [impaired fasting glucose (IFG) and impaired glucose tolerance (IGT)] as defined by the American Diabetes Association (ADA) (46, 47). In a study of 683 patients with CHC who underwent a single fasting plasma glucose test, 131 (19.2%) had T2DM at baseline, 146 (21.4%) had IFG and 406 (59.4%) had normoglycaemia (48). When 2-h OGTT was subsequently performed in the 552 patients not known to have diabetes at baseline, over half of the patients previously classified as ‘normoglycaemic’ actually demonstrated impaired glucose tolerance or T2DM based on the result of the 2-h OGTT; a further 127 patients were diagnosed with T2DM. Additionally, a higher prevalence of T2DM was found in patients with CHC with a normal FPG compared with controls. These findings indicate that disturbances in glucose metabolism in CHC may go undetected by single fasting plasma glucose results, and may only be detected by the result of a 2-h OGTT (48). Identification of diabetes or prediabetes allows for an early intervention to reverse these disease states. Both lifestyle modification and/or pharmacotherapy can delay diabetes and its complications (49), but whether patients with CHC should all be subjected to 2-h OGTT remains open to debate (50); the emerging evidence of the adverse impact of diabetes on outcome in CHC highlights the importance of such considerations.

Consequences of metabolic disturbances in chronic hepatitis C

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References

Unearthing disturbed glucose metabolism in CHC has allowed us to recognize that both IR and T2DM worsen morbidity and mortality in infected individuals.

Insulin resistance

One report indicates that IR is associated with a lower rate of treatment-induced viral clearance (10). Furthermore, IR identified by measuring HOMA-IR has been shown to be an independent predictor for the degree of fibrosis and the rate of fibrosis progression (9). Advanced liver fibrosis impairs insulin clearance, resulting in increased serum insulin levels independent of the insulin secretion status (51); however, hyperinsulinaemia (and hyperglycaemia) may promote fibrosis through the stimulation of hepatic stellate cells, thereby increasing the production of connective tissue growth factor and the accumulation of extracellular matrix (52). Once end-stage liver disease is reached, the presence of IR post-liver transplant is strongly associated with more rapid progression of fibrosis (21).

Diabetes

Table 1 summarizes the evidence for adverse outcomes among patients with CHC and diabetes. Like IR, individuals with T2DM are less likely to achieve sustained virological response (SVR) (12, 13). In addition, diabetics are more likely to experience side effects of the treatment (13). Compounding this, more rapid progression of fibrosis occurs in diabetics; hence, cirrhosis-free survival rates are significantly lower in diabetics than those in non-diabetics (14, 15).

Table 1.   Adverse outcomes associated with type 2 diabetes mellitus in chronic hepatitis C
OutcomenStudy design% diabeticOutcome measureResultReferences
  1. Results reported pertain to outcomes observed in diabetics (or insulin resistant) cases as compared with non-diabetics.

  2. CI, confidence interval; HR, hazard ratio; IR, insulin resistance; PTDM, post-transplant diabetes mellitus; SVR, sustained virological response.

Sustained virological response183Retrospective case–control33%SVR23 vs 46%, P=0.003(13)
Fibrosis68Prospective longitudinal68%Fibrosis progressionHR 8.395, 95% CI 2.234–31.541(14)
201Prospective, cross-sectional14% (IR: 38%)Presence of advanced fibrosis60 vs 30%, P=0.006(15)
Hepatocellular carcinoma (HCC)68Prospective longitudinal68%Hepatoma-free survival10 years: 92.5 vs 100% 20 years: 66.4 vs 95.5% 30 years: 40.9 vs 81.6%(14)
541Retrospective16%Incidence of HCC13 vs 5.9% 11.4% (95% CI, 3.0–19.8) vs 5.0% (95% CI, 2.2–7.8) (P=0.013)(16)
5929Retrospective9.2%Incidence of HCCHR 3.1 (95% CI, 1.7–5.4)(17)
197Retrospective11.7%Incidence of HCCHR 4.627, 95% CI 1.677–12.766(18)
Liver transplant outcomes39Retrospective64% [post-transplant diabetes mellitus (PTDM)]Mortality56 vs. 14%, P=0.01(19)
435Retrospective10.5% (PTDM)Complications  Cardiac  Major infections  Minor infections  Neurological  Neuropsychiatric  Acute rejection Survival48 vs 24%, P=0.005 41 vs 25%, P=0.07 28% vs 5%, P=0.001 22% vs 9%, P=0.05 22 vs 6%, P=0.009 50 vs 30%, P=0.03 No difference(20)
16Prospective cohort study16% (23%: prediabetic, HOMA-IR>2.5)Fibrosis progressionHR 2.07, 95% CI 1.10–3.91(21)

Diabetes and hepatocellular carcinoma

Diabetes is also associated with a higher incidence of HCC in patients with CHC (14, 16–18). Hyperinsulinaemia has been reported to enhance the proliferation of human HCC cells in vitro (53). Diabetes is also a risk factor for non-alcoholic fatty liver disease and steatohepatitis. Hepatic steatosis occurring concomitantly with CHC has been reported to be an independent risk factor for development of HCC (54); this may explain the higher incidence of HCC among diabetics with CHC.

Diabetes and liver transplantation

We have shown that the pretransplant and 1-year post-transplant prevalence of diabetes is higher in patients with CHC than in other causes of liver disease independent of antirejection steroid dose (22), a finding that has since been reaffirmed (55–58). Diabetics who undergo liver transplantation have a higher rate of liver-related (e.g. acute cellular rejection) and non-liver-related complications (eg infection, neurological and vascular) than those without T2DM (19, 20).

Obesity

Obesity is a recognized risk factor for both IR and T2DM and may therefore co-exist with these disturbances of glucose metabolism in CHC. Obesity is independently associated with reduced response to antiviral therapy (59), higher incidence of HCC (60) and higher post-transplant morbidity and mortality (61, 62). Therefore, management of obesity may have independent benefits over and above the potential reduction in the risk of IR and T2DM in CHC.

Metabolic syndrome

The relative contribution of the cluster of metabolic risk factors may also play a role in the development of these adverse outcomes. After adjusting for confounding variables, MetS was found to be independently associated with a lack of SVR; individuals with MetS were 3.8 [95% confidence interval (CI) 1.4–10.5] times more likely to fail treatment than those without MetS (63). Metabolic syndrome is also associated with adverse outcomes in the post-transplant setting. In a study of the relationship between MetS and orthotopic liver transplantation (OLT), 95 patients (including those with CHC and non-CHC-related liver disease) with at least two post-transplant liver biopsies were evaluated (63). MetS (by NCEP ATP III criteria) was present in 50% 1-year post-OLT. In multivariable analysis, MetS was independently associated with progression of fibrosis beyond 1 year after OLT (OR 6.3, P=0.017) (63).

It is reported that 69.5% of individuals with CHC and MetS have impaired glucose homeostasis. It therefore remains to be determined whether altered glucose metabolism (IR or T2DM) independently impairs the response to antiviral therapy and increases fibrosis per se, or whether this occurs in the context of inflammatory cytokines present in the obese state and metabolic syndrome, which may co-exist with and promote IR and T2DM (36).

Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References

In addition to the liver-related adverse outcomes in patients with CHC, a higher incidence of vascular disease has been observed. In a large epidemiological study of 10 259 anti-HCV positive blood donors and their matched controls, an unexpected increase in cardiovascular mortality was observed among the HCV-positive donors [hazard ratio (HR) 2.21, 95% CI=1.41–3.46] (64). Furthermore, reports suggest an association between the HCV and atherosclerosis (65, 66), and MetS (with or without coexistent CHC) is independently associated with an increased risk of major vascular events in the liver transplant population (67). As both IR and T2DM are known to be associated with vascular complications in the uninfected, it is conceivable that these disturbances of glucose homeostasis are the common link between CHC and vascular risk. If this is the case, eradicating HCV (potentially ‘curing’ IR and T2DM) may secondarily reduce vascular morbidity and mortality. Perhaps then the focus of antiviral therapy in CHC should not just be on the prevention of liver disease but also the consideration of these extrahepatic associations of CHC.

Treatment of insulin resistance and diabetes – is there any role?

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References

As IR and T2DM are associated with adverse outcomes in CHC, the use of insulin-sensitizing agents may theoretically reduce their incidence; to date, there is limited evidence to support this practice. Insulin-sensitizing agents have been used specifically to reduce IR in an attempt to improve the response to antiviral treatment (68–70), but there are no reports of whether this is actually the case. In patients with genotype 1 CHC and IR, metformin co-administered with pegylated interferon and ribavirin reduced IR significantly, but did not improve the rate of SVR (68). Pioglitazone, a thiazolidinedione, in combination with pegylated interferon and ribavirin, in obese, non-diabetic, treatment-naïve patients with genotype 1 CHC improves viral kinetic responses during the first 4 weeks of therapy (69) but not the rate of SVR (70). In view of these findings, the use of insulin-sensitizing agents to enhance the antiviral treatment response cannot be routinely recommended. Furthermore, among patients with CHC and overt diabetes, no studies (to date) have ever examined whether hypoglycaemic agents optimize glycaemic control and/or reduce the incidence of adverse events, or improve long-term outcomes; this important question remains to be answered by future studies.

An alternative to pharmacotherapy, namely the impact of a dietary and/or an exercise intervention on IR in patients with CHC, requires further evaluation, and attention should be paid to its role in enhancing response to antiviral treatment and/or reducing the progression to diabetes and its associated adverse outcomes. Diet- and exercise-induced weight loss has the potential to reduce IR through multiple mechanisms including the reduction in obesity-related inflammatory mediators and adipokines and a reduction in fatty acid/lipid-mediated IR (36). As the prevalence of IR is significantly higher among patients with CHC who are obese (41), and weight loss achieved through a combination of diet and exercise has been shown in a small cohort of patients to improve liver enzymes and histology and reduce insulin levels in patients with both HCV and non-HCV liver disease (71, 72), obesity is a potential target for intervention. Current antiviral therapies overall have limited efficacy in achieving viral clearance, a problem further exacerbated by IR and T2DM. This underscores the importance of considering both pharmacological and lifestyle interventions in the prevention and management of IR and T2DM. We need to determine how best to treat these potentially modifiable risk factors, and determine whether the long-term outcome is improved in patients with CHC.

Effect of viral clearance: what do we know so far?

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References

Chronic infection with hepatitis C is inherently associated with IR and T2DM (and their associated complications), but the role of insulin sensitizers and lifestyle intervention in the reduction of IR and T2DM is limited. Although the response to antiviral therapy is impaired in the setting of T2DM and IR, studies have demonstrated that in those who do achieve treatment-induced viral clearance, glucose homeostasis may be improved and hence the risk of T2DM may be potentially reduced (73, 74). Kawaguchi et al. (73) demonstrated a significant improvement in the IR index (HOMA-IR 3.1±1.1 to 1.7±0.8, P<0.05), pancreatic β-cell function (as measured by HOMA-%B) and hepatic IRS1/2 expression in patients who achieved SVR when compared with non-responders and relapsers to antiviral therapy. Fasting plasma glucose and percentage glycosylated haemoglobin are significantly reduced in patients with genotype 4 CHC who achieve an SVR (75). Whether viral clearance reduces the risk of the clinical consequences of IR and T2DM is unknown, and this may be difficult to establish.

Two large longitudinal studies of patients with CHC with normal pretreatment fasting plasma glucose have demonstrated that SVR is associated with a reduced incidence of impaired fasting glucose and T2DM (Fig. 2) (76, 77). Simo and colleagues studied a cohort of 244 non-cirrhotic patients treated with interferon with or without ribavirin; in this series, no case of diabetes was diagnosed in patients with SVR whereas nine cases of diabetes were detected in non-responders (P=0.007) and the incidence of IFG or T2DM was significantly lower in those who achieved SVR. After adjustment for the known predictors of T2DM, the HR for glucose abnormalities in patients with SVR was 0.48 (95% CI 0.24–0.98, P=0.04) (76). In a larger study of 734 patients, abnormal glucose homeostasis developed in 124 (16.9%) after an average follow-up of 27±17 months post-treatment; seven patients developed T2DM (all non-responders) and 117 developed impaired fasting glucose (67 non-responders and 50 SVR) (77), i.e. the post-treatment incidence of abnormal glucose metabolism was lower in sustained responders than that in non-responders (11.4 vs 24.3%, P=0.00002). Logistic regression analysis demonstrated that SVR (OR 0.44, 95% CI=0.20–0.97, P=0.004) and fibrosis stage (OR 1.46, 95% CI=1.06–2.01, P=0.02) were independent predictors of incident IFG or T2DM.

image

Figure 2.  Incidence of altered glucose metabolism (impaired fasting glucose or diabetes) after completion of antiviral therapy. Note: sustained virological response (SVR) achieved by *39.3% and ¶58.8% of patients with normal pretreatment fasting plasma glucose. Follow-up periods were ≥3 years and 2.25±1.4 years respectively (76, 77). IFG, impaired fasting glucose; T2DM, type 2 diabetes mellitus.

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These findings are supported by a retrospective cohort study of 2842 HCV-positive patients treated with interferon with or without ribavirin who were followed for a mean of 6.4 years (78). The cumulative rate of development of T2DM was significantly lower among those who achieved SVR (Fig. 3). The presence of T2DM was associated with a lack of an SVR, prior diagnosis of prediabetes, advanced histological stage and age >50 years (78).

image

Figure 3.  Cumulative development rate of type 2 diabetes mellitus (T2DM) in patients treated with interferon based on response to therapy (78). Reprinted with permission, copyright 2009 Wiley–Liss Inc. a subsidiary of John Wiley & Sons Inc.

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In contrast to all these findings (76–78), one study concluded that the long-term response to antiviral therapy did not reduce the risk of developing glucose abnormalities (79). The former studies did not consider the possibility that the non-responder groups may have had a larger proportion of patients with pretreatment IR (which had not been tested for), therefore predisposing them to both non-response to antiviral therapy and a higher risk of T2DM. Another retrospective study of 202 patients without pretreatment IFG or T2DM followed for a median of 8 years (range 5–16) noted that the cumulative risk of DM (n=7) or IFG (n=33) was 16.9% (95% CI 11.3–22.5), there being no significant difference between those who had achieved SVR (14.5%) compared with non-responders (18.8%) (79). The HOMA-IR had also been performed at baseline and the proportion of patients with pretreatment IR (defined as HOMA-IR>2) was no different between the responders and the non-responders. Despite the consideration of pretreatment IR as a confounding factor for the primary outcome, this study was limited by the relatively small sample size, reducing the power to detect a small statistically significant difference in the incidence of glucose abnormalities between responders and non-responders.

Neither are the benefits of viral clearance well defined in the liver transplant population. There is some evidence to suggest that use of successful antiviral therapy in the peri-operative period with eradication of HCV reduces the risk of acute cellular rejection (80); whether ‘cure’ of concomitant IR or diabetes contributes to this reduced risk has not yet been evaluated. Furthermore, any potential benefits of antiviral therapy must be balanced against the risks; for example, a higher rate of bacterial infections has been observed in liver transplant patients receiving antiviral therapy when compared with those who did not receive therapy (81). As diabetes may be associated with an increased risk of infection in individuals without CHC, consideration must be given to the utility and safety of antiviral therapy in liver transplant patients with diabetes. Therefore, the role of antiviral therapy in the post-transplant setting warrants further evaluation of the potential hepatic and metabolic benefits in this high-risk population.

Future directions – one treatment for two diseases?

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References

There is no doubt that CHC is associated with disturbances of glucose homeostasis, and on balance, the current evidence suggests that the incidence of diabetes may be reduced by successful antiviral therapy. The effects of viral clearance on the abnormalities of glucose metabolism and the risk of T2DM warrant further study. It is important to establish whether the incidence of diabetes and its adverse outcomes (fibrosis progression, hepatoma, complications of liver transplantation, vascular risk and mortality) can be reduced by viral clearance in a cost-effective manner. As novel (and more potent) antiviral therapies develop, the burden of disease because of IR and diabetes in CHC may be further reduced. These insights into the relationship between CHC, IR and diabetes highlight the fact that CHC is a complex disease with systemic effects that require a multidisciplinary approach to both its study and its therapy.

References

  1. Top of page
  2. Abstract
  3. Hepatitis C virus and diabetes
  4. Insulin resistance and type 2 diabetes mellitus in chronic hepatitis C: is it more common than we think?
  5. Consequences of metabolic disturbances in chronic hepatitis C
  6. Vascular morbidity and mortality in chronic hepatitis C – is altered glucose homeostasis the link?
  7. Treatment of insulin resistance and diabetes – is there any role?
  8. Effect of viral clearance: what do we know so far?
  9. Future directions – one treatment for two diseases?
  10. References
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