Scholarly article on topic 'Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality?'

Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality? Academic research paper on "Health sciences"

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Digestive and Liver Disease
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{"Chronic hepatitis C" / "Diabetes mellitus" / "Hepatitis C virus" / "Impaired fasting glucose" / "Insulin resistance" / Interferon / Microangiopathy / Ribavirin}

Abstract of research paper on Health sciences, author of scientific article — Ester Vanni, Elisabetta Bugianesi, Giorgio Saracco

Abstract Chronic hepatitis C is a systemic disease inducing metabolic alterations leading to extrahepatic consequences. In particular, hepatitis C virus (HCV) infection seems to increase the risk of incident type 2 diabetes mellitus in predisposed individuals, independently of liver disease stage. The mechanisms through which hepatitis C induces T2DM involve direct viral effects, insulin resistance, pro-inflammatory cytokines and other immune-mediated processes. Many studies have reported the clinical consequences of type 2 diabetes mellitus on hepatitis C outcome, but very few studies have addressed the issue of microangiopathic complications among patients with hepatitis C only, who develop type 2 diabetes mellitus. Moreover, clinical trials in HCV-positive patients have reported improvement in glucose metabolism after antiviral treatment; recent studies have suggested that this metabolic amelioration might have a clinical impact on type 2 diabetes mellitus-related complications. These observations raise the question as to whether the HCV eradication may also have an impact on the future morbidity and mortality due to type 2 diabetes mellitus. The scope of this review is to summarise the current evidence linking successful antiviral treatment and the prevention of type 2 diabetes mellitus and its complications in hepatitis C-infected patients.

Academic research paper on topic "Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality?"

Digestive and Liver Disease

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Review Article

Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality?

Ester Vannia, Elisabetta Bugianesia, Giorgio Saraccob *

a Gastro-hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy b Gastroenterology Unit, Oncology Department, University of Turin, Italy


Chronic hepatitis C is a systemic disease inducing metabolic alterations leading to extrahepatic consequences. In particular, hepatitis C virus (HCV) infection seems to increase the risk of incident type 2 diabetes mellitus in predisposed individuals, independently of liver disease stage. The mechanisms through which hepatitis C induces T2DM involve direct viral effects, insulin resistance, pro-inflammatory cytokines and other immune-mediated processes. Many studies have reported the clinical consequences of type 2 diabetes mellitus on hepatitis C outcome, but very few studies have addressed the issue of microangiopathic complications among patients with hepatitis C only, who develop type 2 diabetes mel-litus. Moreover, clinical trials in HCV-positive patients have reported improvement in glucose metabolism after antiviral treatment; recent studies have suggested that this metabolic amelioration might have a clinical impact on type 2 diabetes mellitus-related complications. These observations raise the question as to whether the HCV eradication may also have an impact on the future morbidity and mortality due to type 2 diabetes mellitus. The scope of this review is to summarise the current evidence linking successful antiviral treatment and the prevention of type 2 diabetes mellitus and its complications in hepatitis C-infected patients.

© 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.




Article history: Received 13 May 2015 Accepted 16 October 2015 Available online 27 October 2015

Keywords: Chronic hepatitis C Diabetes mellitus Hepatitis C virus Impaired fasting glucose Insulin resistance Interferon Microangiopathy Ribavirin

1. Introduction

Infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide [1,2]. Chronic HCV infection has been associated with several extrahepatic complications, such as essential mixed cryoglobulinaemia, por-phyria cutanea tarda, glomerulonephritis, autoimmune thyroiditis, sialadenitis, and cardiomyopathy [3-7]. The available data suggest that patients with chronic hepatitis C (CHC) might be characterised by a high prevalence of metabolic derangements [8-10], some of which appear to be profoundly modified following viral eradication [8,11,12]. Growing evidence shows that HCV increases the risk of incident type 2 diabetes mellitus (T2DM) in predisposed individuals [12-16]. The mechanism whereby HCV induces T2DM is insulin resistance (IR) [17]. HCV was shown to impair the hepatocyte insulin signalling pathway by several mechanisms [18], including

* Corresponding author at: Gastroenterology Unit, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10100 Orbassano, Torino, Italy. Tel.: +39 011 9026600; fax: +39 011 9026799.

E-mail address: (G. Saracco).

the stimulus to the production of tumour necrosis factor-a (TNF-a), the serine phosphorylation of the insulin receptors (IRS), the overexpression of the suppressor of cytokines (SOC-3) [19,20] and the induction of SOC-7 [21]. However, although HCV infects mainly the liver, whole body insulin sensitivity is also impaired in CHC patients without metabolic syndrome, as shown by recent studies [22,23]. This suggests that the infected hepatocytes might produce mediators that induce endocrine effects at extrahepatic sites, such as the skeletal muscle (Fig. 1). The virus-induced metabolic derangements may interact with host-related genetic and environmental factors, aggravating insulin resistance and possibly leading to the development of T2DM. An imbalance in the adipocytokine profile and the presence of liver steatosis/steatohepatitis could contribute to this scenario [24-32]. Once it has occurred, T2DM contributes to the acceleration of the progression of liver damage, to an increase in the risk of hepatocellular carcinoma (HCC) development and to impairment of the response to antiviral therapy. Finally, a possible direct viral effect, together with a systemic chronic inflammatory state and the interaction with metabolic derangements, could play a role in the development of cardiovascular disease.

T2DM seems not only to accelerate the course of CHC [33-39], but also to influence the response to antiviral therapy [40-45].

1590-8658/© 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Fig. 1. Tentative explanation ofthe pathogenesis of hepatitis C virus-induced type 2 diabetes mellitus and related clinical outcomes. SVR, sustained virological response; TNF-a, tumour necrosis factor-a; 1L-6, interleukin-6; 1L-18, interleukin-18; 1L-28B, interleukin-28B; IR, insulin resistance; PNPLA3, patatin-like phospholipase domain-containing protein 3; HCC, hepatocellular carcinoma; CVD, cardiovascular disease.

Importantly, T2DM occurring in the course of CHC greatly increases the risk of HCC [46-50], even in patients without cirrhosis and after the eradication of HCV infection [51].

If HCV is directly involved in the development of IR and T2DM, it is reasonable to hypothesise that its clearance might result in a parallel decrease in the risk of T2DM incidence. Conversely, a successful eradication of HCV would improve clinical outcomes in patients with established T2DM.

The aim of this review is to carry out an extensive examination of data on the response of HCV-induced IR to successful antiviral treatment to evaluate its efficacy in preventing the development of T2DM in CHC patients and in improving the clinical outcomes of diabetic patients.

To analyse the pertinent data, we searched for published studies in English in selected databases, including PubMed, ISI Web of Science, Google Scholar, and Scopus, covering the period from 1998 to December 2014. The literature search was performed using combinations of selected key- and text-words including "insulin resistance", "diabetes", "type 2 diabetes mellitus", "T2DM", "microangiopathy", "diabetic microangiopathy", "hepatitis", "chronic hepatitis C", "hepatitis C virus", "HCV", "risk factor", "meta-analysis", "systematic review", "review".

2. Impact of SVR on T2DM incidence

Studies addressing the clinical impact of sustained virological response (SVR) on IR or T2DM incidence are reported in Table 1. Several studies [41,52-57] reported a reduction in the number of patients with IR treated with interferon (IFN)-based plus ribavirin (RBV) therapies after achievement of SVR. Aghemo et al. [58] confirmed the persistence of this beneficial effect in cured patients during a prolonged follow-up, preventing the potential bias represented by weight loss during IFN/RBV treatment. The mechanism through which antiviral therapy ameliorates IR has not been fully established, but it is most likely mediated via viral clearance, rather than a direct pharmacological effect of IFN/RBV. Anyway, the above-mentioned studies provided the proof-of-concept on the possibility of obtaining a significant decrease in IR incidence in patients with

SVR; however, this epidemiological finding did not by default translate into any definite clinical benefit for patients; in fact, the really strong endpoint is the reduction in the incidence of T2DM and its complications. This issue was addressed by a few studies [52,55,59] that reported a significantly reduced incidence ofT2DM among sustained responders. Only one study [60] failed to show a statistically significant lower incidence of T2DM in eradicated patients compared with non-responders. The discrepancy may be explained by the different baseline features (low number of cirrhotics, predisposition to hepatogenous T2DM) of the patients and by the weight increase observed among sustained responders included in the Italian study. T2DM occurrence is associated with a genetic predisposition, but it is also influenced by lifestyle-related aspects, such as dietary habits and physical activity. For this reason, epidemiologi-cal variations concerning T2DM in CHC patients should always take into account important demographic and clinical features such as family history, age, sex, obesity, smoking habit and physical activity. In other words, how much is the virus and how much is lifestyle (and genetics) responsible for inducing T2DM? Does viral eradication per se afford protection from T2DM development, or do the above-mentioned factors play a pivotal role in disease occurrence?

According to Arase et al. [59], viral eradication induced a two-thirds reduction in the risk of incident T2DM, independent of age, presence of cirrhosis and of pre-diabetes before therapy. Unfortunately, the authors did not report data regarding important baseline variables such as family history for T2DM, smoking habit, physical activity and IR. Moreover, the retrospective design of the study did not provide us with results on BMI at the end of follow-up and, last but not least, patients included in this study showed pre-therapy characteristics (low BMI, high rate of genotype 2, high antiviral efficacy) that are infrequent in most Western countries. Caution is thus recommended before extrapolating the results to non-Asian populations. On the other hand, analysis of Western series [52,55] led to similar conclusions; in particular, Romero-Gomez et al. [55] showed that eradication of HCV reduced the incidence of T2DM by half in a large cohort of CHC patients during the post-treatment follow-up. Interestingly, the authors reported older age, abnormal glucose values and steatosis, all

Table 1

Reported impact of sustained virological response on insulin resistance or type 2 diabetes mellitus incidence in patients treated for hepatitis C.

Author, year (ref) Type of study Genotype IR improvement DM incidence reduction Comments

Romero-Gomez, 2005 [41] Prospective 1-4 Yes - No follow-up data

Simo, 2006 [52] Retrospective 1-4 Probable Yes No measurement ofinsulin resistance

Kawaguchi, 2007 [53] Prospective 1,2 Yes - - Genotype 1-2 only

- Small sample size

- Baseline IR not considered in the


Romero-Gomez, 2008 [55] Prospective 1-4 Probable Yes No measurement ofinsulin resistance

Giordanino, 2008 [60] Retrospective 1-4 n.a. No - Small sample size

- Low numberofcirrothics

Kawaguchi, 2009 [54] Prospective 1,2 Yes - - Genotype 1-2 only

- Small sample size

Arase, 2009 [59] Retrospective 1,2 - Yes - No data on confounding variables

(family history, smoking habits, BMI at

Delgado-Borrego, 2010 [56] Prospective n.a. Yes - f.u.) f.u.) - Genotype 3 excluded

- No data regarding SVR

Aghemo, 2012 [58] Prospective 1-4 Yes - Small sample size

Thompson, 2012 [57] Retrospective 1-3 Partially - Genotype 4 excluded

IR, insulin resistance; DM, diabetes mellitus; BMI, body mass index; SVR, sustained viriological response; n.a, not available.

factors related to IR, to be independent predictors of non-response. It is reasonable to think that patients who did not respond to therapy were those more prone to developing T2DM, even though the incidence of T2DM remained statistically different even when corrected by multivariate analysis considering variables strongly related to the risk of developing T2DM.

In conclusion, the incidence of IR and T2DM appears to be reduced in CHC patients who obtain SVR after therapy, but the extent of this reduction is questionable and probably depends on the genetic, demographic, clinical, histological and lifestyle characteristics of the patients, owing to the multifactorial aetiology of T2DM. For this reason, the eradication of HCV in patients with predisposing factors for T2DM should not preclude proper counselling on diet and physical activity.

3. Hepatogenous vs. HCV-related T2DM

T2DM, which develops as a complication of advanced liver disease, is a well-known condition defined as "hepatogenous diabetes" [61]. The pathogenesis of hepatogenous T2DM is not yet fully understood. Generally, IR in the peripheral tissues, secondary to muscle depletion and cytokine production, and in the liver because of liver damage, is the main metabolic disturbance [62,63]. Another important factor is hyperinsulinaemia induced by reduced insulin extraction by the cirrhotic liver due to altered function or por-tosystemic shunts, along with raised levels of counter regulatory hormones and free fatty acids [62]. However, the aetiology of liver disease seems important: HCV in particular plays a direct role in inducing IR and T2DM by interfering with glucose metabolism independently of age and stage of liver disease [64,65], while other aetiologies of liver disease, such as alcohol and hepatitis B virus (HBV), require the presence of cirrhosis. This statement has been recently revisited by Ruhl et al. [66], who showed that T2DM is associated with liver enzyme elevation, rather than with HCV infection per se, confirming the previous results of an Italian study that did not show a different prevalence of T2DM among cirrhotics with HCV, HBV infection or alcohol abuse [67]. According to Ruhl et al. [66], other metabolic and histological factors play a crucial role in the association between HCV and T2DM. However, many studies [15,68,69] indicate that HCV, rather than HBV infection, is specifically associated with T2DM, suggesting that HCV probably impairs insulin sensitivity independent of chronic hepatitis, although, of course, hepatic fibrosis increases the risk of T2DM. HCV infection was independently associated with an increased risk of T2DM and

IR in the US population over a decade ago, but assessment of the later NHANES cycles has shown that this relationship may have been weakened by the rapid rise of other risk factors for T2DM, specifically obesity [70]. Future studies should probably take into account, and control carefully for, the link between cirrhosis (a major factor in T2DM) when assessing HCV infection in clinic-based studies [71].

The distinction between hepatogenous T2DM and "classical" T2DM is not trivial; in fact, according to some studies [72-75], hepatogenous T2DM is considered clinically different from the "classical" T2DM, because it is less frequently associated with microangiopathy. However, this conclusion is mainly derived from the results of cross-sectional studies including patients with dissimilar aetiologies of liver cirrhosis (Table 2).

Marchesini et al. [72] showed a lower prevalence of micro-and peripheral macroangiopathy in diabetic cirrhotics compared with non-cirrhotic diabetic patients; however, the study was cross-sectional, the aetiology of cirrhosis was heterogeneous (HBV, HCV, alcohol, primary biliary cirrhosis, Wilson's disease, alpha1-antitrypsin deficiency, haemochromatosis) and the duration of diabetes was significantly longer in diabetic patients without cirrhosis. Holstein et al. [73] reported an overall rate of 8% retinal complications in 52 patients with cirrhosis and T2DM; no T2DM-related complications were observed among 20 patients with newly diagnosed T2DM during follow-up. However, only 19% of patients were HCV-positive and the follow-up period was short (3.9 years). Kuriyama et al. [74] showed a significantly lower incidence of microangiopathy among diabetics with chronic liver disease (mainly HCV-positive) compared with a matched group of diabetic patients without liver disease. The main criticisms are the cross-sectional study design and the fact that the duration of diabetic disease was not reported. In contrast to the above-mentioned studies, a recent study [75] reported a significantly higher prevalence ofT2DM complications among HCV-positive diabetics compared with HCV-negative diabetics; however, no data regarding baseline liver histology, methods of assessing microan-giopathy/macroangiopathy and duration of T2DM were described. The duration of diabetic disease is crucial in determining the real incidence of T2DM-related complications; to date, only one study [76] has recruited patients with only newly diagnosed T2DM without baseline micro-/macroangiopathy. Coppo et al. [76] compared the occurrence of diabetic complications in a CHC cohort with that of a similar control group of new-onset T2DM, HCV-negative patients without baseline microangiopathy, comparable for age,

Table 2

Reported risk of microangiopathic complications in hepatitis C virus-infected diabetic patients.

Author, year (ref) Type of study (country) Follow-up (years) Study subjects (n) Genotype Risk ofmicroangiopathy Comments

Marchesini 1999 Cross-sectional - 66 HCV pos N/A Lower prevalence of - Cross- sectional design

[53] (Italy) 56 HCV neg All cirrhotics retinopathy in cirrhotic diabetics than in non-cirrhotic diabetics (17% vs 48%) - Heterogeneous aetiology of cirrhosis - Longer duration ofdiabetes in non-cirrhotic diabetics than in cirrhotic diabetics (10.1 vs 5.9 years; p<0.01)

Holstein 2002 [54] Prospective 3.9 10 HCV pos N/A Reduced incidence of -Only 19% HCV pos

(Germany) 42 HCV neg All cirrhotics retinopathy: 8% ofall diabetics (3/37), 0% (0/20) of newly diagnosed diabetics - Short follow-up period - Small sample size

Kuriyama 2007 Cross-sectional - 178 HCV pos N/A Lower prevalence of - Cross-sectional design

[55] (Japan) (47% cirrhotics) 51 HCV neg (41% cirrhotics) microangiopathy in diabetics with CLD than in diabetics without CLD (30% vs 65%; p< 0.001) - Duration of diabetes not reported

Chehadeh 2011 Case/control - 24 HCV pos 8% geni Increased prevalence of - Lack of histological

[56] (Kuwait) 414 HCV neg All non-cirrhotics 92% gen 4 micro/macroangiopathy in HCV pos than in HCV neg diabetics (96 vs 73%; p = 0.014). HCV viraemia significantly associated with increased risk of diabetes-related complications (OR 23.65, CI 95% 2.36-236.64; p = 0.007) evaluation - Methods to assess micro/macroangiopathy not reported - Duration of diabetes not reported

Coppo 2015 [57] Retrospective 7.2 54 HCV pos N/A Similar incidence of - Retrospective study

(Italy) (62.9% cirrhotics) 119 HCV neg (2.52% cirrhotics) microangiopathy in HCV pos and in HCV neg (24.1% vs 31.1%; p = ns). No significant association between HCV pos and risk of diabetes-related complications (HR 0.74, 95% CI 0.33-1.7; p = 0.49) - Small sample size

HCV, hepatitis C virus; CLD, chronic liver disease.

T2DM duration and length of follow-up. After a 7-year follow-up, the authors did not find any meaningful difference in the incidence of both microangiopathic and macroangiopathic complications between patients with newly diagnosed T2DM with or without CHC. Even in this study, some methodological limitations (the retrospective nature, the small number of patients recruited) should be taken into consideration when interpreting the results.

To explain the discrepancy between these studies, we think that a reduced life expectancy due to complications of liver disease among patients with HCV-cirrhosis and T2DM at least partly accounts for the lower number of diabetes-related complications observed in HCV-positive compared with HCV-negative diabetics in a series with a high rate of cirrhosis. When cohorts of diabetic patients (with and without CHC) well matched for baseline demographic features, duration and therapeutic control ofT2DM disease are prospectively considered, the incidence of microangiopathic complications is not different from that observed in patients in whom viral eradication is not achieved.

4. Hepatic steatosis and diabetes: HCV infection vs. NAFLD

In general, hepatic steatosis is considered to be an important risk factor for T2DM. However, it is crucial to disentangle the relative roles of HCV infection and NAFLD in the onset of fatty liver and the impact of virus-related vs. NAFLD-related steatosis in the development of glucose intolerance. Given the high prevalence of both NAFLD and CHC in the general population, the chances of interactions between these two conditions are significant and clinically relevant, not only because of the potential synergism on liver disease severity, but also because of their interactions on

metabolism. The association between HCV and steatosis is well-known and both host and viral factors concur with it [10,77]. After the common causes of fatty liver, including alcohol abuse and overweight/obesity, have been excluded, steatosis occurs in about 40% of chronic hepatitis C cases [78]. Genotype 3 HCV directly causes steatosis through several mechanisms, including the inhibition of triglyceride output from the liver [79]. In genotype 3 CHC, the severity of steatosis correlates with the level of HCV replication and decreases upon successful treatment with antivirals [80,81]. In contrast, in most patients with genotype non-3, steatosis correlates with metabolic variables, such as BMI, and tends to persist even in the case of SVR [81,82]. CHC patients with the highest degrees of viral steatosis (e.g. infected with genotype 3) do not necessarily present with the highest levels of IR, and vice versa. HOMA-IR score levels are higher in patients with genotypes 1 and 4, while patients with genotype 3, which displays the highest degree of steatosis, are those in whom HOMA-IR levels are the lowest [35,69]. Thus, it is likely that a percentage of steatosis and of related risk of incident diabetes is due to overlapping NAFLD, particularly in genotype non-3 HCV. The increased risk of prevalent and incident diabetes linked with NAFLD is the most frequently documented in the literature. In a systematic review and meta-analysis [83] of 21 prospective, population-based studies in different ethnic groups, 1 log (x10) higher alanine aminotransferase (ALT) values (in U/L) conferred a hazard ratio (HR) of 1.85 (95% confidence interval [CI] 1.57-2.18), even if within the range of normal values. In the same meta-analysis, the pooled relative risk for incident T2DM comparing mild US-diagnosed NAFLD versus absence was 2.52 (CI 1.07-5.96). Notably, the incidence rate ofT2DM increases progressively according to the ultrasonographic severity of NAFLD at baseline (normal:

7.0%, mild: 9.8%, moderate-to-severe: 17.8%, p < 0.001) after adjusting for multiple confounders [84]. Only one study evaluated incident T2DM in adults with biopsy-proven NAFLD [85]. The prevalence of known T2DM was 8.5% at baseline. After a mean period of 13.7 years, 78% of these patients developed either T2DM (58%) or impaired glucose tolerance (20%). Of note, patients with NASH had an approximately three-fold higher risk of developing T2DM than those with simple steatosis. Importantly, it is conceivable that the T2DM risk attributable to NAFLD would persist even after complete viral eradication achieved by DAAs. Furthermore, HCV infection can also increase the risk of carotid atherosclerosis [86]. An Italian study comparing 326 treatment-naive CHC (151 without steatosis) with 292 healthy subjects without steatosis and 185 age- and gender-matched NAFLD controls, found that both viral load and steatosis contribute to carotid atherosclerosis in CHC [87].

In conclusion, after successful HCV eradication by antiviral therapy, both the cardiometabolic risk and the residual risk of progressive liver disease, particularly in the presence of persistent NAFLD, should not be overlooked and certainly deserve further investigation.

5. Impact of SVR on T2DM complications

What happens to CHC patients with T2DM obtaining SVR? This issue has important clinical and public health implications. In fact, the vast majority of CHC patients have not yet been diagnosed and will not be treated in the near future despite the high efficacy of novel antiviral treatments. Thus, the metabolic complications of HCV will probably represent a serious clinical and economic burden for the next few decades; for this reason, it is of importance to assess whether HCV eradication in diabetic patients significantly decreases T2DM-related complications.

The clinical impact of successful antiviral therapy on the long-term outcome of T2DM in diabetics with CHC remains largely unknown. This is mainly due to the lack of prospective studies that specifically address this important issue. According to a nationwide population-based research conducted in Taiwan [88], antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. The reduction rate of T2DM complications is impressive: patients given antiviral treatment showed an 84% reduction in the risk of end-stage renal disease (ESRD), 47% in that of ischaemic stroke and 36% in acute coronary syndrome compared with the untreated cohort. However, as correctly acknowledged by the authors, several methodological limitations may have affected the results and the conclusions of the study. Patients with significant comorbidity were excluded from the study, no data regarding SVR were reported and many important variables regarding T2DM were lacking (length of diabetic history, BMI, smoking habit, alcohol intake, physical activity, presence of steatohepatitis). Last but not least, data concerning glycaemic control assessed by glycosylated haemoglobin were not provided. In diabetic patients, good glycaemic control prevents the onset and progression of acute and long-term diabetes-related complications [89] and, conversely, poor metabolic control could enhance or accelerate diabetes-related events. Further investigations should be performed before the clinical message coming from this study can be accepted. The striking reduction in ESRD observed among the treated patients may have other reasons and mechanisms, in particular the therapy-related disappearance of cryoglobulinaemia and/or glomerulonephritis induced by HCV [90]. Moreover, the significantly higher incidence of ESRD in the untreated HCV cohort compared with the uninfected cohort shows that diabetic microangiopathy was not the only reason for renal failure. Cardiovascular events (ischaemic stroke and ACS) seem significantly reduced among treated patients compared with uninfected or untreated patients, but only in those without

peripheral arterial disease. According to the authors, the presence of peripheral arterial disease indicates a more diffuse process, suggesting that the pathogenic role of HCV might be limited to the early phase of atherosclerosis and that antiviral therapy cannot reduce cardiovascular morbidity at an advanced stage. These conclusions, however, as correctly underlined by the authors, need to be moderated. First, no data regarding metabolic syndrome (MS) among diabetic patients have been reported. The ultimate importance of MS is that it helps to identify individuals at high risk of cardiovascular disease [91]: without this information, the authors cannot rule out the possibility of an excess of patients with MS in the untreated/uninfected cohort. Second, the issue of whether the reduction in cardiovascular events observed in diabetic patients with CHC treated with IFN/RBV is due to a beneficial effect on T2DM or to the disappearance of systemic chronic inflammation [92-99] remains to be addressed. Finally, whether HCV is an independent risk factor for cardiovascular diseases remains controversial. A recent review [100] reporting the results of several cross-sectional and longitudinal studies suggests that patients with CHC might show a high risk of cardiovascular dysfunction; the final conclusion of another review [17] on the same topic is more cautious, suggesting the need for further carefully conducted, prospective cohort studies.

Another question pertains to the incidence of retinopathy and/or peripheral neuropathy. In diabetic patients with CHC treated with IFN/RBV [76], none of those who obtained SVR developed retinopathy and/or neuropathic symptoms, but the relatively small number of patients does not allow definite conclusions to be drawn. For this reason, a well-designed prospective study with a large series of patients and a well-matched control group of diabetic patients without CHC is needed.

6. Conclusions

Infection with HCV should be regarded as a systemic disease associated with IR and T2DM. Curing HCV results in a reduced incidence of T2DM, and an improvement of T2DM-related clinical outcomes is possible in diabetic CHC patients who obtain SVR. However, a definite verdict is not possible; for this reason, large prospective cohort studies using appropriate stratifications are urgently needed to evaluate the extent of such an amelioration. The high therapeutic efficacy of novel antivirals will ensure that a large number of diabetic cirrhotic patients will achieve eradication; this will enable us to understand the relative contribution of the virus and of lifestyle (and genetics) onT2DM outcome. Meanwhile, we can hypothesise that only early diagnosis and treatment of HCV infection might be associated with regression ofT2DM-related clinical manifestations and complications, according to what is known for other HCV-induced extrahepatic diseases. However, we maintain that the clearance of HCV in patients predisposed to T2DM should not discount the adequate management of IR through lifestyle changes.

Conflict of interest

None declared.


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