Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients
A. Antonelli,
C. Ferri1,
P. Fallahi,
M. Sebastiani,
C. Nesti,
L. Barani,
R. Barale2 and
E. Ferrannini
Department of Internal Medicine, University of Pisa School of Medicine, Pisa, 1Rheumatology Unit, University of Modena, Modena and 2Department of Human and Environmental Sciences, University of Pisa, Pisa, Italy.
Correspondence to: A. Antonelli, Department of Internal Medicine, University of Pisa, via Roma, 67, 56100, Pisa, Italy. E-mail: a.antonelli{at}med.unipi.it
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Abstract
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Objectives. Mixed cryoglobulinaemia (MC) is a systemic vasculitis frequently associated with hepatitis C virus (HCV) infection. A possible link between HCV infection and type 2 diabetes has been suggested. This study evaluated the prevalence and clinical phenotype of diabetes in MC-HCV+ patients.
Methods. Two hundred and twenty-nine consecutively recruited MC-HCV+ patients were compared with 217 sex- and age-matched controls without HCV infection.
Results. The prevalence of type 2 diabetes was significantly higher in MC-HCV+ patients than in controls (14.4 vs 6.9%, P < 0.01). Diabetic MC-HCV+ patients were leaner than diabetic patients without MC-HCV (P < 0.0001), and showed significantly lower total and low-density lipoprotein cholesterol levels (P < 0.001) and lower systolic (P = 0.01) and diastolic blood pressure (P = 0.005). MC-HCV+ diabetic patients had non-organ-specific autoantibodies more frequently (34 vs 18%, P = 0.032) than non-diabetic MC-HCV+ patients.
Conclusions. The prevalence of type 2 diabetes is higher in patients with MC-HCV than in controls. Diabetic MC-HCV+ patients show an attenuated diabetic phenotype and are more likely to carry non-organ-specific autoantibodies.
KEY WORDS: Mixed cryoglobulinaemia, HCV, Type II diabetes, BMI, LDL cholesterol, Non-organ-specific autoantibodies.
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Introduction
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Mixed cryoglobulinaemia (MC) is a systemic vasculitis which, in over 90% of cases, is associated with hepatitis C virus (HCV) infection (MC-HCV+) and is frequently complicated by multiple organ involvement (e.g. autoimmune hepatitis, glomerulonephritis, polyarthritis, thyroid disorders, B-cell lymphoma) [15]. HCV lymphotropism may trigger B-lymphocyte expansion; the resulting production of different autoantibodies, including rheumatoid factor and cryoprecipitable immune complexes, may lead to cryoglobulinaemic vasculitis with cutaneous and visceral organ damage [13].
An increased prevalence of type 2 diabetes mellitus (DM) infection has been observed among persons with HCV in several clinic-based casecontrol studies [6, 7] and has been confirmed recently in a representative sample of the general population of the USA [8]. Cumulative reports from diverse geographic regions have shown a 2- to 10-fold increase in the prevalence of diabetes in patients with HCV infection compared with liver disease controls [9]. A negative study, however, has also appeared [10]. Although MC represents the most frequent extrahepatic complication of HCV infection, the prevalence and clinical phenotype of DM in MC-HCV+ patients have not been determined.
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Patients and methods
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Patients
Two hundred and twenty-nine consecutive MC patients referred to the Rheumatology Unit of the University of Pisa were studied prospectively over a 5-yr period (19962001). The diagnosis of MC was based on the presence of serum mixed (IgGIgM) cryoglobulins with rheumatoid factor activity, and the classical clinical triad of purpura, weakness, arthralgias after exclusion of other systemic disorders [2, 3]. Skin biopsy, carried out in 40% of the patients, showed leucocytoclastic vasculitis in all cases. HCV infection was systematically evaluated in all patients and HCV- patients were excluded from the present analysis. Other exclusion criteria were the presence of cirrhosis or hepatocarcinoma, steroid therapy during the last 2 months, plasma exchange, cytotoxic and/or immunosuppressive treatment, and interferon treatment. The control group consisted of 217 individuals over 50 yr of age extracted from a random sample of the general population. Subjects with a history of alcohol abuse, drug addiction, present or past alanine aminotransferase elevation or positivity for markers of viral hepatitis were excluded. Patients receiving insulin therapy or hypoglycaemic drugs were considered diabetic. When this condition was previously unknown, fasting blood glucose levels greater than 126 mg/dl (6.1 mmol/l) on more than one occasion were taken to be diagnostic of DM, in agreement with WHO criteria [11].
In both patients and controls, arterial blood pressure and serum concentrations of glucose, cholesterol and triglycerides were measured after an overnight fast.
The study was approved by the local ethics committee and informed consent was obtained from each patient included in the study.
Analytical measurements
Plasma glucose was measured by a hexokinase method (Boehringer Mannheim, Mannheim, Germany). Serum cholesterol, triglycerides and lipoprotein fractions were determined by enzymatic methods using commercial kits (Boehringer Mannheim) [12]. Alanine-aminotransferase, aspartate aminotransferase,
-glutamyl transpeptidase, alkaline phosphatase and bilirubin were assayed in HCV+ patients by conventional methods. Cryocrit, haemolytic complement activity (CH50) and C3C4 fractions, antinuclear (ANA), anti-smooth muscle (ASMA), anti-mitochondrial (AMA) and anti-extractable nuclear antigen (ENA) autoantibodies were measured as described previously [2, 3].
Antibodies for HCV were assayed by a third-generation enzyme-linked immunoassay that employed recombinant antigens derived from different HCV regions (core, NS3, NS4, NS5). Sera were tested for HBsAg, HBeAg and anti-HBcAg using commercial kits (Ausria; Ausab Abbott Chicago, IL, USA). In patients who tested positive for both hepatitis B virus (HBV) and HCV markers, the presence of viral nucleic acids was evaluated with a nested polymerase chain reaction (PCR) and a reverse transcriptase (RT)-nested PCR, as described previously [4, 5]. Patients were linked aetiologically to HCV infection when they tested positive for HCV RNA and negative for HBV DNA; on the contrary, HBV DNA+ but HCV RNA- samples were considered as HBV-infected and were excluded.
Statistical methods
Data are mean ± S.D. Analysis of variance (ANOVA) and the
2 test were used to test for group differences for continuous and nominal variables respectively. Two-way ANOVA was used to test the separate influences of diabetes and MC on the clinical phenotype.
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Results
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MC patients and controls were well matched for gender distribution and age (Table 1). Body mass index (BMI), serum total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations were significantly lower in patients than in controls, whereas serum high-density lipoprotein (HDL) cholesterol and triglyceride concentrations and systolic and diastolic blood pressure levels were similar. The prevalence of DM was twice as high in MC patients (14.4%) as in controls (6.9%).
The clinical DM phenotype was characterized by higher BMI, serum triglyceride concentration and blood pressure and lower HDL cholesterol concentration. The features specifically associated with MC, on the other hand, were a lower BMI and lower total and LDL cholesterol concentrations (Table 2). MC patients had raised liver enzyme concentrations but similar serum alkaline phosphatase concentrations, bilirubin levels and platelet count compared with controls. MC patients with DM had non-organ-specific autoantibodies (ANA, ASMA, AMA or ENA) more frequently (34 vs 18%, P = 0.032) than MC patients without DM, whereas liver enzyme levels, platelet count, C3, C4, CH50 and cryocrit were comparable. No relationship was observed between diabetes and the duration of MC. No difference was observed in antidiabetic therapy (diet, oral agents or insulin) between diabetic patients with and without MC.
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Discussion
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The present study documents a high prevalence of type 2 diabetes in patients with MC-HCV+. In northern Italy, the estimated prevalence of DM is in the range of 2.53.3% and increases progressively with age [13]. A surprisingly high rate of DM (14.4%) was found in our MC-HCV+ patients; this finding is particularly significant if compared with the 6.9% rate observed in HCV, age-matched controls. These data are in keeping with several recent casecontrol studies in patients with chronic HCV infection [6, 7] and with a population-based study [8]. Contrasting observations may be related mainly to a difference in the selection of HCV+ patients and control subjects, such as a higher prevalence of cirrhosis in HCV+ patients [10].
Of further interest is the comparison between the clinical phenotype of MC and diabetic patients. DM per se was associated with older age, being overweight, dyslipidaemia and higher blood pressure, i.e. the typical features of the metabolic syndrome commonly seen in these patients. In contrast, diabetic patients with MC were leaner and had lower total and LDL cholesterol concentrations in comparison with HCV- diabetic patients (Table 2). Thus, MC-DM comorbidity results in an intermediate clinical phenotype. Interestingly, low LDL cholesterol levels have been linked with HCV-induced hypobetalipoproteinaemia resulting from binding competition between the virus and the hepatic LDL receptor [14].
Many studies suggest that HCV infection causes type 2 diabetes through progressive liver damage [10]. In our series, the severity of liver involvement in MC-HCV+ patients did not correlate with the presence of DM. Also, the prevalence of DM is increased among persons with HCV infection in the general population [8], in which individuals are less likely to have advanced liver disease. These findings suggests that the pathogenetic link between HCV infection and DM may be other than severe liver damage.
Given the biology of HCV, which is both hepato- and lymphotropic, an immune-mediated mechanism may be postulated to explain the raised prevalence of DM in MC-HCV+ patients. Indeed, in our series non-organ-specific autoantibodies were detected more frequently in MC patients with diabetes compared with those without diabetes. MC is a human model of virus-driven immunological disorder; the presence of a large panel of immune complexes and autoantibodies is called upon to explain the occurrence of different organ- and non-organ-specific disorders [2, 3, 5, 15, 16]. Few studies have found a link between HCV infection and autoimmunity against pancreatic islets [17]. Thus, it is conceivable that, in patients with a high level of autoimmune reactivity, such as MC patients, an autoimmune process could be the pathogenetic basis of diabetes. This hypothesis is strengthened by the finding that autoimmune phenomena in patients with classical type 2 diabetes are more common than previously thought [12, 18].
In conclusion, our study demonstrates a high prevalence of DM in patients with MC and HCV infection, and suggests that MC-HCV+ diabetic patients have a different phenotype from classical type 2 diabetic patients, with more pronounced autoimmune reactivity. During the clinical follow-up of MC-HCV+ patients, it may be advisable to screen for glucose intolerance and dyslipidaemia.
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Submitted 7 April 2003;
Accepted 24 July 2003