Mehta SH, Brancati FL, Strathdee SA, Pankow JS, Netski D, Coresh J, Szklo M, Thomas DL.

Departments of Epidemiology and Medicine, Johns Hopkins University, Baltimore, MD; and the Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, MN.

Although hepatitis C virus (HCV) infection is more common among adults with type 2 diabetes, it is uncertain whether HCV precedes the development of diabetes. Thus, we performed a prospective (case-cohort) analysis to examine if persons who acquired type 2 diabetes were more likely to have had antecedent HCV infection when enrolled in a community-based cohort of men and women between the ages of 44 and 65 in the United States (Atherosclerosis Risk in Communities Study [ARIC]). Among 1,084 adults free of diabetes at baseline, 548 developed diabetes over 9 years of follow-up evaluation. Incident cases of diabetes were identified by using fasting glucose and medical history and HCV antibodies were assessed at baseline. A priori, persons were categorized as low-risk or high-risk for diabetes based on their age and body mass index, factors that appeared to modify the type 2 diabetes-HCV infection incidence estimates. The overall prevalence of HCV in this population was 0.8%. Among those at high risk for diabetes, persons with HCV infection were more than 11 times as likely as those without HCV infection to develop diabetes (relative hazard, 11.58; 95% confidence interval, 1.39-96.6). Among those at low risk, no increased incidence of diabetes was detected among HCV-infected persons (relative hazard, 0.48; 95% confidence interval, 0.05-4.40). In conclusion, pre-existing HCV infection may increase the risk for type 2 diabetes in persons with recognized diabetes risk factors. Additional larger prospective evaluations are needed to confirm these preliminary findings.

PMID: 12829986 [PubMed - in process]  

HCV/HIV Coinfected Patients at
Increased Risk for Diabetes

Patients with an ICD-9 diagnosis of HIV were identified from the VA
administrative database from 1991 onwards. Data on age, gender, race, history of and first date of HIV, HCV and DM diagnoses, and history of alcohol use was extracted from the VA administrative database. The disease data was based on ICD-9 codes. The ICD-9 codes for HIV and HCV have been validated in the Veterans Aging Cohort Study (VACS).

These researchers performed an analysis on 41,262 male veterans in care with HIV infection between October 1991 and September 2001. Among these patients, 17.9% were co-infected with HCV. Of the 41,262 HIV infected patients, 14.8% had a diagnosis of DM. The prevalence of DM in HCV infected patients was 19.7% compared with 13.7% (chi square = 167; p < 0.001) in the HCV negative patients. In a logistic regression model, the unadjusted odds ratio of having a DM diagnosis in HCV infected patients was 1.53 (95% CI 1.43 - 1.63). After controlling for age, race, history of drug and alcohol use, the adjusted odds ratio was 1.71 (95% CI 1.59 - 1.84). Age, Black or Hispanic race and a history of an alcohol related diagnosis were significantly associated with a diagnosis of DM in the multivariate model. Adjustment was not made for two important predictors of DM in general population, body mass index and family history, because of lack of this information in the administrative database.

These researchers report their study shows that veterans in care with HIV are at a higher risk of DM than the US population in general. Almost 14% of HIV infected veterans in care were diagnosed to have DM. This compares with a prevalence of 11.83% in veterans in care overall, and 6.2% in the general population in the United States.
http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#7   accessed Jan 08, 2003

Co-infection with HCV increased this risk to 19.7%, a relative increase of 44% in this study. The risk increased with increasing age and was higher in African American and Hispanic as compared with White veterans. Traditional risk factors for DM include body mass index, family history of DM, increasing age, and Black or Hispanic race. While these researchers could not adjust for the body mass index or family history, (because this information was not available in the VA Administrative database) age, Black and Hispanic race, and a diagnosis of an alcohol related illness were significantly associated with a diagnosis of DM.

The researchers also reported this background information. A link between HCV and DM has been established by several investigators. It is not surprising since HCV is a major cause of liver cirrhosis, which in turn predisposes patients to DM though insulin resistance. While some of the HCV related DM is due to the liver damage it induces, it does not completely explain the association. In patients with comparable liver damage due to hepatitis B virus (HBV) or other causes of liver disease, the risk of DM is lower than in patients with HCV related liver disease. In a large retrospective study, 21% of the HCV infected patients but only 12% of the HBV infected patients were found to have DM. Among patients with cirrhosis, HCV was associated with a higher prevalence of DM than HBV.

The authors concluded that these findings are significant for patient care as well as policy issues. A higher risk of DM in HCV-HIV co-infected veterans suggests that this group should be targeted for screening and early intervention to reduce the long-term complications of DM. Abst. 836. Butt et al.
 

  Autoimmune Liver Disease
Viral Causation May Associate With Chronic Diseases 

2001 OCT 23 - (NewsRx.com) -- by Sonia Nichols, senior medical writer -
Researchers at the Richard Freeman Research Institute in New Orleans have  performed several studies demonstrating the possibility of a link between viruses like hepatitis C with chronic diseases such as type 2 diabetes.

"Cross-sectional studies performed worldwide have shown that hepatitis C virus (HCV) infection is linked with type 2 diabetes, but these endocrine and liver diseases have an insidious onset, and it has been difficult to establish that patients acquire HCV infection before the development of diabetes," remarked Andrew Mason of the New Orleans, Louisiana research facility.

Mason believes small animal models and more laboratory analysis will be needed in order to confirm that causation. Meanwhile, in vitro studies and clinical trials performed by Mason's group have shown a link between viral infection and another autoimmune disease, called primary biliary cirrhosis (PBC), that affects the liver and occurs most often in women.

"We have developed an in vitro model to study the viral induction of PBC based on the phenotype of the diseased biliary epithelial cells," Mason described in the Journal of Nutrition.

Their model showed that when normal biliary epithelial cells were cocultured with the lymph nodes of patients with disease, those cells acquired PBC phenotypes, but remained unchanged when coculured with the lymph nodes of patients with liver diseases other than PBC ("Viral induction of type 2 diabetes and autoimmune liver disease, J Nutr, October 2001;131(10):2805S-2808S).

"We have also cloned a novel human retrovirus from a PBC biliary epithelium cDNA library and confirmed that the development of the PBC phenotype in vitro coincides with the presence of this virus," Mason said.

Finally, PBC patients in clinical trials who were given antiretroviral therapy showed marked hepatic improvement and disease reversal, according to Mason.

Although the research may be difficult, Mason's team anticipates laboratory models and clinical trials will be useful for showing viral causation in some chronic diseases.

The corresponding author for this study is Andrew Mason, Richard Freeman Research Institute, Alton Ochsner Medical Institutions, New Orleans, LA 70121, USA. E-mail: amason@ochsner.org.

Key points reported in this study include:

• It is extremely difficult to establish viruses as a cause of chronic
diseases such as diabetes

• In laboratory models and clinical trials, scientists have seen a link
between viruses and primary biliary sclerosis

• The use of animal and laboratory models may some day establish hepatitis C virus as a cause of type 2 diabetes

This article was prepared by Virus Weekly editors from staff and other
reports. Copyright 2001, Virus Weekly via NewsRx.com.

HCV Linked to Type 2 Diabetes

DG DISPATCH - ISVHLD: Hepatitis C Infection Linked to Type 2 Diabetes
By Emma Patten

ATLANTA, GA -- April 14, 2000 -- Type 2 diabetes (diabetes mellitus) may be associated with hepatitis C virus (HCV) infection, according to researchers at the 10th International Symposium on Viral Hepatitis and Liver Disease (ISVHDL).

Shruti Mehta, a doctoral student at the School of Hygiene & Public Health, Johns Hopkins University, Baltimore, MD., and colleagues from the Johns Hopkins University, examined data from the third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988-1994 in the US. Of the 9,841 subjects over the age of 20 who were assessed for diabetes and HCV infection, 1,242 (8.4 percent) had diabetes (type 1 and type 2) and 230 (2.1 percent) were anti-HCV positive.

After adjusting for factors such as age, race, and socioeconomic status, the researchers found that HCV-infected subjects were four times more likely to have type 2 diabetes than those without HCV infection (adjusted odds ratio 3.77; 95 percent confidence interval, 1.80-7.87).

They found no association, however, between HCV infection and type 1 diabetes. Similarly, they found no association between hepatitis B virus (HBV) infection and diabetes type 1 or 2.

Suggesting a cause for the association, Mehta told Doctor's Guide that "it might be a combination of factors that produce this association. Hepatitis C virus has been shown to replicate outside the liver and in the pancreas so it could be that HCV may be causing some concomitant beta cell dysfunction."

Mehta could not confirm whether the fact that diabetics have to inject themselves could cause HCV transmission or if HCV transmission caused beta cell dysfunction and, consequently, diabetes. "We're not sure what the mechanisms are or which condition causes which," she said.

"Providers should consider screening persons with one condition for the other since the adverse outcomes of each can be medically prevented," she added.

Hepatitis C Virus: Associated With New Onset Diabetes Mellitus 

Dr. Terrault and Dr. Khalili from the University of California, San Francisco, also presented very careful data from a study assessing the association of new onset diabetes after liver transplantation in patients with hepatitis C.[6] It has been previously shown by Drs. Mason and Perillo that the incidence of diabetes mellitus is 2 to 16 times higher in patients with hepatitis C compared to those with hepatitis B infection or other types of liver disease. As a corollary, these investigators attempted to determine the rate of diabetes mellitus in patients who were hepatitis C positive after liver transplantation. Their results also indicate that chronic hepatitis C was predictive of persistent diabetes mellitus and that the risk was increased approximately 2- to 3-fold compared to the HCV noninfected population. The authors carefully controlled for immunosuppression -- which may influence glucose intolerance -- and found through multiple analyses that the strongest independent predictor of diabetes post liver transplantation was chronic hepatitis C infection. Again, these findings suggest a possible etiologic relationship between both chronic hepatitis C and diabetes mellitus. References Mika BP, Lam NP, McCarthy ME, Layden TJ, et al: Pretreatment Histology activity index (HAI) is an indicator of early HCV viral clearance with IFN therapy [Abstract L0290]. Digestive Disease Week, Orlando, Fla, 1999. Bonkovsky HL, Israel J, Fontana R, et al: Iron reduction prior to and during interferon therapy of chronic hepatitis C: Initial results of a multicenter, randomized, controlled trial in previously untreated patients [Abstract L0051]. Digestive Disease Week, Orlando, Fla, 1999. Brillanti S, Levantesi F, Foli M, et al: Amantadine and RebetronTM exert a synergistic antiviral effect on HCV replication in Interferon-a non-responders with chronic hepatitis C [Abstract L0057]. Digestive Disease Week, Orlando, Fla, 1999. Bellobuono AA, Tempini SS, Mondazzi LL, et al: Breakthrough incidence may be decreased by alpha Interferon and Ribavirin combination treatment in chronic hepatitis C [Abstract L0044]. Digestive Disease Week, Orlando, Fla, 1999. Yoshida H, Arakawa Y, Yokosuka O, et al: How long will the virological sustained responder to IFN remain at risk of developing hepatocellular carcinoma? [Abstract L0493]. Digestive Disease Week, Orlando, Fla, 1999. Khalili M, Watson J, Bass N, et al: Hepatitis C virus (HCV) is associated with new onset diabetes mellitus (DM) after orthotopic liver transplantation (OLT) [Abstracts L0457]. Digestive Disease Week, Orlando, Fla, 1999.
   

Hepatitis C Infection Increases Diabetes Risk

Monday October 16 5:36 PM ET

NEW YORK (Reuters Health) - People who are 40 years of age or older and infected with hepatitis C have more than triple the risk of developing type 2 diabetes, the type of diabetes that commonly occurs in adulthood. Nearly 3 million Americans have chronic hepatitis C, a viral infection of the liver. The virus can lead to cirrhosis and liver cancer and is the leading cause of liver transplant in the US. In the new study, Shruti Mehta and associates from Johns Hopkins University in Baltimore, Maryland looked at more than 9,800 adults who took part in a health survey. Just over 8% of the study participants had type 2 diabetes and about 2% had evidence of hepatitis C virus (HCV) infection, according to a report in the October 17th issue of the Annals of Internal Medicine. The rate of type 2 diabetes was notably higher in the HCV-positive group than in the HCV-negative group, the researchers note, except in persons younger than 40 years of age. In the 40 to 49 year age group, those with HCV infection were 3.1 times as likely to have type 2 diabetes as those without HCV infection. Previous studies have linked HCV to diabetes, but only in people with severe liver disease. These results confirm that type 2 diabetes occurs at higher rates even among patients with milder forms of HCV infection, the authors conclude. Further research is needed to determine exactly how HCV contributes to the development of diabetes. However, Mehta and colleagues believe that the findings are ''consistent with the inference that HCV infection causes type 2 diabetes through progressive liver damage.''

SOURCE: Annals of Internal Medicine 2000;133:592-599.

Audrey Spolarich

Health Policy Analysts, Inc.

Washington, DC

202-638-0551.

Diabetes Care 1996;19:998-1000. WESTPORT Sep 20 (Reuters)

The prevalence of hepatitis C virus infection was found to be four times higher among diabetics than controls in a recent study from Spain, leading the researchers to speculate the virus may play a role in the etiology of the disease. 

Among 176 Type I and II diabetic patients, the rate of serologic detection of anti-HCV was 11.5%, compared with 2.5% among the 6,172 blood donors evaluated as controls. Dr. Rafael Simo of the Hospital General Universitari Vall d'Hebron in Barcelona, Spain, reports that both groups had the same prevalence of prior blood transfusion, intravenous drug abuse, hospital admissions and surgical procedures. 

Among the diabetics who tested positive for hepatitis C, 72.3% had abnormal liver function test (LFT) findings, compared with 24.7% of the controls. "In consequence, based on our results, testing for HCV infection in diabetic patients with an abnormal LFT is mandatory," Dr. Simo concludes. 

Dr. Simo adds that although the study is the first demonstration that diabetics have an abnormally high prevalence of the virus, it found no reason for the difference. However, he suggests the lack of any pertinent epidemiological factor "...supports the hypothesis that HCV may have a direct role in the development of diabetes," either by attacking the pancreas directly or contributing to the immune system activation directed against islet cells.

 

SERUM CHOLESTATIC ENZYMES AND PREVALENCE OF DIABETES AND GALLSTONES IN CHRONIC VIRAL LIVER DISEASE.

G. Budillon. L. Cimino, A. D'Arienzo, M.R. Franco, B. D'Ascoli, N. Caporaso*, A. AscioneX. C. Del Vecchio Blanco*. Cattedre di Gastroenterologia Universita "Federico II" Napoli, *II Ateneo Napoli, XUnita Fegato Ospedale A. Cardarelli Napoli - Italy 

 The prevalence of intrahepatic cholestasis in viral chronic liver disease is still undefined; it was estimated to be higher than 30% in a population from Italy and from the London area (Bartolini et al. Drug Invest. 1992; 4 suppl., 83-9). Cholestasis can negatively affect the evolution of cirrhosis and the responsiveness to interferon (IFN) treatment in viral chronic hepatitis. In this retrospective multicentre survey we evaluated 1557 consecutive virus hepatitis patients (1993-1994) from South Italy, of whom 770 with chronic hepatitis (mean age 47 yrs; range 14-81) and 787 with cirrhosis (mean age 56; range 18-86 yrs). An increase of both the cholestatic enzymes, (alcaline phosphatase [ALP] and gamma-glutamyl-transferase [GGT] was detected in 230 patients (14.7%), 50% of whom with hyperbilirubinemia. The liver disease originated from C-hepatitis virus in 80.4% of patients and from B hepatitis virus in 17.4% The serum increase of cholestatic enzymes was similar in degree and frequency in C and B virus cases (11% vs 12.6%; p = n.s.). The cholestatic enzymes were increased in 7.4% of patients with chronic hepatitis (23% of them with hyperbilirubinemia) and in 22% of cirrhotics (64% with hyperbilirubinemia) (p < 0.01). The prevalence of asymptomatic gallstones and diabetes was evaluated in relation to the increase in cholestatic enzymes. In chronic hepatitis, diabetes was present in 20.4% of subjects with versus 6.8% of subjects without serum increase of ALP and GGT (p < 0.005). In the cirrhotic group the frequency of diabetes was similar in both subgroups of patients (26.6% vs 33.8%; p = n.s.). Gallstones were detected in 11.9% and in 6.5% of patients with and without enzyme increase respectively (p = n.s.). In the cirrhotic group gallstones were significantly more frequent in the cholestatic group (28.8 versus 19.8% non cholestatic; p < 0.05).

In conclusion diabetes, gallstones and serum increases of ALP and GGT were significantly more frequent in cirrhosis than in chronic hepatitis. In chronic hepatitis diabetes was more frequent in patients with cholestasis, while gallstones were observed more frequently in cholestatic cirrhosis. The physiopathologic relationships of diabetes and gallstones with cholestasis and their effects on antiviral therapy require further evaluation in viral chronic liver disease.

Association of Diabetes Mellitus and Chronic Hepatitis C Virus Infection 

Hepatology, February 1999, p. 328-333, Vol. 29, No. 2Andrew L. Mason1, Johnson Y. N. Lau2, Nicole Hoang1, KePing Qian2,  Graeme J. M. Alexander3, Lizhe Xu1, Linsheng Guo1, Sheraj Jacob1, Fredric G. Regenstein1, Robert Zimmerman4, James E. Everhart5, Clive  Wasserfall6, Noel K. Maclaren6, and Robert P. Perrillo1 

From the 1Section of Gastroenterology and Hepatology, Alton Ochsner  Medical Institutions, New Orleans, LA; 2Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL; 3 Department of Medicine, Cambridge University School of Clinical  Medicine, England; 4Section of Endocrinology, Alton Ochsner Medical  Institutions, New Orleans, LA; 5Division of Digestive Diseases and Nutrition, National Institute of Diabetes, and Digestive and Kidney  Diseases, Bethesda, MD; and 6Department of Pathology and Laboratory  Medicine, University of Florida, Gainesville, FL. 

ABSTRACT 

While patients with liver disease are known to have a higher prevalence  of glucose intolerance, preliminary studies suggest that hepatitis C  virus (HCV) infection may be an additional risk factor for the  development of diabetes mellitus. To further study the correlation of  HCV infection and diabetes, we performed a retrospective analysis of 1,117 patients with chronic viral hepatitis and analyzed whether age,  sex, race, hepatitis B virus (HBV) infection, HCV infection, and  cirrhosis were independently associated with diabetes. In addition, a  case-control study was conducted to determine the seroprevalence of HCV  infection in a cohort of 594 diabetics and 377 clinic patients assessed  for thyroid disease. In the former study after the exclusion of patients  with conditions predisposing to hyperglycemia, diabetes was observed in  21% of HCV-infected patients compared with 12% of HBV-infected subjects  (P = .0004). Multivariate analysis revealed that HCV infection (P = .02)  and age (P = .01) were independent predictors of diabetes. In the  diabetes cohort, 4.2% of patients were found to be infected with HCV  compared with 1.6% of control patients (P = .02). HCV genotype 2a was  observed in 29% of HCV-RNA-positive diabetic patients versus 3% of local HCV-infected controls (P < .005). In conclusion, the data suggest a  relatively strong association between HCV infection and diabetes,  because diabetics have an increased frequency of HCV infection,  particularly with genotype 2a. Furthermore, it is possible that HCV  infection may serve as an additional risk factor for the development of  diabetes, beyond that attributable to chronic liver disease alone. (H EPATOLOGY 1999;29:328-333.) 

INTRODUCTION 

Individuals with type II diabetes have an increased prevalence of  cirrhosis, and a proportion of patients with acute and chronic liver  disease develop diabetes mellitus.1,2 Also, patients with various forms  of liver disease can be predisposed to impaired glucose tolerance  because of corticosteroid and hydrochlorthiazide therapy or  hemochromatosis.1,3 In addition to these known risk factors, there is  now emerging epidemiological data to suggest that hepatitis C virus (HCV) infection may also contribute to the development of diabetes. For  example, glucose intolerance is observed more often in patients with HCV  infection compared with controls with liver disease,4-7 and the  frequency of HCV infection in European populations with type II diabetes  has been reported to be higher than expected compared with the general  population.8-10 While these investigations suggest an epidemiological  association between HCV infection and type II diabetes, no large,  controlled studies have been performed to support this conclusion.  To establish a potential relationship between HCV infection and  diabetes, we performed three studies: 1) a retrospective cross-sectional  study to determine the prevalence of diabetes in patients with HCV  infection compared with those with chronic hepatitis B virus (HBV)  infection; 2) a seroprevalence study of anti-HCV antibody in a cohort of  diabetics and a population of patients undergoing thyroid evaluation to  determine the prevalence of HCV infection in diabetics and a  representative outpatient control group; and 3) an HCV genotype study of  diabetic and nondiabetic patients with HCV infection, because certain  HCV genotypes have previously been shown to be associated with  extrahepatic manifestations of disease.11,12 

PATIENTS AND METHODS 

Chronic Viral Hepatitis Cross-sectional Study. Available records from  all outpatients referred to the St. Louis Veterans Administration  Medical Center (n = 517), from 1978 to April 1994, or to the Ochsner  Clinic, New Orleans, LA (n =600), from 1988 to June 1995, for evaluation  of chronic viral hepatitis were abstracted. All chronic viral hepatitis  patients with adequate documentation of abnormal serum aminotransferases  for greater than 6 months, viral hepatitis serology, and endocrine  assessment were included in the database. A diagnosis of HBV infection  was made if patients had evidence of hepatitis B surface antigen, with  or without hepatitis B e antigen or HBV DNA. HCV infection was diagnosed  if patients were seropositive for anti-HCV, and confirmational testing  was performed by either radioimmunoblot assay or HCV-RNA determination  if the diagnosis was in doubt. Patients with a diagnosis of non-A, non-B  hepatitis before 1989 who were subsequently found to have HCV infection  were also included in the study. 

Patients were assigned a diagnosis of diabetes mellitus if there was  documented use of oral hypoglycemic medication or insulin; random  glucose in excess of 200 mg/dL, or fasting glucose greater than  140 mg/dL on two occasions; or primary management for the treatment of  diabetes.13 Liver biopsy data was available from 574 patients, and a diagnosis of cirrhosis was either established by histology (n = 207), or  a presumptive diagnosis was made when patients developed ascites,  hematologic evidence of hypersplenism, or a marked coagulopathy that  contraindicated a liver biopsy (n= 35). Records were also evaluated for  age, sex, and race. Patients were excluded from the final analysis if  they had conditions that may predispose to hyperglycemia (n = 201), such  as hemochromatosis, chronic pancreatitis, carcinoma of the pancreas,  total parenteral nutrition, and corticosteroid or hydrochlorthiazide  therapy. 

Diabetes Case-Control Study. Consecutively collected serum samples were  obtained from the pathology laboratory at Ochsner Clinic, New Orleans,  LA, from 594 patients undergoing glycosylated hemoglobin estimation and  377 patients referred for radionucleotide thyroid scan. All patients  were attending the main campus and peripheral affiliated clinics in the  New Orleans and Baton Rouge regions; the former group was comprised of  diabetics, and the latter patients were nondiabetic. Each sample was  tested for anti-HCV (HCV EIA II Abbott Laboratories, Abbott Park, IL)  without knowledge of the patients' serological or endocrine status. The  records of each diabetic patient were subsequently assessed for age,  sex, race, and serum aminotransferases, which were categorized as either  always normal, intermittently abnormal, or always abnormal. 

The frequency of HCV genotypes was assessed in all reproducibly positive  samples and compared with the distribution of genotypes of  95 HCV-infected patients attending the hepatology clinic. In addition,  the serum samples from the HCV-infected diabetics were assessed for  autoantibodies to insulin by radioimmunoassay, islet cell antigens by  indirect immunofluorescence, and glutamate decarboxylase by a depletion  enzyme-linked immunosorbent assay, as previously described.14-16 

Records from each HCV antibody-positive diabetic were reviewed for the  date of diagnosis of diabetes, type of diabetes mellitus, and dates of  possible exposure to HCV infection or onset of hepatitis when known. All  patients over the age of 40 presenting with diabetes and those without  an insulin requirement were assigned a diagnosis of type II diabetes.  Subjects who had a history of diabetic ketoacidosis or those presenting  below the age of 30 with a clinical requirement for insulin were  assigned a diagnosis of insulin-dependent or type I diabetes. The risk  factors for HCV infection that were analyzed included intravenous drug  abuse, blood or blood-product transfusion, major surgery, hemodialysis,  household contact, sexual exposure, and tattoos. Patients were then  classified into three categories: onset of diabetes mellitus before  recorded risk factors for exposure to HCV infection; onset of diabetes  occurring after risk of exposure to HCV infection; and an indeterminate  onset of HCV infection having either no discernible risk factors, or  risk factors both before and after the onset of diabetes. These studies  were approved by the Ochsner Medical Foundation Clinical Investigations  Committee. 

HCV Genotyping. We used the nomenclature for HCV genotypes proposed by Simmonds et al.17 HCV genotypes were determined by restriction fragment length polymorphism of the nested polymerase chain reaction product using primers derived from the HCV 5' untranslated region.18,19 Briefly, the 5' untranslated region was reverse-transcribed and amplified by  nested polymerase chain reaction using outer primers (antisense:  5'-TCATGGTGCACGGTCTACGAGACCT-3', sense: 5'-CTGTGAGGAACTACTGTCTT-3') and inner primers
 (antisense: 5'-CACTCGCAAG CACTATCAGGCAGT-3'; sense: 
5'-TCACGCAGAAAGCGTCTAG-3') as described previously.18,19 The amplicons were then digested by two sets of restriction enzymes, Hae III/Rsa I and Mva I/Hinf I, to differentiate HCV into various major genotypes (types  1-6). Subtypes la/c and lb were further differentiated by restriction  with the enzyme, BstU I. Subtypes 2a/c and 2b, as well as subtypes 3a  and 3b, were further differentiated by digestion with ScrFI. 

Statistical Analysis. Univariate methods included a t test to compare  means of groups for continuous variables, and for categorical variables,  2 analysis was used unless Fisher's exact test was required for  frequency tables when greater than 20% of the expected values were less  than 5. The Bonferroni adjustment was used to correct the interpretation  of significance for multiple comparisons. Following the removal of  patients with conditions predisposing to hyperglycemia from the chronic  viral hepatitis cohort, the categorical variables of sex, race,  virological diagnosis, and histological diagnosis, as well as the  continuous variable of age, were assessed in a multiple logistic  regression model using the null hypothesis that their coefficients were  statistically not different from zero. The multiple logistic regression  models were constructed to process data by both forward selection and  backward elimination, and were constructed to test the interaction of  independent variables. 

RESULTS 

Factors Associated With Diabetes in the Chronic Viral Hepatitis  Cross-sectional Study. Diabetes was detected in 24% of HCV-infected  individuals as compared with 13% of those with HBV infection alone (P < .0001; 95% CI: 1.4-2.4). However, other significant differences were  observed between patients with HBV infection and HCV infection in other  characteristics such as age, sex, race, and the number of diabetics  excluded from the final analysis (Table 1). For example, the HCV cohort  had a higher proportion of patients over the age of 61, women, subjects  of European descent, and fewer patients of African or Asian descent. A  total of 201 patients were excluded for criteria predisposing to  hyperglycemia (Table 1). The majority of the patients excluded were on  corticosteroid immunosuppression following orthotopic liver  transplantation. The proportion of patients with exclusion criteria were  similar in the groups with HBV and HCV infection, but 34% of the  excluded patients in the HCV cohort were diabetic, compared with 18% of  the HBV-infected population (P = .015; 95% CI: 1.1-3.0). 

After the removal of patients with conditions causing hyperglycemia   (Table 2), diabetes was observed in 21% of patients with HCV infection  compared with 12% of subjects infected with HBV (P = .0004; 95% CI:  1.3-2.4). Patients with cirrhosis were more likely to have glucose  intolerance compared with those without (23% vs. 14%; P < .02), but sex  and race had little impact on the diagnosis of diabetes (Table 2). For  patients with cirrhosis, the prevalence of diabetes was significantly  greater in those with HCV infection compared with subjects infected with  HBV (Fig. 1A and 1B). In the noncirrhotic cohort, however, the frequency  of diabetes was only significantly greater in those with HCV infection  when the entire cohort was entered into the analysis (Fig. 1A). The  effect of aging on the development of diabetes was assessed by  stratifying the chronic viral hepatitis cohort by quintiles for age. In  this analysis, HCV infection was associated with an increased prevalence  of diabetes in all but the youngest quintile (Fig. 2A and 2B). Antiviral  therapy had little impact on the prevalence of diabetes, because 18% of  those with a diagnosis of diabetes and 17% without had a recorded use of  interferon alfa. 

The multivariate analyses revealed that patient age and HCV infection  were the only significant independent predictors for diabetes. The  interaction of cirrhosis and diabetes was assessed in a second logistic  regression for patients with available histological data, and no  relationship was observed between these two variables. In the logistic  regression, the age of the patient (P = .01) and HCV infection (P = .02)  were associated with diabetes, and the relative odds for HCV-infected  patients developing diabetes was calculated to be 2.1 (95% CI:  1.12-3.90) in this data set. 

Characterization of HCV-Infected Patients in the Diabetes Case-Control  Study. In the diabetic cohort, 25 of 596 samples were found to be  reproducibly anti-HCV-positive compared with 6 of 377 samples derived  from thyroid disease controls (4.2% vs. 1.6%; P = .02). With regard to  liver function tests, consistently elevated serum aminotransferases were  seen in 32% of the HCV-infected diabetics compared with 5% of those  without infection (P < .0001) (Table 3). Only 2 patients from the cohort  of HCV-infected diabetics (8%) had type I diabetes, and of the  23 patients with HCV infection and type II diabetes, 12 (52%) had risk  factors for the development of HCV before the onset of diabetes, and  11 (48%) had an indeterminate onset of HCV infection. None of the HCV-infected non-insulin-dependent diabetics had singular risk factors  for HCV infection after the onset of diabetes. Autoantibodies were  detected in 7 HCV-infected diabetics. Two patients had  anti-glutamate  decarboxylase (8%), 1 had anti-islet cell antigens (4%), and 5 had  anti-insulin (20%) antibodies. Four patients in the latter group had  type II diabetes, 1 had type I diabetes, and all were receiving insulin  therapy. 

Analysis of the HCV-infected diabetic samples revealed different  frequencies of HCV genotypes compared with local controls (Table 4). For  example, genotype 2a was detected in 6 of 21 diabetic patients versus  3 of 95 local HCV-infected patients (29% vs. 3%; P < .005; 95% CI:  3.0-27). In contrast, genotype 1a was found in 45% of the local population and was seen in 14% of the diabetic cohort (P < .05; 95% CI:  0.13-0.75). 

DISCUSSION 

These studies provide epidemiological and virological data to link HCV  infection and diabetes. In the liver disease cohort, diabetes was  observed in 21% of patients with HCV infection, as compared with only  12% of HBV-infected patients. In the diabetes cohort, more than 20% of  patients with consistently elevated serum aminotransferases had evidence  of HCV infection. In the whole diabetic population studied, the  prevalence of HCV infection (4.2%) was approximately 2.5 times greater  than our outpatient control group. In marked contrast, the  seroprevalence of hepatitis B surface antigen in our diabetic patients  (0.3%; data not shown) was comparable with the prevalence observed in  our local blood donors and current estimates for chronic HBV infection  reported for the United States.20 Taken together, these data suggest  that HCV infection is more closely associated with diabetes than HBV   infection, and this association cannot be attributed to chronic liver  disease alone. 

Our findings are in concordance with similar epidemiological studies  from Europe and the Middle East. A striking observation from all the  studies with chronic viral hepatitis cohorts of more than 300 patients,  including our own, is the consistent finding that diabetes was observed  in 24% to 26% of patients with HCV infection compared with 9% to 13% of  patients with HBV infection and other liver disease controls.6,7,21 In the smaller studies with a greater proportion of patients with  cirrhosis, the prevalence of diabetes was observed to be even higher in  patients with HCV infection, ranging from 39% to 50%.4,5,7 In agreement,  we also observed that cirrhosis increased the chances of glucose  intolerance, because 33% of HCV-infected patients with cirrhosis had  evidence of diabetes (Fig. 1A). 

Age, cirrhosis, and HCV infection were found to be significant variables  associated with diabetes by univariate analysis in our liver disease  cohort (Table 2). Because there were significant differences between the  cohorts with HCV and HBV infection, no firm conclusions could be drawn  from this analysis concerning the relative contribution of each variable  to glucose intolerance. When patients were segregated by quintiles for age, an increased frequency of diabetes was observed in patients with  HCV infection in all but the youngest age range (Fig. 2). The increased  prevalence of diabetes in the HBV-infected individuals in the youngest  quintile may be partially explained by the high frequency of Asians in  this group (HBV = 13% vs. HCV = 1%), who contributed to the increased  proportion of diabetics in this cohort. 

The logistic regression analysis confirmed that age and HCV infection  were independent predictors for diabetes mellitus. In support of this  finding, Fraser et al. also documented that both HCV infection and  increasing age were independent risk factors for diabetes, while  cirrhosis had an insignificant role in their logistic regression analysis of a large cohort of patients with chronic viral hepatitis.5 Likewise, our multivariate analysis determined that cirrhosis was not  an independent risk factor for diabetes in our population, even though  cirrhosis is known to cause glucose intolerance.1 The diminished  contribution of cirrhosis to the development of diabetes in our patients  is illustrated by Fig. 1, in which the prevalence of diabetes was  similar in HCV-infected individuals without cirrhosis compared with  cirrhotic patients with HBV infection. Taken together, these findings  suggest that HCV infection is a more important predictor of glucose  intolerance than cirrhosis, and the combination of both factors further  increases the risk of diabetes. 

In the chronic hepatitis cross-sectional study, attempts were made to  exclude patients with potentially confounding variables associated with  diabetes. As a result, 34% of the HCV-infected patients excluded from  the final analysis had diabetes compared with only 18% of those with HBV  infection excluded for conditions predisposing to diabetes (Table 1).  However, there were other factors related to either liver disease or  diabetes that were not satisfactorily addressed in this study. For  example, data concerning increased body mass index and evidence of  nonalcoholic steatohepatitis were not derived for the study, both of  which are associated with type II diabetes.22 Another variable not  addressed in this study was alcohol consumption on the assumption that the prevalence of alcohol abuse would be evenly distributed irrespective  of viral diagnosis, and also because patients with evidence for  pancreatitis were excluded from the final analysis. Of note, other  investigators have reported that the prevalence of diabetes is lower in  patients with alcohol-related liver disease alone as compared with those  with chronic HCV infection.6 Although the specific effects of antiviral  regimens were not completely addressed, it is unlikely that interferon  alfa treatment had a substantial effect on the development of diabetes,  because the frequency of diabetes was similar in the treated and  nontreated patients. 

This is the first case-control study known to the authors that assesses  the anti-HCV seroprevalence in a diabetic population using an outpatient  comparison group. Significant differences in the frequency of HCV  infection were observed in our diabetic patients compared with those  being assessed for thyroid disease (4.2% vs. 1.6%) as well as first-time  blood donors (4.2% vs. 0.8%; data not shown). However, the latter group  often does not provide adequate control data for a study of viral  hepatitis, because blood donors are volunteers screened for exposure to  blood products and behavior that increase the risk of developing viral  hepatitis. In agreement with our findings, other studies have reported  an increased seroprevalence of HCV infection, varying from 8% to 11%, in  European diabetic populations in comparison with their local blood  donors or the expected national frequency.8-10 

The unusual distribution of HCV genotypes in our diabetic population  merits further attention, even though the limited number of patients  studied prevents definite conclusions. HCV genotypes 1a and 1b are found  in approximately 70% of HCV-infected individuals in North America23 and  were only demonstrated in 38% of our diabetic cohort (Table 4).  Furthermore, we observed a markedly increased frequency of genotype 2a  in our diabetic cohort (29%) (Table 4). This genotype was only found in  3% of our local population and in 4% of HCV-infected individuals in the  United States.23 This may be a biologically significant finding, because  preliminary reports suggest that HCV genotype 2a is preferentially  associated with extrahepatic syndromes associated with HCV infection  such as mixed cryoglobulinemia and benign monoclonal gammopathy.11,12 Further study of this interesting association between HCV gentoypes and  diabetes is warranted. 

In humans, there is now preliminary evidence to link other viruses, such  as Coxsackie virus, with the development of type I diabetes.24 The P2-C  protein of Coxsackie B virus shares regional amino acid homology with  glutamate decarboxylase, an islet cell antigen, providing a possible  mechanism for the induction of autoimmunity by viral molecular mimicry  of host proteins.24 In regard to the latter, autoantibodies to islet cell antigens were rarely observed in our cohort of HCV-infected  diabetics. 

In conclusion, we have established an association between diabetes 
mellitus and HCV infection. It remains to be determined whether HCV  infection leads to diabetes or vice versa. One could argue that patients  with diabetes mellitus have an increased risk of exposure to HCV  infection. However, the similar frequencies of HBV infection in our  diabetic cohort and the local blood donors argues against diabetics  having a significantly increased risk of exposure to hepatitis agents.  Likewise, the significant abnormalities in distribution of HCV genotypes  observed in our diabetic cohort are unlikely to be attributable to  chance alone. Nevertheless, HCV infection cannot be considered to be a  cause of diabetes without establishing a temporal relationship for the  development of each disorder, and prospective studies are clearly needed  to clarify these issues. In addition, demonstration of the specific  endocrine abnormalities associated with HCV infection and improvement in  glucose tolerance during antiviral therapy would strengthen the  association of HCV infection and diabetes. These studies are warranted  because it could lead to a different means of approaching the management  of this common and serious endocrine disease. 

Acknowledgment 

The endocrine advice from Steven Giddings, M.D., and Janet McGill, M.D. 
(Washington University, St. Louis, MO), as well as Alan Burshell, M.D. 
(Alton Ochsner Medical Institutions, New Orleans, LA), was greatly 
appreciated while planning this study. The authors also thank Abe 
Wattar, M.D., Deborah Baudy, B.S., and Elizabeth Jones, B.A. (Alton 
Ochsner Medical Institutions, New Orleans, LA), for assistance with 
serology and HCV genotyping. In addition, they are indebted to Mary 
Kuhns, Ph.D. (Abbott Laboratories, North Chicago, IL), for providing 
serological reagents. 

Abbreviations 

HCV, hepatitis C virus; HBV, hepatitis B virus 

Footnotes 

Received March 31, 1998; accepted August 24, 1998. 

Supported by research grants NATO (CRG 920697) Collaborative Research Grant (to A.L.M., G.J.M.A., and R.P.P.); a Hans Popper Scholar Award from the American Liver Foundation and a Glaxo Institute of Digestive Health Clinical Investigator Award (to J.Y.N.L.); and (RO1. HD19469-11) National Institutes of Health (to N.K.M.). 

Dr. Lau's current address is: Schering Plough Research Institute, 
Kenilworth, NJ. 

Dr. Regenstein's current address is: Department of Surgery, Tulane 
University Medical Center, New Orleans, LA. 

Noel K. Maclaren's current address is: Research Institute for Children, Harahan, LA. 

Address reprint requests to: Dr. Andrew L. Mason, Section of 
Gastroenterology and Hepatology, Alton Ochsner Medical Institutions, 1520 Jefferson Highway, New Orleans, LA 70121. E-mail: 
amason@ochsner.org; fax: (504) 842-3792. 

REFERENCES 

1.Petrides AS. Liver disease and diabetes mellitus. Diabetes Rev 
1994;2:2-18.2.Muting D, Wohlgemuth D, Dorsett R. Liver cirrhosis and diabetes mellitus. Geriatrics 1969;24:91-993.Niedereau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch H, Strohmeyer G. Survival and causes of death in cirrhotic and non-cirrhotic patients with primary hemochromatosis. N Engl J Med1985;313:1256-12624. Allison MED, Wreghitt 
T, Palmer CR, Alexander GJM. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J 
Hepatol 1994;21:1135-11395.Fraser GM, Harman I, Meller N, Niv Y, Porath A. Diabetes mellitus is associated with chronic hepatitis C but not chronic hepatitis B virus infection. Isr J Med Sci 1996;32:526-5306. Grimbert S, Valensi P, Levy-Marchal C, Perret G, Richardet JP, Raffoux  C, Trinchet JC, et al. High prevalence of diabetes mellitus in patients  with chronic hepatitis C. A case control study. Gastroenterol Clin Biol 1996;20:544-5487.Ozyilkan E, Arslan M. Increased prevalence of diabetes mellitus in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1996;91:1480-14818.Ozylikan E, Erbas T, Simsek H, Telatar 
F, Kayhan B, Telatar H. Increased prevalence of hepatitis C virus 
antibodies in patients with diabetes mellitus [Letter]. J Intern Med 
1994;235:283-2859.Gray A, Wreghitt T, Stratton IM, Alexander GJM, Turner RC, O'Rahilly S. High prevalence of hepatitis C infection in 
Afro-Caribbean patients with type 2 diabetes and abnormal liver function  tests. Diabet Med 1995;12:244-24910.Simo R, Hernandez C, Genesca J, Jardi R, Mesa J. High prevalence of hepatitis C virus infection in diabetic patients. Diabetes Care1996; 19:998-100011. Andreone P, Gramenzi  A, Cursaro C, Benardi M, Zignego AL. Monoclonal gammopathy in patients with chronic hepatitis C virus infection. Blood 1996;88:112212.Zignego AL, Ferri C, Giannini C, Monti M, LaCivita L, Careccia C, Longombardo G, et al. Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia. Ann Intern Med 1996;124:31-3413.Fajans S. 
Classification and diagnosis of diabetes. In: Rifkin H, Porte D (eds). 
Diabetes Mellitus: Theory and Practice. 4th ed. New York: Elsevier, 
1990:346-356.14.Mehta HB, Minkin S, Ullman B, Ullman EF. DELISA: a sensitive nonisotopic assay for GAD antibodies [Abstract]. Diabetes 1995;44(Suppl 1):77A.15.Riley WJ, Maclaren NK, Krischer JP, Spiller RP, Silverstein JH, Schatz DA, Shah S, et al. A prospective study of the development of diabetes in relatives of patients with insulin dependent diabetes. N Engl J Med 1991;323:1167-117216.Vardi P, Dib SA, Tuttleman M, Connely JE, Grinbergs M, Riley WJ, Maclaren NK, et al. Competitive insulin antibody RIA. Prospective evaluation of subjects at high risk 
for development of type I diabetes mellitus. Diabetes 1987;36: 1286-129117.Simmonds P, Alberti A, Bonino F, Bradley DW, Brechot C, Brouwer JT, Chan SW, et al. A proposed system for the nomenclature of hepatitis C viral genotypes [Letter]. HEPATOLOGY 1994;19:1321-132418.Lau JYN, Mizokami M, Kolberg JA, Davis GL, Prescott LE, Ohno T, Perrillo RP, et al. Application of six hepatitis C virus genotyping systems to sera from chronic hepatitis C patients in the United States. J Infect Dis 1994;171:281-28919.McOmish F, Yap PL, Dow BC, Follett EAC, Seed C, Keller AJ, Cobanin TJ, et al. Geographical distribution of hepatitis C virus genotypes in blood donors: an international collaborative study. J Clin Microbiol 1994;32:884-89220.Alter MJ, Mast EE. The epidemiology of viral hepatitis in the United States. Gastroenterol Clin North Am 1994;23:437-45521.Caronia S, Taylor K, Pagliaro L, Carr C, Palazzo U, O'Rahilly S, Alexander G. Strong association between HCV and non-insulin dependent diabetes mellitus [Abstract]. J Hepatol 1996;25(Suppl 1):95. 22.Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. HEPATOLOGY
1990;12:1106-111023.Lau YN, Davis GL, Prescott LE, Maertens G, Lindsay K, Qian K, Mizokami M, et al. Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Ann Intern Med 1996;124:868-87624.Clements GB, Galbraith DN, Taylor KW. Coxsackie B virus infection and onset of childhood diabetes. Lancet 1995;346:221-223
Copyright © 1999 by the American Association for the Study of Liver Diseases. 
http://hepatitis-central.com/hcv/diabetes/hcv/infection.html

Diabetes and hepatitis C 

Prof. Dr. med. J. Reichen

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•Hepatitis C - in particular genotype 2A - clearly predisposes to  diabetes mellitus (12); in this study involving over 1'000 patients with  chronic viral hepatitis, 21 % of HCV infected patients had diabetes as  compared to 12 % of patients with chronic hepatitis B (p<0.0004).  Furthermore, in diabetics 4.2 % were infected with HCV as compared to 1.6 of local controls. Finally, genotype 2A was found in 29 % of  patients with diabetes as compared to 3 % in the local HCV cohort (12). •In a cross sectional national survey, 9841 adults were tested for the  presence of diabetes and anti-HCV (15). The prevalence of diabetes and  hepatitis C was 8.4 and 2.1 %, respectively. Persons aged > 40 with hepatitis C had a 3.77x increased risk to suffer from diabetes (15). •Diabetes mellitus is increased in patients with cirrhosis. However,  postviral cirrhosis due to hepatitis C is even more frequent. Thus, in  liver transplant patients, HCV-positive transplant candidates had  diabetes in 50 % of cases as compared to 9 % of patients with other etiologies (1). In another study investigating patients after OLT, 23 %  developped diabetes after transplantation; this figure was 62 % in  patients transplanted for hepatitis C as opposed to 9 % for patients  transplanted for other causes (10). •Interferon has been described to  induce type I (3, 4, 14) as well as type II (2) diabetes. This is a rare  event: in a retrospective study encompassing over 11'000 patients treated in Italian centers, only 10 patients developped de novo diabetes  mellitus (5). In a Japanese study investigating high dose interferon,  this was observed in 5/987 patients (13). •Type I has been described in  a patient with HLA DRB*04/08. DQA1 52 ARG/ARG and DQB1 57 N-ASP ASP  allele developping autoantibodies against islets and glutamic acid  dexarboxylase suggesting that interferon may induced type I diabetes in  genetically predisposed patients (4). This is a rare event since in  prospective studies no islet cell autoantibodies were observed during  interferon treatment (3, 8, 9). •Insulin autoantibodies in a prospective  study were observed in 3.3 and 13.3 % of patients before and after  interferon treatment, respectively (3); none had islet autoantibodies.


Reference List 
1.Allison MED, Wreghitt T, Palmer CR, Alexander GJM. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a  cirrhotic population. J Hepatol 1994; 21(6):1135-1139. 2.Chedin P,  Cahen-Varsaux J, Boyer N. Non-insulin-dependent diabetes mellitus developing during interferon-? therapy for chronic hepatitis C. Ann Intern Med 1996; 125(6):521-521. 3.Di Cesare E, Previti M, Russo F, Brancatelli S, Ingemi MC, Scoglio R et al. Interferon-? therapy may induce insulin autoantibody development in patients with chronic viral hepatitis. Dig Dis Sci 1996; 41:1672-1677. 4.Fabris P, Betterle C, Greggio NA, Zanchetta R, Bosi E, Biasin MR et al. Insulin-dependent diabetes mellitus during alpha-interferon therapy for chronic viral hepatitis. J Hepatol 1998; 28(3):514-517. 5.Fattovich G, Giustina G, Favarato S, Ruol A, Macarri G, Orlandi F et al. A survey of adverse events in 11241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996; 24:38-47. 6.Hadziyannis S, Karamanos B. Diabetes mellitus and chronic hepatitis C virus infection. Hepatology 1999; 29(2):604-605. 7.Hadziyannis SJ. The spectrum of extrahepatic manifestations in hepatitis C virus infection. J Viral Hepat 1997; 4(1):9-28. 8.Harman-Boehm I, Zingman L, Hilzenrat N. No evidence for anti-islet autoimmunity in diabetes mellitus associated with chronic hepatitis C infection. Hepatology 1999; 30(1):342-342. 9.Imagawa A, Itoh N, Hanafusa T, Oda Y, Waguri M, Miyagawa J-I et al. Autoimmune endocrin disease induced by recombinant interferon- ? therapy for chronic active  type C hepatitis. J Clin Endocrinol Metab 1995; 80:922-926. 10.Knobler H, Stagnaro-Green A, Wallenstein S, Schwartz M, Roman SH. Higher incidence of diabetes in liver transplant recipients with hepatitis C. J Clin Gastroenterol 1998; 26(1):30-33. 11.Lopes EPA, Oliveira PM, Silva AE, Ferraz ML, Costa CHRM, Miranda W et al. Exacerbation of Type 2 Diabetes Mellitus During Interferon Alfa Therapy for Chronic Hepatitis B. Lancet 1994; 343:244-244. 12. Mason AL, Lau JY, Hoang N, Qian KP, Alexander GJ, Xu LZ et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology 1999; 29(2):328-333. 13.Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M et al. Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996; 25(3):283-291. 14.Shiba T, Morino Y, Tagawa K, Fujino H, Unuma T. Onset of diabetes with high titer anti-GAD antibody after IFN therapy for chronic hepatitis. Diabetes Res Clin Pract 1995; 30:237-241. 15.Mehta SH, Brancati FL, Sulkowski MS et al. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Int Med 2000; 133: 592-599 
http://www.ikp.unibe.ch/lab2/HCVDM.htm

The corresponding author for this study is Rafael Simo, Department of Endocrinology, Hospital General Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain. October 25, 1996 Disease Associations (HCV) Hepatitis Weekly via Individual Inc. :

Hepatitis C virus may have a direct role in the development of diabetes, according to a report from Spain. Researcher Rafael Simo and colleagues found a high prevalence of hepatitis C virus (HCV) infection in patients with diabetes, and found that most HCV patients presented with abnormal liver function tests. "Testing for HCV infection of diabetic patients with an abnormal liver function test is mandatory," Simo et al. wrote ("High Prevalence of HCV Infection in Diabetic Patients," Diabetes Care, September 1996;19(9):998- 1001). "The lack of any particular epidemiological factor for HCV infection in our diabetic population suggests that HCV may have a direct role in the development of diabetes." Mild asymptomatic elevations of serum aminotransferases in a diabetic patient do not receive much attention because they are often attributed to fatty infiltration. It has been hypothesized that, during the course of the disease, diabetic patients are more prone to acquire an HCV infection because they are subjected to more frequent medical interventions. While a link between diabetes and HCV has recently been suggested, a controlled study of prevalence and risk factors for HCV infection has not yet been performed. "The aim of this study was to evaluate the prevalence of HCV infection in diabetic patients attending our outpatient clinic in comparison with blood donors who were matched for the main risk factors associated with anti-HCV seropositivity," Simo et al. wrote. "Furthermore, we investigated the influence of several epidemiological and clinical factors on HCV infection in diabetic patients, including type of diabetes, duration of the disease, mode of therapy, and presence of late complications." A total of 176 consecutive diabetic patients were compared with 6172 blood donors, matched by recognized risk factors to acquire HCV infection. Serologic testing for anti-HCV was done using a second-generation commercial enzyme-linked immunosorbent assay (ELISA), and an immunoblot assay was performed in anti-HCV positive samples to confirm HCV specificity. Diabetic patients were divided into two groups according to their HCV antibody status and analyzed for age, sex, type of diabetes, duration of disease, mode of therapy, late diabetic complications, previous blood transfusion, intravenous drug addiction, hospital admissions, major surgical procedures, and liver function tests. Anti-HCV was detected in 18 diabetic patients and 156 blood donors (11.5 versus 2.5 percent; P < 0.001). The estimated risk for HCV infection in diabetic patients was 4.39 times higher (95 percent CI 2.61-7.24) than in the control group. In addition, Simo et al. did not observe a significant difference for previous blood transfusion (21.8 versus 16.7 percent) and intravenous drug addiction (10.2 versus 5.5 percent) between blood donors and diabetic patients with HCV infection, respectively. Only age (63.8 +/- 10.2 versus 49.4 +/- 17.8 years) and previous blood transfusion (16.7 versus 1.2 percent; P < 0.05) were statistically related to HCV infection. After excluding the three anti-HCV positive diabetic patients with previous blood transfusion, the global prevalence of anti-HCV seropositivity in the diabetic population (15 of 175, or 8 percent) remained significant in comparison with the control group (P < 0.001; odds ratio 3.59; 95 percent CI 2.04-6.23). Furthermore, the three anti-HCV positive diabetic patients with previous blood transfusion were transfused for unrelated diseases seven, 15, and 23 years before diagnosis of diabetes. In anti-HCV positive diabetic patients, abnormal liver function tests were seen in 72.3 percent, compared with only 24.7 percent of anti-HCV negative diabetic patients (P < 0.001). "Diabetic patients have a high prevalence of abnormal liver function tests that are often attributed to fatty infiltration without further investigation," Simo et al. wrote. "In this study, we have demonstrated for the first time that diabetic patients present a higher prevalence of HCV infection than control subjects who are matched for the main risk factors, such as age, previous blood transfusion, and intravenous drug addition. In addition, most of anti-HCV positive patients presented with an abnormal liver function test, being a combination pattern of cytolysis and cholestasis as the predominant biochemical alteration. We feel that this is an important point, since none of these patients had been previously diagnosed with liver disease, and diabetes was the only reason for referral to our unit. In consequence, based on our results, testing for HCV infection in diabetic patients with an abnormal liver function test is mandatory." The authors suggest their results could be interpreted to mean either that diabetic patients have some undiscovered epidemiological factor that increases the risk of acquiring HCV infection or that HCV infection may have some etiopathogenic role in the development of diabetes. In recent studies Allison et al. reported a significantly increased rate of diabetes in patients with HCV related cirrhosis, compared with other causes, and suggested that HCV infection has some etiopathogenic role in the development of diabetes (J Hepatol 1994;21:1135-1139). "Several possible mechanisms can be postulated to link HCV to diabetes," Simo et al. wrote. "It may be possible that HCV, similar to the hepatitis B virus, could infect pancreatic islet cells and thereby induce damage to (alpha)-cells. On the other hand, HCV has been related to diseases in which the autoimmune phenomena play an important role, such as cyroglobulinemia, glomerulonephritis, thyroiditis, and Sjogren disease. Therefore, an autoimmune destruction of endocrine pancreatic tissue related to HCV antigens or immunocomplexes cannot be excluded."

High Prevalence of Hepatitis C Virus Infection in Diabetic Patients

Diabetes Care; Volume 19, Number 9, September 1996, Page 998
Rafael Sim, MD, PHD; Cristina Hernandez, MD; Joan Genesc, MD, PHD; Rossend Jard, MD, PHD; Jordi Mesa, MD, PHDOBJECTIVE

To evaluate the prevalence of hepatitis C virus (HCV) infection in diabetic patients and to investigate the influence of several epidemiological and clinical factors on HCV infection.

RESEARCH DESIGN AND METHODS
A total of 176 consecutive diabetic patients were compared with 6,172 blood donors, matched by recognized risk factors to acquire HCV infection. Serologic testing for anti-HCV was done using a second-generation commercial enzyme-linked immunosorbent assay (ELISA), and an immunoblot assay was performed in anti-HCV positive samples to confirm HCV specificity. Diabetic patients were divided in two groups according to their HCV antibody status and analyzed for the following variables: age, sex, type of diabetes, duration of disease, mode of therapy, late diabetic complications, previous blood transfusions, intravenous drug addiction, hospital admissions, major surgical procedures, and liver function tests (LFTs).

RESULTS
A higher prevalence of HCV infection was observed in diabetic patients in comparison with blood donors (11.5 vs. 2.5%; P < 0.001; odds ratio 4.39; 95% CI 2.61-7.24). We did not detect any particular epidemiological factor for HCV infection in anti-HCV positive diabetic patients. In these patients, abnormal LFTs were observed in 72.3%, compared with only 24.7% of anti-HCV negative diabetic patients (P < 0.001).

CONCLUSIONS
A high prevalence of HCV infection was detected in diabetic patients, and most of anti-HCV positive patients presented with abnormal LFTs. Therefore, testing for HCV infection of diabetic patients with an abnormal LFT is mandatory. The lack of any particular epidemiological factor for HCV infection in our diabetic population suggests that HCV may have a direct role in the development of diabetes.