By Author
  By Title
  By Keywords

July 2002, Volume 52, Issue 7


Association of Diabetes Mellitus and Chronic Hepatitis C Infection

H. Qureshi  ( PMRC Research Center, Jinnah Postgraduate Medical Center, Karachi. )

The association between diabetes mellitus and cirrhosis has been speculated since decades. The hypotheses that have been put forward for this association are summarized by Hadzyiyannis1 as follows:
a.) Diabetes could be the cause of associated liver disease because the nuclear and cytoplasmic glycogen deposit, fat deposit in the hepatocytes and perisinusoidal fibrosis seen in diabetes are also seen in liver cirrhosis. It has been proven that cirrhosis is a rare consequence ‘of diabetes2, but recently diabetes was implicated in the pathogenesis of cirrhosis through lesions of non-alcoholic steato-hepatitis (NASH). About 25-75% patients with NASH have diabetes and similarly 90% of NASH patients have been found to be obese. In many diabetics progression of NASH to cirrhosis has been documented3,4. The known causes of chronic liver disease like HCV infection may also coexist in diabetics and thus result in cirrhosis.
b.) The other possibility is implication of chronic liver disease in the etiology of diabetes. Liver plays a pivotal role in the carbohydrate metabolism. This metabolism is deranged in terms of impaired glucose tolerance in about 70% of the cases suffering from liver cirrhosis while frank diabetes occurs in few5,7. Hyperinsulinem ia, insulin resistance and hypergiucagonemia characterize this abnormal glucose metabolism. These patients with chronic liver disease develop hyperglycemia with therapeutic doses of steroids or interferon8,9.
c.) Thirdly the association of chronic liver disease with diabetes may be due to common causes like alcohol, hemochromatosis and autoimmune conditions. Hepatitis B and C are common liver diseases and they tend to occur more in diabetics than in general population. Frequent parenteral exposures in diabetics may be the cause of this high association of HBV and HCV infections. Extra hepatic sites of viral replication i.e. kidneys, pancreas, spleen etc. may also produce many comorbid conditions especially in relation to organ of extra hepatic manifestation7,10,11.
There are several studies pointing to possible link between HCV infection and Type 2 Diabetes Mellitus12. In one of the retrospective studies on 100 orthotoptic liver transplantations for end stage liver disease, Type 2 Diabetes Mellitus was found in 50% of the cases with HCV related liver cirrhosis vs 9% in patients having liver disease unrelated to HCV7. In another study there was an increased incidence of HCV infection in 200 Type 2 Diabetes Mellitus patients recruited from UK for a prospective study13. Reports from Europe, Middle East and North America also show an increased prevalence of diabetes in patients having chronic liver disease when compared with other chronic liver diseases like primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic liver disease or for that matter chronic HBV related disease14-20.
Mason et al reported a case controlled study on the association of chronic hepatitis C with diabetes mellitus20. Though many studies have been done in the past to see this association but the study by Mason et al deals systematically with all known causal possibilities in relation to diabetes and chronic liver disease. In this study all possible factors related to abnormal glucose handling were excluded. The prevalence of diabetes was found to be higher in HCV related chronic liver disease (21%) than in chronic HBV (12%). Moreover prevalence of chronic HCV infection was much higher in diabetics (4.2%) than in controls (1.6%). Similar association was reported in advanced liver disease cases when transplant was not available.
The food for thought is - should diabetes be included in the list of extrahepatic manifestations of HCV infection? The reasons for debating this association is the chances of introduction of HCV infection in diabetics as a result of frequent admissions and venepunctures that occur in these patients. Moreover, chronic HCV infection in adults has a very high transition rate to convert to chronicity when compared to HBV, therefore if exposure to the two viruses is similar the prevalence of chronic HCV infection is expected to be much higher than that for chronic HBV.
The mechanism involved in this extrahepatic disease is not yet clear but (a) cytopathic damage due to the viral replication at these extrahepatic sites (b) immunological tissUe damage (c) virus associated autoimmunity are the possibilities21. In this context, the HCV infection may either trigger latent autoimmunity or induce de novo an autoimmune disease through molecular mimicry and immunological dysregulation. The reasons to support the latter are thyroiditis, thrombocytopenia and lichen planus and aggravation of these disorders by interferon therapy8-10. Studies have shown some association of HCV genotype 2a with extrahepatic disease especially diabetes22,23.
In Pakistan the HBsAg carrier rate varies between 4- I 996;24:38-47.
1O%24,25. The Meta analysis of various HBV studies gives a figure of 4% HBV carrier rate (unpublished data). The anti HBs figures in various population groups are around 32% indicating a natural seroconversion, as these figures are of pre vaccination era24. The HCV positivity rate in blood donors and healthy population varies from 1 ,4..4%26-28. Keeping these figures in mind it appears that the two viruses are hitting the Pakistani population at almost the same rate of 4%. Qureshi et al29 in this issue of the journal report a rather unusual fmding of equal occurrence of diabetes in both HBV and HCV. Their plea is that as two viruses have the same exposure rate therefore their extrahepatic involvement is also similar. The National Health survey of Pakistan reports a 5% prevalence of diabetes mellitus30, which again appears to confirm the above hypothesis. Most of the above figures for HBV are of pre or early HBV vaccination era. It would be interesting to study these figures 2-3 decades after the HBV vaccination when the HBV figures are likely to fall, and see if this equal predisposition of diabetes mellitus persists in chronic HCV and HBV cases.


1.Hadzyiyannis S. Karamanos B. Diabetes mellitus and chronic hepatitis C virus infection. (editorial). Hepatology 1 999;29:604-5.
2.Cruzelfeldt W, Frerichs H, Sickinger K. Liver disease and diabetes mellitus. In: Popper H, Schaffner F,(eds.). Progress in liver disease. Vol 3. New York: Grune and Stratton, 1970, pp. 371-407.
3.Falchuk K, Fiske SC, Haggitt RC, et al. Pericentral hepatic fibrosis and intracellular hyalin in diabetes mellitus. Gastroenterology, 1980;78:535-41.
4.Katamna BH, Petrelli M, Mc Cullough AJ. The liver in diabetes mellitus and hyperlipidemia. In: Gitlin N,ed. The Liver and systemic disease. New York,Churchill Livingstone, 1997, pp.73-113.
5.Bacon BR, Farahvash MJ, .Janney CG, Neuschwander-Tetri BA. Non alcoholic steatoheapatitis: an expanded clinical entitiy. Gastroenterology, 1994;107:1103-9.
6.Kruszynska YT, Mc Intyre N. Carbohydrate metabolism. In Mc Intyre N. Benhamou J-P, Bircher J, Rizzetto M, Rodes J, (eds.). Oxford Text book of clinical Hepatology Oxford: University Press, 1991, pp.1 29-143.
7.Allison MED. Wreghitt T, Palmer CR, et al. Evidence for a link between hepatitis C virus infection and diabetes melltius in a cirrhotic population. J. Hepatol., 1994;21:1135-9.
8.Farbis P. Betterle C, Floreani A, et al. Developement of type I diabetes mellitus during interferon alfa therapy for chronic HCV hepatitis. Lancet, 1992;340:548.
9.Fattovich G, Giustina 0, Favarato S, Roul A and investigators of the Italian Association for the Study of the Liver. A survey of adverse events in 241 patients with chronic viral hepatitis treated with alfa interferon. J. Hepatol.,
10.Hadziyannis SJ, The spectrum of extrahepatic manifestations in hepatitis C virus infection. J. Viral. Hepatol., 1997;4:9-28.
11.Pawlotsky JM, Roudot- Thoraval F, Simmonds P. et at. Extrhepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes. Ann. Intern. Med., 1995;122:169-73.
12.Caronia S, Tayl R, Pagliaro L, et al, Further evidence for an association between Non insulin dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology, I 999;30: 1059-64.
13.Gray H, Wreghitt T, Stratton IM, et al. High prevalence of hepatitis C infection in Afro-Carribbean patients with type 2 diabetes and normal liver function tests. Diabet. Med., 1995;12:244-9.
14.El-Zayadi A, Selim 0, Daddous H, et al. Prevalence of diabetes mellitus among HCV positive chronic liver disease Egyptian patients and its control with alpha interferon in some cases. Hepatology, 1994;19:43.
15.Fraser GM, Harman I, Meller N,et al. Diabetes mellitus is associated with chronic hepatitis C but not chronic heaptitis B virus infection. Isr. J. Med. Sci., 1996;32:526-30
16.Grimbert S,Valensi P. Levy-Marchal C et al. High prevalence of diabetes mellitus in patients with chronic heaptitis C. A case control study. Gastroenterol. Clin. Biol., 1996;20:544-8.
17.Mangia A, Schiavone G, Casavilla I, et al. Is HCV directly involved in the onset of of diabetes mellitus in patients with chronic liver disease. (Abstract). Hepatology, 1 996;24:379A.
18.Ozylkan E, Arsham M. Increased prevalence of of diabetes mellitus in patients with chronic hepatitis C infection. Am. J. Gastroenterol., 1996;91 :1480-1.
19.Uzunalimoglu 0, Cetinkaya H, Sipahi N, et al. High prevalence of diabetes mellitus in patients with chronic hepatitis C infection. (Abstrat). Hepatology, 1996;24:593A.
20.Mason AL, Lau JY, Hoang N, et al. Association of Diabetes Mellitus and Chronic Hepatitis C virus infection. Hepatology, 1999;29:328-333.
21.Strassburg CP, Obermayer-Straub P, Manns MP. Autoimmunity in hepatitis C and D virus infection. J. viral. Infection, l996;3;49-59.
22.Andreone P, Gramenzi A, Cursaro C, et al. Monoclonal gammopathy in patients with chronic hepatitis C virus infection. Blood, 1996;88:1122.
23.Zignego Al, Ferr C, Giannini C, et al. Hepatitis C virus genotype analysis in patients with type ii mixed cryoglobulinemia. Ann. Intern. Med., 1996;124:31-4.
24.Zuberi SJ, Samad F, Lodi TZ, et al. Hepatitis B surface antigen in health care personnel. J. Pak. Med. Assoc., 1977;27:373.
25.Mujeeb SA, Hussain W, Haq A. Prevalence of hepatitis B infection in professional and family blood donors. J. Pak. Med. Assoc., 1994;44: 226.
26.Luby SP, Qamaruddin K, Shah AA, et al. The relationship between therapeutic infection and high prevalence of hepatitis C infection in Hafizabad, Pakistan. Epidemiol. Infect., 1997:119;349-56.
27.Mujeeb SA, Amir K, Mahmood K. Seroprevalence of HBV, HCV and HIV among College. going voluntary blood donors. J. Pak. Med. Assoc., 2000:50;269-70.
28.Kakepota GN, Bhally HS, Khaliq G. et al. Epidemiology of blood borne viruses, A study of healthy blood donors in southern Pakistan Southeast. Asian J. Trop. Med. Public. Hyg; 1996; 27:703-6.
29.Qureshi H, Ahsan T, Mujeeb SA et al. Diabetes is equally frequent in chronic HCV and HBV infection. J. Pak. Med. Assoc., 2002; 52: 280-83.
30. Pakistan Medical Research Council National Health Survey Of Pakistan­
1990-94. Islamabad, Pakistan Medical Research Council, 1998, pp. 56-7.

Journal of the Pakistan Medical Association has agreed to receive and publish manuscripts in accordance with the principles of the following committees: