Association between Hepatitis C Virus Infection and Diabetes Mellitus

Epidemiologic Reviews Copyright © 2001 by the Johns Hopkins University Bloomberg School of Public Health All rights reserved Vol. 23, No. 2 Printed i...
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Epidemiologic Reviews Copyright © 2001 by the Johns Hopkins University Bloomberg School of Public Health All rights reserved

Vol. 23, No. 2 Printed in U.S.A.

Association between Hepatitis C Virus Infection and Diabetes Mellitus

Shruti H. Mehta,1 Steffanie A. Strathdee,1 and David L.Thomas 12

INTRODUCTION

HCV

A number of infectious agents have been linked to chronic diseases, including the linkages of human immunodeficiency virus with acquired immunodeficiency syndrome, Epstein-Barr virus with Burkitt's lymphoma, human papillomavirus with cervical cancer, and hepatitis B virus (HBV) with hepatocellular carcinoma (1-4). Both biologic plausibility and strong epidemiologic evidence were used to demonstrate that these infectious agents caused the associated chronic disease. Epidemiologic associations can be made by detecting either an increased prevalence of the chronic disease among persons with the infection or an increased prevalence of the infection among persons with the chronic disease. The biologic link is strengthened by demonstration of the infectious agent in the diseased tissues, but it can also be made indirectly by observation of overlapping features in the pathophysiology of the infection and the chronic disease. Hepatitis C virus (HCV) infection is mainly a disease of the liver. However, HCV has also been linked to a variety of chronic conditions involving several other organ and tissue systems, including the kidneys and skin. For some of these diseases, there is strong epidemiologic evidence and biologic plausibility, while for others there is only epidemiologic evidence. Diabetes mellitus is one such chronic condition that has recently been associated with HCV infection. In the past 5 years, at least 22 reports either supporting (n = 19) (19, 28-37, 40, 41, 4 5 ^ 7 , 52-54) or refuting (n = 3) (38, 49, 50) an association between these two conditions have been published. However, the literature on this subject and the potential biologic mechanisms involved have not been recently reviewed. This review considers the existing literature with respect to both the epidemiologic evidence and the biologic evidence for a causal relation between these two common conditions.

HCV was recognized in 1989 as the primary etiologic agent of non-A, non-B hepatitis, which at the time accounted for almost 90 percent of all transfusion-associated hepatitis cases in the United States (5). Currently, nearly 4 million persons in the United States are infected with HCV, and 2.7 million of these people have persistent infection (6). Approximately 30,000 new cases of HCV are diagnosed annually, and more than two thirds appear to be related to injection drug use (7). HCV chiefly affects the liver, and the cardinal disease manifestation is cirrhosis. More severe and late-stage complications include hepatocellular carcinoma and end-stage liver disease (8). HCV-associated chronic liver disease is responsible for 8,000-10,000 deaths per year and for 25 percent of all liver transplantations in the United States (7, 9). A number of extrahepatic manifestations have also been associated with HCV infection. The strongest epidemiologic and biologic links are with essential mixed cryoglobulinemia, membranoproliferative glomerulonephritis, and sporadic porphyria cutanea tarda (10-13). Other conditions that have been associated with HCV infection include B-cell non-Hodgkin's lymphoma, lichen planus, Sjb'gren's syndrome, sialadenitis, Mooren's corneal ulcers, and Hashimoto's thyroiditis (14-18). Diabetes mellitus has also recently been included in the list of conditions considered extrahepatic manifestations of HCV (19). DIABETES MELLITUS

Diabetes mellitus is a metabolic disease of multiple etiologies characterized by chronic hyperglycemia that is caused by defects in insulin secretion, insulin action, or both. In 1998, approximately 15.7 million persons in the United States had diabetes mellitus, but only 50 percent had been diagnosed with diabetes at the time (20). Approximately 650,000 new cases are diagnosed each year. Diabetes is the seventh-leading cause of death in the United States and the leading cause of blindness, end-stage renal disease, and lower-extremity amputations (20, 21). The majority of diabetes cases fall into two categories: type 1 and type 2. Type 2 diabetes can be distinguished from type 1 diabetes by its epidemiology, etiology, and pathogenesis. Persons with type 1 diabetes (10 percent of all US diabetes cases) demonstrate an absolute deficiency in insulin secretion that is typically due to an autoimmune process affecting the pancreatic islet cells, which produce insulin

Received for publication January 15, 2001, and accepted for publication August 27, 2001. Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; LADA, latent autoimmune diabetes in adults; NHANES III, Third National Health and Nutrition Examination Survey. 1 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD. 2 Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD. Reprint requests to Dr. David L. Thomas, Johns Hopkins Medical Institutions, 424 North Bond Street, Baltimore, MD 21231 (e-mail: [email protected]).

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Association of HCV Infection and Diabetes

(22). Disease onset typically occurs before the age of 20 years, and persons with type 1 diabetes are dependent upon insulin throughout their lifetime. Type 2 diabetes represents 85-90 percent of all diagnosed diabetes cases in the United States. These persons have a combination of resistance to the actions of insulin and an insulin secretory response that is enhanced but insufficient to adequately compensate for insulin resistance (23, 24). Most cases of type 2 diabetes occur after the age of 40 years, and most of these individuals do not require insulin to survive. Risk factors for type 2 diabetes include older age, familial/genetic predisposition unrelated to human leukocyte antigens, obesity, and a lack of physical activity (25, 26). Type 2 diabetes may go undiagnosed for many years, because hyperglycemia develops gradually, and early symptoms are often not indicative of diabetes (27). PREVALENCE OF DIABETES AMONG PERSONS WITH LIVER DISEASE

A link between HCV infection and diabetes mellitus has been suggested by both studies in which diabetes was detected among persons with chronic HCV infection (28-30) and studies in which the occurrence of HCV infection was examined among persons with diabetes (31, 32). Studies in the first category can be categorized further according to the cause of liver disease (HCV, HBV, alcohol drinking, or cholestatic liver disease) and the stage of liver disease (end-stage liver disease, cirrhosis, or chronic liver disease without cirrhosis). In this review, the studies in the first category were all cross-sectional in design. Patients

303

with HCV infection and patients with other forms of liver disease were both selected from populations of liver clinic patients, and the prevalence of diabetes was determined in the different groups. Diabetes was classified according to a combination of fasting glucose measurements, casual glucose measurements, and reported medication use. Much of the information on diabetes was obtained from retrospective chart review. Cause of liver disease

In this review, the prevalence of diabetes among patients with HCV infection was compared with the prevalence among patients with HBV infection, patients with alcoholic liver disease, and patients with cholestatic liver disease. All but one of eight studies reported an increased occurrence of diabetes among persons with chronic HCV infection in comparison with persons with chronic HBV infection (table 1) (19, 28-30, 32-38, 40). Two studies found an increased prevalence of diabetes among persons with chronic HCV infection as compared with those with cholestatic liver disease (table 2) (34, 35). Three studies demonstrated a higher prevalence of diabetes in persons with chronic HCV infection than in control groups of persons with a variety of other chronic liver diseases (19, 36, 37). The results of the three studies that compared the occurrence of diabetes among HCV-infected persons with that among persons with alcoholic liver disease are conflicting. One study found that diabetes occurred more frequently among HCV-infected persons than among persons with alcoholic liver disease (29), while two other studies found

TABLE 1. Prevalence of diabetes among persons with hepatitis C virus infection and persons with hepatitis B virus infection Authors, year, and Dlace of studv (reference no.)

Prevalence of diabetes (%) Cases

Controls Among Among cases controls

Fraseretal., 1996, Israel (28) Grimbert et al., 1996, France (29) Ozyilkan and Arslan, 1996, Turkey (30) Mangia et al., 1998, Italy (38) Caronia et al., 1999, Italy (33) Mason et al., 1999, United States (32) Bigam et al., 2000, Canada (34) Bigam et al., 2000, Canada (34)

Chronic HCVf infection (n= 128) Chronic HCV infection (n= 180) Chronic HCV infection (n = 271) Chronic HCV infection (n= 134) HCV-related cirrhosis (n = 1,151) Chronic HCV infection (n = 604) Chronic HCV infection* (n= 110) Chronic HCV mfectionft (n = 99)

Knobler et al., 2000, Israel (40)

Chronic noncirrhotic HCV Chronic noncirrhotic HBV infection (n = 45) infection (n = 88)

Chronic HBVf infection (n = 40) Chronic HBV infection (n = 51)§ Chronic HBV infection (n=156) Chronic HBV infection (n = 54) HBV-related cirrhosis (n=181) Chronic HBV infection (n = 486) Chronic HBV infection* (n = 53) Chronic HBV infectionft (n=33)

39

3***

25

2***

26

g**»

23

24D

Epidemiol Rev Vol. 23, No. 2, 2001

ORt.t

95% confidence interval

16.3

(Not given)

2.8

1.6,4.8

2.1

1.1,3.9

2.1

0.6, 7.1

Adjustment factors

Age

20 9**,H

24

13*«*

29

6"

37

15**

33H

12*,H

* p < 0.01; **p < 0.001; * * * p < 0.0001. t OR, odds ratio; HCV, hepatitis C virus; HBV, hepatitis B virus. j Odds ratio of diabetes for persons with HCV infection as compared with those without. § Matched 1:1 to cases on age (±10 years), gender, and presence of cirrhosis. H Prevalence of type 2 diabetes only. # Patients requiring liver transplantation, t t Patients after liver transplantation.

Adjustsd

Age, gender, and severity of liver disease Age

Age, gender, body mass index, steroids, alcohol intake, and number of rejection episodes

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Mehta et al.

TABLE 2.

Prevalence of diabetes among persons with hepatitis C virus infection and other forms of liver disease Prevalence of diabetes (%)

Authors, year, and place of study (reference no.)

Cases

Controls Among Among cases controls

Grimbert et al., 1996, France (29) Mangiaetal., 1998, Italy (38) Zein et al., 2000, United States (35) Zein et al., 2000, United States (35) Bigam et al., 2000, Canada (34) Bigam et al., 2000, Canada (34)

Chronic HCVf infection (n= 180) Chronic HCV infection (n=134) Chronic HCV infection (n = 64)H Chronic HCV infection (n = 64)H Chronic HCV infection (n =110)H Chronic HCV infection (n = 99)tt

Alcohol-induced disease (n=101)§ Alcohol-induced disease (n = 92) Alcohol-induced disease (n = 53)H Cholestatic liver disease (n = 79)D Cholestatic liver disease (n=115)H Cholestatic liver disease (n=101)tt

25

11*»

23

22

25#

19#

Allison et al., 1994, United States (19)

Anti-HCV-positive (n = 34)H

el-Zayadi et al., 1998, Anti-HCV-positive Egypt (36) (n = 591) Knobleretal., 1998, Chronic HCV infection United States (37) (n=13)tt

Adjusted ORt.t

95% confidence interval

25#

2**,#

29

4*

37

5*

5.8

1.9, 17.9

Anti-HCV-negative (n = 66)H

50

9**

10.0

3.4, 29.3

Anti-HCV-negative (n = 223) Other chronic liver disease (n = 34)tt

25

11**

62

9*

16.9#

(p

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