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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 2  |  Page : 101-108

prevalence of diabetes mellitus in newly detected patients with hepatitis C


1 Department of Gastroenterology, Government Medical College, Srinagar, Jammu and Kashmir, India
2 Department of Medicine and Gastroenterology, Government Medical College, Srinagar, Jammu and Kashmir, India
3 Department of Medicine, Government Medical College, Srinagar, Jammu and Kashmir, India
4 Department of Endocrinology, Government Medical College, Srinagar, Jammu and Kashmir, India

Date of Submission18-Apr-2019
Date of Decision23-Aug-2019
Date of Acceptance21-Sep-2019
Date of Web Publication24-Jun-2020

Correspondence Address:
Dr. Nisar A Shah
Department of Medicine and Gastroenterology, Governtment. Medical College, Srinagar, J&K.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JOD.JOD_14_19

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  Abstract 

Introduction: Hepatitis C, in addition to liver disease, also causes extrahepatic manifestations in almost 35% of patients, resulting in a spectrum of autoimmune conditions. The prevalence of type 2 diabetes has been reported to be more in these patients. There is a compelling reason to believe this because studies have shown an increased prevalence of hepatitis C virus (HCV) in type 2 diabetes mellitus (DM). The study was conceived to find the prevalence of type 2 DM in HCV-positive patients and its relation to genotype. Materials and Methods: This was a hospital-based case-control study, conducted in the Department of Gastroenterology, Government Medical College Srinagar, Jammu and Kashmir, India. All patients with hepatitis C were enrolled and investigated as per the study design. According to the standard protocol already in vogue, the cases were thoroughly investigated which included all base line investigations, GTT, HbA1c and HOMA-IR. However, majority of the controls were subjected to GTT, HbA1c and homeostatic model assessment of insulin resistance (HOMA-IR) only. Results: Among the cases, the mean age was 45.97 ± 11.982 years; 67.14% had genotype 3 and 32.85% had genotype 1. Cases and controls were compared on the basis of fasting blood sugar levels in three different ranges (≤100 mg%, 101–125 mg%, and ≥126 mg%) and a 2-h GTT at three different levels (<140 mg%, 140–199 mg%, and ≥200 mg%). Other parameters of comparison included HbA1c, serum insulin levels, HOMA-IR, body mass index, liver function test, and lipids. Among all these, only the difference in the level of HOMA-IR (<2.5 in 45.71% of cases and 65.71% of controls) was statistically significant (P = 0.0063). On comparing the diabetogenic potential of two genotypes on the basis of fasting blood sugar and a 2-h GTT, genotype 3 was found to be more diabetogenic. Conclusion: Hepatitis C causes 2.1-fold increase in the prevalence of type 2 diabetes in patients without the evidence of chronicity or complications with increased predisposition to genotype 3 over genotype 1.

Keywords: Diabetes mellitus, glucose tolerance test, hepatitis C, hepatitis C virus genotype, homeostatic model assessment of insulin resistance


How to cite this article:
Kadla SA, Shah NA, Pathania R, Khan BA, Mir SA, Shah AI, Sheikh SA. prevalence of diabetes mellitus in newly detected patients with hepatitis C. J Diabetol 2020;11:101-8

How to cite this URL:
Kadla SA, Shah NA, Pathania R, Khan BA, Mir SA, Shah AI, Sheikh SA. prevalence of diabetes mellitus in newly detected patients with hepatitis C. J Diabetol [serial online] 2020 [cited 2020 Jul 13];11:101-8. Available from: http://www.journalofdiabetology.org/text.asp?2020/11/2/101/287602




  Introduction Top


Hepatitis C is a global hepatotropic, ubiquitous viral infection, involving around 1% of the world population. Currently, there are 170–200 million patients all over the world infected with this virus, majority of them belong to Asian subcontinent.[1],[2] The prevalence varies markedly from one geographic area to another and within the population assessed.[3] Although the virus affects the liver predominantly, many extrahepatic manifestations of this disease are present in 35% of the infected patients.[2],[4] These extrahepatic manifestations are supposed to be due to autoimmunity.[5] The prevalence of type 2 diabetes mellitus (DM) among people infected with hepatitis C virus (HCV) has been reported to be increased, which is postulated to be an extrahepatic manifestation of HCV infection. There is a compelling reason to believe this because studies have shown an increased prevalence of anti-HCV antibodies in the population with type 2 DM than that in general population, that is, 1.78%–12.1%.[6],[7] Increased prevalence of type 2 DM in HCV-infected patients does not seem to have relation with the usual risk factors associated with type 2 DM in general population, for example, obesity, insulin resistance, and metabolic syndrome. On the contrary, there are 400 million patients of DM in the world with the prevalence of type 2 DM being 2%–9.4% in the developed world.[8] It seems that it is the HCV infection, which causes metabolic and pathological disturbances in the body, which in turn culminate into the development of type 2 DM. A point that deserved to be mentioned is that among the patients of HBV infection, the prevalence of type 2 DM is similar to the prevalence in general population,[9],[10],[11] whereas the third National Health and Nutrition Examination Survey (NHANES-III) showed that persons older than 40 years and those with HCV infection are three times more likely to have type 2 diabetes.[12] Since the discovery of HCV in 1989, attention has been paid to the association of chronic hepatitis C with the development of DM, and from 1994 until now, several epidemiological studies on the seroprevalence of HCV have shown higher prevalence of hepatitis C in patients with diabetes than that in controls.[13] HCV genotype 3 is supposed to be more diabetogenic, with approximately fivefold probability of having diabetes as compared to non-3 genotype.

Patients with liver disease are at a higher risk of developing dysglycemia and diabetes in a report published from the NHANES-III, and it has been observed that the HCV-infected persons older than 40 years had an adjusted odds ratio of 3.77 for the development of type 2 DM compared to HCV-negative persons.[14]

The prevalence of type 2 DM in HCV-infected persons is higher than that in hepatitis B virus (HBV)-infected persons, patients with alcoholic liver disease, and in patients who have primary biliary cirrhosis. What causes DM in HCV-infected patients is not exactly known but the following are the possible mechanisms involved in the pathogenesis of type 2 DM in HCV:

  1. Autoimmunity[5]


  2. Direct damage to beta cells[15],[16]


  3. Iron overload[16],[17]


  4. Hepatic steatosis[18],[19]


  5. Pro-inflammatory cytokines[20],[21]


  6. Insulin resistance[5],[19],[22],[23]


The aims of this study were the following:

  • To find the prevalence of dysglycemia and type 2 DM in HCV-positive patients


  • To find which genotype is associated more with abnormal blood sugar levels and DM



  •   Materials and Methods Top


    This case-control hospital-based study was conducted in the Department of Gastroenterology, Government Medical College Srinagar, Jammu and Kashmir (North India) from October 1, 2015 to June 30, 2017. All incidentally detected patients with hepatitis C were enrolled and were called as cases, which were further confirmed by an enzyme-linked immunosorbent assay (ELISA), and those detected positive by ELISA underwent HCV ribonucleic acid (RNA) estimation and genotype testing. A total of 70 cases were included in the study with the exclusion of those with known cirrhosis/portal hypertension, known diabetics, patients with liver disease of a definite etiology other than HCV, and patients with human immunodeficiency virus (HIV) coinfection.

    Seventy age- and sex-matched healthy volunteers who were HCV negative by ELISA and nondiabetic with normal clinical examination were taken as controls. After the institutional ethical committee clearance and a proper consent from all cases and controls, a detailed history was obtained and a clinical examination was carried out. Cases were subjected to all baseline investigations, which included a complete blood count (CBC), liver function test (LFT), and kidney function test (KFT). Lipid profile test was also conducted to rule out metabolic syndrome. In addition to this, oral glucose tolerance test (GTT) using 75g of glucose to check for glucose intolerance that has been proved by earlier studies to be more common in patients with HCV infection, an glycated hemoglobin (HbA1c) using Abbott analyzer, Abbott Healthcare Private -Limited, Mumbai, Maharashtra, India, serum fasting insulin levels using RK Tech–I–2000 array flow analyzer, Toshiba Japan, New Delhi, India, ultrasonography focusing on features of portal hypertension and cirrhosis, upper gastrointestinal endoscopy for varices and portal hypertensive gastropathy, and quantitative HCV RNA estimation using COBAS AmpliPrep and TaqMan 48 (Roche) were carried out.

    Seventy controls underwent analysis for GTT, HbA1c, serum insulin levels, and HOMA-IR. However, LFT, KFT, lipid profile test, and ultrasonography were performed in those who volunteered (23 patients). A fibroscan would have been ideal to demonstrate fibrosis and/ or cirrhosis in both cases and controls. However, the facilities for the same were not available in this hospital.

    Diabetogenic potential of different genotypes was compared.

    Statistical analysis: Continuous variables were summarized as mean ± standard deviation (SD). Categorical variables were summarized as percentage. Difference between two proportions was evaluated using chi-square test. Independent samples t test was used to evaluate difference between two mean values. Logistic regression analysis was used to calculate odds ratios, which were reported along with their 95% confidence intervals. Analysis was carried out using OpenEpi 3.01 (www.openepi.com). A P value <0.05 was considered statistically significant.


      Results Top


    All incidentally detected patients with hepatitis C were enrolled and were called as cases, which were further confirmed by an ELISA, and those detected positive by ELISA underwent HCV RNA estimation and genotype testing. A total of 70 cases were included in the study, with the exclusion of those with known cirrhosis/portal hypertension, known diabetics, patients with liver disease of a definite etiology other than HCV, and patients with HIV coinfection.

    Seventy age- and sex-matched healthy volunteers who were HCV negative by ELISA and nondiabetic with normal clinical examination were taken as controls.

    Among both cases and controls, a slight male predominance was observed, and majority of the cases as well as controls were in the age-group of 41–50 years [Table 1]. As the patients with clinical and radiological features of cirrhosis were excluded from the study, clinical examination was unremarkable in all cases and controls.
    Table 1: Age and demography

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    Among cases, LFT in majority was normal, and only 5.7% of patients had serum bilirubin >2.1 mg/dL, 22.9% patients had serum alanine aminotransferase >62 mg/dL, 24.28% patients had serum aspartate aminotransferase levels >57 mg/dL, and 11.4% patients had serum alkaline phosphatase levels >115 mg/dL. However, when we compared them with controls (in whom LFT and lipid profile were available), it was not statistically significant. Lipid profile of cases and controls was comparable except for high-density lipoprotein (HDL), which was significantly high in cases with a P value of 0.000 [Table 2]. On comparing the glucose homeostasis in cases and controls with regard to fasting glucose levels, a statistically significant number of controls had an impaired blood sugar level than cases (P value of 0.001). On comparing 2-h GTT and HbA1c, a P value of 0.08 and 0.027 was achieved [Table 3]. On comparing the serum insulin, body mass index (BMI), and HOMA-IR in cases and controls, no statistically significant difference was found between the two [Table 4].
    Table 2: Lipid profile—cases and controls

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    ,
    Table 3: Fasting blood sugar levels, glucose tolerance test (2h), and glycated hemoglobin—cases and controls

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    ,
    Table 4: Serum insulin, body mass index, and HOMA-IR—cases and controls

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    Among 70 cases, 23 (32.85%) had genotype 1 and 47 (67.14%) were infected with genotype 3 HCV. On comparing the diabetogenic potential of these predominant genotypes of our study population, no statistically significant difference between the two was found [Figure 1].
    Figure 1: Glucose homeostasis and genotype

    Click here to view



      Discussion Top


    Hepatitis C and DM are two highly prevalent diseases in the world. As the prevalence of metabolic syndrome and as such the DM is increasing day by day in many parts of the world, especially in developing countries, and hepatitis C, in recent years, has taken the shape of leading causes of cirrhosis all over the world, many people tried to link these two diseases in one way or other. Since the first report published in 1999 about the relationship of HCV infection with increased prevalence in type 2 DM, a lot of studies have been published in the literature.[9] Most of these studies have shown an increased prevalence of type 2 DM in HCV-infected population but some have negated the association.[24]

    We conducted a cross-sectional case-control study to observe the association of these two modern day diseases in this part of the world. Of 70 cases of hepatitis C, 42 (60%) were from rural areas and 28 (40%) belonged to urban areas. There were 33 (47.14%) males and 37 (52.85%) females making a ratio of 1:1.21; whereas among 70 controls, 37 (52.85%) were males and 33 (47.14%) were females making a ratio of 1.21:1. The baseline investigations, including CBC, LFT, KFT, lipid profile test, and ultrasound examination, were all the more same in both cases and controls as we had chosen only those patients with hepatitis C who were non-cirrhotic without clinical evidence of cirrhosis or portal hypertension. The 2-h GTT revealed that 15 (21.43%) cases had fasting blood sugar of more than 126 mg/dL as compared to 11 (15.71%) controls, 20 cases (28.57%) had impaired fasting blood sugar level as compared to 41 (58.57%) controls, and 35 (50%) cases had normal fasting blood sugar level as compared to 18 (25.71%) controls. At 2h, blood sugar levels were impaired (140–199 mg/dL) in 21 (30%) cases as compared to 16 (22.86%) controls, blood sugar levels were in diabetic range in 13 (18.57%) of the cases as compared to 6 (8.57%) of the controls. The overall assessment of this observation is a complex one, DM was seen more in hepatitis C-positive cases as compared to HCV-negative controls; however, impaired sugar levels as per fasting blood sugar levels were seen more in controls. At 2h, however, both impaired as well as the diabetic range of sugar levels were more in patients with hepatitis C, blood sugar levels were in diabetic range in 13 (18.57%) of the cases as compared to 6 (8.57%) of the controls. The differences were not statistically significant. To overcome this mixed bag of observations, we tried to observe the difference in HbA1c of cases and controls, and found that HbA1c in the range of >6.5 was seen in 11 cases and 2 controls; HbA1c of 5.7%-6.4% was seen in 11 cases and 10 controls, clearly indicating that the dysglycemia was more in patients with hepatitis C. Similar observation was made by Lecube et al.[25] who had found that patients with chronic hepatitis C had threefold increase in the prevalence of glucose abnormalities as compared to the HCV-negative subjects with liver disease of other etiology other than hepatitis C. Our results showed less prevalence of dysglycemia as compared to other studies; possibly because we had removed almost all confounding factors by including only HCV-positive cases having no evidence of cirrhosis. A study conducted by Kalar et al.[26] on 165 patients with chronic liver disease had revealed that the overall frequency of type 2 DM was 27.9%, of which, 25.5% were HBV positive and 73.3% were HCV positive. This also shows more prevalence of diabetes and prediabetes in patients with hepatitis C as do many other studies[9],[12],[13] [Table 5]. Two more studies conducted by Mehta et al.[12] and Knobler et al.[27] have reported a prevalence of type 2 DM of 20%–39% in patients with hepatitis C, which is much higher than that in our study.
    Table 5: Prevalence of type 2 diabetes in hepatitis C virus-positive versus hepatitis C virus-negative subjects

    Click here to view


    The possible reason for this seems to be our strict inclusion criteria of HCV-positive patients without the evidence of cirrhosis and portal hypertension. Data from NHANES-III have revealed a prevalence of type 2 DM to be five times more than the HCV-negative cohorts. A review of 22 studies has revealed that HCV infection was 3.5 times more in patients with type 2 DM as compared to patients who were nondiabetic.[14] In our study, the lipid profile pattern in HCV-positive cases and controls was same except for high HDL in cases, which was a statistically significant difference with a P value of 0.000, which could not be explained on the basis of currently available literature and needed further studies to see whether HCV has something to do with the same. None of the cases or controls had any metabolic syndrome, as those with metabolic syndrome were excluded from the study. This means that the abnormal blood sugar levels in HCV-positive cases were most probably not related to the confounders. Similarly, BMI was also studied among two groups; no statistically significant differences were observed between the two groups [Table 4].

    We studied insulin resistance, which is a possible mechanism for causing Type 2 Diabetes Mellitus. To study this, we used HOMA-IR as an evidence of insulin resistance [Table 4]. When the level of HOMA-IR was taken more than 3.5 as an index of insulin resistance, we found that 25 (35.71%) cases had insulin resistance as compared to 11 (15.71%) controls; however, when the level of HOMA-IR was taken as 4.6 or above as an index of insulin resistance, we found that 7 (10%) cases had insulin resistance as compared to 8 (11.42%) controls, which is statistically insignificant. A study of 462 patients with nondiabetic chronic hepatitis C revealed a HOMA-IR of more than 3 in 32.4% as compared to HBV-positive-matched patients.[28] The same study further revealed that insulin resistance was more prevalent in genotype 1 and 4.[29] The genotype analysis of our cases revealed that HOMA-IR of more than 3.5 was seen in 9 (12.85%) cases with genotype 1 as compared to 15 (21.42%) controls. This is statistically insignificant. The results of our study are in accordance with the results of the aforementioned study.

    The analysis of serum insulin level with respect to cases and controls revealed normal insulin level of 2–25 mIU/L in 60 (85.71%) cases as compared to 63 (89.99%) controls. Insulin level of more than 25 mIU/L was found in 5 (7.13%) cases as compared to 3 (4.27%) controls. This again nullifies the role of insulin resistance in HCV-induced type 2 DM. Beta cell dysfunction could be one of the possible mechanisms behind this but we have not assessed HOMA-B in our study to prove this.

    A thorough search of the literature on patients with hepatitis C and the prevalence of type 2 DM in HCV-infected patients is summarized in [Table 5].

    The main difference between the published data and our data was that most of the published data have been consolidated by meta-analysis or from retrospective series. These studies included HCV-positive patients with chronic hepatitis or with cirrhosis. Further, they compared HCV-infected patients with liver disease with non-HCV-infected patients with liver disease.

    The main advantage of our study was that we only included HCV-positive patients without evidence of cirrhosis based on clinical and biochemical assessment. The main two limitations of our study were the less number of cases and the nonavailability of FibroScan that was required for the analysis of the cases in order to get idea about the degree of fatty liver and fibrosis of liver in HCV-positive cases.

    The conclusion of our study was that HCV causes 2.1-fold increase in the prevalence of type 2 diabetes in patients without evidence of chronicity, cirrhosis, and portal hypertension with increased predisposition to genotype 3 over genotype 1. However, further studies are needed with large number of cases with FibroScan status of the liver to make any recommendation.[30-37]

    Financial support and sponsorship

    Nil.

    Conflicts of interest

    There are no conflicts of interest.



     
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