|Year : 2012 | Volume
| Issue : 1 | Page : 17-23
Study of diabetes mellitus among patients with hepatitis C virus
Mona Abdel Raouf1, Zeinab A. Yousry1, Olfat M. Hindy2, Somayh S. Eissa1, Dalia S. Soliman3
1 Department of Internal Medicine, Faculty of Medicine for Girls, AL-Azhar University, Egypt
2 Department of Clinical Pathology, National Liver Institute, El-Menoufya University, Egypt
3 Department of Internal Medicine, Police Authority Hospital, Egypt
|Date of Submission||15-Feb-2012|
|Date of Acceptance||15-Apr-2012|
|Date of Web Publication||16-Jul-2014|
Somayh S. Eissa
131 Saker Quriesh, New Maadi, Cairo
Source of Support: None, Conflict of Interest: None
Hepatitis C virus (HCV) infection and type 2 diabetes are two common disorders with high impact on health worldwide. There is growing evidence to support the concept that HCV is associated with type 2 diabetes.
This work aimed to study the clinical phenotype of type 2 diabetes in HCV patients.
Patients and methods
Our study was conducted upon 100 nonobese, noncirrhotic hepatitis C positive patients who were classified into two groups according to homeostatic model assessment (HOMA) test for insulin resistance (HOMA IR). This study also included 15 nonobese type 2 diabetic patients negative for HCV and hepatitis B virus infection classified as control groups. We excluded alcoholics and drug addicts and patients with conditions that affect blood glucose such as endocrine diseases associated with disordered glucose metabolism and use of drugs. All participants were subjected to full history taking and complete clinical examination including BMI and the following investigations: complete blood count, fasting blood sugar, 2 h postprandial blood sugar, glycosylated hemoglobin, fasting insulin level, cholesterol level, HDL, LDL, triglyceride, serum urea, creatinine, complete urine analysis, liver function tests: total bilirubin, alkaline phosphatase, albumin, prothrombin time, INR, SGOT, SGPT, quantitative PCR for determination of HCV-RNA, surface antigen (HbsAg), abdominal ultrasonography, liver biopsy when needed and possible for HCV patients, and ECG.
In this study, we found that the prevalence of type 2 diabetes in group I is 24%. HCV can independently contribute to IR with viral genotypes 1 or 4. We noticed significant positive correlation between fasting insulin and HOMA IR in hepatitis C +ve patients. IR in HCV-infected patients is high irrespective of the degree of liver injury even before a minimal fibrosis is present. Both IR and diabetes can adversely affect the course of chronic hepatitis C, leading to enhanced steatosis and liver fibrosis, and even increase the risk of hepatocellular carcinoma. A significant correlation between HOMA IR and steatosis, a significant positive correlation between fasting insulin and steatosis and a negative correlation between steatosis and BMI in HCV patients was found. No correlation was found between HOMA IR and the viral load (quantitative HCV RNA).
We can concluded that diabetic HCV patients had intermediate clinical phenotype lower BMI and LDL than control and development of type 2 diabetes mellitus in HCV patients was significantly higher in nontreated patients than treated patients. Antiviral therapy and clearance of HCV improves IR, β-cell function, the blood glucose abnormalities.
Keywords: hepatitis C virus, insulin resistance, type 2 diabetes mellitus
|How to cite this article:|
Raouf MA, Yousry ZA, Hindy OM, Eissa SS, Soliman DS. Study of diabetes mellitus among patients with hepatitis C virus. Egypt J Intern Med 2012;24:17-23
|How to cite this URL:|
Raouf MA, Yousry ZA, Hindy OM, Eissa SS, Soliman DS. Study of diabetes mellitus among patients with hepatitis C virus. Egypt J Intern Med [serial online] 2012 [cited 2020 May 31];24:17-23. Available from: http://www.esim.eg.net/text.asp?2012/24/1/17/136021
| Introduction|| |
Hepatitis C virus (HCV) infection and type 2 diabetes are two common disorders that adversely affect health worldwide. A high prevalence of type 2 diabetes among HCV-infected patients with chronic hepatitis has been reported, and there is growing evidence indicating that HCV is associated with type 2 diabetes (Albert et al., 2006) 1. An increased prevalence of type 2 diabetes has been found in liver cirrhosis irrespective of the etiology. It is less clear whether HCV is associated with type 2 diabetes in the absence of cirrhosis 2. HCV may directly damage B cells or disturb their function, leading to diabetes 1. HCV can induce insulin resistance, disturbing the insulin signal pathway because of the effect of the HCV core protein. Moreover, a significant association between diabetes and stage of fibrosis in HCV patients, independent of obesity and steatosis, has been found on liver biopsy (Marcin et al., 2006) 3. Insulin resistance mediated by proinflammatory cytokines, rather than defects in insulin secretion, could be the primary pathogenic mechanism involved in the development of diabetes associated with HCV infection 1. There is a strong link between diabetes and hepatic steatosis or non alcoholic steatohepatitis. Hyperglycemia and hyperinsulinemia have been suggested to be important factors for the progression of fibrosis 4. Advanced fibrosis was observed more frequently in patients with diabetes than in patients without diabetes 5.
This work aimed to study the insulin resistance and clinical phenotype of type 2 diabetes in HCV patients.
| Patients and methods|| |
This work was carried out on 100 patients with chronic HCV infection, diagnosed by anti-HCV antibodies, PCR for HCV-RNA, ranging in age from 42 to 60 years, with mean±SD (46.2±3.69) years, and mass index (BMI) ranging from 22.2 to 25.6 kg/m2, with mean±SD (23.8±0.8). Twenty-four of these patients were women; 69 of them received combined therapy interferon and ribavirin, 12 of them received interferon monotherapy, and 19 did not receive treatment for HCV. Fifteen patients with type 2 diabetes diagnosed on the basis of a fasting plasma glucose level of at least 126 mg/dl, negative for both HCV and hepatits B virus, ranging in age from 42 to 60 years, with mean±SD (48.7±5.69) years, and BMI ranging from 24.5 to 25.7 kg/m2, with mean±SD (25.2±0.36), were included in the control group. Five of them were women; 12 received oral hypoglycemic drugs and three received insulin for diabetes. We excluded obese, cirrhotic patients, alcoholics, drug addicts and individuals with any condition that affects blood glucose such as endocrine diseases and those using drugs associated with glucose metabolism disorder. The patients and control groups were selected from the outpatient clinic of Al Zahra University Hospital, National Liver Institute El-Menoufya University, and Police Authority Hospitals. Consent was obtained from all patients included in the study.
All the patients studied were subjected to (a) full medical history and a complete clinical examination including assessment of BMI [weight in kg divided by the square of height in meters 6; (b) laboratory investigations including: complete blood count using an automated hemology analyzer (Baker system 8210); fasting blood sugar (FBS), 2 h postprandial blood sugar; lipid profile including cholesterol, HDL, LDL, and triglyceride; serum urea, creatinine, and liver functions including SGPT, SGOT, alkaline phosphatase, total bilirubin, albumin, prothrombin concentration and time, INR, using an autoanalyzer (Hitachi-911, USA). Glycosylated hemoglobin (HAc1) was determined using the fast, optimized ion-exchange resin procedure-separation direct in the tube 7. Fasting insulin levels for homeostatic model assessment (HOMA IR) indices are used as markers of insulin resistance and calculated as follows 8:
It is considered to be elevated at HOMA ratio of at least 3 9. Quantitative PCR for the determination of HCV-RNA was carried out using a Roboscreen Taqman reagent mix Germany for HCV and an ABI PRISM 7000 Sequence Detection System (Applied Biosystems Germany); surface antigen for hepatitis B virus; and complete urine analysis. (c) Abdominal ultrasonography was carried out using a real-time scanner (Hitachi, EUD 200). (d) Liver biopsy was performed when needed and only for patients. The biopsy was performed using a gun and a modified 18-gauge or 16-gauge Trucut needle and was guided by ultrasonography using a complete sterile technique and local anesthesia 10. (e) ECG was also performed for all patients.
Data were analyzed using Microsoft Office 2003 (excel) and the Statistical Package for Social Science version 10. Parametric data were expressed as mean±SD and nonparametric data were expressed as number and percentage of the total. Comparison of the mean±SD of two groups was carried out using Student’s t-test. The mutual correspondence between two values was determined using the Spearman correlation coefficient.
| Results|| |
Twenty-four patients with chronic HCV infection developed type 2 diabetes after HCV infection (24%), and they had high FBS (160.25±48.75), high post prandial (PP) (220.33±80.12), and HBA1c (7.90±2.56) [Figure 1]. All 24 patients had HOMA IR above 3 (5.85±3.33); 18 of these patients did not receive treatment for HCV and six patients who received combined therapy interferon and ribavirin developed type 2 diabetes after HCV infection.
|Figure 1: Number of patients HCV positive for diabetes and the number of patients HCV negative for diabetes. HCV, hepatitis C virus.|
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[Table 1] showed histological scoring system 11.
[Table 2] showed that: the mean BMI, FBS, PP, HA1C, HOMA IR, cholesterol, and triglyceride are significantly lower in HCV patients than in the control individuals and platelets were nonsignificantly lower in HCV patients.
|Table 2: Comparison between hepatitis C virus patients and the control group|
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[Table 3] shows that the mean BMI, FBS, and PP are significantly lower in HCV patients positive for diabetes than the control individuals and platelets were nonsignificantly lower in HCV patients positive for diabetes than the control individuals.
|Table 3: Comparison between hepatitis C virus patients positive for diabetes (HOMA IR≥3) and the control group|
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[Table 4] shows that the mean age, BMI, FBS, PP, HA1C, insulin, HOMA IR, cholesterol, and triglyceride are significantly higher in HCV patients positive for diabetes (HOMA IR≥3) than HCV patients negative for diabetes (HOMA IR<3); platelets were significantly lower in HCV patients positive for diabetes (HOMA IR≥3) than HCV patients negative for diabetes (HOMA IR<3).
Our results showed a significant positive correlation between fasting insulin, HOMA IR, and steatosis among HCV patients, whereas the correlations between fasting insulin, HOMA IR, and stage of fibrosis among HCV patients were nonsignificantly positive. Moreover, the correlation between steatosis and BMI in HCV patients was negative [Figure 2], [Figure 3], [Figure 4], [Figure 5] and [Figure 6]. High fasting insulin, HOMA IR, and diabetes were detected even before minimal fibrosis and steatosis in chronic HCV infection [Figure 8], which indicates that insulin resistance is an independent factor in predicting fibrosis in HCV-infected patients. Surprisingly, no correlation was found between HOMA IR and the viral load (quantitative HCV-RNA) [Figure 7].
|Figure 2: Comparison of steatosis between HCV+DM+ patients (HOMA IR≥3) and among HCV+DM− patients (HOMA IR<3). HCV, hepatitis C virus; HOMA IR, homeostatic model assessment test for insulin resistance.|
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|Figure 3: Comparison of the stage of fibrosis between HOMA IR≥3 and HOMA IR<3. HOMA IR, homeostatic model assessment test for insulin resistance.|
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|Figure 4: Highly significant positive correlation between fasting insulin and HOMA IR HCV patients. HCV, hepatitis C virus; HOMA IR, homeostatic model assessment test for insulin resistance.|
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|Figure 5: Significant positive correlation between fasting insulin and stage of fibrosis in HCV patients. HCV, hepatitis C virus.|
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|Figure 6: Negative correlation between steatosis and BMI in HCV patients. HCV, hepatitis C virus.|
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|Figure 8: Section from liver tissue case no. 27 showing a preserved architecture (stage of fibrosis 0/6, negative steatosis) and a mild portal lymphocytic infiltrate (Masson trichrome staining).|
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| Discussion|| |
An increased prevalence of type 2 diabetes has been found in liver cirrhosis irrespective of the etiology 12. No association was found between type 1 diabetes and HCV infection 13. Type 2 diabetes mellitus is associated with a chronic infection of HCV 14. HCV causes extrahepatic manifestations including insulin resistance and type 2 diabetes mellitus 15. HCV infection increases the risk of development of diabetes as a consequence of HCV-induced liver damage. Advanced cirrhosis induces dysregulation of glycemic control, which may result in overt diabetes 16. Our study showed that the prevalence of type 2 diabetes in HCV patients was 24%, and fasting insulin level was significantly higher in noncirrhotic HCV+DM+ patients (HOMA IR≥3) than in noncirrhotic HCV+DM− patients (HOMA IR<3); this result is in agreement with that of 17. Insulin resistance is a common condition in chronic hepatitis; it occurs at an early stage during the course of HCV infection 2. β-cell dysfunction as indicated by C-peptide levels and a limited insulin response 18 as well as insulin resistance was found in patients with chronic hepatitis C infection 19; Albert and his colleagues (2006) reported that a high fasting insulin level has been observed in HCV-infected patients with a moderate or a severe degree of hepatic fibrosis 1. Virus-induced insulin resistance may be a mechanism for fibrogenesis in HCV. Activation of the tumor necrosis factor system in chronic HCV infection correlates with the disease activity 20. The presence of visible hepatocyte triglyceride droplets is a consequence of insulin resistance, hyperinsulinemia, and the resulting excessive flux of free fatty acids through the liver. Triglyceride droplets may be inert with respect to promoting injury and altered cellular homeostasis 21. HCV infection promotes insulin resistance mainly through increased production of tumor necrosis factor-α and cytokine suppressor (SOCS-3). Both events inhibit the insulin receptor and insulin receptor substrate-1 22.
An increase in insulin resistance even before a minimal degree of hepatic fibrosis was observed in our study, that is, insulin resistance may be an independent factor in predicting fibrosis in HCV-infected patients and may not attributable to advanced liver disease, which is in agreement with Nagao et al. 15 and Negro et al. 23, who reported that HCV infection may induce insulin resistance irrespective of the severity of liver disease, and its effect seems to be genotype specific. Also, Tsochatzis et al. 16 reported that insulin resistance is an early event in chronic HCV infection, occurring in 20% of nonobese patients with minimal fibrosis. Metabolic abnormalities further exacerbate insulin resistance and contribute toward progression of fibrosis. In contrast, there was no association between HOMA IR values and the presence of advanced fibrosis or a faster progression of fibrosis 24. Our study showed that the clinical phenotype associated with type 2 diabetes is characterized by higher blood pressure, older age, higher BMI, serum triglycerides, and lower HDL cholesterol levels than HCV-positive patients; similar results were obtained by Antonelli et al. 2. We found that patients with type 2 diabetes, noncirrhotic HCV positive (NC-HCV+), had lower BMI than the type 2 diabetic control group; the same result was obtained by Antonelli et al. 25. In this study, a highly significant positive correlation was found between HOMA IR and BMI among HCV patients. Negro et al. 23 reported that BMI is an independent predictor of insulin resistance in HCV infection. Also, we found a negative correlation between steatosis and BMI in hepatitis C-positive patients, which is in agreement with the findings of Lecube et al. 26. Similar findings were obtained by Castera et al. 27, who concluded that mild steatosis may be associated with high BMI and moderate to severe steatosis is more likely to be caused directly by the virus, favoring liver fibrosis. We found a significant positive correlation between HOMA IR and steatosis and a nonsignificant positive correlation between HOMA IR and stage of fibrosis among HCV patients, which is in agreement with the previous study carried out by Albert et al. 1. Also, we observed that steatosis was higher in HCV+DM+ patients (HOMA IR≥3) than in HCV+DM− patients (HOMA IR<3). A similar result was obtained by Machado and Cortez Pinto 22. Insulin resistance and diabetes can adversely affect the course of chronic hepatitis C and lead to enhanced steatosis, steatohepatitis, and liver fibrosis 1. Both increased adipocity and the presence of steatosis have been associated with a decreased rate of response to antiviral treatment 19. Clearance of HCV improves insulin resistance 28. Eradication of HCV infection reduces the incidence of glucose abnormalities in chronic HCV patients 29. Insulin resistance and type 2 diabetes not only accelerate the histological and clinical progression of chronic hepatitis C but also reduce the early and sustained virological response to interferon-α (IFN-α)-based therapy 23. In contrast, IFN-α has been observed to be associated with the development of diabetes 30. The acute administration of IFN-α may induce some degree of insulin resistance in both healthy individuals and in patients with chronic hepatitis C 31.
| Conclusion|| |
HCV itself can contribute toward insulin resistance, as evidenced by high HOMA IR among HCV patients. Insulin resistance is a predictor of the stage of fibrosis and the rate of fibrosis progression. Insulin resistance and diabetes increase the risk of advanced liver disease, including steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma. Diabetic HCV-positive patients had an intermediate clinical phenotype (lower BMI and LDL) compared with the control group (HCV–DM+). A sustained response to IFN-α-based therapy may result in improvements in blood glucose abnormalities, insulin resistance, and diabetes. Early antiviral therapy decreases the risk of type 2 diabetes and progression of fibrosis in patients with chronic hepatitis C and insulin resistance.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4]