|Musleh Uddin Kalar1*, Ali Abbas Mohsin Ali2, Sidra Ali2, Syed Monis Ul Hasan2, Syeda Jabeen Zahra Kazmi2, Khusboo-e-Fatima2, Huda Zainab Hasan2 and Syed Zohaib Ahsan3
|Corresponding Author: Musleh Uddin Kalar MBBS, MPH, (USA) Senior Registrar, Department of Community Health Sciences Karachi Medical & Dental College, Pakistan, Email: [email protected], Tel: 9221 03312587070, Fax: 009221 36675655|
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Introduction: The presence of hepatitis and diabetes is a known factor. Insulin resistance in muscular, hepatic and adipose tissues as well as hyperinsulinemia, seem to be pathophysiologic bases for hepatogenous diabetes. World Health Organization (WHO) ranks Pakistan 7th on diabetes prevalence list.
Objective: The objective of this study was to determine the prevalence of type 2 diabetes in chronic liver disease.
Methods: The descriptive cross-sectional survey based study was carried out at public sector government hospitals of Karachi, Pakistan. Patients with positive diagnosis of hematologic parameters were included. ANOVA was conducted to observe the difference between the clinical parameters between hepatitis B and C. Data was normally distributed as evaluated by Shapiro- Wilk test (p > 0.05). The study protocol was approved by ethical review committee.
Results: The two groups of hepatitis B and C showed statistically significant difference when compared with diabetes mellitus on chi square test. This study showed diabetes associated with HCV is more as compared to HBV.
Study Limitation: Small sample size was the study limitation.
Conclusion: diabetes associated with HCV is more as compared to HBV.
|Diabetes, HBV, HCV, Chronic liver disease|
|The association between liver disease and Diabetes Mellitus (DM) is well established, the overall prevalence being significantly higher than that expected by chance and such an association increases the risk of morbidity and mortality significantly.1 The most common liver diseases include infection with Hepatitis A Virus (HAV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV), fatty liver disease, such as alcoholic and Non Alcoholic Fatty Liver Disease (NAFLD), hemochromatosis and advanced disease states such as Non Alcoholic Steatohepatitis (NASH), cirrhosis, liver failure and Hepatocellular Carcinoma (HCC). Autoimmune hepatitis and drug induced liver disease also have an important impact on liver.2 Diabetes Mellitus is a chronic disease that has increased in prevalence and incidence around the world over the last few decades. According to WHO, 347 million people worldwide have diabetes and as an estimate, diabetes will be the 7th leading cause of death in 2030.3,4|
|Diabetes developed as a complication of cirrhosis is known as hepatogenous diabetes.5 In physiological conditions, hepatocytes are the main site of hepatic glucose metabolism; nevertheless, a small, but significant, role in insulin metabolism is played by non-parenchymal liver cells, that is Kupffer cells, endothelial sinusoidal cells and hepatic stellate cells (HSC) that contribute to insulin degradation and are involved in the modulation of hepatocyte glucose metabolism during inflammatory processes via the release of cytokines. Insulin is a key mediator in glucose homeostasis and any change in its action results in the impairment of glucose metabolism.6|
|Insulin resistance in muscular, hepatic and adipose tissues as well as hyperinsulinemia, seem to be pathophysiologic bases for hepatogenous diabetes. An impaired response of the β-islet cells of the pancreas and the hepatic insulin resistance are also contributing factors. Diabetes develops when defective oxidative and nonoxidative muscle glucose metabolism develops. Non-alcoholic fatty liver disease (NAFLD), alcoholic cirrhosis, chronic hepatitis C, and hemochromatosis are more frequently associated with hepatogenous diabetes. Hepatogenous diabetes in early cirrhosis stages may be sub clinical. Only insulin resistance and glucose intolerance may be observed. As liver disease advances, diabetes becomes clinically manifest, therefore hepatogenous diabetes may be considered as a marker for liver function deterioration.5 In CLD patients, the prevalence of impaired glucose tolerance (IGT) is estimated to be about 60–80% and that of overt diabetes is about 7–15%.5|
|According to surveys it was proved that more than 80% of diabetes deaths occur in low- and middle-income countries.7 WHO ranks Pakistan 7th on diabetes prevalence list .In Pakistan; 6.9 million people are affected by diabetes with the International Diabetes Federation estimating that this number will grow to 11.5 million by 2025 unless measures are taken to control the disease.8|
|Hepatitis C is a global health problem. The World Health Organization has estimated that approximately 3.3 per cent of the world’s populations (200 million people) have been infected with the hepatitis C virus. Hepatitis C is one of the commonest causes of chronic liver disease in Pakistan and is one of the leading indications for liver transplant. Several studies have looked at the prevalence of hepatitis C in chronic liver disease in Pakistan. The role of hepatitis C in the causation of liver cancer has been well documented.|
|According to WHO Pakistan is standing at second position in prevalence of hepatitis C in the whole world after Egypt. "The Shadow Epidemic," it's been labeled because In Pakistan more than 10 million people are living with Hepatitis C virus (HCV) with high morbidity and mortality. According to Pakistan medical research Council approximately 7% of total population of Pakistan is infected with Hepatitis C virus. The Silent Killer," health professionals call this virus that can slowly destroy the liver. Hepatitis C earned its label as the Silent Killer precisely because the virus leaves so few noticeable tracks of its presence. The Lancet termed Pakistan as a cirrhotic state in one of its articles. Hepatitis C is responsible for a significant proportion of liver disease in various regions of Pakistan. The high risk of chronicity of this blood-borne infection and association with cirrhosis and liver cancer underscores its public health importance. Hepatitis c like a ticking time bomb for health authorities9 Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have become endemic in our community.10 This study was therefore conducted to determine the prevalence of type 2 diabetes mellitus in chronic liver disease in patients of Karachi, Pakistan.|
Materials and Methods
Study design and study cases
|This descriptive cross-sectional survey based study was carried out at public sector government hospitals of Karachi, Pakistan namely; Jinnah Post Graduate Medical Center (JPMC), Civil Hospital and Abbasi Shaheed Hospital during the period of 4 months from July – October 2013. A total of 165 known cases of chronic liver disease (CLD), both inpatient and outpatient and irrespective of their type, were included in the study based on purposive sampling. The subjects with confirmatory diagnosis from lab or biopsy results along with complete supportive lab data of clinical parameters like CBC (complete Blood Count), LFT (Liver Function Test), and serum Glucose level were considered as a part of the study. Diabetes mellitus was confirmed if the RBS (Random Blood Sugar Level) was above 200 mg/dl or they were already on medications for hypoglycaemic therapy. Undiagnosed symptomatic patients of CLD, diagnosed CLD patients with incomplete supportive lab data as per the study requirements were not included in the study.|
|Categorical and continuous variables were presented as mean ± SD or percentages. All analysis was performed using statistical package for social sciences version 20 (SPSS, Inc., Chicago, IL, USA). Data was presented as mean ± standard deviation. Outliers were assessed by Shapiro- Wilk test and homogeneity of variances was assessed by Levene’s test. Results were analyzed using one-way analysis of variance (ANOVA). Chi square was used to assess significant differences between the groups of hepatitis B and C with type 2 diabetes mellitus.|
|A one-way ANOVA was conducted to determine if the clinical parameters of body mass index (BMI), systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), glucose levels (mg/dl), platelets103, hemoglobin g/dl, alanine aminotransferase (ALT U/L), aspartate amino transferase (AST, U/L), alkaline phosphatase (U/L), gamma glutamyl transferase (U/L), total proteins (g/dl), total albumin (g/dl), total proteins (g/dl) total albumin (g/dl), total bilirubin (gm/dl), direct bilirubin (mg/dl), indirect bilirubin (mg/dl), prothrombin time (sec), activitated partial thromboplastin time (sec), international normalized ratio (sec) were different for hepatitis B and C. There were no outliers and data was normally distributed for each group, as assessed by Shapiro-Wilk test (p > 0.05); and there was homogeneity of variances, as assessed by Levene’s test (p > 0.05). Data is presented as mean ± standard deviation. The differences between the groups of hepatitis B and C was not statistically significant (p > 0.05). Chi square test showed statistically significantly difference between hepatitis B and C with type 2 diabetes mellitus (p < 0.05). All the subjects were briefed about the nature of the study and an informed consent was taken.|
|Although the research has reached its aims, there was a limitation that needs to be mentioned. Due to time limit this research was conducted only on a small size of population who attended the department.|
|The study protocol was approved by ethical review committee. Written informed consent was taken from the participants before their enrolment in this study. The participants’ involvement in this study was voluntary and no financial incentives were provided to any study participant.|
|There is a wide range in the prevalence of altered glucose metabolism in chronic liver disease patients in various studies.11. The total number of patients included in our study was 165 which were CLD positive. The frequency of type 2 diabetes mellitus was 27.9% among them 25.5% were HBV positive and 73.3% were HCV positive. This study found the prevalence of diabetes in CLD patients which was 38.2% during the 4th and 5th decades of life followed by 23.6% in 5thand 6th decades of life which is similar to a result found in a study carried out in Peshawar.11 Mason et al found that there is increase frequency of Diabetes associated with young age group who were HCV positive.12 The result which we found showed there is second highest age related association in the 5th-6th decade of life i.e. 23.6% and >60 yrs i.e. 16.4%. Cacoub P et al showed that the advanced age is the most frequent risk factor for extra hepatic manifestation.13|
|Mehta SH and Knobler H have reported the prevalence of HBV in association with DM is up to 8-12% 14-15 and HCV in association with DM is up to 20-39%.16-1 7 The result in our study showed that the prevalence of HBV in DM was 20.5% and HCV in DM was 86.4%. In a study carried out in JPMC there was equal occurrence of Diabetes in HBV and HCV. The reason for this distribution is thought to be due to equal exposure of HBV and HCV, while in developed countries HBV has been controlled by active HBV Vaccination programme which means HBV and its complication are very low.18 The prevalence of HCV in association with diabetes is quite high as compared to HBV in our study that might be due to the fact that HBV vaccine is now included in that vaccine health program. Mason et al surveyed a large cohort of patients with viral chronic hepatitis showed a strong association between DM and HCV; they suggested HCV infection may serve as an additional risk factor for the development of DM.12|
|The pathophysiological mechanism for the development of DM in patients with HCV has not been clearly established, a generally accepted pathogenesis for DM includes impaired insulin secretion , peripheral insensitivity to insulin and dysregulation of hepatic glucose production.19 Another important finding in our result is 1.9% cirrhotic patients were DM positive this is a valuable finding suggesting that as cirrhosis takes a longer time to develop therefore the associated pancreatic damage also takes longer, finally resulting in Diabetes (as pancreas is a extra hepatic site of viral replication leading to B cell damage). This theory is also confirmed b Caronia S et al. Progress of HBV is over a prolonged period of time therefore very few patients reach the cirrhotic process this is the reason DM is low in that population.20 The frequency of chronic liver disease in patients with HBV infection was 32.1% while in HCV infection was 67.6%, this increased frequency in HCV infection may be corresponding to the fact that most of the patients with HCV remain asymptomatic with 85% of the patients progressing to chronic liver disease it is diagnosed only on routine biochemical study, there is mild elevation of serum aminotransferases which may be fluctuating. Whereas in HBV infection patients presents with fatigue, persistent or intermittent jaundice and serum aminotransferases are markedly raised.|
|Our results are suggestive of diabetes associated with HCV is more as compared to HBV, might be that is because of active HBV vaccination the other step which is needed to reduce HCV is health education and multidimentional public health programs should be addressed and by following the international guidelines in surgeries and blood transfusions as these two are major sources of transmition of HCV.|
|Thanks to Dr Musleh Uddin Kalar regarding his statistical write up and to Ali Abbas Mohsin Ali regarding his intellectual contribution.|
Conflict of Interest
|The authors declare that they have no competing interests.|
|1. Simona Moscatiello, Rita Manini, Giulio Marchesini. Diabetes and liver disease: an ominous association. Nutrition, Metabolism & Cardiovascular Diseases. 2007.
2. Kobashi-Margáin RA, Gutiérrez-Grobe Y, Ponciano-Rodríguez G, Uribe M, Méndez- Sánchez N. Prevalence of type 2 diabetes mellitus and chronic liver disease: a retrospective study of the association of two increasingly common diseases in Mexico. Ann Hepatol. 2010 Jul-Sep; 9(3):282-8.
3. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 countryyears and 2.7 million participants. Lancet, 2011, 378(9785):31–40.
4. Global status report on noncommunicable diseases 2010. Geneva, World Health Organization, 2011.
5. Diego García-Compean; Joel Omar Jaquez-Quintana; Héctor Maldonado-Garza. Hepatogenous diabetes. Current views of an ancient problem. Ann Hepatol. 2009 Jan- Mar;8(1):13-20.
6. Antonio Picardi, Delia D'Avola, Umberto Vespasiani Gentilucci, Giovanni Galati, Enrica Fiori, Sandro Spataro, Antonella Afeltra. Diabetes in chronic liver disease: from old concepts to new evidence. 28 FEB 2006. DOI: 10.1002/dmrr.636.
7. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med, 2006, 3(11):e442
8. WHO ranks Pakistan 7th on diabetes prevalence list. The Nation. 2014 Nov 15.
9. Usman C. Pakistan: a cirrhotic state in need of a savior! The Nation. 2014 Jan 06.
10. Hamid S, Tabassum S, Jafri W. Hepatitis C has replaced hepatitis B as major cause of chronic liver disease in Pakistan. Hepatology 1990; 30:212
11. Sobia S. Ali, Irum Sabir Ali, A H Aamir, Zahid Jadoon, Saima Inayatullah, Frequency of hepatitis C infection in diabetic patients . J Ayub Med Coll Abbottabad 2007;19(1).
12. Mason AL, Lau JY, Hoang N, Qian K, Alexander GJ, Xu Let al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999; 29(2): 328-33.
13. Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette JC et al. Extra hepatic manifestations of chronic hepatitis C.MULTIVIRC Group. Multidepartment Virus C. Arthritis Rheum. 1999; 42(10): 2204-12.
14. Mehta SH, Strathdee SA, Thomas DL. Association between hepatitis C virus infection and Diabetes Mellitus. Epidemiol Rev 2001; 23(2): 302-12
15. Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schanter A. Increased risk of type 2 diabetes in noncirrhotic patients with chronic patients with chronic hepatitis C virus infections. Mayo Clinic Proc 2000; 75(4): 355-9
16. Fraser GM, Harman I, Meller N, Niv Y, Porath A. Diabetes mellitus is associated with chronic hepatitis C but not chronic hepatitis B infection. Isr J Med Sci. 1996;32(7):526-30.
17. Arao M, Murase K, Kusakabe A,et al. Prevalence of Diabetes mellitus in Japanese patients infected chronically with hepatitis C virus. J Gastroenterol 2003; 38: 355-60
18. Qureshi H, Ahsan T, Mujeeb SA, Jawad F, Mehdi I, Ahmed W et al. Diabetes mellitus is equally frequent in chronic HCV and HBV infection. J Pak Med Assoc. 2002 Jul;52(7):280-3.
19. Bahtiyar G, Shin JJ, Aytaman A, Sowers JR, McFarlane SI. Association of diabetes and hepatitis C infection: epidemiologic evidence and pathophysiologic insights. Curr Diab Rep. 2004 Jun;4(3):194-8.
20. Caronia S, Taylor K, Pagliaro L, CarrC, Palazzo U, Petrik J et al. Further evidence for an association between non insulin dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology.1999 Oct;30(4):1059-63.
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