study of diabetes mellitus among patients with hepatitis c

Study of diabetes mellitus among patients with hepatitis C virusMona Abdel Raoufa, Zeinab A. Yousrya, Olfat M. Hindyb, Somayh S. Eissaa

and Dalia S. Solimanc

aDepartment of Internal Medicine, Faculty of Medicinefor Girls, AL-Azhar University, bDepartment of ClinicalPathology, National Liver Institute, El-MenoufyaUniversity and cDepartment of Internal Medicine,Police Authority Hospital

Correspondence to Somayh S. Eissa, 131 SakerQuriesh, New Maadi, Cairo, EgyptTel: + 01 113 754 668;e-mail: [email protected]

Received 1 February 2012Accepted 15 April 2012

The Egyptian Journal of Internal Medicine

2012, 24:17–23

Introduction

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.

Purpose

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.

Results

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).

Conclusion

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, b-cell function, the blood glucose

abnormalities.

Keywords:

hepatitis C virus, insulin resistance, type 2 diabetes mellitus

Egypt J Intern Med 24:17–23& 2012 The Egyptian Society of Internal Medicine1110-7782

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 dia-

betes [1]. HCV can induce insulin resistance, disturbing

Original article 17

1110-7782 & 2012 The Egyptian Society of Internal Medicine DOI: 10.7123/01.EJIM.0000415588.62804.fc

Copyright © The Egyptian Society of Internal Medicine. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

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 hyperinsuli-

nemia 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 methodsThis 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 Author-

ity 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]:

Fasting insulin IU/mlð Þ�fasting serum glucose mmol/lð Þ22:5

:

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 ultrasono-

graphy 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 deter-

mined using the Spearman correlation coefficient.

ResultsTwenty-four patients with chronic HCV infection devel-

oped 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) (Fig. 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.

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 1 Histological scoring systems [11]

Stage Metavir system Ishak system

0 No fibrosis No fibrosis1 Periportal fibrosis

expansionFibrous expansion of some portal areas

with or without short fibrous septa2 P–P septae

(41 septum)Fibrous expansion of most portal areas,

with or without short fibrous septae3 P–C septae Fibrous expansion of most portal areas,

with occasional P–P bridging4 Cirrhosis Fibrous expansion of portal areas, with

marked bridging (P–P or P–C)5 – Marked bridging (P–P or P–C) with

occasional nodules (incompletecirrhosis)

6 – Cirrhosis

18 The Egyptian Journal of Internal Medicine


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 nonsigni-

ficantly lower in HCV patients positive for diabetes than

the control individuals.

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 IRZ3) than HCV patients negative for diabetes

(HOMA IRo3); platelets were significantly lower in

HCV patients positive for diabetes (HOMA IRZ3) than

HCV patients negative for diabetes (HOMA IRo3).

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 (Fig. 2–6). High fasting insulin, HOMA IR,

and diabetes were detected even before minimal fibrosis

and steatosis in chronic HCV infection (Fig. 8), which

indicates that insulin resistance is an independent factor

in predicting fibrosis in HCV-infected patients. Surpris-

ingly, no correlation was found between HOMA IR and

the viral load (quantitative HCV-RNA) (Fig. 7).

DiscussionAn 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. Ad-

vanced cirrhosis induces dysregulation of glycemic con-

trol, 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 signifi-

cantly higher in noncirrhotic HCV + DM + patients

(HOMA IRZ3) than in noncirrhotic HCV + DM –

patients (HOMA IRo3); 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]. b-cell dysfunc-

tion 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-aand 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

Table 2 Comparison between hepatitis C virus patients and the control group

HCV patients Age BMI FBG (mg/dl) PP (mg/dl) HBA1c Insulin HOMA IR Cholesterol HDL LDL TG Platelets

Mean 46.2 23.8 102 134.2 5.69 8.78 2.25 187.73 47.4 117.2 147.1 187.4SD 3.69 0.8 41.16 64.19 2.04 5.29 1.92 33.57 13.5 34.39 76.23 42.62Control group

Mean 48.7 25.2 213.7 298.9 8.4 11.56 5.85 240.07 43.74 147.8 205.3 187.53SD 5.69 0.36 43.93 77.03 1.47 7.24 3.33 47.35 11.24 36.14 59.29 34.85P value 0.110 0.000 0.000 0.000 0.000 0.171 0.001 0.001 0.261 0.006 0.003 0.990

FBG, fasting blood glucose; HCV, hepatitis C virus; HOMA IR, homeostatic model assessment test for insulin resistance; TG, triglyceride.

Table 3 Comparison between hepatitis C virus patients positive for diabetes (HOMA IRZ3) and the control group

HCV patients positive fordiabetes (HOMA IRZ3) Age BMI

FBGmg/dl PP mg/dl HBA1c Insulin

HOMAIR Cholesterol HDL LDL TG Platelets

Mean 48.08 24.43 160.25 220.33 7.90 14.47 5.08 212.42 44.21 136.29 201.79 163.04SD 3.57 0.54 48.75 80.12 2.56 6.60 2.06 43.17 10.86 43.16 77.68 52.07Control group

Mean 48.73 25.17 213.73 298.93 8.40 11.56 5.85 240.07 43.74 147.79 205.33 187.53SD 5.69 0.36 43.93 77.03 1.47 7.24 3.33 47.35 11.24 36.14 59.29 34.85P value 0.696 0.001 0.001 0.005 0.448 0.218 0.434 0.077 0.899 0.376 0.873 0.087

FBG, fasting blood glucose; HCV, hepatitis C virus; HOMA IR, homeostatic model assessment test for insulin resistance; TG, triglyceride.

Study of diabetes mellitus Raouf et al. 19


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 character-

ized 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 2Ta

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Figure 1

Number of patients HCV positive for diabetes and the number ofpatients HCV negative for diabetes. HCV, hepatitis C virus.

Figure 2

Comparison of steatosis between HCV + DM + patients (HOMAIRZ3) and among HCV + DM – patients (HOMA IRo3). HCV,hepatitis C virus; HOMA IR, homeostatic model assessment test forinsulin resistance.

Figure 3

Comparison of the stage of fibrosis between HOMA IRZ3 and HOMAIRo3. HOMA IR, homeostatic model assessment test for insulinresistance.



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 be-

tween 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

IRZ3) than in HCV + DM – patients (HOMA IRo3).

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 progres-

sion of chronic hepatitis C but also reduce the early and

sustained virological response to interferon-a (IFN-a)-

based therapy [23]. In contrast, IFN-a has been observed

Figure 4

Highly significant positive correlation between fasting insulin andHOMA IR HCV patients. HCV, hepatitis C virus; HOMA IR,homeostatic model assessment test for insulin resistance.

Figure 5

Significant positive correlation between fasting insulin and stage offibrosis in HCV patients. HCV, hepatitis C virus.

Figure 6

Negative correlation between steatosis and BMI in HCV patients.HCV, hepatitis C virus.

Figure 7

Correlation between HOMA IR and HCV RNA (PCR) among patients.

Figure 8

Section from liver tissue case no. 27 showing a preserved architecture(stage of fibrosis 0/6, negative steatosis) and a mild portal lymphocyticinfiltrate (Masson trichrome staining).



to be associated with the development of diabetes [30].

The acute administration of IFN-a may induce some

degree of insulin resistance in both healthy individuals

and in patients with chronic hepatitis C [31].

ConclusionHCV 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 inter-

mediate clinical phenotype (lower BMI and LDL)

compared with the control group (HCV–DM +). A

sustained response to IFN-a-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.

AcknowledgementsConflicts of interestAll members of Internal Medicine Departments of Al-Zahraa UniversityHospital, National Liver Institute and Police Authority Hospital.

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study of diabetes mellitus among patients with hepatitis c

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