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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 1  |  Page : 91-96

Inadequate serum hepcidin levels in chronic hepatitis C infection-induced type 2 diabetes mellitus


1 Department of internal medicine, Faculty of Medicine For Girls, Al-Azhar University, Cairo, Egypt
2 Department of clinical and chemical pathology, National Research Center, Cairo, Egypt

Date of Submission05-Nov-2018
Date of Acceptance06-Nov-2018
Date of Web Publication3-Jun-2019

Correspondence Address:
Samia T Ali
Department of internal medicine, Faulty of Medicine for girls, Al-Azhar University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_59_18

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  Abstract 


Background Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. In addition to established liver injury, type 2 diabetes mellitus (T2DM) is one of the most important extrahepatic metabolic disorders that are attributed to HCV infection.
Aim The aim of this study is to investigate the impact of HCV infection in the development of T2DM through the assessment of serum hepcidin levels.
Patients and methods The study included 60 Egyptian patients with chronic HCV infection who were divided according to the presence and absence of diabetes into two groups: 30 HCV-positive patients who developed diabetes mellitus during the course of HCV infection (HCV-T2DM patients) and 30 HCV-positive patients without T2DM (HCV patients) and 20 healthy individuals as a control group (age and sex matched). They were subjected to a full assessment of medical history, clinical examination, abdominal ultrasound, and laboratory investigations including complete blood count, liver function tests, fasting blood sugar (FBS), glycosylated hemoglobin, fasting insulin, serum hepcidin, serum ferritin, serum iron, and transferrin saturation. Serum hepcidin, ferritin, and insulin were measured using an enzyme-linked immunosorbent assay.
Results We found that serum hepcidin was statistically significantly lower in HCV patients than in controls (P<0.0001). Also, serum hepcidin in HCV-T2DM patients was statistically significantly lower than that in HCV-positive patients (P<0.05). Serum ferritin was statistically significantly higher in HCV-positive patients than in controls (P<0.0001). Also, serum ferritin was statistically significantly higher in HCV-T2DM patients than in HCV patients (P<0.0001). Serum iron and serum transferrin saturation were statistically significantly higher in HCV-T2DM patients than HCV-positive patients (P<0.0001 and <0.0001, respectively). There was a statistically significant increase in fasting blood glucose, glycosylated hemoglobin, and fasting insulin in HCV-T2DM patients compared with HCV nondiabetic patients (P<0.0001 for all). Also, we found that the serum albumin was statistically significantly lower in HCV-T2DM patients compared with HCV-positive patients (P<0.0001).
Conclusion HCV infection is associated with a decreased level of hepcidin in relation to body iron store, which plays a crucial role in the development of T2DM in chronic HCV infection patients.

Keywords: chronic hepatitis C virus, serum ferritin, serum hepcidin, serum iron, transferrin, type 2 diabetes mellitus


How to cite this article:
Ali ST, Mohamed NA. Inadequate serum hepcidin levels in chronic hepatitis C infection-induced type 2 diabetes mellitus. Sci J Al-Azhar Med Fac Girls 2019;3:91-6

How to cite this URL:
Ali ST, Mohamed NA. Inadequate serum hepcidin levels in chronic hepatitis C infection-induced type 2 diabetes mellitus. Sci J Al-Azhar Med Fac Girls [serial online] 2019 [cited 2020 Feb 25];3:91-6. Available from: http://www.sjamf.eg.net/text.asp?2019/3/1/91/259535




  Introduction Top


Infection with hepatitis C virus (HCV) is a worldwide problem affecting more than 170 million individuals. As many as one in five will develop cirrhosis and its complications [1]. HCV infection becomes chronic when its RNA virus persists in blood for more than 6 months and is associated frequently with extrahepatic manifestations such as diabetes, arthralgias, and thyroiditis. About one-third of the chronically infected population develops diabetes [2]. The pathogenesis of HCV with diabetes is through the development of insulin resistance (IR) [3].

IR plays an important role in the development of various complications associated with chronic hepatitis C (CHC) infection. Recent evidence indicates that HCV-associated (IR) may result in accelerated hepatic fibrosis, steatosis, hepatocellular carcinoma, and resistance to antiviral treatment [4].

Numerous mechanisms have been proposed to explain this IR including upregulation of inflammatory cytokines, hypophosphorylation of insulin receptor substrate-1 and 2, upregulation of gluconeogenic and lipogenic genes, accumulation of lipids, and targeting lipid storage organelles.

The hepatocyte injury caused by chronic infection with HCV is linked to an increased risk for type 2 diabetes mellitus (T2DM), especially when HCV infection is accompanied by high ferritin levels [5]. Hepatocyte injury and iron overload have been identified as one of the factors that develop type 2 diabetes mellitus [6].

Hepcidin is a biologically active hepatic peptide that is predominantly secreted from the liver and excreted in the urine. However, kidney tissue, pancreatic beta cells, macrophages, and adipocytes have also been reported as other sites of hepcidin production [7].

Hepcidin is a novel peptide because of its dual role as an ‘iron-hormone’ and an ‘antimicrobial peptide’ [8]. Its synthesis is increased in response to inflammation and systemic infection. Hepcidin is likely to play a role in innate immunity [7]. The synthesis of hepcidin is homeostatically increased by iron loading and decreased by anemia, hypoxia, oxidative stress, and erythropoietin or vitamin D therapy [9].

Hepcidin regulates serum iron levels during inflammation, infection, and possibly also in cancer. Under these conditions, iron shifts from circulation into the cellular store in hepatocytes and macrophages, making it less available for invading microorganisms and tumor cells [10].

At the opposite side of the spectrum, hepcidin deficiency appears to be the ultimate cause of most forms of haemochromatosis, either because of mutations in the hepcidin gene itself or because of mutations in the regulators of hepcidin synthesis [7],[11].

HCV infection is associated with alterations in body iron homeostasis through a poorly understood mechanism. The regulation of iron homeostasis is mainly carried out by binding iron efflux channels called ferroprotein, which are responsible for iron export from enterocytes and macrophages [12],[13].

Few studies have investigated the relation between hepcidin and the development of type 2 diabetes mellitus. Chronic HCV infection causes iron accumulation by hepcidin suppression, which has been proposed as a major mechanism responsible for causing glucose intolerance by influencing insulin signaling [14]. The accumulated iron causes increased glucose production by hepatocytes, increased fatty acid oxidation, and decreased glucose oxidation in skeletal muscles and adipocytes and altered levels of adipokines in adipocytes [15].

Furthermore, it causes oxidative stress, a factor that is responsible independently for causing IR. The resultant hyperinsulinemia then causes rapid iron uptake by liver as insulin redistributes transferrin receptors from an intracellular compartment to the cell membrane and further exacerbates iron overload [4]. The relation between HCV infection and the development of T2DM remains unknown. The aim of this study was to investigate the presence of an association between hepcidin (the major iron-regulating hormone) and T2DM in chronic HCV infection.


  Patients and methods Top


This control study included 60 [45 (75%) males and 15 (25%) women] HCV-positive patients (previously diagnosed by PCR for HCV-RNA) recruited from the Internal Medicine Department, Al-Zahraa University Hospital aged between 35 and 65 years, mean age 54±6.3 years, who were divided according to the presence and absence of diabetes into two groups: 30 HCV-positive patients who developed diabetes mellitus during the course of HCV infection (positive HCV, positive T2DM) and 30 HCV-positive patients without T2DM (positive HCV, negative T2DM). In addition, 20 [15 (75%) men and five (25%) women] healthy individuals (age and sex matched) as a control group (negative HCV, negative T2DM) aged between 30 and 65 years, mean age 50.5±8.89 years, were included. All patients and controls provided their informed consent before participating in the study. The study was approved by our Ethical Committee of Faculty of Medicine, Al-Azhar University.

Exclusion criteria included patients with hepatitis B virus infection, obesity, iron deficiency anemia, haemochromatosis and other causes of chronic liver diseases are excluded from the study.

Both the patient and the control groups were matched carefully for age, sex, and BMI. The severity of liver disease was assessed according to modified Child–Pugh’s classification. They were subjected to the following:
  1. Full assessment of medical history.
  2. Clinical examinations including calculation of BMI as follows: BMI=weight (kg)/height (m2).
  3. Abdominal ultrasonography was performed to assess liver echogenicity, size, surface, any focal lesions, size of spleen, and presence or absence of ascitic fluid.
  4. The following laboratory investigations were carried out:
    1. Complete blood count.
    2. Evaluation of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and synthetic liver function tests including serum albumin, serum bilirubin, and prothrombin concentration.
    3. Evaluation of serum iron, transferrin, and ferritin.
    4. Fasting blood glucose (FBG), glycosylated hemoglobin percent (HbA1c), and fasting insulin levels.
    5. Determination of serum hepcidin and ferritin levels were performed using an enzyme-linked immunosorbent assay and the kits were supplied from DRG (DRG Instruments GmbH, Frauenbergstr. 18, D-35039 Marburg, Germany.


Statistical analysis

Results are expressed as mean±SD. Student’s t-test for parametric data and the Mann–Whitney U-test for nonparametric data were used. Fisher’s exact analysis was also used to compare proportions between groups. Pearson’s coefficient was used to study the correlations between different parameters. P more than 0.05 was considered nonsignificant, P less than 0.05 was considered significant, and P less than 0.01 was considered highly significant. All statistical analyses were carried out using the statistical package for the social sciences (SPSS Inc., Chicago, Illinois, USA) software version 16.


  Results Top


In this study, there was a statistically significant decrease in serum hepcidin in HCV patients compared with the healthy controls (P<0.0001). For serum ferritin, there was a statistically significant increase in HCV patients compared with the healthy controls (P<0.0001) as shown in [Table 1].
Table 1 Serum hepcidin and ferritin levels in all hepatitis C virus-positive patients versus controls

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There was no statistically significant difference in both groups in age and sex (P>0.05). Serum hepcidin was statistically significantly lower in HCV-T2DM patients than in HCV-positive patients (P<0.05). Serum ferritin was statistically significantly higher in HCV-T2DM patients than in HCV-positive patients (P<0.0001). FBG, HbA1c, and fasting insulin were statistically significantly higher in HCV-T2DM patients than in HCV-positive patients (P<0.0001 for all). Also, the comparison showed that serum iron, transferrin saturation, white blood counts, and total bilirubin levels were significantly higher in HCV-T2DM than in HCV patients (P<0.0001 for all). HCV-T2DM patients had statistically significantly lower serum albumin and hemoglobin than HCV patients (P<0.0001 and <0.001, respectively). Also, the comparison showed that there was no statistically significant difference among alanine transaminase, aspartate transaminase, prothrombin concentration, and platelets (P>0.05 for all) between the two groups studied as shown in [Table 2].
Table 2 Comparison between the main laboratory results and clinical examination in both groups

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[Table 3] shows the correlation coefficient between serum hepcidin levels and other parameters in both groups. There was a significant positive correlation between serum hepcidin and serum ferritin in HCV patients (r=+0.511, P=0.001) and HCV-T2DM patients (r=+0.160, P=0.001). Also, there was a significant correlation between serum hepcidin and FBG, HbA1c, and fasting insulin in HCV-T2DM patients. There was a significant correlation between serum hepcidin and serum albumin in HCV patients (r=−0.069, P=0.0001) and HCV-T2DM patients (r=+0.111, P=0.0001). There was a significant correlation between serum hepcidin and serum iron in HCV patients (r=−0.307, P=0.0001) and HCV-T2DM patients (r=+0.050, P=0.0001). Also, there was a significant correlation between serum hepcidin and serum transferrin saturation in HCV patients (r=+0.420, P=0.0001) and HCV-T2DM patients (r=0.079, P=0.0001).
Table 3 Correlation between serum hepcidin level and different parameters in hepatitis C virus and hepatitis C virus-type 2 diabetes mellitus patients

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  Discussion Top


HCV infection and T2DM are two chronic conditions that contribute to significant morbidity and mortality [16]. HCV has been identified as one of the leading causes of chronic liver disease with severe complications such as end stage cirrhosis and liver cancer [17]. A high prevalence of iron overload has been shown in patients with HCV infection characterized by different genetic backgrounds and exposure to environmental factors, suggesting that several mechanisms are involved, including inflammation, alteration of iron sensing, and deregulation of hepcidin released by hepatocytes [16].

T2DM is associated closely with elevated iron store. The hormone hepcidin is the key regulator of iron homeostasis [16]. Low hepcidin levels were recently reported in a patient with T2DM. Hepcidin expression in the liver was correlated negatively with the total iron stores [18]. Iron accumulation in the liver, where hepcidin is synthesized exclusively, is common in patients with chronic liver diseases, especially in patients with chronic HCV infection [19]. Excess iron deposition in the liver is known to be hepatotoxic and may exacerbate liver injury in patients with CHC [20].

In the present study, the serum hepcidin level of HCV-positive patients was statistically significantly lower than that of healthy controls (P<0.0001). The results are in agreement with those of Fujita et al. [21], who reported that the expression of hepcidin in patients with CHC was relatively lower than the hepcidin expression in HBV-positive patients and noninfected patients. Also, the results of our study are comparable to those of Girelli et al. [22], who measured serum hepcidin in 81 untreated CHC patients and 57 healthy controls. Also, the author found a significant decrease in HCV patients: 33.7 versus 90.9 ng/ml, respectively (P<0.001). The author postulated that hepcidin downregulation is likely to contribute to liver iron accumulation in this condition. Moreover, the results are in agreement with the findings reported by Penkova et al. [23].

Tsochatzis et al. [24] found a decrease in serum hepcidin levels in CHC patients compared with healthy controls. The association of hepcidin with standard endocrine T2DM has been reported by Wang et al. [12]. In Sprague-Dawley rats, the author showed a 40% decrease in hepatic hepcidin expression in rats with streptozotocin-induced T2DM. Arif et al. [25], who measured serum hepcidin levels in 60 individuals, including 30 patients with both hepatitis C infection and diabetes mellitus, showed that glucose levels in the blood increased significantly with decreasing hepcidin levels in patients with CHC-induced diabetes. The mean values of serum hepcidin were found to be statistically significantly lower in HCV-T2DM patients compared with HCV-positive nondiabetic patients at P value (P<0.05). Several studies have reported that HCV infection may also contribute toward the development of diabetes, and a higher prevalence of T2DM has been observed in the developed countries (2–9.4%) in patients with HCV infection than in those with other forms of chronic hepatitis [26].

In our study, serum ferritin was statistically significantly higher in HCV-positive patients and HCV-T2DM than healthy controls (P<0.0001). Also, there was a statistically significant increase in serum ferritin in HCV-T2DM patients than HCV nondiabetic patients. These results were in agreement with the previous studies by Lecube et al. [3], who reported that liver injury caused by chronic infection with HCV in linked to an increased risk for T2DM, especially when HCV infection is accompanied by high ferritin levels. Inadequate hepcidin levels may induce diabetes by causing iron overload and subsequent tissue iron accumulation [13],[27]. Iron-generated reactive oxygen species can then cause beta cell failure, which reduces insulin synthesis [28],[29].

Our study showed that FBG, HbA1c, and fasting insulin were higher in HCV-T2DM patients than in HCV patients. This result was in agreement with that of El-Zayadi et al. [4], who reported that the resultant hyperinsulinemia then causes rapid iron uptake by liver as insulin redistributes transferrin receptors from an intracellular compartment to the cell membrane and further exacerpates iron overload. This relationship may indicate that in cases of advancing liver disease, there may be increased susceptibility of HCV-positive patients to develop T2DM. Parolin et al. [30] observed that the odds of developing T2DM among HCV-infected patients with cirrhosis were doubled compared with non cirrhotic HCV-positive patients. Other studies have described similar trends for T2DM to be observed more frequently in patients with cirrhosis compared with noncirrhotics, ranging from 19.5 to 50% [30]. Also, we found that HCV-T2DM patients had significantly lower serum albumin than HCV-positive patients. Also, our results showed that serum hepcidin was correlated negatively with serum albumin in HCV patients and correlated positively with HCV-T2DM patients. A statistically significant association of liver dysfunction was observed in HCV-T2DM patients than HCV-positive patients. This is in agreement with the results obtained by Fujita et al. [21], who reported that the serum albumin level was not correlated with the hepcidin level and serum bilirubin was correlated positively with hepcidin. Very recent studies in animal and cellular models have suggested that HCV infection may modulate hepcidin expression directly [31]. Strikingly, Arase et al. [32] recently showed that HCV treatment may decrease the annual incidence of diabetes in HCV-infected patients, independent of other predisposing factors.


  Conclusion Top


Our study showed that a low level of hepcidin in chronic HCV might be involved in the pathogenesis of iron overload and development of T2DM. Moreover, there is a positive relationship between hepcidin levels and synthetic liver function, suggesting that suppression of hepcidin might be linked to disease progression, iron overload, and development of T2DM. This study concluded that there is a strong association between serum hepcidin level and T2DM in patients with chronic HCV infection.

Recommendation

By correcting the hepcidin level, we can prevent cellular iron overload and reduce the risk of T2DM in chronic HCV patients. HCV treatment may decrease the annual incidence of diabetes in HCV-infected patients, independent of other predisposing factors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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