Published online Apr 27, 2020. doi: 10.4254/wjh.v12.i4.137
Peer-review started: December 29, 2019
First decision: February 16, 2020
Revised: February 28, 2020
Accepted: March 22, 2020
Article in press: March 22, 2020
Published online: April 27, 2020
Processing time: 115 Days and 11.6 Hours
Chronic hepatitis C (CHC) is associated with an elevated prevalence of type 2 diabetes mellitus. Although, some mechanisms underlying the modified glucose metabolism in hepatitis C virus (HCV) infection have been elucidated, several aspects remain unknown. Growing scientific evidence has suggested a role of pro-inflammatory immune response. Increased serum concentrations of interleukin-6 (IL-6) have been associated with insulin resistance, type 2 diabetes mellitus as well as advanced forms of liver disease in chronic hepatitis C infection.
Patients with CHC, with insulin resistance or type 2 diabetes mellitus are likely to have a more complicated course of the infection. Based on previous reports, it is important to keep in mind, if on the one hand insulin resistance is recognized as a risk factor for the progression of HCV-related liver disease, on the other hand, preceding HCV infection significantly increases the risk of developing type 2 diabetes mellitus. Additionally, diabetic patients are at an increased risk of acquiring HCV infection. Thus, this two-way interface, i.e., the relationship linking HCV and type 2 diabetes mellitus, is possibly determined by complex and multifaceted interactions among the hepatitis virus, the environment and the host.
The objectives of this study were therefore to investigate the frequency of IL-6-174G/C (rs1800795) single nucleotide polymorphism in CHC patients and in healthy subjects of the same ethnicity. Furthermore, the association between type 2 diabetes mellitus (dependent variable) and demographic, clinical, nutritional, virological and IL-6 genotyping data was also evaluated in patients chronically infected with HCV.
Two hundred and forty-five patients with CHC and 179 healthy control subjects (blood donors) were prospectively included. Type 2 diabetes mellitus was diagnosed according to the criteria of the American Diabetes Association. Clinical, biochemical, histological and radiological criteria were applied to make the diagnosis and staging of the liver disease. IL-6-174G/C (rs1800795) genotyping was Taqman assayed by Real Time PCR System 7.500 by using oligonucleotide primers previously described by Fishman et al[44]. The Hardy-Weinberg equilibrium of alleles at individual loci was assessed by two-tailed chi-square test or Fisher’s exact test. The associations of each variable including IL-6-174G/C, sex, increasing age, blood hypertension, nutritional status, liver fibrosis stage (chronic hepatitis and cirrhosis) with type 2 diabetes mellitus were tested in univariate analysis. All variables with P values < 0.20 were included in the full model of logistic regression. Odds ratio (OR) and 95%CI were used as an estimate of the risk. P values ≤ 0.05 were considered significant.
Type 2 diabetes mellitus, blood hypertension and liver cirrhosis were observed in 20.8% (51/245), 40.0% (98/245) and 38.4% (94/245) of the patients, respectively. The frequency of the studied IL-6 single nucleotide polymorphism did not differ between the CHC patients and controls (P = 0.81) and the alleles were in Hardy-Weinberg equilibrium (P = 0.38). In the multivariate analysis, type 2 diabetes mellitus was inversely associated with GC and CC genotypes of IL-6-174 (OR = 0.42; 95%CI = 0.22-0.78; P = 0.006) and positively associated with blood hypertension (OR = 5.56; 95%CI = 2.79-11.09; P < 0.001).
In the current study, we demonstrated for the first time that the IL-6-174G/C gene promoter polymorphism is inversely associated with type 2 diabetes mellitus in patients with CHC. This finding reinforces the need for additional investigations focusing on the biological mechanisms of diabetes mellitus in patients chronically infected with HCV.
The identification of potential inflammatory mediators involved in the crosstalk between HCV and the axis pancreas-liver remains important issues that deserve further investigations. Moreover, better understanding of these processes may positively affect the management strategies for reducing the extra-hepatic manifestations and their negative impact on health status in CHC patients.