Association of Hepatitis B Virus Serological Markers with Glycemic Control and Diabetes Duration in Type 1 and Type 2 Diabetes Patients in the Najaf Government

Prepared by the researche 

• Baneen Abdul Hadi Jalaout (1) MSc in Medical Microbiology, Faculty of Medicine, University   of    Kufa, Najaf, Iraq
• Saif Jabbar Yasir (2) Ph. D. in Medical Microbiology, Faculty of Medicine, University of Kufa, Najaf, Iraq

Democratic Arabic Center

Journal of Progressive Medical Sciences : First issue – May 2025

A Periodical International Journal published by the “Democratic Arab Center” Germany – Berlin

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Abstract

Background: Diabetes mellitus (DM) and hepatitis B virus (HBV) infection are two major global health concerns. Growing evidence suggests a possible association between chronic viral infections and glucose metabolism disorders .Objective: To investigate the association between HBV serological markers and glycemic control, as measured by fasting blood glucose levels and the duration of diabetes, among patients with type 1 and type 2 diabetes mellitus. Subjects and methods: A cross-sectional study was performed from July to October 2024. The serum was taken from 200 individuals. All of the patients were tested using an ELISA technique for HBc IgG and by an immunochromatographic assay for HBsAb, HBsAg, HBcAb, HBeAg, and HBeAb. The statistical analysis approach was conducted using SPSS version 26. Results: HBcAb-positive diabetic patients showed significantly higher fasting blood glucose levels (P=0.044). HBcIgG was detected in 83 out of 200 patients, mainly in those with 5–15 years of diabetes duration (P = 0.049). No significant association was found between HBV markers and diabetes type.Conclusions: a potential link between HBV exposure and impaired glycemic control , suggesting a possible role of chronic HBVexposure in the progression of metabolic dysfunction over time This suggests that the activation of a previous HBV infection may be an underlying factor in the progression of diabetes mellitus or the development of pre-existing conditions  and  the relationship between HBV and glycemic markers may be independent of diabetes type.

Introduction

       Hepatitis B virus has the capacity of generating various types of antigens, like core, surface, and envelope antigens, the key features of which are their immunogenicity, which can mediate an immune response (Cao et al., 2018). Despite the success of immunization strategies and the reduction in HBsAg seroprevalence since 2000, the hepatitis B virus continues to be a widespread worldwide health concern due to the ongoing complications associated with chronic infection, which continue to contribute significantly to morbidity and mortality. Annually mortality rate due to cancer and liver cirrhosis is 820,000 people, demonstrating the seriousness of being infected with this hepatitis virus (Lazarevic et al., 2023). The simultaneous presence of HBV infection and diabetes mellitus represents a life-threatening situation that demands urgent attention (Mirzaei et al., 2020). Diabetes mellitus is a chronic disease characterized by an imbalance in glucose homeostasis.The link between hepatitis B and diabetes mellitus is still a topic of contention. Studies have been conducted on the rising occurrence of HBV, but there is less evidence on its connection with diabetes patients. Diabetic patients are susceptible to viral infections because of their impaired T lymphocyte numbers, which weaken their immune system. Individuals with diabetes mellitus are at a considerably greater risk of acquiring infectious diseases, including bacterial, fungal, parasitic, and viral infections. This susceptibility is due to impaired cellular immunity and dysfunction of phagocytes caused by high blood sugar levels and reduced blood flow. Among the viruses, hepatitis B and C are the most widespread (Gutiérrez-Grobe et al., 2011). There is limited information on the correlation between HBV indicators, infection conditions, and subtypes of DM. The recent study investigation of Iraqi individuals aged 18–80 years yielded several interesting findings. This study aims to investigate the relationship between hepatitis B virus (HBV) serological markers and fasting blood glucose (FBG) levels in adult patients, aiming to explore whether HBV infection may influence glucose homeostasis and the duration of diabetes, among patients with type 1 and type 2 diabetes mellitus.

Methods

Methodology and data collection process

The current study is a cross-sectional research project included only Iraqi participants who were medical patients in the specialized endocrinology and diabetes center at the Al-Sader Teaching Hospital in Najaf city from July to October 2024. The study comprised 200 patients (either type 1 or type 2 only DM based on a clinical diagnosis by an endocrinologist and serological tests). The patients’ data were obtained through the implementation of a questionnaire and the collection of a blood sample. The specimens were obtained by extracting approximately 10 mL of venous blood from every participant. Blood samples were placed into a gel tube and allowed to coagulate at room temperature for thirty minutes. The serum was extracted using centrifugation and thereafter divided into 1.5-ml Eppendorf tubes. A part of the serum was immediately utilized for a fasting blood glucose test. The other part was then preserved in a refrigerator at a temperature of -80°C for immunological investigation until further examination. Enzyme-linked immunosorbent assays (ELISA) and rapid diagnostic tests are the main methods used in clinical laboratories to find HBV serological markers. A fraction of the serum was used for a human hepatitis B virus panel test (five panel kit): HBc Ab, HBs Ag, HBs Ab, HBe Ag, HBe Ab (Eugene Biotech/China), After that, an ELISA method (Sun Long Biotech, China) was used to find a qualitative HBc IgG. The measurement of fasting plasma glucose (FPG) was conducted using an enzymatic colorimetric method and a kit available commercially from Spinreact, a company in Spain. The procedures for all tests were conducted according to the instructions outlined in the kit’s manual. Before enrolling in the research study, all patients received a comprehensive briefing on the study’s aims and objectives and were then given their informed consent to participate.

Statistical analysis

The statistical analysis in this study was conducted with Version 26 of the Statistical Package for the Social Sciences (SPSS). The relationship between categorical data was illustrated using chi square. The findings are displayed in tables and figures, accompanied by a descriptive narrative, utilizing MS Word and Excel 2016.

Ethics Committee approval

The ethics council of the University of Kufa’s Faculty of Medicine gave its approval before starting this research project. All participants gave their consent, and the Al-Sader Teaching Hospital in the province of Najaf gave its approval.

Limitations of this research

Firstly, obtaining the individual’s HBV vaccination history through self-reporting poses a potential risk of bias recall. Secondly, the limitation of the study is its restriction to a single center with a small sample size.

Results

The present study included a sample of 200 patients, who had undergone testing for HBV infection between July and October 2023, was screened to detect the presence of HBc Ab, HBsAg, HBsAb, HBeAg, HBeAb, Hbc IgG, . Fig 1 presents an overview of the general scheme followed in this investigation. Patients who tested positive for HBsAg, and patients with inadequate clinical data were excluded. This study found that 10.5% of patients who tested negative for HBsAg, but positive for HBc IgG were also positive for HBs Ab. The study also revealed that 75.5% of patients had HBc IgG, 77% had HBc Ab, 10.5% had HBs Ab, and 16.5% had Hbe Ab.

Figure (1): Distribution of HBV biomarkers in diabetes mellitus patients

Individuals who tested positive for HBc IgG had a substantially higher mean rank level of FBG [104.31 (mg/dl)] compared to individuals who tested negative for HBc IgG [88.77 (mg/dl)]. Additionally, the disparity was statistically nonsignificant (P = 0.102).The patients who tested positive for HBc Ab had a considerably higher average rank level of FBG [105.00 (mg/dl)] compared to the patients who tested negative for HBc Ab [85.43 mg/dl]. Simultaneously, the disparity was assessed statistically significant as demonstrated by a p-value of 0.044. As seen in Tab1.

Table (1): Association between HBV markers and level of blood sugar

Table (2): Association between HBV markers and diabetic duration.

Additionally, there was no significant link found between HBc Ab, HbsAb, Hbe Ab and diabetes duration (P > 0.05).

Table (3): Association between HBV markers and duration of diabetic

 In the present study, it was observed based on the results obtained, as well as the study of the relationship between the diagnosis of anti-HBc IgG and the investigation of HBs antibodies. The table also demonstrates that there were highly significant findings for anti-HBs antibody values among patients who tested positive for anti-HBc IgG, with a p-value of < 0.05.

Table (4): Comparison between anti-HBs antibody seropositivity and anti-HBc-IgG results

There was no significant association between type of diabetes and HBc IgG, HBc Ab, HBs Ab, or HBe AB positivity, as seen in Tab. 5.

Table (5): Association between HBV markers and types of diabetes

Discussion

           Serological markers of HBV infection revealed the highest rate of HBcAb (77%) among diabetes patients screened in the current study. Different with other studies were done in China (Lu et al., 2017) and the US (Huang et al., 2015), which related the prevalence of HBcAb in diabetic patients of 62.3% and 6.35%, respectively. It is also higher, than the percentage observed in individuals with diabetes (8.2%), as reported by Schillie et al. (2018). Significantly surpasses the prevalence among patients in Brazil, which stands at just 16.8%, according to Arrelias et al. (2018). Ndako and colleagues (2021) found that 54.2% of individuals tested for HbcAb positivity received results, while Saitta and team (2022) discovered that 15.5% of those tested showed positive results when using anti-HBc as an alternative indicator. The research was conducted in various geographical regions with various sample sizes and did not come to a compromise. Variations in HBV exposure risk, diagnostic method accuracy, study period, sociodemographic characteristics. The variations in antibody frequencies can originate from variations in the assay, sensitivity levels of the technique, sample size, or study methodology.

The present study found that the HBs Ab 21 (10.5%) result was lower than a study conducted in the US population of 19.66% (Huang et al., 2015) of individuals tested positive for HBsAb. In a study conducted in China, the average percentage of HBsAb positivity among diabetic patients was found to be 37% (Lu et al., 2017), which is higher than the frequency in the current study. A study by Ndako et al. (2021) found an 8.3% positive rate among individuals with HBsAb, which is lower compared to the current study. There are variations in vaccination status, danger indicators, and the rate of HBV infection in the whole population. Due to the serologic window during the incubation period after infection, other studies have not been able to identify infected patients, and this HBs Ab positive result is from an infection that was not vaccinated.

On the other hand, a study by Chi et al. (2019) & Tseng et al. (2018) found that in HBeAg patients greater anti-HBc levels were correlated with recurrence and hindered the attainment of HBsAg seroclearance. For individuals without HBe Ag they enter a period of dormancy marked by a robust immune reaction, where the anti HBc level mirrors the presence of HBc Ag in the liver. Guner et al. (2011) revealed that this level is also correlated with the transcriptional activities of cccDNA in hepatocytes. HBeAg has been observed in serum as a sign of active viral replication in previous studies (Zhang et al., 2011). The current investigation reveals no cases of HBeAg positivity.

Nevertheless, Caviglia et al. (2020) indicated that the negativity of HBsAg in the blood does not certify the eradication of the virus. Likewise, Yan and colleagues (2015) clearly demonstrated that the HBV genome has a high mutation rate because it doesn’t have the proofreading function during the replication period. The inability of HBsAg to be detected in cases of occult hepatitis B, involving as well the presence of covalently closed circular DNA (cccDNA), is commonly explained by cccDNA being hindered by epigenetic regulation pathways and/or the immune system of the host, which is believed to be its main cause. The data coming from these studies are showing that patients harboring OBI seem to have a higher chance of mutation in pre-S/S region comparing to patient with HBV chronic infection. It is likely that it will lead to a fall in the antigenicity of HBsAg detection or the production/release of HBsAg is going to be altered (Huang et al., 2017; Zhang et al., 2019). The detection of anti-HBc antibodies has been the main diagnostic marker of occult HBV infection in most research studies on HBV reactivation (Cholongitas et al., 2018). Occult hepatitis B infection (OBI) constitutes both seropositive and seronegative categories according to the presence of serum markers that point at exposure to HBV. People who are seropositive for occult hepatitis B infection (OBI) have anti-HBC and anti-HBs antibodies in their serum specific to the core antigen or/and the surface antigen of hepatitis B, respectively. Such a form of OBI makes up around 80% of all OBI observed (Raimondo et al., 2019). The diagnostic method that is the gold standard for identifying occult hepatitis B infection is when HBV genomes are found inside DNA extracted from hepatocytes. Instead, the HBc Ab tests may be applied as an alternative biomarker for OBI screening (Raimondo et al., 2019; Raimondo et al., 2008).

The study by Pollicino et al. (2021) categorized the HBsAg-negative/antibody HBc-positive condition as a phase in the “occult” stage of the disease progression. If HBsAg becomes undetectable, HBc antibodies are identified as the only clinical evidence of past HBV infection. Consider the HBsAg-negative/HBc-Ab-positive status like an OBI stage in the course of the natural HBV infection. Over 90% of people who are anti-HBc positive could have OBI. The “alternative” antiHBc test is considered the most acceptable and practicable marker for occult hepatitis B infection diagnosis (Wang et al., 2023).

Diabetes patients who are exposed to HBV and have positive HBc Ab show higher levels of FBG, with a significant correlation (P <0.05) in the present study. Furthermore, HBV infection can exacerbate diabetic patients’ glucose control and raise their risk of hyperglycemia (Gundling et al., 2013; Gutierrez-Grobe et al., 2011), (Lecube et al., 2006). Hyperglycemia in diabetes mellitus is believed to induce impairment of the immunological reaction, resulting in inadequate control of the increase of invading microorganisms in individuals with diabetes. Consequently, individuals with diabetes are recognized to be more predisposed to infections. The rising prevalence of Type 2 Diabetes (T2D) would lead to an increase in the occurrence of infectious illnesses as well as comorbidities (Berbudi et al, 2020). The fasting plasma glucose levels of individuals with diabetes type 2 and adult-onset autoimmune diabetes were greater than those of the controls (P < 0.05) compared to patients with adult-onset autoimmune diabetes, but with a shorter duration of diabetes (P < 0.01) in those with the chin (Lu et al., 2017), which agrees with current study results.

As the virus does not show symptoms, the complications could happen when the patient has been sick for a long period (Komatsu, 2014). As Younossi et al. (2017) found out, DM, along with HBV infection, generates liver complications including cirrhosis, hepatocellular carcinoma, and even death. From the 200 patients with a duration of diabetes ranging from 5 to 15 years, the HBc IgG was detected as positive in as many as 83 patients. The statistical evaluation resulted in a considerable result (P = 0.049) in the present study. In 2021, Han et al. made a study of the relationship between the duration of diabetes and the higher risk of HBV infections, and it was found out that patients who have been diabetic longer than six years had a greater risk of getting the infection compared to the ones who have normal blood glucose levels. This is consistent with the current study results. Individuals who have CHB infection or test positive for HBc Ab may be at a higher risk of developing diabetes. This association may have been influenced by many metabolic factors as well as age, according to Lei et al. in 2020.

The relationship between HBV exposure and a prolonged duration of DM might be considered a cumulative danger of being exposed to the virus, likely due to the management of the condition, as DM itself does not lead to hepatitis B. The co-related existence of HBV infection and longer DM duration has been documented in the Polish study of 2002 (Halota et al., 2002), the Turkish one in 2008 (Gulcan et al., 2008), and the Nigerian one of 2016 (Onyekwere et al., 2016). In contract, the investigation done in Italy showed the absence of a correlation between the infection and the DM duration (Sangiorgio et al., 2000). The results of the Kombi et al. (2018) study showed that there was no significant P = 0,892 relationship between the length of DM and HBV infection. That most individuals with diabetes were exposed to HBV infection within ten years of DM.

 In present study show that in people with diabetes type 2, the incidence of HBV markers was not significantly greater compared to individuals with type 1 diabetes. Though DM has long been known to increase the risk of many co-morbidities, such as chronic liver disease, a connection between HBV-related liver dysfunction and Type 2 DM development has just recently been identified. According to theories, viral hepatitis may affect important liver-regulated metabolic processes that are linked to the onset of diabetes mellitus (DM) through the interaction of inflammatory mechanisms brought on by liver infection, which in turn causes insulin resistance and glycometabolic dysfunction. According to a Schillie et al. (2012) meta-analysis, those who have HBV infection have a higher chance of developing diabetes than those who do not. Farshadpour et al.’s (2022) research revealed that among 733 diabetic patients in an Iranian population, 12.82% tested positive for HBcAb and 3.82% tested positive for HBsAg. The difference in HBcAb seroprevalence between diabetic patients and non-diabetic controls was not statistically significant (P = 0.23). This study aligns with the findings of Kombi et al. (2018), which indicated a prevalence of HBV in Type 1 (n = 1, 3.3%) and Type 2 (n = 4, 3.4%) with a non-significant p-value of 0.994. The occurrence of hepatitis B in this study may be attributed to variations in geographical location or the challenge of detecting infected individuals during the serologic window in the incubation period post-infection. This could be due to the activation of insulin resistance linked to persistent inflammatory reactions triggered by HBV infection, as well as the excess production of nitric oxide and tumor necrosis factor-α in the liver. These factors are implicated in impairing insulin metabolic action, damaging β-cells in the pancreas through HBV replication, and causing glycometabolism disorders because of hepatic damage from HBV infection (Cai et al., 2015; Lei et al., 2020). Kaya & Kaya (2020) revealed that vaccination is a crucial and successful strategy for controlling and preventing it. The national immunization program has significantly reduced the disease’s occurrence.

Conclusion

The study revealed a statistically significant association between HBcAb positivity and elevated fasting blood glucose levels, indicating a potential link between HBV exposure and impaired glycemic control. Additionally, HBcIgG was significantly associated with a diabetes duration of 5 to 10 years, suggesting a possible role of chronic HBV exposure in the progression of metabolic dysfunction over time. This suggests that the activation of a previous HBV infection may be an underlying factor in the progression of diabetes mellitus or the development of pre-existing conditions. No significant differences were observed in the distribution of HBV markers between type 1 and type 2 diabetes, indicating that the relationship between HBV and glycemic markers may be independent of diabetes type. These findings underscore the importance of considering viral comorbidities in diabetic care and metabolic monitoring.

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