Hepatitis B is an infectious disease of liver caused by hepatitis B virus (HBV) [1,2]. Outcomes of hepatitis B infection can be divided into acute and chronic hepatitis 3. The continuous replication of HBV in chronic hepatitis induces oxidative stress which in turn causes liver inflammation over years thereby increasing risk of fibrosis, cirrhosis and liver cancer.

The term “metabolic syndrome” (MS) refers to a clustering of specific cardiovascular (CV) disease risk factors including central obesity, hypertension, high triglycerides, hyperglycemia and low HDL levels and whose underlying pathophysiology is thought to be related to insulin resistance 4. Recently other abnormalities such as prothrombotic states, non-alcoholic fatty liver disease and sleep apnea have been added to the syndrome making the definition more complex [5].

Recently, Chronic Hepatitis B (CHB) infection has been linked with metabolic syndrome like other chronic infection viz HIV, HCV. Several studies have explored the link of CHB infection with atherosclerosis or cardiovascular disease 6,7,8,9,10 and there has been a paucity of studies in studying metabolic syndrome in CHB infection in India.

Therefore, the present study was undertaken to study metabolic syndrome in treatment naïve CHB infection patients.

Population and study design

The present study was a hospital based prospective, observational and cross-sectional study done for a period of one year.  The study was conducted in the Department of Medicine, Silchar Medical College and Hospital. Silchar, Assam India.

CHB was diagnosed on the basis of the presence of hepatitis B surface antigen HBsAg) and anti-hepatitis B core antibody (IgG). Age and sex matched healthy volunteers from the general population was taken as control. Exclusion criteria for cases and controls were: chronic hepatitis other than HBV infection, neoplastic disorders, e.g. hepatocellular carcinoma; chronic kidney disease, nephrotic syndrome; chronic infection like HIV; patients on lipid- lowering drugs, urate- lowering drugs, hormone replacement therapy; cirrhosis, hypothyroidism, heart failure, chronic inflammatory disease like rheumatoid arthritis, SLE;  familial dyslipidaemia, age <18 years,  female patients on oral contraceptive pills and pregnant patients.

For each subject, data of demographic characteristics, family history, physical exercise, addiction to tobacco and alcohol and diet were collected. Physical examination variables measured were the following: waist circumference measured at the midpoint between the lower border of the rib cage and the iliac crest by a non-stretchable measuring tape; blood pressure was measured after a rest of five minutes in sitting position in the right arm with the help of a sphygmomanometer. The average of two readings taken in 5 minutes apart was recorded.

Blood samples were collected by venipuncture after 12 hours fasting. Laboratory variables measured were triglycerides (TG), HDL-C, Total Cholesterol, fasting plasma glucose (FPG) and hepatitis B serology. Both current and previous smokers, as well as active and passive smokers, were taken into consideration. Amount of alcohol consumption per week was documented, if the patient was an alcoholic. The duration, extent and nature of physical activity and exercise were documented in every case.

Definition of metabolic syndrome

Metabolic syndrome was diagnosed using NCEP-ATP III 2004 criteria - presence of three or more of the following conditions: increased waist circumference (> 88 cm in women and >102 cm in men), high triglyceride level (> 150 mg/dl), low HDL‐C -  <50 mg/dl in women and <40 mg/dl men, high fasting plasma glucose > 100 mg/dl and high systolic or diastolic blood pressure > 130/85 mm Hg or self‐reported use of drugs for hypertension.

Biochemistry and viral serology

Blood samples were tested for TG, HDL-C, TC and FPG using standard laboratory test criteria. Qualitative detection of Hepatitis B Surface Antigen (HBsAg) in Human Serum or Plasma was done by HEPACARD kit which was a visual, rapid, sensitive and one - step immunoassay. HBV DNA load was estimated by PCR method. Qualitative detection of antibody to hepatitis B core antigen (anti-HBc) in human serum and plasma was done by The ARCHITECT Anti-HBc II assay by chemiluminescent microparticle immunoassay (CMIA).

Statistical Methods

The Collected data were tabulated and analyzed as descriptive statistics using SPSS version 22.0 software. Continuous variables were expressed as mean ± Standard Deviation. Categorical variables were presented as frequencies and percentages and nominal categorical data between the groups were compared using the Chi-square test or Fisher’s exact test as appropriate. p<0.05 was considered statistically significant. Graphical and diagrammatic representations were made whenever felt necessary.

Approval was taken from the Institutional Ethics Committee.

Baseline Demographic Features

Comparison Of Baseline Characteristics Between Cases and Controls (Table 1): Both case and control groups had almost similar sex distribution. CHB patients comprised of 6 female (14.6%) and 41 male patients (85.4%), whereas, the control group had 13 female (26%) and 37 male patients (74%). (p = 0.1276). Most CHB patients were in the age group 51-60 years (23.4%). The mean age of both cases and control were similar (p = 0.157). There were no differences between the two groups for smoking, alcohol consumption and sedentary lifestyle these factors (Chi-square test, p>0.05).

Table 1:  comparison of baseline characteristics between cases and controls

Table 2: Event rates between case and control

Table 3: Relation between Metabolic syndrome with HBV DNA levels and ALT levels (n=47)

Association Between Metabolic Syndrome and Chronic Hepatitis B

Event Rates Between Case and Control (Table 2): Prevalence of metabolic syndrome was found to be 19.1% in CHB group and 20% in control group. CHB patients had higher waist circumferences and mean systolic blood pressure than controls but these were not found to be statistically significant.

Mean total cholesterol in CHB patients (126.34±43.97 mg/dL) was significantly lower than controls (155.3±42.4 mg/dL), (p=0.001). 

        Serum Triglyceride was significantly lower in CHB patients (109.04±40.75 mg/dL) than in the control group (136.33±60.88 mg/dL, p<0.01). 

        Serum HDL level was significantly lower in CHB patients (25.25±12.05 mg/dL) than controls. (35.61±11.47 mg/dL, p<0.001). 

        CHB patients had lower fasting plasma glucose, slightly higher systolic BP and waist circumference than controls though it did not reach statistical significance.

Relation between Metabolic syndrome with HBV DNA levels and ALT levels (Table 3)

In the study population, 9 out of 47 patients -19.1% against 20% of controls had MS.

        The median HBV DNA level was 82200 IU/mL in CHB patients. Of the CHB cases, a total of 24 patients had DNA above median while 23 patients had DNA level below the median. Out of 24 cases of HBV DNA above median, 5 had MS. 

                Elevated serum ALT was found in 11 (45.8%) out of 24 patients having HBV DNA level at or above median. On the other hand, elevated ALT level was found in 9 (39.1%) out of 23 patients with HBV DNA below the median. (P=0.7702).

In this cross-sectional study, we found a lower incidence of metabolic syndrome in chronic hepatitis B patients.

In the current study, the mean weight in CHB patients and controls was 60.2 ± 10.91 kg and 57.64±9.04 kg, respectively. This difference was not statistically significant (p=0.2108). There was no significant difference in height in CHB and controls. Mean BMI in CHB patient was 22.55 ± 2.31 Kg/m2. Mean BMI in the control population was 22.07 ± 2.54 Kg/m2. The difference was found to be statistically insignificant p=0.3327. These are similar to the findings of Chiao Yu Huang et al. [11] and Tae-Heum Chung et al. [12].

Mean waist circumference in CHB patients was 84.81 ± 9.37 cm which was higher than that in control group, 84.28 ± 7.77 cm, but not statistically significant. p>0.05, which is similar to the findings of Chung et al. [12] and Ja Sung Choi et al. [13].

The present study did not find a significant difference in the systolic and diastolic blood pressure between CHB patients and controls. The findings were in accordance with the findings of Huang et al. [11] and Chung et al. [12].

In the present study, CHB patients had significantly lower median serum cholesterol than the control population in the present study. Jarčuška et al. [14] and Janicko et al. [15] found reduced total serum cholesterol in chronic hepatitis B group in their study.

In our study, median serum triglycerides in CHB and controls were 109.04 mg/dL and 136.33 mg/dL respectively. Serum Triglycerides in CHB were significantly lower than controls. (p<0.05). Wong et al. [16], Hsu et al. [17] and Huang et al. [11] also found in their study that serum TGL was significantly lowered in the patients with CHB than the controls. 

In our study, CHB patients had significantly lower HDL cholesterol than controls, p<0.0005. Median serum HDL level was 25.25 mg/dL and 35.61 mg/dL in CHB and controls respectively. Huang et al. [11] and Su et al. found 18 a significant reduction in serum HDL cholesterol in the CHB group compared to the control group.

The impact of chronic HBV infection over lipid metabolism has been a subject under study worldwide. Conflicting results have been obtained regarding the development of atherosclerosis in patients with chronic HBV infection. 

Altered lipid metabolism in chronic Hepatitis B infection patients has been attributed to alter expression of different enzymes and receptors. It has been postulated that HBV infection alters the expression of certain genes. Two such targets have been identified-low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methyl glutharyl-coenzyme A reductase (HMGCoAr) and HBV infection increases the activity of these proteins leading to cholesterol accumulation 19.

In addition to these factors, several other proteins in HBV genome have been postulated to alter the lipid profile in patients with chronic HBV infection one of which is HBx protein which has been implicated in causing Hepatocellular carcinoma. HBx is a multifunctional protein encoded by the HBV genome and stimulates HBV replication, regulation of transcription, progression of cell cycle, DNA repair, apoptosis and genetic stability [20]. Studies have found that HBx can disturb cellular metabolism by interacting with peroxisome proliferator-activated receptor-γ (PPAR-γ) and sterol regulatory element binding protein 1, increase their respective mRNA and protein expression and leading to hepatic lipid accumulation [17]. Thus, the liver becomes more adipogenic sequestering most of the lipids that diffuse into it, creating a steatotic condition in the infected liver. The underlying mechanisms causing an inverse relationship between chronic HBV infection and low HDL levels are not clear. It is plausible that chronic inflammatory cytokines involved in liver inflammation might play a role. Higher level of HBV DNA levels was associated with lower HDL level [21].

This study reports a lower prevalence of metabolic syndrome in CHB (19.1%) than the control population (20%). This finding was very similar to that of Huang et al. [11] who reported a lower prevalence of metabolic syndrome in CHB than control population. (15.5% vs. 16.9%). Cross-sectional studies done as a part of the Nhanes III [22] and in Taiwan [23] found an inverse association between metabolic syndrome and chronic HBV, supporting current study. Jarcuska et al. [14] in a recent systemic review have found that many studies, but not all, have found a lower incidence of metabolic syndrome in patients with chronic HBV infection. In other studies, patients with chronic hepatitis B infection have found to have a lower incidence of diabetes mellitus, ischemic stroke and myocardial infarction - all of which are related to metabolic syndrome. The reason is not clear but may be related to reduce levels of clotting factors II and VII and fibrinogen in HBsAg-positive individuals than the HBsAg-negative ones [24].

We found that patient with metabolic syndrome had higher HBV DNA level [above the median (82200 IU/L)] than patient without metabolic syndrome. 5 (55.6%) out of 9 patients with metabolic syndrome had HBV DNA above median. On the other hand, out of 38 patients without metabolic syndrome, 19 (50%) had HBV DNA above median. (p value is >0.05).

We also found elevated serum ALT in 45.8% patients having HBV DNA level above median. On the other hand, elevated ALT level was found in 39.1% of patients with HBV DNA above the median (p=0.7702). Ashraf Mohamadkhani et al. [21] mentioned that higher HBV DNA levels were associated with higher serum ALT and higher serum triglycerides. However, Hsu et al. [17] found an inverse correlation between ALT level and serum triglyceride. The higher values of serum ALT in patients with increased HBV DNA levels can be explained by the fact that with increased HBV DNA there was increased ongoing inflammation of liver thus elevating the transferase level in serum [26,27].

The result of this study must be viewed within limitations of the methods used. The major limitation was the relatively a smaller number of patients studied. The study had lower number of females patients than male counterparts. The study being cross- sectional, so, it was not possible to make any cause-effect inferences on the relationship between chronic hepatitis B characteristic and metabolic syndrome. Hepatitis B genotypes were not considered in our study.

In conclusion, this study found that patients with chronic HBV infection had a lower risk of metabolic syndrome irrespective of obesity. This inverse relationship may be due to a lower triglyceride level and total cholesterol in patients with chronic HBV infection. The study finds the paradoxically favourable outcome of chronic HBV infection on lipid profile.

Conflict of Interest

Authors declare no conflict of interest. No financial aid was received for the study.

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