Cardiac Parameters and Interleukin-6 Differences between Adolescents with Hepatitis B Infection versus those Complicated with Hepatocelluar Carcinoma

Subjects and Methods: Cross sectional study that included 24 adolescents with HBV, another 24 with HCC with age ranging from 12 and up to 17 years. They were selected from those admitted to Tropical Medicine Department, Menofia University and Tropical Medicine Department, Zagazig University. All patient underwent laboratory assessment of interleukin6 (IL6) and were further examined at the Cardiology Unit in Pediatric department of Ain Shams University hospitals for complete echocardiographic and anthropometric evaluation.


INTRODUCTION
Liver cancer is the second most common cause of cancer-related deaths worldwide, and there are approximately 850,000 new cases per year worldwide [1,2].Unlike HCC in adults, which commonly arises in the setting of prolonged chronic hepatitis and cirrhosis, tumors in adolescents have been observed with HBV infection acquired perinatally or due to inherited metabolic disorders [3].In Egypt, HCC had been accounted for nearly 4.7% of chronic liver disease (CLD) patients [4,5].The incidence of new cases is about 500 000 -1 000 000 annually, giving rise to 600 000 deaths globally per year [6][7][8].
Hepatitis B virus (HBV) infection is a major public health problem worldwide.Hepatitis B is an infectious disease, associated with an estimated 350 million chronically infected patients [9].Recently, there has been recognition of the recognized significance of HBV infection in hypertrophic or dilated cardiomyopathy and myocarditis patients [10].It is also thought that there is a relation between HBV and coronary artery disease.Conflicting findings on the possible association between HBsAg-positivity, indicating inactive HBsAg carrier status, and atherosclerosis have been reported [11,12].Also, it is known that liver diseases are associated with abnormalities in cardiac geometry and function in adults (cirrhotic cardiomyopathy) but rarely explored in cirrhotic infants or children [13].
The most commonly used screening tests for HCC are serum alpha feto-protein (AFP) and ultrasonography.However, the results of the AFP screening in adolescents have not been satisfactory, with a sensitivity of 39% and specificity of 76%, when using 20 ng/mL as a cutoff value [14].The role of using an AFP measurement for screening or diagnosis of HCC has not been precisely investigated for adolescents who developed HCC associated with chronic HBV infection Finally, chronic HBV can be differentiated by a chronic inflammatory state in the liver with an elevated output of pro-inflammatory cytokines like interleukin 6 (IL-6) [15].The inflammatory cytokine, IL-6, is a cytokine with several functions that performs a master role in the reply of hepatic epithelia to inflammation [16].Therefore, the existing project was done to estimate the cardiac functions and grades of IL-6 in adolescents with HCC and HBV.

SUBJECTS AND METHODS
The current project is a comparative crosssectional study of subjects who visited the Tropical Medicine Department Menofia University and Tropical Medicine Department Zagazig University from attendants of outpatient clinic and from inpatients at the time between September 2012 to April 2017 with the approval of the ethical committee of Tropical Medicine Department Menofia University and Tropical Medicine Department Zagazig University.24 patients (12 males and 12 females) diagnosed as chronic HBV by detectable HBsAg for greater than six months with anti HBc IgG +ve and proved by quantitative PCR; another 24 patients (13 males and 11 females) have HCC on top of chronic HBV infection.HCC diagnosed based on Alpha feto-protein (AFP), pelvi-abdominal ultrasound and confirmed with triphasic CT based on AASLD guidelines [17].Both groups were subjected to the following: Full medical history taking and Complete clinical examination.Liver functions test (serum albumin, serum bilirubin (total and direct), ALT & AST using colorimetric method).kidney functions test (Serum creatinine and blood urea nitrogen (BUN) by colorimetric method) and Complete blood count (Hemoglobin, white blood cells and platelets using automated blood counter).Blood samples for the measurement of serum IL-6 levels were collected via venipuncture performed between 8:00 and 12:00 AM.Blood IL-6 grades were detected utilizing the ELISA using a commercial kit (Ray Biotech, Inc., USA).Also, cardiac assessment by Echocardiography (2D) and ECG was done at the Cardiology Unit in Pediatric department of Ain-Shams University hospitals to assess both systolic and diastolic functions, cardiac geometry, dimensions and Cardiac Index that relates the cardiac output (CO) from left ventricle in one minute to body surface area (BSA) were also assessed.

Exclusion criteria :
 Patients with chronic hepatitis C  Patients with chronic liver disease due to any cause rather than chronic hepatitis B  Patients with HCC due to any cause rather than chronic hepatitis B  Patients with congenital heart diseases

Statistical analysis
Data were checked, entered and analyzed using SPSS 22 for Windows.Data were expressed as mean ± SD for quantitative variable, number and percentage for qualitative one.Chi-squared (X2) or t test and paired t test were used when appropriate.P<0.05 was considered significant.P<0.001 was considered high significant.

RESULTS
The current study documented that 24 patients of HCC (13 males and 11 females) were examined with mean age (14.15±3.01)years and another 24 having HBV (12 males and 12 females) with mean age (14.64±3.13)years.
Statistically significant difference between HCC and HBV patients was found in relation to IL-6 (p=0.001) (Table 1).It was noticed that no differences were found between the 2 previous groups in relation to Z scores of left atrial diameter, left ventricle mass, left ventricular end diastolic diameter, posterior wall thickness and interventricular septum in diastole as (p= 0.424, 0.075, 0.120, 1.000 and 0.369 respectively) (Table 2).Also, comparing both echocardiographic functions between the studied groups (Tables 3,4) no significant differences were found regards both systolic functions; ejection fraction, fraction shortening, stroke volume, cardiac output, end diastolic volume and cardiac index where (p value= 0.351, 0.312 0.799, 0.851, 0.706, and 0.212).and diastolic functions; E/A ratio where (p value= 0.604) But in Table 5 shows significant difference between corrected QT interval in both groups as the mean QTc interval in HCC patients was (0.46 ± 0.04) that is mildly elevated and in HBV patients (0.42 ± 0.02) that is in normal range as p value= (0.039).
Moreover table 6 shows that no statistically significant differences were found between the 2 studied groups as regards anthropometric measurements as in comparison of the 2 groups regards Z scores of body weight, height and body mass index as (p value= 0.620, 0.892 and 0.904)   Importantly, no major differences were found in all echocardiographic parameters between Hepatitis B patients and HCC group including systolic and diastolic functions even most of the data remains similar to the normal healthy population unlike [13] who stated that cirrhotic liver diseases are associated with abnormalities in cardiac geometry and function in adults, unfortunately we found no other previous studies to compare our results with in adolescents, on the contrary there was a significant difference regards corrected QT interval during ECG study between the 2 groups as p value= (0.043), thought both values (0.45 and 0.42 Sec) remains in the normal range and theoretically tends to resolve with treatment, also during comparison of the anthropometric measurements no statistically significant differences were found between Z scores of body weight, height and body mass index.These results need to be confirmed by further studies even if it was in agreement with Desai et al. [13] as different liver conditions tend to affect the growth velocity in the adolescence stage of life.

CONCLUSION
We could find out from our study and based upon these findings that cardiac and anthropometric evaluation have failed to compare and differentiate between Hepatitis B and HCC in adolescents, though instead we can rely on biological markers that showed to be helpful as IL6.

Conflicts of interest: None.
Ethical approval:Approved ;written consents have been taken from all included patients.

Table (
zLAD: Z score of left atrial diameter, zLVM: Z score of left ventricle mass, zLVEDD: Z score of left ventricular end diastolic diameter, zPWD: Z score of posterior wall thickness, zIVS Z score of interventricular septumTable (3) :Comparison between systolic functions between the studied groups t-Independent sample t-test was used in that comparison.EF: ejection fraction, FS: fraction shortening, SV: stroke volume, CO: cardiac output, EDV: end diastolic volume, CI: cardiac index t-Independent sample t-test was used in that comparison.P value considered significant if < 0.05.

Table ( 5
) : Comparison between the studied groups as regards increased QTc interval

Table ( 6
) : Comparison of the anthropometric measurements of the studied groups