| Abstract|| |
Aim: To evaluate the occurrence of Hepatitis B surface antigen positivity in family members of HBsAg-positive patients, to assess the profile of HBV infection in them, to identify possible risk factors in a close family environment, and to evaluate the burden of liver disease in these family members.
Materials and Methods: All Hepatitis B surface antigen-positive patients who attended the Liver Clinic of the Gastroenterology Department of the Calicut Medical College, from January 2009 to December 2010, were studied. The index case was evaluated with HBeAg, anti HBeAb, HBV DNA, liver function tests (LFTs), ultrasonogram of the abdomen, and alpha fetoprotein, as also liver biopsy in indicated cases. The index patient was interviewed and a detailed history with special emphasis on probable risk factors was taken. All first-degree relatives and relatives staying in the same house of the index case were screened for HBsAg. The relatives who tested negative for the infection were advised HBV vaccination, while the relatives who tested positive were evaluated for disease activity using LFTs, HBeAg, anti-HBeAb, HBV DNA, ultrasonogram of abdomen, alpha fetoprotein, and biopsy as per indication.
Results: There were 376 index cases available for the study, 230 males (61.17%) and 146 females (38.83%). Male : Female ratio was 1.57 : 1. Mean age was 32.8 years (range 6-76). Seventy-six persons (20.21%) were detected to be HBsAg-positive during various preprocedural screenings, 42 (11.17%) were detected during medical checkup for jobs in gulf countries, and 30 (7.98%) were detected during screening for blood donation. Among the female patients, 88 (60.27%) were detected during antenatal screening. Ninety-six patients (25.53%) did not turn up after the initial visit.
Among the remaining 280 patients, 48 (17.14%) were HBeAg positive. LFT abnormalities were seen in 153 (54.64%) cases. Out of 280 patients, 46 (16.43%) had established cirrhosis and 10 (3.57%) had HCC. Twenty-one cases (7.5%) presented as acute hepatitis. Complete family screening was done for 173 (61.78%) index cases. Out of the 280 index cases, 47 (16.79%) patients were reluctant for family screening.
Among the 173 cases whose family members were screened, 95 (54.91%) had at least one family member who was HBsAg positive. Among the 95 index cases with at least one family member affected, 25 (26.31%) were HBeAg positive . On HBsAg screening of the relatives, it was found that brothers were affected in 45 (26.01%), sisters in 33 (19.08%), mothers in 18 (10.40%), fathers in 19 (10.98%), sons in nine (6.08%), and daughters in two (1.35%) cases. Ten (5.78%) index cases had second-degree relatives affected. Among a total of 173 index cases screened, 148 were married and among them 4.72% of the spouses were found to be HBsAg positive on screening.
A total of 1115 family members of the 173 index cases were screened, of whom 162 (14.53%) were HBsAg positive. Of the 162 family members who were HBsAg positive, complete evaluation to find the stage of liver disease was performed in 43 family members. Among them 31 (72.09%) had LFT abnormality, four (9.3%) had underlying cirrhosis, and one had HCC. Twelve cases (27.9%) were HBeAg positive. Even though HBV screening was advised for all family contacts of the index cases, there was not much enthusiasm among the patients to get their relatives screened.
Conclusion: The occurrence of hepatitis B positivity among family members of HBsAg-positive patients was 14.53% in our study. This prevalence was twenty-eight times more than the community prevalence of HBV infection in our population, which was earlier found to be 0.52% by our group. Brothers and sisters were the most commonly affected group, as against mothers who were positive for HBsAg, only 11.3%. Hence, the infection among siblings and parents may also be due to horizontal transmission. Index cases of 16.79% were totally reluctant for family screening due to various reasons like social stigma, high cost of the investigations, and reluctance to believe that they were having a problem, because they were asymptomatic. In view of the very high occurrence of HBV infection in family members, there is an urgent need for better counseling and vigorous screening of family members, to identify asymptomatic cases in the community and target this pool for curative as well as preventive measures.
Keywords: Family, HBV infection, hepatitis B, intrafamilial spread, maternal, paternal, transmission
|How to cite this article:|
Kavitha R, Kumar K S, Sandesh K, Ramachandran T M, Varghese T. Intrafamilial occurrence of hepatitis B virus (HBV) infection and the profile of liver disease in close relatives of patients with HBV infection. Hep B Annual 2011;8:4-16
|How to cite this URL:|
Kavitha R, Kumar K S, Sandesh K, Ramachandran T M, Varghese T. Intrafamilial occurrence of hepatitis B virus (HBV) infection and the profile of liver disease in close relatives of patients with HBV infection. Hep B Annual [serial online] 2011 [cited 2020 Jan 18];8:4-16. Available from: http://www.hepatitisbannual.org/text.asp?2011/8/1/4/190075
| Introduction|| |
Hepatitis B is a major health problem in the world, with over two billion people with evidence of infection and more than 350 million chronically infected.  Chronic hepatitis B virus (HBV) infection is responsible for 60-80% of hepatocellular carcinomas, and it is the tenth leading cause of death worldwide.  HBV infections result in
5,00, 000 to 1.2 million deaths per year caused by chronic hepatitis, cirrhosis, and hepatocellular carcinoma; the last cause alone accounting for 320,000 deaths per year. In Western countries, the disease is relatively rare and acquired primarily in adulthood, whereas, in Asia and most of Africa, chronic HBV infection is common and usually acquired perinatally or in childhood. More efficacious treatments, mass immunization programs, and safe injection techniques are essential for eliminating the HBV infection and reducing global HBV-related morbidity and mortality.
The world is conceptually divided into zones of high, intermediate, and low endemicity for HBV carrier rate. India, according to the World Health Organization is in a region of intermediate endemicity. Although there are many reports on HBV prevalence from different parts of India, the exact data on HBV prevalence does not exist for all the regions in the country as a whole. In the region of intermediate endemicity, prevalence of the chronic carriage of the hepatitis B surface antigen (HBsAg) ranges from 2 to 8% of the general population and the infection is generally acquired during childhood and early adulthood.  Hepatitis B infection is often transmitted among household contacts and it is not a rare situation to have several members of same household having evidence of HBV infection. 
Precise mechanisms of intrafamilial spread, however, are not clearly established.  First, studies that addressed Intrafamilial transmission of HBV were published at the start of the research into HBV epidemiology.  Several studies from different geographical areas have been published since then. ,,,,, We have conducted a prospective study in Calicut, which is a very well-characterized geographical area in the Northern part of the state of Kerala, where the prevalence of HBV infection in the general population and the high-risk group of this region have been well-characterized.  As there was dearth of data from India on the prevalence of HBV infection among close family contacts, we decided to evaluate the prevalence of HBV infection in family members of HBsAg-positive patients, and to assess the profile of HBV infection in them, to identify the possible risk factors in a close family environment, so as to evaluate the burden of liver disease in the family members
| Materials and methods|| |
All Hepatitis B Surface Antigen-positive patients, who attended the Liver Clinic of the Gastroenterology Department, Calicut Medical College, from January 2009 to December 2010, were studied. The index case was evaluated with HBeAg, anti HBe, HBV DNA, LFTs, ultrasonogram of the abdomen, and AFP. Liver biopsy was done in indicated cases. The index patient was interviewed and a detailed history with special emphasis on the probable risk factors was taken. Anti HCV and retroviral screening was done for all patients. Baseline investigations including CBC, renal function tests, and electrolytes were checked for all patients. All first-degree relatives and other relatives staying in the same household of the index case were screened for HBsAg initially by the card test and later confirmed by the visual enzyme-linked immunosorbent assay (ELISA) technique. Relatives who tested negative for the infection were advised vaccination against HBV, while relatives who tested positive were evaluated for disease activity using LFT, HBeAg, antiHBe, HBV DNA, ultrasonogram of the abdomen, alpha fetoprotein, and biopsy in indicated cases.
Statistical tests were performed using the statistical software SPSS 17.0 (SPSS Inc., Chicago, Illinois, USA). Standard tests of descriptive statistics have been used for determination of baseline characteristics of the groups. For identification of significant relations between variables, the chi-square test was used; and a P value lower than 0.05 was considered significant
| Results|| |
Profile of index cases
There were 376 index cases available for the study. This group included 230 males (61.17%) and 146 females (38.83%). M : F ratio was 1.57 : 1. Mean age was 32.8 years (range 6-76). Seventy-six persons (20.21%) were detected to be HBsAg positive during various pre-procedural screenings, 42 (11.17%) were detected during medical checkup for jobs in gulf countries, and 30 (7.98%) were detected during screening for blood donation. Among the female patients, 88 (60.27%) were detected during antenatal screening. Ninety-six patients (25.53%) did not turn up after the initial visit. Among the 280 patients available for detailed evaluation, 48 (17.14%) were HBeAg positive, 21 (7.5%) patients presented with acute hepatitis, and LFT abnormalities were present in 153 (54.64%) cases, Cirrhosis of the liver was present in 46 (16.43%) and Hepatocellular carcinoma (HCC) was present in 10 (3.57%) [Table 1].
Profile of the index cases with complete family screening
Hepatitis B Virus screening was done for all family members in case of the 173 (61.78%) index cases. Of these, 95 (54.91%) had at least one family member positive for HBsAg. HBeAg was positive in 25 (26.31%) index cases with family members positive and in 10 (7.8%) index cases with family members negative, which was statistically significant (OR; 95% CI: 2.43; 1.02-5.89). There was a higher chance of the family members being HBV positive if the index case had chronic hepatitis, but they would be significantly low risk if the index case was only an asymptomatic carrier.
Profile of the index cases who had at least one family member positive (n = 95)
Mean age of this group was 29.4 years. M : F - 0.97 : 1. HBeAg was positive in 25 (26.31%) patients. Of these 22 (23.2%) were asymptomatic carriers, seven (7.3%) had acute hepatitis, 51 (53.68%) had chronic hepatitis, 15 (15.79%) had cirrhosis, and none had HCC. The median HBV DNA level was 67,870 IU / ml (range < 100 - 1.2 x10 7 )
Complete family screening
A total of 1115 family members were screened, of whom 162 (14.53%) were HBsAg positive. Among the family members screened, 14.53% were HBsAg positive. Nineteen out of 162 (11.7%) knew their HBV positivity status earlier, but had not undergone any further evaluation. Brothers were HBV positive in 45 (26.01%), sisters in 33 (19.08%), father in 19 (10.98%), mother in 18 (10.4%), sons in nine (6.08%), daughters in two (1.35%) and second-degree relatives in 10 (5.78%) casts. Of the 148 married cases, seven (4.72%) spouses were affected [Table 2].
Analysis was also done to find out whether there was any difference in the intrafamilial incidence of HBV infection if the index case was a female. There was no significant difference in the family member positivity when the index case was a female [Table 3].
|Table 3: Total family members involved according to the gender of the index case |
Click here to view
Profile of the affected family members (n = 43)
Of the 162 affected family members, 43 were evaluated in detail in a similar manner as the index cases. HBeAg was positive for 12 (27.9%) patients. LFT abnormalities were present in 31 patients (72.09%). Cirrhosis was present in four (9.3%) patients, and one had hepatocellular carcinoma, which was in a resectable stage, a single lesion, 3 x 2 cm in size.
| Discussion|| |
Our study looked at the prevalence of HBsAg positivity among family members of HBsAg-positive patients and assessed the profile of HBV infection in the affected family members. The majority of the index cases were asymptomatic and detected during various routine pre-procedural screenings (20.21%), medical checkup for jobs abroad (11.17%), screening for blood donation (7.98%), and majority (60.27%) of the females were detected during the routine antenatal screening. The prevalence of HBsAg positivity among family members of HBV positive index cases was 14.53% in our study. The prevalence of HBsAg positive persons among the normal population of North Kerala was found to be 0.52% in our earlier study,  which was below the average prevalence of HBV infection in different parts of India. The occurrence of HBV infection in family members of HBV positive index cases was 28 times more than the community prevalence of HBV infection in our region. Our study brought out the very high occurrence of HBV infection in the family members of HBV positive index cases.
According to a study from Bosnia by Salkic et al., the prevalence of hepatitis B surface antigen positivity was 12.2% among family members of index cases  and in a study by Kim et al,  the prevalence was 14%, which clearly demonstrated that family members of index cases had a higher rate of HBV infection. Household contacts of chronic HBsAg carriers were at a very high risk of acquiring HBV infection and thus becoming chronic carriers. It was previously demonstrated that family members of HBsAg carriers had different risks for HBV infection according to their relation to the index case. ,,, Our study showed that the carrier rate was high among the brothers and sisters and less among mothers, which emphasized the possibility of horizontal transmission. Studies by Zervou et al,, and Thakur et al., showed that high rates of prevalence among siblings of index cases were a result of horizontal transmission. ,,, Siblings shared the same environment and family habits, which might be associated with increased risks of transmission. According to Kim et al., the offspring of carriers showed significantly higher risk of HBV infection (relative risk; 6.6). Sharing of towels, handkerchiefs, and vessels were found to be associated with an increased risk of HBV infection via intrafamilial transmission. in Korea (relative risk 11.5 for towel and handkerchief, 12.1 for drinking vessels). 
Furthermore, mothers were affected in 11.3%, whereas, offsprings had significantly higher rates of HBsAg positivity. Previous studies showed that children from families with a HBsAg-positive mother had a higher risk of becoming a chronic HBV carrier compared to offsprings with a HBsAg-positive father.  This study illustrated the role of the mother in transmission of HBV. In a study conducted in Chinese families in Hongkong by Lok et al.,  the carrier rate was higher among siblings (53%) and offsprings (50.5%) of females affected with HBV infection. We could not find any such association in the case of female index cases. The HBsAg-positive siblings were reportedly clustered within certain families, suggesting that most of the infections occurred at a young age. Infections could have been transmitted through a common source from maternal carriers or horizontally among siblings. It could not be ascertained whether the index cases were the source or the recipients of the infection. In some families, family members other than the index case also might have contributed to the intra-familial spread of hepatitis B virus infection. It is also conceivable that when the index patient was the only carrier in the family, hepatitis B virus infection could have been acquired by the index case during adult life from sources outside the family.
In our study, spouses were affected in only 4.7%, which substantiates the minor role of sexual transmission in our population. In some studies, it has been shown that sexual contacts are at higher risk for HBV infection than nonsexual contacts [7, 8, and 12]. Presence of HBsAg was detected more frequently (16.3% vs 2.0%) in the nonsexual (siblings, parents, and offspring) than in sexual (spouses) contacts of the index cases as per a study by Salkic et al. This observation was similar to our observation, but on the contrary the offsprings of the index cases in our study group were less affected than the siblings.
It has been observed that pre-school children have an HBV carrier rate of between 2 and 3%, which is the same rate as recorded among adults in India. , This suggests that most of India's HBV carrier pool is established during early childhood. The combined factors of low HBeAg positivity rates among pregnant females, poor hygienic living conditions, and close person-to-person contact due to crowded living conditions have led to the conclusion that horizontal spread during early childhood may account for about 75% of all HBV transmission in India and less than 30% is thought to result from perinatal vertical transmission.  It has been reported that children could be infected through close contact during play, perhaps via exposure of open wounds, sharing towels or toothbrushes, exchange of chewing gum and candies, etc.
A study from Taiwan  showed paternal transmission playing a minor role in the intrafamilial spread of hepatitis B virus infection, but our study showed that 13.8% of the fathers were HBV infected. HBeAg-positive patients usually have higher titers of HBV DNA and are generally considered more infectious. Our results are in accordance with this observation as significantly higher rates of HBsAg positivity were found among family members whose index cases were HBeAg positive (26.31% vs. 12.8%). The Bosnian study  showed significantly higher rates of HBsAg positivity among family members whose index cases were HBeAg positive (38.5% vs. 7.5%), with RR for HBsAg positivity of 5.10. Our study compared the occurrence of HBsAg positivity in family members of female and male index cases, but statistically no significant difference was found. According to Salkic et al., a combination of female sex and HBeAg positivity of the index case significantly increased the rates of the chronic carrier state and exposure among family members. 
Hepatitis B virus is reported to be responsible for 50% of the cases of chronic hepatitis and 35-60% of the cases of cirrhosis of liver in India and about 60% of the patients with hepatocellular carcinoma are HBV marker positive.  Our study identified four patients with cirrhosis and one person with hepatocellular carcinoma among the family members who were HBsAg positive and asymptomatic. Hence, screening and detailed evaluation may detect asymptomatic liver disease, including malignancy, at an early stage.
As family members of HBsAg carriers are indeed a risk group for both exposure and chronicity, it is absolutely necessary to investigate all family members of HBsAg carriers for the presence of HBV markers and to immediately offer HBV vaccination. In the initial part of our study we had asked the family members to attend the liver clinic of our department for screening. We found that only a small percentage of family members turned up for the screening initially. On enquiry it was observed that the indirect cost of transportation, loss of work, and the reluctance to believe that asymptomatic persons could be harboring HBV infection, resulted in reluctance for family screening. Hence, we changed our strategy of screening and asked the index case to report with the HBsAg card test of the family members and there was a dramatic success rate of screening. The family members found to be HBV positive by the card test e were recalled, and the HBsAg status confirmed by ELISA.
The drawbacks of our study were that we could not rule out vertical transmission as a major route of transmission of HBV, as the anti-HBc status of the mother was not performed. The major hindrance was the cost of investigations. Many were reluctant for family screening because of social stigma, economic burden, and ignorance regarding the course and prognosis of the disease.
Our data suggest that in the area studied, that is, North Kerala, both horizontal and vertical transmission of HBV exists, but the horizontal route is probably more predominant. Family members of chronic carriers have a very high risk for HBV infection. Susceptible family members and all subjects who live in close contact with HBV carriers should therefore be vaccinated. As a large proportion of family members may already be infected, they should be screened prior to vaccination.
| Conclusion|| |
The occurrence of Hepatitis B positivity in family members of HBsAg-positive patients in our study was 14.53%. This was 28-fold higher than the community prevalence of HBV infection in our population, which was found to be only 0.52% as per our earlier study, in 2006. Contrary to the general belief, mothers were found to be affected in only 11.3% of the index cases. Hence, the infection among siblings and between parents and siblings could be due to horizontal transmission. Possible modes of transmission might be, close contact in childhood, perhaps via exposure of open wounds, sharing towels or toothbrushes, exchange of chewing gums and candies, using common knives, sharing of razors among males, etc. In 16.79% of the index cases, the family members did not turn up for screening due to various reasons like social stigma, high cost of the investigations, and reluctance due to ignorance about HBV infection. In view of the very high prevalence of HBV infection in family members and the occurrence of asymptomatic chronic liver disease, including Hepatocellular carcinoma, in them, there is an urgent need for better counseling and vigorous screening of family members, to identify the asymptomatic cases in the community.
| References|| |
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepatol 2004;11:97-107.
Hollinger FB, Liang TJ. Hepatitis B Virus. In: Knipe DM, Howley PM, Eds. Fields Virology. 4 th
ed. Philadelphia: Lippincott Williams and Wilkins; 2001: 2971-3036.
Zuckerman JN, Zuckerman AJ. The epidemiology of hepatitis B. Clin Liv Dis 1999;3:179-87.
Szmuness W, Prince AM, Hirch RI, Brotman B. Familial clustering of hepatitis B infection. N Eng J Med 1973;289:1162-6.
Zervou EK, Gatselis NK, Xanthi E, Ziciadis K, Georgiadou SP, Dalekos GN. Intrafamilial spread of hepatitis B virus infection in Greece. Eur J Gastroenterol Hepatol 2005;17:911-5.
Erol S, Ozkurt Z, Ertek M, Tasyaran MA. Intrafamilial transmission of hepatitis B virus in the eastern Anatolian region of Turkey. Eur J Gastroenterol Hepatol 2003;15:345-9.
Thakur V, Guptan RC, Malhotra V, Basir SF, Sarin SK. Prevalence of hepatitis B infection within family contacts of chronic liver disease patients: Does HBeAg positivity really matter? J Assoc Physicians India 2002;50:1386-94.
Milas J, Ropac D, Mulic R, Milas V, Valek I, Zoric I, Kozul K. Hepatitis B in the family. Eur J Epidemiol 2000;16:203-8.
Kim YS, Ahn YO. Factors associated with intrafamilial transmission of hepatitis B virus infection in Korea. J Korean Med Sci 1993;8:395-404.
Lok AS, Lai CL, Wu PC, Wong VC, Yeoh EK, Lin HJ. Hepatitis B virus infection in Chinese families in Hong Kong. Am J Epidemiol 1987;126:492-9.
Sandesh K, Varghese T, Harikumar R, Beena P, Sasidharan VP, Bindu CS, et al.
Prevalence of Hepatitis B and C in the normal population and high risk groups in north Kerala. Trop Gastroenterol 2006;27:80-3.
14. Salkic NN, Zildzic M, Muminhodzic K, Pavlovic-Calic N, Zerem E, Ahmetagic S, et al
. Intrafamilial transmission of hepatitis B in Tuzla region of Bosnia and Herzegovina. Eur J Gastroenterol Hepatol 2007;19:113-8.
Irshad M, Singh YN, Acharya SK. HBV-status in professional blood donors in North India. Trop Gastroenterol 1992;13:112-4.
Nayak NC, Panda SK, Zuckerman AJ, Bhan MK, Guha DK. Dynamics and impact of perinatal transmission of hepatitis B virus in North India. J Med Virol 1987;21:137-45.
Kiire CF. The epidemiology and prophylaxis of Hepatitis B in sub- Saharan Africa: A view from tropical and subtropical Africa .
Acharya SK, Madan K, Dattagupta S, Panda SK. Viral Hepatitis in India. Natl Med J India 2006;19:203-17.
Department of Gastroenterology, Calicut Medical College, Kozhikode 673008
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]