Prevalence of Hepatitis a Antibody in Children and Adolescents with Chronic Liver Disease

ORIGINAL ARTICLE

Prevalence of hepatitis A antibody in children and adolescents with chronic liver disease

Cristina Targa Ferreira,1 Adriano N.R. Taniguchi,2 Sandra Maria Gonçalves Vieira,3 Jorge P. Lima,4 Themis Reverbel da Silveira5

Abstract Objective: to evaluate the prevalence of Hepatitis A virus (HAV) in children and adolescents with chronic liver disease in a unit of pediatric hepatology. Methods: between May 1999 and February 2001, we studied the prevalence of anti-HAV in 60 children and adolescents with chronic liver disease, aged between 1 and 16 years, from the Unit of Pediatric Hepatology of the Hospital de Clínicas de Porto Alegre. The total anti-HAV was determined by a commercially available competitive ELISA method (Abbott), and compared with age, sex, race, etiologic diagnosis and family income of each patient. Results: a one-year old child was not included in the study because she presented twice with undetermined anti-HAV results. Among the other 59 patients, 14 (24%) presented a positive result of total anti-HAV. The ages of test-positive subjects varied between 1 and 16 years old (mean = 7.7 years, median = 8.5). The differences between positive and negative groups in relation to age, sex and race were not statistically significant. Family income was lower in anti-HAV positive patients, but this difference was not significant. The differences between the etiologies of liver diseases were probably more related to the age than to the etiologies of the diseases. Conclusions: in the studied population, the majority (76%) of children and adolescents with chronic liver disease are susceptible to hepatitis A virus infection and, consequently, they could present a more severe disease or even fulminant hepatitis A. We strongly suggest that these subjects receive Hepatitis A inactivated vaccine. J Pediatr (Rio J) 2002;78(6):503-8: viral hepatitis A, prevalence, anti-HAV antibody, chronic liver disease.

Introduction Acute viral hepatitis A (HAV) is a ubiquitous infection a chronic form, distinguish it from Hepatitis B and C.1 that results in significant morbidity. From an epidemiological Infection by the A virus can also cause fulminant hepatitis point of view, the rapid dissemination and the large outbreaks and be fatal, with an estimated mortality rate of 0.14 to 2%.2 of HAV, in addition to the fact that there is no evolution to There is growing evidence in medical literature that individuals with chronic liver disease exhibit an increased risk of developing more serious forms of HAV or even 1,3 1. Pediatric Gastroenterologist and Hepatologist, Hospital de Clínicas de fulminant hepatitis. Porto Alegre (HCPA). 2. Medicine student, Universidade Federal do Rio Grande do Sul. Recipients of liver transplants should avoid further 3. Pediatric Gastroenterologist and Hepatologist, HCPA. lesions to the graft, and should be immunized against HAV, 4. Associate Professor, Fundação Faculdade Federal de Ciências Médicas even when the risk of exposure is low.4 Furthermore, de Porto Alegre. 5. Associate Professor, Department of Pediatrics, School of Medicine, patients with chronic liver disease, who require liver Universidade Federal do Rio Grande do Sul. PhD. transplants, should undergo all vaccinations in advance of Manuscript received Feb 18 2002. Accepted for publication Aug 28 2002. the surgical procedure, since afterwards they will be more

503 504 Jornal de Pediatria - Vol. 78, Nº6, 2002 Prevalence of hepatitis A antibody... - Ferreira CT et alii immunocompromised than before the transplant. For this The etiologic diagnoses of the liver diseases are shown reason, this specific group of patients is indicated for in Table 1. vaccination against viral hepatitis A.4-6 Children with chronic liver disease would theoretically benefit from the HAV vaccine, since it has been shown to be Table 1 - Etiologic diagnoses of the chronic liver diseases immunogenic and safe in controlled studies with immunocompetent children.6-8 The fact that the vaccine is Diagnosis n (%) safe and effective in healthy adults and children does not guarantee similar results in populations with chronic liver EHBA 26 (43) disease.1 Studies performed with adults suggested that Autoimmune hepatitis 13 (22) while patients with chronic liver diseases are not at increased Cryptogenic cirrhosis 11 (18) risk for infection, they have a greater risk of fulminant Cystic fibrosis 2 (3) hepatitis caused by the A virus.2,9,10 American death records Hepatitis B 2 (3) indicate a greater prevalence of chronic liver disease in Hepatitis C 1 (2) people who died from fulminant HAV than in people who Histiocytosis 1 (2) died from other causes.5,6,9,10 Sclerosing cholangitis 1 (2) Congenital hepatic fibrosis 1 (2) Neither an immunization scheme nor a seroconversion Budd-Chiari syndrome 1 (2) rate for populations with chronic hepatic diseases have been Alagille syndrome 1 (1) defined yet.1 The purpose of this study was to evaluate the prevalence EHBA = Extrahepatic biliary atresia of HAV in children and adolescents with chronic liver diseases at a pediatric hepatology service.

Patients and Methods The average age of patients with extrahepatic biliary A study with 60 children and adolescents with chronic atresia (EHBA) was 3.9 years; for the patients in the liver disease was conducted between May 1999 and February autoimmune group it was 11.8 years; for those with 2001. The patients belonged to the Pediatric cryptogenic cirrhosis it was 6.2 years and for the others it Gastroenterology Unit and the Pediatric Liver Transplant was nine years. Project of the Pediatric Service of the Hospital de Clínicas The family income of these patients varied between 150 de Porto Alegre. This is a tertiary care hospital, considered and 3,000 reais (40 to 800 US dollars), with a mean average a benchmark in Pediatric Hepatology. of 595.50 reais (US$ 165). The family income of 73% of the Patients with chronic liver disease between one and 16 patients was less than or equal to 500 reais (US$ 138), that years of age, with no previous history of hepatitis A or of 63% of the patient’s families was below R$ 300 (US$ vaccination against HAV, and not carrying the human 83). The minimum salary at this time was R$ 136 (US$ 50). immunodeficiency virus (HIV) were included. They were The median of family incomes was 300 reais with all being assessed or had already been assessed for liver interquartile ranges of R$ 200 (25th percentile) and R$ transplants, some of them were already on the waiting list, 675.00 (75th percentile). others yet to be referred at the time of assessment. The The anti-HAV was obtained using a laboratory test patients suffered from chronic liver diseases confirmed which is commercially available in our setting (Abbott - histologically by liver biopsy or ultrasound scans and HAVAB MEIA - AXSYM system). Venous blood was laboratory tests. collected normally in combination with the patient’s routine blood sampling, and was centrifuged and frozen for later This was a cross-sectional study which evaluated the evaluation. The anti-HAV (total) tests were all performed in presence of the anti-HAV (total) antibody, a marker of the same clinical analysis laboratory (Laboratório hepatitis A infection. The total anti-HAV was determined Weinmann), in Porto Alegre. The results were considered and assessed according to age, sex, color, etiological positive, negative or indeterminate according to positive diagnosis of liver diseases, and patient’s family income. and negative controls. A cutoff value was calculated, below Ages varied between 12 months and 16 years, with an which the sample was positive, and above which it was average (+/- SD) of 7 years (+/- 4.9). There were 25 children negative. Tests with an absorbance within the gray scale, between one and four years old, nine between 5 and 8, 19 which corresponds to more or less 10% of the cutoff value, between 9 and 12 and seven adolescents between 13 and 16 were considered indeterminate. These tests were repeated, years old. using a fresh sample, and if they continued to yield values Thirty-three children (55%) were female and 92% were within the gray scale, i.e. indeterminate, they were eliminated white. from the study. Prevalence of hepatitis A antibody... - Ferreira CT et alii Jornal de Pediatria - Vol. 78, Nº6, 2002 505

The two groups (anti-HAV positive and negative) were Table 2 - Positivity of anti-HVA related to age compared using the chi-squared test with Yates’ correlation Age group Positive Total Percentage (for the sex variable), Fisher’s exact test (for color), the anti-HVA (n) (n) of positivity* Student’s t test (for age) and the Mann-Whitney U test (for family income). In addition, the chi-squared test for linear 1 to 4 years 5 25 20% trend was used to check the association between anti-HAV 5 to 8 years 2 9 22% and increase in the age of the patients. The significance 9 to 12 5 19 26% level was set at 0.05. 13 to16 2 7 29%

The study was approved by the Ethics and Research * Chi-squared test for linear trend (p = 0.6) Committee of the Hospital de Clínicas de Porto Alegre. All of the patients’ parents or legal guardians signed consent forms after being informed of the nature of the study. The comparison between the positive and negative groups is shown in Table 3. Of the children who were anti-HAV positive, chronic Results autoimmune liver disease was detected in five, cryptogenic Of the 60 children and adolescents with chronic liver cirrhosis in four, EHBA in three, Budd-Chiari syndrome in disease, only one was excluded because, on two different one and biliary cirrhosis with associated histiocytosis in occasions, the anti-HAV antibody result was indeterminate. one. Another boy, one year old, also had indeterminate results The family incomes of the group of anti-HAV positive for the first test, but, when repeated two weeks later, the patients were between 150 and 2,000 reais, the mean result was negative. average being 441.00, a little below that of the group of 45 Of the 59 remaining children and adolescents, 14 (24%) anti-HAV negative patients (R$ 642.62). Twelve anti-HAV showed positive results for (total) anti-HAV. patients (86%) had a family income of less than 500 reais, The ages of patients with anti-HAV positive results while 69% of the negative group was within this range. varied from one to 16 years (x = 7.7 years and median of 8.5 Eleven of the anti-HAV positive children (79%) had family years). There was a tendency for the percentage of positive incomes below R$ 300. The median family income of anti- results to rise with age, although there was no statistical HAV positive patients was R$ 300 (p-25 R$ 150 - p-75 R$ evidence ( χ2 for linear trend = 0.6) (Table 2). 350).

Table 3 - Patients’ characteristics (positive and negative anti-HVA)

Characteristic Total (n = 60) Positive (n = 14) Negative (n = 45) p

Age (years) Mean 7 7.7 6.76 0.59* Standard deviation 4.93 4.94 4.97 Median 7 8.5 6.5 Color White n (%) 55 (92) 13 (93) 42 (93) 1.0† Sex Male n (%) 27 (45) 7 (50) 20 (44) 0.95‡ Family income 150 - 3,000 150 - 2,000 150 - 3,000 Mean 595.50 441.00 642.61 Standard deviation 676.49 498.74 720.03 Median 300.00 300.00 300.00 0.26¶ < 500 n (%) 44 (73) 12 (86) 32 (71) > 500 < 1,000 n (%) 8 (13) 1 (7) 7 (15.5) > 1,000 n (%) 8 (13) 1 (7) 7 (15.5)

* Student’s t test ; † Fisher’s exact test; ‡ chi-squared test with Yates’ correction; ¶ Mann-Whitney test. 506 Jornal de Pediatria - Vol. 78, Nº6, 2002 Prevalence of hepatitis A antibody... - Ferreira CT et alii

The ages of the five anti-HAV positive patients with adolescents between one and 19 years old in Porto Alegre.13 autoimmune liver disease varied between seven and 13 In this first study we found a highly significant difference in years, with a mean average of 11 years and a median of 12. prevalence between children from a low socioeconomic All were girls and one was black. The mean average of background and those from a high level (51% against 11%). family income for this group was R$ 380 while the median This shows that, while HAV is endemic in our setting, there was R$ 300. Two of the four positive patients with is a significant number of people who are susceptible to cryptogenic cirrhosis were male. Their ages were 1, 3, 6 and infection: 89% of the children up to 19 years old from a high 10 years with a mean of 5. Their families’ incomes ranged socioeconomic background, and 49% of those who live from R$ 150 to R$500 with a mean average of R$ 267.50. under less favorable socioeconomic conditions.13 In the The three anti-HAV positive patients with EHBA were 1, 2 same study, the prevalence of anti-HAV was 60% and 11% and 16 years old. They were all white males. Their family for children up to 14 years old, from low and high incomes were R$ 300 for two of them and R$ 2.000 for the socioeconomic classes, respectively. Other studies have other (Table 4). been performed in Brazil which show different prevalence rates, depending upon location, all of which are higher than those found in Rio Grande do Sul.15 In the current study, the Discussion prevalence of anti-HAV was 24% up to 16 years of age, Different anti-HAV antibody prevalence patterns have lower than the earlier study, probably due to differences in been described, showing variations in economic the socioeconomic background of the individuals studied. development.11 In areas with a high endemicity, 90% of As the criteria employed to evaluate socioeconomic level in children are infected by around ten years of age. The each study were different, comparison becomes difficult. infections are asymptomatic, and viral hepatitis A is not a HAV, following chronic liver disease, has been clinical problem. In areas of medium endemicity the 90% associated with more serious cases or with fulminant seroprevalence level is not reached before early adulthood. forms.1,2,9,10,16,17 It is possible that the acute insult caused In these communities the disease occurs in different age by viral hepatitis can result in substantial involvement of the groups (children, adolescents and young adults). These hepatic functions already compromised by chronic lesions. populations exhibit large epidemics, at regular intervals, The exact incidence of hepatic insufficiency due to HAV in which last for long periods of time, or have high sustained chronic liver disease is not known.17 6,12,13 levels of the disease for many years. Emmet Keefe9 reviewed cases of acute hepatitis A in Although it is convenient to think of these different populations with underlying chronic liver disease in patterns as mutually exclusive, they are a simplification of epidemics which occurred in Taiwan, in 1988, and in the a very complex epidemiology. In many countries the three United States, from 1983 to 1988. He also revised smaller patterns can occur within different sections of a single series and case reports. According to this author, the literature community.14 These general endemicity patterns, therefore, suggests that HAV, following a chronic B infection, is can vary within a single country, city or region. In 1994 we associated with altered laboratory results and more serious studied the prevalence of HAV in 387 children and illness, including the fulminant form, and also a higher

Table 4 - Patients’ age and family income according to the etiology of the chronic liver disease

Groups Total (60) Positive (14) Negative (45)

Biliary atresia 26 3 (12%) 22 (88%) Mean age (years) 3.9 6.3 3.56 Mean family income (reais) 578.46 866.66 540.87 Autoimmune hepatitis 13 5 (38.5%) 8 (61.5%) Mean age (years) 11.8 11 12.3 Mean family income (reais) 483.84 380.00 548.75 Cryptogenic cirrhosis 11 4 (36%) 7 (64%) Mean age (years) 6.2 5 7 Mean family income (reais) 309.09 267.50 332.85 Other 10 2 (20%) 8 (80%) Mean age (years) 9 7 9.5 Mean family income (reais) 830.00 300.00 962.00 Prevalence of hepatitis A antibody... - Ferreira CT et alii Jornal de Pediatria - Vol. 78, Nº6, 2002 507 mortality rate amongst such patients. Furthermore, there did not find an association between fulminant hepatitis A also appears to be a higher mortality rate related to HAV in and underlying chronic hepatitis B or C. patients with other types of chronic liver disease.9,17 In over 6,000 cases of HAV notified between 1992 and The analysis of epidemiological data reported to the 1996 to SEIEVA, acute viral hepatitis notification system in CDC (Centers for Disease Control and Prevention), in the Italy, no deaths were recorded.23 Amongst these HAV United States, from 1983 to 1988, revealed a hepatitis A cases there were 179 individuals with chronic hepatitis B or mortality rate of 11.7% in patients diagnosed with chronic C. hepatitis B, and 4.6%, in patients with other pre-existing Since 1996, the ACIP (Advisory Committee on chronic liver diseases. Deaths occurred mainly within the Immunization Practices to the CDC in the United States) older population (72% of those who died were over 49 years has recommended the immunization of all patients with old). These rates are, respectively, 58 and 23 times higher chronic liver disease against HAV.5,6,24 The than in the population without underlying chronic liver recommendation is based upon the assumption that if an disease.9,10,18 individual already has a chronic liver disease, an additional All of these studies have methodological problems hepatic lesion might be poorly controlled. which limit the possibilities of comparison and Currently, immunization guides clearly state that patients generalizations. Nevertheless, there appears to be evidence with chronic liver disease should receive the HAV vaccine.5.6 of an increased risk of death in patients with chronic The World Health Organization and the CDC recommend hepatitis when they contract HAV, particularly in population- immunization against HAV in people with chronic liver based studies which survey deaths.10 disease due to the increased rate of mortality amongst those 5,6,24 The association between death from fulminant hepatitis who contract an infection by the A virus. The American A and chronic liver disease was recently demonstrated in a Academy of Pediatrics has indicated vaccination against 25 study based upon death certificates between 1981 and 1997 HAV for patients with chronic liver disease since 1996, 26,27 from the National Health Statistics Center.18 In this case- and so has the Brazilian Society of Pediatrics. control study, 63% of the deaths due to HAV mentioned In order to indicate vaccination against HAV for patients chronic liver disease on the death certificate, compared to with chronic liver disease, just as for any other group of 8 to 11% of deaths due to other gastrointestinal causes. individuals, it is necessary to know the prevalence of 28,29 Considering the 1988 epidemic in Taiwan, in which infection for that specific group. more than 300 thousand people were contaminated by In the studied sample, of 59 patients with etiologically seafood with the A virus, the mortality rate for individuals different chronic liver diseases, 24% tested positive for the carrying the B virus was 0.05%, which is 5.6 times higher anti-HAV antibody. This is a low percentage considering than for patients without chronic liver disease type B. In this age and the fact that the majority of the group have family epidemic, the affected population was younger, which incomes of less than R$ 500.00. There was a slight increase perhaps explains the lower mortality.9 in the percentage of anti-HAV positive patients with relation to age, however this was not statistically significant. In Sandro Vento et al.2 performed a seven-year prospective addition, there appears to be a tendency for those patients study of 595 adults with either chronic hepatitis B or C, who are positive to belong to low-income families. However previously seronegative for HAV. Twenty-seven patients the difference is not statistically significant, which probably (10 with HBV and 17 with HCV) presented acute hepatitis results from the small number of patients. The relationship A during this period. Fulminant hepatitis occurred in 7 with diagnosis is probably explained rather by age than by hepatitis C patients, and only one individual survived. They etiology. Thus the patients with autoimmune hepatitis, with concluded that patients with chronic hepatitis C run a a higher average age, showed a higher rate of positive anti- substantial risk of death when associated with a HAV tests. Although the group of patients with biliary superinfection by the A virus. atresia is larger, it showed less positive results, as the 19 Evangelos Akriviadis and Redeker describe four adult average age was lower than those of the other two groups patients who died after developing HAV. All four, on (3.9 years against 11.8 in the autoimmune hepatitis group necropsy, displayed underlying chronic liver disease. and 6.2 years in the cryptogenic cirrhosis group). In contrast to these and other series of individuals, Koçak et al.,28 from Turkey, found a seropositivity rate certain authors do not indicate any difference in prognosis for anti-HAV of 44% amongst 403 children and adolescents for patients who had chronic liver disease when they acquired with chronic liver diseases, between 1.5 and 20 years old. 16 the A virus, mainly in those who are younger. Viola et Of these, 267 suffered from chronic hepatitis B, and 136 had 20 21 al. and Zachoval et al. did not encounter differences in other chronic liver diseases. The 140 children who had no bilirubin or transaminases, nor in the evolution of chronic liver disease showed 31% seropositivity for anti-HAV. The patients with B virus acutely infected by HAV. Both prevalence of anti-HAV antibodies increased with age: suggested that there could be some type of viral interference, 16% of the children less than 5 years old, 35.5% in those since they recorded reduction in the patients’ HBsAg levels between 6 and 10, 59.5% in those between 11 and 15 years 22 during HAV. Helbling and Kammerlander, in Switzerland, old and 67% in patients older than 15. 508 Jornal de Pediatria - Vol. 78, Nº6, 2002 Prevalence of hepatitis A antibody... - Ferreira CT et alii

Diago et al.,29 in Spain, studied the prevalence of anti- 8. Werzberger A, Mensch B, Kuter B. A controlled trial of a formalin- HAV in 425 adult patients with liver disease (x = 40 years inactivated hepatitis A vaccine in healthy children. N Engl J Med 1992;327:453-7. old), and found that 75% were positive, ranging from 20% 9. Keeffe EB. Is hepatitis A more severe in patients with chronic at 19, to 93% in those who were over 40 years old. hepatitis B and other chronic liver diseases? Am J Gastroenterol The reduction of a population’s susceptibility, through 1995;90:201-5. vaccination, can eliminate diseases and their complications, 10. Bell BP. Hepatitis A and hepatitis B vaccination of patients with chronic liver disease. Acta Gastroenterol Belg 2000;63:359-63. but periodical updating of seroepidemiological data is 11. Alter MJ, Mast TE. The epidemiology of viral hepatitis in the United necessary to assess natural immunity levels and to identify States. Gastroenterol Clin North Am 1994;23:437-55. those who are susceptible to infection. 12. Tapia-Conyer R, Santos JI, Cavalcanti AM, Urdaneta E, Rivera L, Vaccinating patients with chronic liver diseases, in Manterola A, et al. Hepatitis A in Latin America: a changing order to protect them from hepatic lesions caused by the A epidemiologic pattern. Am J Trop Med Hyg 1999;61:825-9. 1,10,22 13. Ferreira CT, Barros FC, Silva GL, Pereira-Lima J. Soroepidemiologia virus, appears to be a correct and intelligent decision. da Hepatite A em dois grupos populacionais economicamente This study shows that the majority (76%) of pediatric distintos de Porto Alegre. Gastroenterologia Endoscopia Digestiva patients with chronic liver disease are anti-HAV negative, 1996;15:85-90. which makes them susceptible to infection by the A virus 14. Gust ID. Epidemiological patterns of hepatitis A in different parts and to its possible complications. It should also be taken of the world. Vaccine 1992;10 (Suppl 1):56-58. into account that, in countries such as Brazil, the risk of 15. Costa-Clemens SA, Fonseca JC, Azevedo T, Cavalcanti AM, Silveira TR, Castilho MC, et al. Soroprevalência para hepatite A e hepatite acquiring the infection is very high, since the virus is B em 4 centros no Brasil. Rev Soc Bras Med Trop 2000;33:1-10. 13,15 endemic and there exist people who are susceptible. 16. Gust ID, Feinstone, SM. Hepatitis A. Prog Liver Dis 1990;9:371-8. Neither an immunization scheme nor a seroconversion 17. Keeffe EB, Iwarson S, McMahon BJ, Lindsay KL, Koff RS, Manns rate for patients with chronic liver diseases are well M, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology 1998;27:881-6. established. Studies of anti-HAV prevalence, with later 18. Datta D. Association between deaths due to hepatitis A and chronic vaccination of patients with chronic liver diseases, can liver disease: United States, 1981 - 1997. Antiviral Ther 2000;5 assist in the establishment of immunization criteria for this (Suppl 1):79. group of individuals. 19. Akriviadis EA, Redeker AG. Fulminant hepatitis A in intravenous drug users with chronic liver disease. Ann Int Med 1989;110:838-9. 20. Viola LA, Barrison IG, Coleman JC, Murray-Lion IM. The clinical course of acute type A hepatitis in chronic HBsAg carriers-a report Acknowledgments of 3 cases. Postgrad Med J 1982;58:80-8. Thanks to Laboratório Weinmann for performing the 21. Zachoval R, Roggendorf M, Deinhardt F. Hepatitis A infection in anti-HAV tests and to Vânia Hirakata for the statistical chronic carriers of hepatitis B virus. Hepatology 1983;3:528-31. 22. Helbling B, Kammerlander R. Acute Hepatits A in patients with analysis. chronic hepatitis C. Ann Int Med 1999;131:314. 23. Mele A, Tosti ME, Stroffolini T. Hepatitis associated with hepatitis A superinfection in patients with chronic hepatitis C. N Engl J Med 1998;338:1771-3. 24. Centers for Disease Control. Recommended Childhood Immunization Schedule - United States, 2001. JAMA 2001;285:8 75-6. References 25. American Academy of Pediatrics. Committee on Infectious Diseases. 1. Sjogren MH. Prevention of acute liver disease in patients with Prevention of Hepatitis A infection: guidelines for use of Hepatitis chronic liver disease. Hepatology 1998;27:887-8. A vaccine and immune globulin. Pediatrics 1996;98:1207-15. 2. Vento S, GarofanoT, Renzini C, Cainelli F, Casali F, Ghironzi G, et 25. Sociedade Brasileira de Pediatria. Indicações - Guia de Adolescência: al. Fulminant hepatitis associated with hepatitis A virus orientação para profissionais da área médica. Rio de Janeiro; 2000. superinfection in patients with chronic hepatitis C. N Engl J Med 26. Sociedade Brasileira de Pediatria. Indicações de Vacinas. Disponível 1998;338:286-90. em: