Ghent University Hospital, Ghent, Belgium
Correspondence to Dr. E. Robberecht, Hospitalo-Universitaire d'Anderlecht, Brussels, ULB CP610, route de Lennik 808, 1070 Bruxelles.
This editorial accompanies an article. Please see Histologic Activity of Childhood Chronic Hepatitis B Related to Viremia Levels, Genotypes, Mutations, and Epidemiologic Factors. A Söderström, G Norkrans, N Conradi, M Krantz, P Horal, M Lindh. J Pediatr Gastroenterol Nutr 2002;35:487–494.
More than any other clinical specialty, pediatric medicine has a double field of interest. The pediatrician should not only treat the immediate inconveniences of the present illness but also continuously consider its potential future complications in a patient who will long have outgrown the pediatric age group and does not even remember the original disease. Hepatitis B virus (HBV) infection is an important example.
Apart from some exceptional cases of fulminant liver failure, acute hepatitis B mostly runs a mild and subclinical course. In the developed West, infection of children is rather uncommon thanks to different prophylactic measures and the subsequent rarity of vertical transmission. At this moment, most cases of childhood chronic HBV infection in the West are diagnosed in immigrants or adopted children from endemic areas. Worldwide, however, 350 million people would carry the virus according to WHO and it would be the tenth most common cause of death (1). These dramatic figures are the result of the frequent progression of the infection to chronicity, especially when acquired at birth. About 90% of all babies born to mothers with active viral replication will be infected. In the majority, the infection becomes chronic; when the reproductive age is reached the virus is passed to the next generation and the vicious circle restarts. For about 40%, the development of chronic liver disease, cirrhosis, and primary liver cell cancer must be feared at any age (2).
Avoidance of these complications in children but also in adults is the ultimate goal of any treatment. To institute this early but efficiently and to evaluate the efficacy of any chosen strategy, detailed knowledge of any aspect of chronic HBV-infection as well in children and later in life is paramount. Many authors have already contributed to the elucidation of this complicated disease. In this issue of the Journal, A. Söderström et al. report their cross sectional data on 71 chronic HBV carriers of allochthonous origin, living in Sweden, aged 2 to 18 years (3). Acquisition of infection was presumed to be by vertical transmission in 16 (22.5%) and horizontal in 17 (24%) while it was uncertain in the remaining 38 carriers.
From all, a liver biopsy was taken and systematically scored for inflammation and fibrosis. At the same time values were recorded of several serologic HBV markers (HBsAg, HBeAg, anti-HBe, core IgM antibodies), of ALT, genotypes, corepromotor, and precore mutations. Serum HBV-DNA levels were quantitatively measured by PCR.
HBeAg was positive in 49 patients and negative in 22 patients. The mean age of the group with HBeAg positivity was significantly lower than that of those negative for HBeAg. Furthermore the HBeAg positives had on average a HB-DNA level ten thousand times that of the negatives. It is therefore concluded that HB viremia and the proportion of HBeAg positive carriers decrease with age. This is in accordance with several other reports such as a long-term follow up study from Taiwan where an annual seroconversion rate was found of 4 to 5% in children older than 3 years of age and of less than 2% in younger ones. The age at seroconversion varied individually between infancy and more than 40 years, the most common age being between 15 and 30 years (4). It can be expected that the age in the presented group might be somewhat lower since the East Asian study contains a higher proportion of vertically infected patients who are known to lose HBeAg after a longer time than the horizontally infected.
The authors tried to predict in the least aggressive way which children with chronic HBV infection are at risk for developing severe liver complications. For that purpose they investigated the relations between biochemical markers of HBV infection, HBV-DNA serum levels, genotypes, corepromotor, and precore mutations with the occurrence and degree of liver damage.
Neither genotypes nor mutations seem to have much influence. HBeAg in contrast is the most important discriminating criterium associated with liver inflammation. When patients are positive for HBeAg they more often show a raised ALT, anti-core-IgM, a much higher HBV-DNA level, and an increased inflammation score. On the other hand it is improbable to find severe hepatic damage when HBeAg is negative and biochemical markers and the DNA level are low. Within the groups, however, it was, in contrast to the situation in adults, impossible to demonstrate a more sensitive relation between the level of DNA and the degree of liver inflammation. In HBeAg positive patients the scoring of liver inflammation ranged from almost normal to severe, thus reducing the value of finding HBeAg positivity for the prediction of the degree of liver damage in an individual patient; when HBeAg is negative on the contrary it is very probable that the liver damage is mild and even improves with time after seroconversion from HBeAg positivity to anti-HBe. This confirms the results of a study in which pre- and post-seroconversion liver histopathology was compared (5).
In general, the presented study leaves a very optimistic impression of chronic childhood hepatitis B. Without any treatment, none of the children shows any severe complication, neither cirrhosis nor hepatocellular carcinoma. This seems in contrast with East Asian reports, which cautioned against these complications. Maybe this is caused by the important difference in route of transmission: in the Eastern hyper endemic areas it is mostly vertical and children infected in that way remained HBeAg positive for a longer time. It is in this phase of active viral replication that inflammation and necrosis occur while they tend to improve at the end of the replicative period when HBeAg disappears in favour of anti-HBe. Except in the rare cases were cirrhosis has become established (mostly after vertical infection) the patient becomes an asymptomatic carrier with mild or no liver lesions. Nevertheless it is “pushing it” to cry victory at the moment of HBeAg seroconversion to anti-HBe, because reactivation of viral replication with aggressive liver disease is well established in adult life. Progression to liver cancer would even occur in 10 to 14% of those affected who are more than 30 years old (6). This is, however, doubted by the authors since these observations might date from before recognition of hepatitis C and delta.
Söderström et al. succeed quite well in their objective to distinguish between little and severe pathological liver abnormalities in chronic childhood hepatitis B only using noninvasive tests. Serious complications of infection at a young age have however mainly to be feared in adulthood. This provocative cross sectional study should therefore certainly be followed by a long-term longitudinal one. Hepatitis B is a to capricious disease to rely exclusively on present days observations for its prognosis over years.
1. World Health Organization: Fact Sheet: Hepatitis B October 2000 (2000)(2001).
2. Chang MH. Natural history of Hepatitis B virus infection in children. (Towards Control of Hepatitis B in the Asia-Pacific Region: Epidemiology and Natural History). J Gastroenterol Hepatol 2000; 15 suppl.:E16–E19.
3. Söderström A, Norkrans G, Conradi N, et al. Histologic activity of childhood chronic hepatitis B related to viremia levels, genotypes, mutations and epidemiological factors. J Pediatr Gastroenterol Nutr 2002; 35:487–494.
4. Chang MH, Sung JL, Lee CY, et al. Factors affecting clearance of hepatitis B-e-antigen in hepatitis B surface antigen carrier children. J Pediatr 1989; 115:385–90.
5. Ruiz-Moreno M, Othero M, Millan A, et al. Clinical and histological outcome after hepatitis B-e antigen to antibody seroconversion in children with chronic hepatitis B. Hepatology 1999; 29:572–75.
6. Beasley RP. The major etiology of hepatocellular carcinoma. Cancer 1988; 6:1942–5.
© 2002 Lippincott Williams & Wilkins, Inc.