Chronic hepatitis B and C in children

Eve A Roberts

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Year : 1995 | Volume : 1 | Issue : 3 | Page : 157-162

Chronic hepatitis B and C in children

Eve A Roberts
Division of Gastroenterology & Nutrition, The Hospital for Sick Children, and the University of Toronto, Toronto, Ontario, Canada

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Abstract

Chronic hepatitis B & C represent major medical problems in both adults and children. The purpose of this article is to focus on pediatric aspects of these two types of viral hepatitis.

How to cite this article:
Roberts EA. Chronic hepatitis B and C in children. Saudi J Gastroenterol 1995;1:157-62

How to cite this URL:
Roberts EA. Chronic hepatitis B and C in children. Saudi J Gastroenterol [serial online] 1995 [cited 2020 Nov 26];1:157-62. Available from: https://www.saudijgastro.com/text.asp?1995/1/3/157/34053

Since the mid-1960's five distinct hepatotropic viruses have been identified and characterized. Previous trivial names have become obsolete, since these viruses are now designated alphabetically, hepatitis A, B, C, D, and E viruses. The names are abbreviated as HAV, HBV, HCV, HDV, and HEV, respectively. Whether further hepatotropic viruses exist, is a matter of current speculation and research. As their name implies, these viruses target the liver where they proliferate in hepatocytes. In addition, there are extrahepatic reservoirs for these viruses, such as blood mononuclear cells and, for hepatitis B virus, the pancreas. Two of these viruses, HAV and HEV, cause acute hepatitis, usually in epidemics, due to ingestion of contaminated water or food; they do not cause chronic hepatitis. By contrast, HBV and HCV cause chronic hepatitis and are spread mainly by blood and body fluids, including by vertical (mother-to-child) transmission. HDV, originally known as hepatitis delta agent, requires concurrent infection with HBV in order to replicate.

Chronic hepatitis B & C present major medical challenges at this time. These diseases share important clinical characteristics: chronic subclinical infection is common (for HBV, largely because of vertical transmission), clinical features are variable, and hepatocellular carcinoma may develop. However, the causative viruses, HBV and HCV, have important differences. The purpose of this article is to focus on pediatric aspects of these two types of viral hepatitis.

Hepatitis B

HBV is the only DNA virus currently identified among these hepatotropic viruses. It is a member of the hepadnavirus family, which also includes the woodchuck hepatitis virus and the duck hepatitis virus, among others. Multiple genotypes exist. HBV is not easily spread from person to person by casual contact, but the risk of spread is a little higher among a group of toddlers. HBV infection is endemic in different parts of the world, notably China and Southeast Asia, subsaharan Africa, and in peri-Mediterranean countries [1].

HBV is an enveloped spherical virus, 42 nm in diameter [2]. The coat protein is overproduced and spontaneously forms tubular structures or dominutive spheres. HBV coat is more complex than initially thought, as it is composed of three different sizes of components ("major," "medium" and "large"). This is possible because the gene for making coat protein can be transcribed at different start points to produce related proteins of different sizes. Clinically, the coat protein is detected as HBsAg; the antibody toward this protein, anti-HBs, provides protective immunity. The core material of HBV can be identified immunologically as HBcAg, although this is of little practical importance as it is not routinely assayed in serum. The corresponding antibody, anti-HBC, is found in patients with chronic infection and, as an IgM antibody, may be the only immunological trace of recent acute infection in the period between disappearance of HBsAg and appearance of measurable quantities of anti-HBs. Another core protein, originally known as "little e" but now called HBeAg, relates to infectivity; its corresponding antibody is anti-HBe.

A great deal is known about the HBV genome. It consists of double-stranded DNA with four open reading frames. One is for the S gene, another for the core proteins, another for the DNA polymerase, and one for a protein known as "X", whose functions remain unclear. A great deal of genetic information is packed into this genome because the open reading frames overlap. Starting transcription at different start-sites produces different proteins. This accounts for the different types of coat protein in the envelope. It has also clarified what HBeAg is: it is synthesized from the same gene as HBcAg. Starting at the preC start, codon leads to synthesis of HBeAg whereas, starting at the C start codon, generates HBcAg. It is then clear why presence of HBeAg correlates with viral replication and thus with infectivity. In infants, HBeAg may act as a tolerogen by diminishing the responsiveness of T-cells to HBcAg and HBeAg and thus, enhances the efficacy of vertical infection [3].

The DNA of HBV is very small. Moreover, the negative strand is longer than the positive strand: there is a single-stranded gap. This implies that replication will involve an innovative-or at least, non-traditional-mechanism; in this case, via reverse transcription. HBV replication mechanism is rather complicated [2],[4]. The gap is repaired prior to replication of the genetic material. The DNA is then reproduced as RNA. From this RNA, viral proteins are produced and the viral DNA is replicated. Although the asymmetric DNA is repaired to a cyclic form in the nucleus and transcription takes place there, protein production and viral assembly, take place in the cytoplasm. Most newly-produced viruses exit the hepatocyte, but some return to the nucleus for further viral replication. As a matter of anti-viral strategy, interfering with the cyclic form would be most efficacious.

Although acute hepatitis B occurs in children, the great problem is chronic infection [5],[6],[7],.[8]. The natural history of chronic hepatitis B, for example, after vertical transmission, can be divided into three phases. Initially, there is a period of apparent immune tolerance, when HBV replicates freely in hepatocytes without major evidence of damage to the liver. At some point, most patients lose this immunotolerance toward the virus. The timing of this change seems to be highly variable from individual to individual, and there are no obvious predictors of when this change is likely to take place. With the emergence of an immune response toward the viral infection, liver damage evidenced by elevated serum aminotransferases may occur. If the host's response prevails, viral replication stops, and viral DNA integrates into the host hepatocellular DNA. Serum HBV DNA and HBeAg disappear, and eventually anti-HBe is expressed. Few patients show ongoing liver damage once anti-HBe appears, but in the last phase of chronic infection, hepatocellular carcinoma may develop. Variations on this typical natural history include the emergence of mutant hepatitis B viruses as the predominant virus; some of these mutants fail to express HBeAg, but others show mutations in the coat protein so that anti-HBs is no longer protective.

Although chronic hepatitis B in children is usually a mild disease, clearly some children progress to serious chronic liver disease with cirrhosis. Chronic hepatitis B may also be associated with immune-complex disease, notably in adults, systemic arteritis presenting as polyarteritis nodosa. In children, membranous glomerulonephritis has been a common association with chronic hepatitis B [9],[10],[11].

Many anti-viral and immunomodulatory drugs have been tried for treating chronic hepatitis B. These include interferons, corticosteroids, levamisole, thymosin, acyclovir, ribavirin, foscarnet, and others. Only alpha-interferon has been shown to be effective, causing HBeAg seroconversion to anti-HBe durably in approximately 40% of adults [12]. Some anti-virals, such as vidarabine and fialuridine, are extremely toxic and have been dropped from clinical use. The newest agent of interest is lamivudine. This is a nucleoside analogue which interferes with viral replication. It can be taken orally, and early clinical trials suggest that it is effective. Its safety is not yet fully established. No studies in children are available at present.

Therefore at this time alpha-interferon is the best available treatment for hepatitis B [1],[13]. Only patients with ongoing viral replication (HBeAg-positive) and some evidence of immune response, that is, significantly-elevated alanine aminotransferase (ALT), are suitable for treatment. Contraindications currently include: advanced liver disease with hepatic decompensation, concomitant HIV infection, and HDV infection; but further research is needed to define the role of alpha-interferon treatment in such patients. Patients with autoimmune hepatitis worsen if treated with alpha-interferon. Factors associated with success of alpha-interferon treatment include: low viral load, marked elevation of ALT, and history of acute hepatitis. Clearly, the latter rarely applies in children.

Alpha-interferon has formidable side effects. Most patients develop a "flu-like" syndrome with fever, myalgia, malaise that lasts weeks to months. Some degree of bone marrow suppression, with lowered white cell and platelet counts, is universal-thus, patients with leukopenia or thrombocytopenia may not be suitable for treatment. A margin of adult patients develop psychiatric abnormalities manifested as depressed or impulsive behavior. Patients with known psychiatric problems should not be treated with alphainterferon. Autoimmune phenomena may develop during treatment with alpha-interferon. Autoimmune thyroid disease is the most common of these problems.

Experience in treating children with chronic hepatitis B with alpha-interferon is limited, and the drug is not yet licensed for use in children. There are few clinical trials of alpha- interferon treatment in children with chronic hepatitis B [14],[15],[16],[17],[18]. The studies are small and difficult to compare because of differences in design and dosage schedules. A general impression is that alphainterferon, in doses comparable to the adult dose, appears to be as effective in children as in adults. Ethnic background is not a factor, so long as the period of immunotolerance is over - that is, the serum ALT is elevated. Brief pre-treatment with prednisone is controversial because it risks provoking fulminant hepatic failure [19], it should be avoided in children. Side effects may be somewhat different in children and adults. Treatment in teenagers may prove problematic because of the difficulties in evaluating their emotional status. Most adult patients develop anorexia; but children may lose a considerable amount of weight and require dietary supplements. Alopecia may be a nuisance for adults, but quite worrisome for a child or young teenager. Even the prolonged "flulike" syndrome may assume greater importance in a child if it affects schoolwork.

Hepatocellular carcinoma in children is uncommon [20]. Nevertheless, in the past ten years, we have encountered five patients with chronic hepatitis B infection and hepatocellular carcinoma at the Hospital for Sick Children in Toronto. The average age at presentation was 10 years old, and the course was marked by the sudden development of a liver mass with a rapidly downhill course. No child had cirrhosis. A patient as young as 4 years old, has been reported [21]; other case reports are similar to our experience [22].

However, in some series, children with chronic hepatitis B and hepatocellular carcinoma have had cirrhosis [23]. The molecular mechanisms by which chronic hepatitis B infection causes hepatocellular carcinoma, remain poorly understood [24]. Liver transplantation may be life-saving for children who present with hepatocellular carcinoma [25], even though the hepatitis B infection may pose special problems [1].

Hepatitis C

Our understanding of hepatitis C, although much advanced in the past 10 years, is really quite limited, compared to what we know about hepatitis B[26],[27]. This RNA virus-causing chronic disease, was responsible for most nonHBV post-transfusion hepatitis until adequate screening methods were developed, and can cause sporadic ("community-acquired") hepatitis.

HCV is the virus we can perceive, but have hardly seen [28]. HCV was identified by employing the methods of molecular biology, not the more orthodox methods of immunology and electron microscopy [29]. It is a single-stranded RNA virus with positive-sense RNA, which means that once inside the hepatocyte, the virus can get right on with replication. However, little is known about the mechanism of replication of HCV. There are multiple genotypes with distinct worldwide geographic distribution. The viral genome has been delineated and has various genes within it; in the single open reading frame, are genes for the core, the envelope, and the several non-structural genes [30]. Moreover, HCV is capable of spontaneous changes in a highly-variable region of its RNA, leading to further variants of the virus which can escape immune defenses. This process is called quasi-speciation. It may make vaccine development difficult, if not impossible.

We diagnose HCV by immunological means, mainly dependent on the presence of anti-HCV antibody expressed by the infected individual. A RIBA (recombinant immunoblot assay) is used to confirm the anti-HCV result. Methods for detecting HCV RNA directly become more common, but serological testing with refined RIBA-type immunoassays is an effective method for detecting HCV. However, there are clinical situations, such as in the anti-HCV positive infant, when direct detection of HCV RNA provides essential diagnostic information.

While HCV is currently doubted to cause fulminant hepatitis, chronic C infection in children who have had multiple transfusions is an important problem. Typically-affected children include: hemophiliacs; children with congenital anemias requiring regular transfusions from infancy onward; children who have had extensive cardiac surgery or leukemia. A major unanswered question is: simply, what is the natural history of chronic hepatitis C? Recent studies suggest, that it may cause severe progressive liver disease in some people, and liver biopsy shows with active inflammation and severe peri-portal fibrosis. Chronic hepatitis C is now a leading indication for liver transplant. In some individuals, however, the course is indolent. Histological abnormalities may then be quite mild. Our understanding of this variable natural history is very dependent on how the natural history studies are designed. Most apply to adults, and there are very few studies in children. Thus, the natural history of chronic hepatitis C in children really is not clear at all. In one large European series (77 patients), approximately 20% were symptomatic when the HCV infection was found. A minority had active disease on initial liver biopsy, and follow-up liver biopsy disclosed active hepatitis in less than a quarter of the patients, and cirrhosis in only two patients. In follow-up that averaged six years, approximately 10% achieved spontaneous remission [31]. Chronic HCV infection has been shown to be associated with development of hepatocellular carcinoma in adults [32].

Vertical transmission of HCV occurs. This was doubted in the past because initial studies were conflicting. Maternal co-infection with HIV is not essential for vertical transmission of HCV, but it facilitates vertical infection. The major determinant for vertical transmission is viral load [33]. Increased viral load makes vertical transmission more likely. Spread by. breast milk is uncertain; anti-HCV positive mothers should probably not breast-feed.

Treatment of hepatitis C poses problems. The current treatment of choice is alpha-interferon, but sustained response rates are disappointing, on the order of 17-23% of patients treated [34]. Chronic suppression of HCV appears to be an unrealistic goal for children infected early in life. Moreover, experience with using alpha-interferon to treat children who have chronic hepatitis C is extremely limited [35]. At this time both the indications for treating children and the best treatment protocol have not been determined adequately. The anti-viral ribavirin has been tried in adults, but recent results are equivocal with respect to efficacy.

In conclusion, HBV and HCV are important causes of viral hepatitis in children. Chronic infection is common, and may lead to severe chronic liver disease and/or hepatocellular carcinoma. Although vertical transmission of HCV occurs, it is a much more common pattern of infection with HBV. The natural course of chronic hepatitis B acquired in childhood is well known; after a variable period of viral replication while the host is comparatively immunotolerant of the virus, HBV DNA integrates randomly into hepatocellular DNA and becomes quiescent. Prior to this integration, host immune defenses against HBV may lead to liver damage. Later in the quiescent phase, hepatocellular carcinoma may develop. Vaccination against HBV immediately after birth can break this chain of chronic infection. By contrast, HCV is currently spread mainly by blood and body fluid exposure, usually by transfusion of infected blood or blood products. The determinants of whether chronic HCV infection leads to severe liver disease or not, especially in children, remain unclear. The inherent variability of the HCV makes vaccine-production difficult, but effective screening of blood products should reduce the incidence of post-transfusion hepatitis. Unquestionably, HCV can cause hepatocellular carcinoma.

Since HCV is an RNA virus, the mechanism of tumor production likely differs from that of HBV. The contribution of the host's genetic complexion and of environmental factors requires further examination in relation to development of HCC in both types of chronic hepatitis.

References

1.	Wright TL, Lau JYN. Clinical aspects of hepatitis B infection. Lancet 1993;342:1340-4.
2.	Tiollais P, Pourcel C, Dejean A. The hepatitis B virus. Nature 1985;317:489-95. [PUBMED]
3.	Thomas HC, Carman WF. Envelope and pre-core/core variants of hepatitis B virus. Gastroenterol Clin NA 1994;23:499-514.
4.	Robinson WS, Marion PL, Miller RH. The hepad naviruses of animals. Sem Liver Dis 1984;4:347-360.
5.	Anderson MG, Murray-Lyon IM. Natural history of the HBsAg carrier. Gut 1985;26:848-60. [PUBMED] [FULLTEXT]
6.	Bortolotti F, Cadrobbi P, Crivellaro C, et al. Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B infection in childhood. Gastroenterology 1990;99:805-10.
7.	Lee PI, Chang MH, Lee C.Y, et al. Changes in serum hepatitis B virus DNA and aminotransferase levels during the course of chronic hepatitis B virus infection in children. Hepatology 1990;12:457-660.
8.	Moyes CD, Milne A, Waldon J. Liver function of hepatitis B carriers in childhood. Pediatr Infect Dis J 1993;12:120-5. [PUBMED]
9.	Kleinknecht C, Levy M, Peix A, Broyer M, Courtecuisse V. Membranous glomerulonephritis and hepatitis B surface antigen in children. J Pediatr 1979;95:946-52. [PUBMED]
10.	Wiggelinkhuizen J, Sinclair-smith C, Stannard LM, Smuts H. Hepatitis B virus associated membranous glomerulonephritis. Arch Dis Child 1983;58:488-96. [PUBMED]
11.	Southwest Pediatric Nephrology Study Group. Hepatitis B surface antigenemia in North American children with membranous glomerulopathy. J Pediatr 1985;106:571-8. [PUBMED]
12.	Wong DKH, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon in patients with hepatitis B e antigen-positive chronic hepatitis B: a meta- analysis. Ann Intern Med 1993;119:312-23.
13.	Perrillo RP, Mason AL. Therapy for hepatitis B virus infection. Gastroenterol Clin NA 1994;23:581-601.
14.	Lai CL, Lok ASF, Lin HJ, Wu PC, Yeoh EK, Yeung CY. Placebo-controlled trial of recombinant alpha_z interferon in Chinese HBsAg-carrier children. Lancet 1987;ii:877-80.
15.	Lai CL, Lin HJ, Lau JYN, et al. Effect of recombinant alpha_z interferon with or without prednisone in Chinese HBsAg-carrier children. Quart J Med 1991;78:155-63.
16.	Ruiz-Moreno M, Rua MJ, Molina J, et al. Prospective, randomized-controlled trial of interferon-alpha in children with chronic hepatitis B. Hepatology 1991;13:1035-9. [PUBMED]
17.	Sokal EM, Wirth S, Goyens P, Depreterre A, Cornu C. Inteferon alpha-₂ B therapy in children with chronic hepatitis B. Gut 1993;Suppl:87S-90S.
18.	Utili R, Sagnelli E, Gaeta GB, et al. Treatment of chronic hepatitis B in children with prednisone followed by alpha-interferon: a controlled randomized study. J Hepatol1994;20:163-7. [PUBMED]
19.	Bird GLA, Smitt. Portmann B, Alexander GJM, Williams R. Acute liver decompensation on withdrawal of cytotoxic chemotherapy and immunosuppressive therapy in hepatitis B carriers. Quart J Med 1989;73:895-902.
20.	Finegold MJ. Tumors of the liver. Sem Liver Dis 1994;14:270-81.
21.	Tanaka T, Miyamoto H, Hino 0, et al. Primary hepatocellular carcinoma with hepatitis B virus-DNA integration in a 4 year-old boy. Hum Pathol 1986;17:2024.
22.	Trounce JQ, Flower AJE, Shannon RS, Tanner MS. A case of hepatocellular carcinoma complicating hepatitis B infection in a nine-year-old boy. Quart J Med 1985;57:791-4.
23.	Hsu HC, Wu MZ, Chang MH, Su IJ, Chen DS. Childhood hepatocellular carcinoma develops exclusively in hepatatis B surface antigen carriers in three decades in Taiwan. Report of 51 cases strongly-associated with rapid development of liver cirrhosis. J Hepatol 1987;5:260-7.
24.	Robinson WS. Molecular events in the pathogenesis of hepadnavirus-associated hepatocellular carcinoma. Annu Rev Med 1994;45:297-323. [PUBMED] [FULLTEXT]
25.	Yandza T, Alvarez F, Laurent J, Gauthier F, Dubosset AM, Valayer J. Pediatric liver transplantation for primary hepatocellular carcinoma-associated with hepatitis virus infection. Transplant Internat 1993;6:95-8.
26.	Sherlock S. Chronic hepatitis C. Disease-A-Month 1994;40:117-96.
27.	Nowicki MJ, Balistreri WF. The hepatitis C virus: identification, epidemiology, and clinical controversies. J Pediatr Gastroenterol Nutr 1995;20:248-74. [PUBMED]
28.	Overby LR. Hepatitis C: looking at a virus that hasn't been seen. Gut 1993;Suppl:6S-9S.
29.	Choo Q.L, Kuo G, Weiner AJ, Overly LIZ, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359-62.
30.	Houghton M, Weiner A, Han J, Kuo G, Choo Q.L. Molecular biology of the hepatitis C viruses: implications for diagnosis, development and control of viral diseases. Hepatology 1991;14:381-8.
31.	Bortolotti F, Jara P, Diaz C, et al. Posttransfusion and community-acquired hepatitis C in childhood. J Pediatr Gastroenterol Nutr 1994; 18:279-83. [PUBMED]
32.	Kew MC. Hepatitis C virus and hepatocellular carcinoma. FEMS Microbiol Rev 1994;14:211-9. [PUBMED]
33.	Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus from mothers to infants. N Engl J Med 1994;330:774-50.
34.	Davis GL, Lau JYN, Lim HL. Therapy for chronic hepatitis C. Gastroenterol Clin NA 1994;23:603-13.
35.	Ruiz-Moreno M, Rua MJ, Castillo I, et al. Treatment of children with chronic hepatitis C with recombinant interferon-alpha: a pilot study. Hepatology 1992;16:882-5. [PUBMED]