Saudi Journal of Gastroenterology
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Year : 1995  |  Volume : 1  |  Issue : 3  |  Page : 157-162
Chronic hepatitis B and C in children


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 Oct 27];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 Top


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 Top


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 Top

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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.  Back to cited text no. 31  [PUBMED]  
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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.  Back to cited text no. 33    
34.Davis GL, Lau JYN, Lim HL. Therapy for chronic hepatitis C. Gastroenterol Clin NA 1994;23:603-13.  Back to cited text no. 34    
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.  Back to cited text no. 35  [PUBMED]  

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Correspondence Address:
Eve A Roberts
Associate Professor of Pediatrics, Medicine and Pharmacology Room 8415, University Wing, Division of Gastroenterology & Nutrition The Hospital for Sick Children 555 University Avenue, Toronto, Ontario M5G 1X8
Canada
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Source of Support: None, Conflict of Interest: None


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