Histologic Activity of Childhood Chronic Hepatitis B Related to Viremia Levels, Genotypes, Mutations, and Epidemiologic Factors

Söderström, Ann*; Norkrans, Gunnar*; Conradi, Nils†; Krantz, Marie‡; Horal, Peter§; Lindh, Magnus*§

Journal of Pediatric Gastroenterology & Nutrition: October 2002 - Volume 35 - Issue 4 - pp 487-494
Original Articles: Hepatology and Nutrition

Background: Despite high viral load, children with chronic hepatitis B virus (HBV) infection may lack significant biochemical signs of liver dysfunction. Failure to develop abnormal liver chemistriesis is probably due to immunologic hyporeactivity. Despite the absence of biochemical abnormalities in these patients, there is still a risk for long-term complications. The pathogenic importance of viral load and genetic variability is less well studied in children than in adults.

Methods: We evaluated viremia levels, genotypes, and mutations related to histologic evidence of liver damage in 71 HBV carriers, aged 2 to 18 years, all of non-Swedish origin.

Results: None of the of 22 children who were hepatitis B e antigen (HBeAg) negative had severe liver disease or had HBV DNA levels greater than 104.6 copies/mL (mean 103.2); 3 (14%) of them had increased alanine aminotransferase (ALT). The 49 HBeAg-positive children had a mean HBV DNA level of 108.0 copies/mL, and increased ALT was seen in 28 (55%). Core promoter mutations (at nt 1764) or precore mutations (at codon 1, 2, or 28) were rare; they were seen in four and one HBeAg-positive children, and in four and nine HBeAg-negative children, respectively, without association to liver damage. C-1858 was associated with more liver inflammation. Genotype did not significantly influence liver damage. Children with horizontal transmission had a faster rate of seroconversion and more inflammation of the liver.

Conclusions: Severe HBeAg-negative hepatitis with high HBV DNA levels and mutations in the core promoter or precore regions seems to be less common in children than in adults. C-1858 strains may be more pathogenic, but this requires further study. Epidemiologic factors influence the course of infection.

Departments of *Infectious Diseases, †Clinical Pathology, ‡Pediatrics, and §Clinical Virology, Göteborg University, Sweden

This study was supported by grants from the Göteborg Medical Society and Stiftelsen Samariten, Stockholm.

Received August 29, 2001; accepted March 12, 2002.

Address correspondence and reprint requests to Ann Söderström, Department of Infectious Diseases, Sahlgrenska University Hospital/Östra, 416 85 Göteborg, Sweden (e-mail: ann.soderstrom@medfak.gu.se).

This article is accompanied by an editorial. Please see The Forecast for Today is Not Only Based on the Weather of Today. Prof. Dr. E. Robberecht. J Pediatr Gastroenterol 2002;35:470–471.

Article Outline

Children with chronic hepatitis B viral (HBV) infection are usually symptom free but nonetheless have a long-term risk for liver cirrhosis and hepatocellular carcinoma. Because the liver damage is immune mediated and HBV infections acquired at birth or during the first year of life frequently induce a state of immunologic hyporeactivity or tolerance to HBV (1–3), children with chronic hepatitis B may lack biochemical signs of liver disease despite a very high viral load. Although this tolerance sometimes lasts more than 30 years, an immune response often develops during childhood, resulting in more or less pronounced inflammation of the liver. In favorable cases, viral clearance and loss of hepatitis B e antigen (HBeAg) seroreactivity occurs (2). The rate of HBeAg seroconversion has been reported to be 2% to 14% annually, with 50% to 80% becoming anti-HBe positive before reaching adulthood. The lower seroconversion rates have been observed in Chinese children (4) and the higher in Spanish (5) and Italian children (6).

Adult HBV carriers may have a highly active infection despite the lack of HBeAg in serum (7). Such infection is in general accompanied by severe liver damage, and the absence of HBeAg is most often due to a stop codon mutation in the precore region of the virus (8,9) or in some cases possibly to mutations in the core promoter region (10). Precore mutations also have been observed in children with chronic HBV infection (11–17), but the impact of these mutations in children has not been well studied.

The aim of this study was to investigate whether epidemiologic factors, viremia levels, genotypes, or mutations in the core promoter and precore regions of HBV are predictors of histologic liver damage in children with chronic hepatitis B.

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Patients and Samples

All children (≤18 years) in Göteborg who had confirmed chronic HBV infection (defined as HBsAg positivity for at least 6 months) and who were HBV DNA positive by in-house nested polymerase chain reaction (PCR) during the two-year period 1994 to 1995 (18) were eligible for the study. Of the 74 children who met these criteria, 71 were included (1 moved abroad, 1 child had a progressive CNS disease, and in one case the parents refused liver biopsy). The patients included 43 boys and 28 girls, with a median age of 11.7 years (range, 2–18 years). The children were attending the Department of Pediatrics or the Department of Infectious Diseases, Sahlgrenska University Hospital, Göteborg, or outpatient pediatric clinics. They originated from 17 countries, and none of them had a biological mother who was of Swedish origin. Most of the children were diagnosed with hepatitis B on arrival in Sweden. The mean time that the patients had lived in Sweden at inclusion in this study was 5 years (range, 1–16 years). The mothers of 27 of the children tested HBsAg positive (16 were also HBeAg positive), whereas 9 of the mothers had anti-HBs. For 18 children, the HBV status of their mothers was unknown: 10 children were adopted, in 5 other cases the mothers were not living in Sweden, and for 3 mothers living in Sweden the HBV-status was unknown. Seventeen mothers had no markers of present or past HBV infection. Serologic markers for past or present HBV infection were observed in the mothers or siblings of 54 of the 59 (92%) children who had mothers or siblings living in Sweden.

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HBsAg, HBeAg, anti-Hbe, and hepatitis C antibodies were analyzed using AxSYM (Abbott, Abbott Park, IL, U.S.A.), and delta-antibodies were analyzed using radioimmunoassay (Abbott). Core IgM antibodies were analyzed with IMx (Abbott); index values below the stated cutoff were registered and used in the analyses as suggested previously (19).

None of the children had delta antibodies. One child was anti-HCV positive but HCV-RNA negative.

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Assessment of Probable Transmission Route

Transmission was considered vertical if the mother was HBeAg positive (n = 16). Transmission was considered horizontal if the mother had no markers of current or past HBV infection (n = 17). If the mother, at the time of this study, was HBsAg and anti-HBe positive (n = 11), had markers of past HBV infection (n = 9), or the HBV status was unknown (n = 18), transmission was considered uncertain. In the adopted children (10 of the 18 with unknown transmission route), HBV infection was discovered on arrival in Sweden at a mean age of 17 months (range, 3–56 months).

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Quantitative PCR

Serum samples from the time of liver biopsy, which had been stored at −20°C, were analyzed using a Amplicor HBV Monitor (Roche Diagnostic Systems, Branchburg, NJ, U.S.A.) (20) according to the manufacturer's instructions. The detection range for the test spans from 103.0 to 107.0 copies/mL. To extend this range, HBeAg-positive samples were analyzed after predilution at 1:100 in negative serum.

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Genotyping and Mutation Analyses

Genotyping was performed using PCR and restriction fragment length polymorphism (RFLP) of S region or pre-S region amplicons (18,21). Mutations at codons 1, 2, or 28 in the precore region or at nt 1764 in the core promoter region were analyzed using RFLP methods as described previously (22,23). Mutations at codons 1 and 2 were analyzed only in HBeAg-negative children without mutation at codon 28. The nucleotide at position 1858 (C or T) was determined using PCR and RFLP, as reported previously (22).

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Histopathology and Alanine Aminotransferase

Histology activity index (HAI) was scored as described by Knodell (24). The biopsy tissue had to have at least three evaluable portal tracts. In the analyses, HAIinfl (the sum of the component scores for piecemeal necrosis, lobular inflammation, and portal inflammation) and HAIfibr (the fibrosis score) were used separately. Alanine aminotransferase levels at the time of liver biopsy were recorded. Indexed alanine aminotransferase (ALTi), that is, ALT divided by the upper reference value (URV; 0.8 μkat/L for boys and 0.6 μkat/L for girls), was used in the analyses.

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HBV DNA values, HAI scores, and ALTi were compared using the Mann-Whitney rank sum test and the Fisher exact test, as appropriate. Logistic regression and Spearman rank correlation were used for univariate analysis of HAIinfl in relation to age, HBV DNA, and core IgM. Multiple logistic regression was used for analyzing HAIinfl as a dependent variable in relation to the different parameters investigated.

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Ethical Considerations

The local ethics committee approved the study, and the parents of all patients gave their informed consent to participation.

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The 49 HBeAg-positive children had a mean age of 10.5 years, and the 22 HBeAg-negative children had a mean age of 14.3 years (Table 1, P < 0.001). In HBeAg-positive carriers, the mean HBV DNA level was 108.0 copies/mL, and only four had levels less than 106 copies/mL. In comparison, the mean HBV DNA level was 103.2 copies/mL in HBeAg-negative children, all of whom had viremia levels less than 104.6 copies/mL. Thus, HBV DNA levels and the proportion of HBeAg-positive carriers decreased with age: 95% (20/21) of children younger than 10 years were HBeAg positive and 58% (29/50) older than 10 years were HBeAg positive. Two children were HBV DNA negative at the time of biopsy; both had been HBV DNA positive by in-house PCR method 14 and 19 months earlier.

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Impact of Route of Infection

The HBeAg status was influenced by the route by which the infection probably had been acquired: 94% of 16 children with presumed vertical transmission as compared with 65% of 17 with presumed horizontal transmission were HBeAg positive (P = 0.085, Table 2). Of the 10 adopted children, who had arrived in Sweden at the median age of 17 months, 9 were HBeAg positive. Many or most of these children probably had been infected vertically. If the adopted children also were assumed to be vertically infected, the difference in HBeAg positivity between vertically (24/26) and horizontally infected (11/17) children was significant (P = 0.042). This could not be explained by a younger mean age because the HBeAg-positivity rate also tended to be higher in children older than 10 years old: 92% (11/12) versus 57% (8/14, P = 0.08).

Probable vertical transmission was seen in 50% (7/14) of the East Asian children compared with none of the 21 African children (P = 0.0005, adopted children not included).

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Viremia and Liver Damage

As described in Tables 1 and 3 and in Figure 1, the liver damage (measured by ALT or HAI score) was associated with the HBV DNA level and the HBeAg status. The HBeAg-positive children had higher HAIinfl (median, 7; range, 1–12) than the HBeAg-negative children (median, 3; range, 1–7;P < 0.001). By contrast, fibrosis did not differ between HBeAg-positive and HBeAg-negative subjects; the median fibrosis score was 1.6 in both groups and in neither group was there a child with cirrhosis.

An increased ALT, (ALTi > 1) was seen in 57% (28/49) of the HBeAg-positive carriers compared with 14% (3/22) of the HBeAg-negative carriers (P < 0.001). All HBeAg-negative children had relatively low HAIinfl and low HBV DNA levels, without differences between those with or without precore stop codon mutation. In the HBeAg-positive children, very high viremia levels were seen in patients with or without signs of inflammation, as measured by HAIinfl or ALT (Fig. 1), whereas lower levels were seen in those with moderate inflammation (HAIinfl, 4–8) or normal ALT.

There was a significant correlation between ALT levels and inflammation score (P < 0.001). A HAIinfl at 9 or greater was seen in 15 of the 31 (48%) children with elevated ALT, in 2 of 40 (5%) with normal ALT, and in none of 8 children with ALTi less than 0.5. (Table 4). The association between ALTi and fibrosis was weaker and not statistically significant (P = 0.35). Liver inflammation decreased with increasing age, reflecting the decreased HBeAg frequency and decreasing viremia levels (Fig. 2).

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Core IgM

As shown in Table 5, there was a significant association between liver inflammation and core IgM, in particular in HBeAg-positive patients. In children with increased ALT (ALTi > 1), severe liver inflammation (HAIinfl ≥9) was more frequent in patients with core IgM greater than 0.2 (P = 0.034), with an odds ratio of 5.0.

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Ten HBeAg-negative children had precore mutation, one of them at the start codon and nine at nt 1896 (creating a TAG stop codon). In two children, codon 1 and 2 could not be analyzed. One HBeAg-positive child had a mixture of wild-type and precore mutant (G/A-1896). In the HBeAg-negative children, there was no difference in liver damage between carriers with precore mutants and precore wild-type strains. However, considering all children, those with precore mutations had milder liver inflammation than those with wild-type (P = 0.01), probably reflecting covariation with HBeAg status. Children with C-1858 strains (n = 17), who more rarely had precore mutations, had or tended to have more severe liver damage than those with T-1858 as measured by ALTi (P = 0.019) or HAIinfl (P = 0.13), despite similar HBV DNA levels (gm 106.7 vs. 106.6 copies/mL). Interestingly, in HBeAg-positive children (12 C-1858 and 37 T-1858), these differences were more pronounced and also were significant for HAIinfl (P = 0.03) Eight children, four of whom were HBeAg positive, had A-1764 mutation in the core promoter. The HBV DNA level tended to be lower in these 8 children with A-1764 compared with the 61 with wild-type G-1764 (gm 105.5 vs. 106.8 copies/mL;P = 0.11).

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Genotypes and Origin

As expected, the observed genotypes reflected the geographic origin of the children, as shown in Table 3. The variation at nt 1858 was linked to genotypes, as reported previously (22,25), with C-1858 strains found in 79%, 0, 40%, and 0 of genotypes A, B, C and D, respectively (Table 3). The HBeAg-positive rate was higher in genotypes B and C than in genotypes A and D, probably due to an increased frequency of children with vertical transmission in the former genotypes. There was no significant difference in liver damage between genotypes.

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Factors Associated With Liver Damage

Table 6 summarizes univariate analysis of parameters possibly associated with inflammation. Most associations were confined to HBeAg-positive patients. Alanine aminotransferase levels, core IgM, HBV DNA levels, and HBeAg status were highly associated with inflammation. Children with vertical transmission and adopted children (the latter group considered mostly vertically transmitted) had less liver inflammation compared with those with horizontal transmission, but this was true only in the HBeAg-positive group. Likewise, children from East Asia had less liver inflammation than those from Africa, but only in the HBeAg-positive subgroup. Accordingly, C-1858, which was found mainly in East African children infected with genotype A, was associated with more liver inflammation in the HBeAg-positive children. Mutations in the precore (1896) or in the core promoter were not associated with liver damage.

In a multiple regression analysis of the variables possibly associated with HAIinfl, only HBeAg status, ALT, and nucleotide at position 1858 in HBeAg-positive children showed statistically significant associations.

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Children with chronic hepatitis B generally have no symptoms, but show a wide range of histologic changes and viremia levels. Many of the children have highly active HBeAg-positive infection, but most spontaneously seroconvert to anti-HBe before reaching adulthood, however with some geographical variation (2,4–6). Currently, there is no known parameter that can predict a severe course of infection. Moreover, our knowledge of how well noninvasive tests such as ALT and HBV DNA levels reflect histologic activity in children is insufficient.

In the current study, we found a nearly 5-log difference in HBV DNA between HBeAg-positive (median, 108.3 copies/mL) and HBeAg-negative (median, 103.4 copies/mL) patients, and no overlap between the groups. Thus, none of the HBeAg-negative children, 10 of whom were infected with precore mutant strains, had a high viremia level (all levels were less than 104.6 copies/mL). This supports previous studies, in which high viremia levels in HBeAg-negative children (detectable by hybridization assays) are rarely observed (4,26–28). This could reflect a difference from the situation in adults in which a significant proportion of HBeAg-negative carriers showed very high HBV DNA levels (and severe liver damage); such carriers almost always carry precore mutant strains (7–9,18). Seroconversion to HBe during childhood may represent a more efficient immune response, explaining the absence in this study of HBeAg-negative carriers with highly active infection. Longitudinal follow-up studies of children are required to see whether, after HBe seroconversion at a young age, low viremia levels are maintained throughout life.

None of the HBeAg-negative children showed an inflammation score greater than 7. Because all HBeAg-negative children had relatively mild inflammation and low viremia levels, no association could be detected between HBV DNA level and liver damage, as has been observed in adults (29,30). There was no association between HBV DNA level and liver damage within the HBeAg-positive children. In this group, similarly high HBV DNA levels were seen in patients with mild (i.e., with putative immune tolerance) and severe inflammation. Previous studies have shown that HBe seroconversion often is preceded by a flare of hepatitis, suggesting that viral clearance is a result of mechanisms that also may induce hepatocellular damage (27). In the current study, HBeAg-positive children with relatively low HBV DNA, who probably were likely to seroconvert, had lower ALTi and intermediate inflammation scores. Although, this study is cross-sectional, this finding suggests that an efficient immune response may parallel relatively mild inflammation of the liver, which supports the recent finding that noncytolytic mechanisms are important for controlling HBV infection (30). Previous longitudinal studies have shown that approximately 30% of children undergo HBe seroconversion in this more silent manner (31).

Core IgM, analyzed by IMx, was associated significantly with liver inflammation, as previously reported for adults (19,32). In children with elevated ALT, the proportion with severe inflammation was higher in those with core IgM index greater than 0.2 (with an odds ratio of 5).

Only 2 of 40 children with normal ALT had more pronounced inflammation (HAIinfl ≥9). Thus, the risk of missing severe inflammation if refraining from liver biopsy in this group seems to be low. In comparison, about half of the patients with increased ALT showed HAIinfl of 9 or greater. Applying a threshold of ALTi greater than 2 did not significantly increase the proportion with HAIinfl of 9 or greater, and two patients with ALT greater than this level had mild histologic changes (HAIinfl ≤3). However, combining core IgM greater than 0.2 and ALTi greater than 1 may be useful for identifying patients for liver biopsy or therapy; a HAIinfl score of 9 or greater was seen in 10 of 14 patients who met these criteria (70%).

Precore mutations have been investigated in several studies, with observed frequencies ranging from a few to 93% (11–17). Precore mutations were seen in only 1 HBeAg-positive and in 10 of the 21 HBeAg-negative children in our study, and showed no association with the degree of liver damage. The relatively low frequency probably was due partly to a large proportion of carriers infected with genotype A, which carries cytosine at nt 1858, and therefore rarely has precore mutations. Children with C-1858 strains showed more severe liver damage than those with T-1858 strains, despite equal viremia levels. The potential pathogenic importance of nt 1858 variability should be examined further because C-1858 previously has been associated with more severe liver damage in adults (18) and was shown recently to influence core promoter mutations that are linked to liver damage (33). However, the difference may reflect the impact of epidemiologic factors, as most C-1858 carriers were from Africa where perinatal infection has been reported to be rarer. An influence of epidemiologic factors on the course of infection was observed in the current study. Probable vertical transmission, which was seen in 50% of East Asian but in none of the African children, was associated with an increased rate of HBeAg positivity late in childhood, supporting the conclusion that the rate of HBe seroconversion depends on age or mode of acquisition.

The HBeAg seroconversion rates could be estimated to 0.6% per year in vertically infected/adopted children, and 4.6% in horizontally infected children, if assuming a mean duration of infection of 14 and 9 years in the respective groups (from 100% to 92% between 0 and 14 years, and from 100% to 52% between 5 and 14 years of age).

In univariate analyses ALT, core IgM, HBV DNA levels, and HBeAg were associated strongly with HAIinfl. Age, geographic origin (Africa vs. East Asia), transmission route (horizontal vs. presumed vertical), and nt 1858 (C vs. T) also showed significant associations with inflammation score, but only for the HBeAg-positive patients. In multiple regression analysis, only ALT, HBeAg status (or HBV DNA when HBeAg was not included in the analysis), and nt 1858 (C vs. T) were independently associated with HAIinfl. The reason for this could be the complex causal relationship for development of liver damage, illustrated in Figure 3, with several factors being dependent on one another. Although many of these factors were analyzed in this study, data on transmission route and age at infection were incomplete. Moreover, we do not have knowledge about HLA group and other genetic differences in the immune response, which most likely are important for the development of liver damage. The finding of more inflammation in patients with C-1858 suggests pathogenic differences between HBV variants. However, this requires confirmation because the association was seen only in the HBeAg-positive subgroup and the statistical model in this analysis was not fully satisfactory.

The AGG → TGA double mutation at nt 1762 and 1764 in the core promoter has been associated recently with more severe liver damage in adults (21,34) and with interferon response rates (35,36), but studies in children are lacking. The low frequency of the A-1764 mutation (which in general is combined with the T-1762 mutation) observed in our study indicates that analysis of the nt 1762/1764 mutation is of little use in the clinical assessment of children.

None of the 71 children in our study had cirrhosis. Other studies have shown cirrhosis in about 3% to 4% (5,37). This difference could have occurred because some of the children in these previous studies were anti-HDV positive or coinfected with hepatitis C since these studies were performed before the use of anti-HCV assays.

In summary, we found in this series of children with chronic HBV infection a nearly 5-log difference in viremia levels between HBeAg-positive and HBeAg-negative subjects, a relatively low frequency of core promoter and precore mutations, and no association of these mutations to the degree of liver damage. We also found more severe liver inflammation in children with C-1858 strains, and a significant association between geographic origin and mode of acquisition of HBV infection and HBeAg status.

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The authors thank Annkatrin Gusdal for expert technical assistance.

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Hepatitis B; Children; Histology; Viremia; Mutations

© 2002 Lippincott Williams & Wilkins, Inc.