Chronic Hepatitis Virus Infection in Chinese Children
Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, TAIWAN
Hepatitis viruses can cause chronic liver diseases both in adults and children. While most of the complications occur in adulthood, primary infection may begin in infancy or childhood. Among hepatitis A to E viruses, hepatitis B , C, and D viruses may lead to chronicity. Chronic hepatitis D is very rare in children in Chinese children, while chronic infection of hepatitis B viruse (HBV) or hepatitis C virus (HCV) can occur in children of any age, as early as perinatal period. Chronic infection of HBV or HCV in children may lead to chronic hepatitis, liver cirrhosis and/or hepatocellular carcinoma during childhood or later in adulthood . Since carcinogenesis takes years or decades, hepatocellular carcinoma related to hepatitis virus infection in children will occur much earlier than those infected in adulthood.
CHRONIC HEPATITIS B VIRUS INFECTION IN CHILDREN
Chronic hepatitis B virus infection is the main cause of chronic hepatitis in chinese children. The HBsAg carrier rate is approximately 7 to 20% in Chinese children from Singapore, Hong Kong, Taiwan, and China . Before the implementation of universal HBV vaccination program, the HBsAg seropositive rate in Taipei city was 5% in infants, and increased to 10% at 2 years of age and remaining at the same rate thereafter. However, the infection rate reflected by anti-HBc seropositivity, reaches 50% by the age of 15 years. This suggests that most chronic HBsAg carriers are infected before 2 years of age in this population.
Perinatal transmission from HBsAg carrier mothers to their infants is a very important route of transmission leading to chronicity. It accounts for the transmission route of 40-50% of HBsAg carriers in hyperendemic areas. Around 90% of the infants of the HBeAg seropositive carrier mothers became HBsAg carriers, irrespective of a high or low HBsAg carrier rate in the population.
The two most important routes of horizontal transmission are highly infectious family members, such as elder siblings, and improperly sterile syringes. Other sources of infection include institutionized children and multiple or large amount of blood transfusions, etc.
I. Natural Course of Chronic HBV Infection
1. Clinical Manifestations
Children with chronic HBV infection are mostly asymptomatic. They are generally active and growing well with very rare exceptions. Even with acute exacerbation of liver function and active inflammation, jaundice or growth failure is uncommon. General malaise is usually subjective in those whose school load is heavy. Extrahepatic manifestations occurs mainly in those transmitted by horizontal infection from sources other than mothers. They include membranous glomerulonephritis, arthritis, and papular acrodermatitis. The outcome is generally good. On rare occasions, the outcome of membranous glomerulonephritis is grave with renal failure and death.
2. Hepatitis B e Seroconversion and Changes of Liver Enzymes
Children with chronic HBV infection are HBeAg seropositive at the initial stage of infection. During this stage, the child is immune tolerant to HBV, and the virus is highly replicative. Serum HBV DNA levels are usually high. The child is highly infectious , thus is an important source of horizontal infection in the family and community. Aminotransferase levels fluctuate within the high upper normal limit or mildly elevated with mean levels higher than that in non-carrier healthy children . Peak ALT level >100 IU/L in this phase is extremely unusual. The status of hepatitis B e antigenemia can persist for years after primary infection.
Serum HBeAg was gradually cleared and the viral replication is reduced while the child is growing. This process of HBeAg clearance is usually preceded by an elevation of aminotransferases. The peak level of aminotransferase elevation can be very mild and transient. An ALT level >600 IU/ml is uncommon, and > 1000 IU/ml is exceptional. This process of HBe seroconversion takes place insidiously in most individuals for a period of 2 to 7 years. After the detection of an elevation of aminotransferases, around 40% of children will clear HBeAg within one year. Children with high aminotransferase levels of > 100 IU/ml and low HBV DNA levels of <1000 pg/ml often seroconvert during the subsequent 1 to 3 years.
3. Hepatitis B Surface Antigen/Antibody Seroconversion
The annual HBsAg clearance rate was very low(only 0.56%) in long-term follow-up of carrier children , . It occurs only after clearance of HBeAg. After loss of HBsAg, its antibody(anti-HBs) remains low or undetectable in the majority (0 to <100 mIU/mL). Hepatitis B immunization are not beneficial to them. In our long-term follow-up study, one of the 420 HBsAg carrier children cleared HBsAg, but hepatocellular carcinoma developed later at the age of 11 years.
4. Histopathologic Findings
Liver histology in HBeAg positive HBsAg carrier children generally reveals very mild inflammation and fibrosis. During the process of HBV and HBeAg clearance , the abnormal changes include various lobular activities, portal inflammation and fibrosis, with or without piecemeal necrosis. The inflammation is usually milder than that observed in adults. Bridging hepatitis necrosis is very uncommon. Within 6 months of HBe seroconversion, the inflammation is less active and , and beyond 6 months, becomes inactive with mild to minimal inflammation and fibrosis in most children.
Immunoprophylaxis of HBV can be divided into passive and active immunization. With combination of passive and active immunization, i.e. one dose of hepatitis B immunoglobulin within 24 hours after birth and three or four doses of hepatitis B vaccine, the efficacy can be increased to 85-95% in high-risk infants.
The first universal hepatitis B vaccination program in the world was launched in Taiwan since July 1984 . During the first two year of this program, only neonates of the HBsAg positive mothers were included. It extended to all the neonates since the third year of the program. It then further extended to preschool, and then school children, and later all the adults gradually. The coverage rate of hepatitis B vaccine for neonates is around 84-94%. The seroprevalence rates of HBsAg, hepatitis B core antibody( anti-HBc) and anti-HBs in Taiwan children before and 10 years after the installation of the vaccination program were shown in Table 2[1,10]. The HBsAg carrier rate decreased significantly after the vaccination program in children of < 10 years old. The infection rate was decreased in all the children even in those above 10 years of age who were not vaccinated during infancy. The decrease of horizontal infection was contributed by both the decline of the infection source and the vaccination of the older children. This vaccination program has indeed reduced both the perinatal and horizontal transmission of HBV . Integration of the hepatitis B vaccination program into the expanded immunization program (EPI) should be seriously considered in all the children in the world. It is particularly urgent in those areas which are hyperendemic for HBV infection.
Although immunoprophylaxis for HBV infection is very successful, still around 5% or less infants of HBeAg positive mothers had HBsAg in the serum at birth or shortly after birth. They become HBsAg carriers in spite of complete immuno- prophylaxis. Intrauterine HBV infection, though infrequent, is possible . Risk factors of immunoprophylaxis failure includes high level of maternal HBV DNA, low level of maternal anti-HBc, uterine contraction and placental leakage during the process of delivery, etc[11,12].
After the universal vaccination program of hepatitis B virus in Taiwan, we have successfully demonstrated the decline of the incidence of hepatocellular carcinoma in children. The average annual incidence of hepatocellular carcinoma in children of 6 to 14 years declined from 0.70 per 100,000 children between 1981 and 1986, to 0.57 between 1986 and 1990,and to 0.36 between 1990 and 1994. Further studies are needed , and are expected to see the further decline of the incidence of hepatocellular carcinoma in adults.
CHRONIC HEPATITIS C VIRUS INFECTION IN CHILDREN
The seroprevalence of hepatitis C virus infection is around 0.8 to 1.5% in the adult population in most part of the world, except some hyperendemic areas. In children, the seroprevalence rate is much lower ( mostly 0 to 0.2) than that in adults . In Taipei , the seroprevalence rate is 0.14. Ywet there are some endemic areas with higher seroprevalence rate.
HCV infection occurs mainly in high risk children, such as children who have been exposed to blood products ( children with hemophilia, thalassemia, blood transfusion, hemodialysis, malignancy, etc.) or children of HCV infected mothers.
II. Route of Transmission
1. Mother-to-Infant Transmission :
Comparing to HBV infection, the level of virus in circulation is much lower. Infants of HCV infected mothers are at risk of being infected by their mothers during the perinatal period[16-23]. Fortunately , the mother-to-infant transmission rate of HCV is much lower than that in HBV. The level of maternal HCV RNA is the most important determinant of the outcome of the infants. Infants of mothers who are anti-HCV seropositive , but with negative serum HCV RNA , are not at risk for maternal transmission of HCV.
In infants of mothers who are HCV RNA seropositive and HIV seronegative, the rate of maternal transmission were reported to be 0 to 15%, with a mean rate of 5.2%. The transmission rate ranged from 0 to 12 % (mean 3.6%) in infants of mothers in whom anti-HCV was detected by second-generation enzyme-linked immunassay (ELISA).
Breast feeding play little role in mother-to-infant transmission of HCV. HCV RNA can be detected in the breast milk , but the titer (10,000 copies/ml) is much lower than that in maternal serum (105 to 2.5 x 107 copies/ml). Transplacental anti-HCV persisted for 3 to 12 months in the majority of infants who were not infected by their anti-HCV seropositive mothers.
2. Parenteral Exposure to HCV
Transfusion is the most important route of HCV transmission in children. We have studied prospectively the children who received open heart surgery and blood transfusion, and found that the transmission rate of HCV infection was around 5%, which is lower than that in adults (8.8 to 12.5%) . Screening of anti-HCV for the donated blood has prevented most of the post-transfusion HCV infection .
Thalassemic children is another high risk group who received multiple transfusion. The HCV infection rate in thalassemic children ranged from 43% to 60%. Among the HCV infected thalassemic patients, more than 90% of them had elevated alanine aminotransferase (ALT) during follow-up, while only around one third of the HCV-uninfected thalassemic patients had elevated ALT. Quantitation of serum HCV RNA in thalassemic patients showed mild fluctuation between 1x10 6 to 5 x 10 8 copies/ml. Approximately 15 to 20 % of pediatric hemodialysis populations and 3 to 4 % of survivors of childhood malignancy were infected by HCV.
3. Sporadic Cases
The proportion of cases without identifiable risk factor has consistently ranged from 35 to 40 %. Intramuscular injection using unproperly steriled syringes or needles is the most likely route of transmission.
III. Clinical Course of HCV Infection in Children
After primary infection with HCV, 60 to 80 % of children ran a chronic course . HCV RNA is detectable in serum by 2 weeks after exposure, and anti-HCV is dtectable in serum by 4 to 8 weeks. Most of chronically infected children remain asymptomatic. The liver function profiles are usually normal in children after HCV infection. However, transient or persistent elevation of aminotransferase levels is not uncommon. It occurs in most of the reported cases through mother-to-infant transmission, although a number of children were reported to clear serum HCV RNA spontaneously. Histologic studies of the liver in chronically infected children is limited. Chronic persistent hepatitis or minimal histologic changes are the main findings.
IV. Genotypes and Quasispecies of HCV in Infected Children
The genotypes of HCV in children is similar to that in adults. The most common genotype in Taiwan is Ib, the second common types are IIa and IIb.
HCV is a RNA virus with a high rate of nucleotide substitution as other RNA viruses. In the host , HCV exists in a quasispecies state. The quasispecies nature of HCV has been observed in the HCV infected mothers. But the infected neonate tends to select one of the multiple strains from the mother. We have studied the hypervariable region of HCV genome longitudinally in the simultaneous sera of mother-infant pairs. HCV sequences in the infants were found to be more homogeneous than that in their mothers, particularly in the initial stage of infection. The nucleotide substitution rate increased with age. Phylogenetic analysis suggested that the initial quasispecies of the infants were very close to that of the mothers.
V. Prevention and Treatment of HCV Infection in Children
Screening of the blood reduces post-transfusion HCV infection and hepatitis very effectively. In our series, post-transfusion HCV infection occurs in 5% of children who received blood transfusion for open hear surgery. The incidence declined to 0% after screening of blood since 1992.
There have been some studies of interferon therapy and little studies of interferon plus ribavirin therapy in children with chronic hepatitis C. Most of the studies had small case number or were uncontrolled trials. In the majority of the studies in children, the response is similar or better than that in adults.
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