Abstract
Hepatitis B virus (HBV) infection continues to be a major global health problem [1]. HBV infection may cause acute, fulminant, or chronic hepatitis, cirrhosis and liver cancer. Although complications occur mainly during adult life, most primary HBV infection occurs during early childhood [1]. To control HBV infection and its complications, it is mandatory to understand the transmission mode and natural history starting from childhood. The age of primary infection is an important factor affecting the outcome. HBV infection during infancy and early childhood leads to high rates of persistent infection. Perinatal transmission from hepatitis B surface antigen (HBsAg) carrier mothers to their infants is an important route of transmission leading to chronicity in endemic areas. Before the era of universal HBV vaccination, perinatal transmission accounted for 40–50% of HBsAg carriers in Asia. Maternal HBsAg and hepatitis B e antigen (HBeAg) status affect the outcome of HBV infection in their infants. Around 90% of infants of HBeAg seropositive carrier mothers become HBsAg carriers. Horizontal transmission from highly infectious family members, improperly sterilized syringes or other contaminated instruments may also occur. HBV vaccination is the most effective way to prevent HBV infection and its complications. Despite the availability of HBV vaccine leading to decreasing incidence of HBV infections, WHO estimates that in 2015, 257 million people were living with chronic HBV infection [2].
Introduction
Hepatitis B virus (HBV) infection continues to be a global health problem [1]. HBV infection may cause acute, fulminant, or chronic hepatitis, cirrhosis and liver cancer. Although complications occur mainly during adult life, most primary HBV infection occurs during early childhood [1]. To control HBV infection and its complications, it is mandatory to understand the transmission mode and natural history starting from childhood. The age of primary infection is an important factor affecting the outcome. HBV infection during infancy and early childhood leads to high rates of persistent infection. Perinatal transmission from hepatitis B surface antigen (HBsAg) carrier mothers to their infants is an important route of transmission leading to chronicity in endemic areas. Before the era of universal HBV vaccination, perinatal transmission accounted for 40–50% of HBsAg carriers in Asia. Maternal HBsAg and hepatitis B e antigen (HBeAg) status affect the outcome of HBV infection in their infants. Around 90% of infants of HBeAg seropositive carrier mothers become HBsAg carriers. Horizontal transmission from highly infectious family members, improperly sterilized syringes or other contaminated instruments may also occur. HBV vaccination is the most effective way to prevent HBV infection and its complications. Despite the availability of HBV vaccine leading to decreasing incidence of HBV infections, WHO estimates that in 2015, 257 million people were living with chronic HBV infection [2].
This chapter details the epidemiology, transmission routes, clinical features, preventative, and therapeutic strategies for HBV infection. To facilitate the discussion of hepatitis B, a glossary of the terminology used throughout this chapter is presented in Table 18.1.
| Terminology | Definition | Significance |
|---|---|---|
| Hepatitis B virus (HBV) | ||
| HBsAg | Hepatitis B surface antigen; found on the surface of the intact virus and as free particles in the serum | Presence in serum indicates acute or chronic HBV infection |
| HBcAg | Hepatitis B core antigen; found in the intact virion but no free particle. | Detectable in liver tissue but not detectable in serum |
| HBeAg | Hepatitis B e antigen; a soluble antigen, translational product of precore and core gene | Presence in serum indicates active HBV infection and correlates with high viral titer in serum; signifies high infectivity |
| Anti-HBs | Antibody to HBsAg | A neutralizing antibody indicates immunity to HBV after infection or vaccination, or passive antibody from HBIG administration |
| Anti-HBc | Antibody to HBcAg | It is not a protective antibody; subclass IgM indicates early infection; subclass IgG indicates active acute or chronic infection, or past infection |
| Anti-HBe | Antibody to HBeAg | Seroconversion of HBeAg to anti-HBe indicates resolution of active HBV replication phase in most cases |
| HBV DNA | DNA of HBV | Indicates HBV replication; a useful marker for infectivity and for monitoring treatment |
The Hepatitis B Virus
The hepatitis B virus is a partially double (long and short) stranded, circular DNA virus with a genome size of 3,200 nucleotides (Figure 18.1). It is a hepatotropic DNA virus that is classified as a member of the Hepadnaviridae family. Its host range is restricted to humans and chimpanzees. The transcript of HBV contains four open reading frames (ORF) S, C, P and X regions, encoding surface protein, core protein, polymerase, and X protein, respectively [3]. The S ORF encodes the HBsAg proteins, and can be structurally and functionally divided into the pre-S1, pre-S2, and S regions, which encode three envelope proteins, i.e., the major, the middle, and the large proteins. The C ORF encodes either the viral nucleocapsid HBcAg or HBeAg depending on whether translation is initiated from the core or pre-core regions, respectively. The nucleocapsid of HBV contains a major protein, the core protein (HBcAg) that encapsidates the viral DNA. The pre-core ORF codes for a signal peptide that directs the translation product to the endoplasmic reticulum, where the protein is further processed to form the secreted HBeAg. HBeAg is a small secretory viral protein present in the serum, which results from proteolytic cleavage of P22C. The presence of HBeAg in serum implicates high viral replication, high viral infectivity, and possible current or later active liver disease. The P ORF encodes a large protein that has DNA polymerase, reverse transcriptase and RNase H activities; it also acts as the terminal protein. The HBV X ORF encodes a 16.5-kd protein (HBxAg), which may be related to productive HBV infection and the oncogenic potential of HBV.
Figure 18.1 Genomic structure and open reading frames of HBV. HBV is a partially double (long and short) stranded DNA virus with a genome size of 3,200 nucleotides. The inner circles illustrate the long (×) strand and short (＋) DNA strands. The terminal protein linked to the 5′end of the (×) strand is marked as a small oval ball. The transcripts of HBV contain four open reading frames (ORS) S, C, P, and X regions, encoding surface protein, core protein, polymerase, and X protein, respectively.
Hepatitis B virus replication is via reverse transcription, including protein priming by the unique extra terminal protein domain of the reverse transcriptase (the polymerase) [4]. The HBV replication cycle is summarized in Figure 18.2. The initial phase of HBV infection involves the attachment of mature virions to host cell membranes, likely involving the binding of the pre-S1 region on the virion envelope to the sodium taurocholate co-transporting polypeptide (NTCP) on the hepatocyte surface, which is a receptor for HBV entry [5]. After entry into the hepatocyte, the virion loses its envelope in a process called uncoating, allowing transport of the viral genomic DNA into the nucleus. The single-stranded gap region in the viral genome is repaired by the viral polymerase protein, and the viral DNA is converted to the covalently closed circular DNA (cccDNA) form. This form of HBV DNA serves as the template for transcription of several species of genomic and subgenomic RNAs.
Figure 18.2 Replication cycle of HBV. The initial phase of HBV infection involves the binding of mature virions to the receptor NTCP on host cell membrane. After entry of the HBV genome into the nucleus, the single-stranded gap region in the HBV genome is repaired by the viral polymerase protein, and the viral DNA is circularized to the covalently closed circular DNA (cccDNA) form. HBV replicates via reverse transcription, including protein priming by the unique extra terminal protein domain of the reverse transcriptase (the polymerase).
Hepatocytes infected by HBV usually secrete 100 to 1,000 times as many empty polymers of HBV envelope proteins with spherical or filamentous shapes made mostly of small HBsAg as infectious virions [6]. HBsAg carries an “a” antigenic determinant, created by two “loops” of amino acids 120–160, that is recognized by most commercial assays and the epitope to which neutralizing antibody is raised.
In primary (new) HBV infection, HBsAg is the first marker detectable in the blood after an incubation period of 4 to 10 weeks, followed shortly by anti-HBc, which are predominantly of the IgM type in the early phase of self-limited infection. The typical serologic pattern of acute HBV infection is illustrated in Figure 18.3 [7]. During acute HBV infection, anti-HBc IgM appears shortly after onset of jaundice, reaches peak titers by five months, then subsequently declines and is replaced by anti-HBc IgG, which persists for years. Serum antibody to hepatitis B surface antigen (anti-HBs), a protective antibody against subsequent HBV infection, may be detectable weeks to months after the elevation of aminotransferase levels and lasts for many years after infection. Anti-HBs appear within six months of disease onset in most patients with acute HBV infection (Table 18.2). Active hepatic inflammation, as indicated by elevated serum aminotransferase values, may occur 14–60 days after HBsAg is detected in serum [8].
Figure 18.3 Typical course of acute HBV infection. Primary HBV infection has an incubation period of 4 to 10 weeks. The earliest detectable serum marker of HBV infection is HBsAg, which may appear between one and 10 weeks following exposure. Subsequently, HBeAg and HBV DNA may be identified. HBsAg is present two to 8 weeks before the onset of symptoms, which coincides with a spike in ALT levels, serum bilirubin, and constitutional signs. Clearance of HBsAg with the appearance of anti-HBs typically occurs within six to eight months following infection. Anti-HBc IgM is present before symptomatic infection and is a marker for acute infection.
Table 18.2 Serologic Markers and HBV DNA Levels in Different Phases of Acute or Chronic HBV Infection
| Phase of Infection | HBsAg | Anti-HBs | HBeAg | Anti-HBe | Anti-HBc | HBV DNA (IU/mL) | ALT | Liver Histology |
|---|---|---|---|---|---|---|---|---|
| Acute HBV Infection | ||||||||
| Early | + | – | + | – | IgM | + | ↑ | Acute inflammation |
| Recovery | – | + | – | + | IgG | – | Normal | Normal |
| Chronic HBV Infection | ||||||||
| Tolerance phase | + | – | + | – | IgG | >2×104 | Normal | Mild/minimal inflammation |
| Inflammatory phase | + | – | + | – | IgG, IgM | >2×104 | ↑ | Active inflammation |
| Inactive phase | + | – | – | + | IgG | <2×104 | Normal | Mild/minimal inflammation |
| HBeAg(-) hepatitis | + | – | – | + | >2×103 | ↑ | Active inflammation | |
ALT: serum alanine aminotransferase.
Viremia is established by the time HBsAg is detected in serum. The presence of HBV DNA in serum is a useful marker of viral replication and is usually associated with active liver disease and infectivity. Comparison of the ranges of quantitation for some commercially available HBV DNA quantitative assays is listed in Table 18.3 [9]. The serum levels of HBV DNA in primary infection are usually high, frequently in the range of 109–1012 copies/mL (108 to 1011 IU/mL). Circulating HBeAg can be detected in early phase, but is cleared rapidly in patients with acute hepatitis B. Persistence of HBsAg in the circulation over six months is considered as chronic HBV infection, while loss of serum HBsAg and appearance of its antibody is considered to indicate the possibility of HBV eradication. In most cases of chronic hepatitis B, viral replication continues, HBsAg remains detectable in blood, while titers of HBV DNA tend to decline gradually over time; HBeAg disappears from the blood along with seroconversion to positivity for anti-HBe. Given the short half-life of HBV virions (approximately one day), detectable HBV DNA levels can be sustained only by ongoing viral replication [1, 8]. Anti-HBc IgG rises later and persists during chronic HBV infection as long as viral replication within the liver cell continues, or even after disappearance of liver HBV replication.
Table 18.3 Comparison of the Ranges of Quantitation for Some Commercially Available Hepatitis B Virus DNA Quantitative Assays
| Detection Method | Approximate Range of Quantification | Commercially Available Assays |
|---|---|---|
| Signal Amplification | 1.4 X 105 to 1.7 X 109 copies/mL | Digene Hybrid Capture II |
| 2.0 X 103 to 1.0 X 108 copies/mL | Bayer Versant HBV 3.0 | |
| Target Amplification | 2.0 X 102 to 2.0 X 105 copies/mL | Roche Cobas Amplicor HBV |
| 2.0 X 102 to 1.0 X109 IU/mL | Artus-Biotech Real Art HBV PCR | |
| 3.0 X 10 to 1.1 X 108 IU/mL | Roche Cobas TaqMan | |
| 1.0 X 10 to 1.0 X 109 IU/mL | Abbott Real-time PCR |
Global Epidemiology
The prevalence of HBV infection varies in different countries and regions in the world as well as among different ethnic groups. HBV endemicity has been classified into three categories, high (>8%), intermediate (2–8%), and low (<2%), depending on the prevalence of (HBsAg) seropositivity. HBV is prevalent in Asia, Africa, southern Europe, and Latin America, where the HBsAg seropositive rate ranges from 2% to 20%. Regions with a high prevalence of HBV infection also have high rates of hepatocellular carcinoma (HCC). HBV causes 60–80% of the primary liver cancer in the world, which accounts for one of the three major causes of cancer deaths in Asia, the Pacific Rim, and Africa. Countries in the Asia-Pacific region have the highest prevalence of endemic HBV infection. In most parts of Asia, the HBsAg carrier rate in the general population is approximately 5–20%. Some countries in this region, such as Japan, Australia, and New Zealand, have low HBsAg prevalence rates.
In contrast, in North America, western and northern Europe, and Oceanic areas where prevalence of HBV infection is relatively low (around 0.1%), primary HBV infection occurs mainly in adolescents and adults. Childhood HBV infection in this population is concentrated in immigrants from endemic areas and in children of high-risk groups, such as intravenous drug users. In the USA, National Health and Nutrition Examination Survey (NHANES) conducted between 1988 through 1994 revealed that the HBsAg seropositive rate was 0.41%, and the prevalence of anti-HBc was 4.9% [10]. The prevalence of HBV infection was low in children until age 12 and increased thereafter in all ethnic groups. Despite successful vaccination in infants and children, recent NHANES found a stable HBsAg prevalence since 1988 (0.3% between 1999–2006 and 0.3% between 2011–2012). This prevalence rate has even been underestimated owing to many HBV carriers immigrated from endemic areas and without inclusion of appropriate samples of population groups with the highest prevalence of HBV [11, 12]. However, NHANES showed the HBsAg prevalence in those aged 6 to 19 years declined from 0.2% in 1988–1994 to 0.03% in 2007–2012.
Hepatitis B surface antigen sero-prevalence rates in Europe vary widely, ranging from a low of 0.1% in some countries in western, northern and central Europe to as high as 6–8% in some countries of eastern Europe [13]. The most frequently reported risk factors for hepatitis B in Europe include heterosexual activity, injection drug use, male homosexual activity, perinatal exposure, and household contact with infected individuals.
In endemic areas, such as Asia and Africa, most people with chronic HBV infection were infected during early childhood. Perinatal infection and household contacts with chronically infected patients during early childhood are the predominant modes of transmission. In highly prevalent areas such as Taiwan, primary HBV infection occurs predominantly during infancy and early childhood [14]. Before the implementation of the universal HBV vaccination program in Taiwan, HBsAg seropositive rate in Taipei city increased with age, ranging from 5% in infants, to 10% in children at two years of age and remained stationary afterward. This suggested that most chronic HBsAg carriers were infected before two years of age in Taiwan and other endemic areas.
In Africa, HBV transmission was considered to occur mainly horizontally during early childhood. Horizontal transmission occurs between two to ten years of age, owing to children with high levels of viremia passing on the virus through cuts and grazes to susceptible siblings [15]. In some countries in western Africa (e.g., Senegal and Gambia), over 90% of the population is exposed to and becomes infected with HBV during their lifetime. In rural areas of western Africa, HBV infection rates increase rapidly from the age of six months; by the age of two years, 25–40% of children have been infected and 15% have developed chronic infection. By the age of 10 to 15 years, 80–90% of children have become infected and 20% are chronic carriers [101]. Despite the introduction of universal hepatitis B vaccination, the estimated overall seroprevalence of HBsAg in Africa remains high at 6.1%, with a high prevalence of HBsAg (>8%) [102] in The Gambia and Senegal and a lower prevalence of HBsAg (6~8%) in East Africa and in South Africa [15, 102].
Routes of Transmission
Hepatitis B virus can be transmitted by body fluid, either through mother-to-infant transmission or horizontally through blood transfusion, injection, sexual exposure, or close contact in the family or with caretakers. Perinatal transmission from highly infectious mothers to their neonates is an important route for HBV infection in Asian countries and many other endemic areas. Before the HBV vaccination era, perinatal transmission accounted for 40–50% of HBsAg carriers in endemic areas. The age of HBV infection is an important factor affecting the outcome of HBV infection. The younger the infection occurs, the higher the rate of chronic infection. Without immunoprophylaxis, more than 90% of infants who were infected by their HBeAg-positive, HBsAg-positive mothers, will develop chronic HBV infection [16] (Table 18.4). For those who are infected at preschool age, the chronicity rate after HBV infection decreases to approximately 25% [16]. Infection occurring in young adults results in a lower chronicity rate of <3%. In most of sub-Sahara Africa, horizontal transmission in early life is the predominant mode of transmission.
Table 18.4 Age of Infection and Maternal HBV Status Influence the Outcome of HBV Infection in Children
| Age of Infection | Rate of Persistent Infection |
|---|---|
| Perinatal Period | |
| Mother HBeAg(+), HBsAg(+) | >90% |
| Mother HBeAg(-), HBsAg(+) | <5%, but with risk of acute or fulminant hepatitis |
| Preschool Age | 23% |
| Young Adults | 2.7~10% |
Mother-to-Infant Transmission of Hepatitis B Virus
Perinatal HBV transmission from a highly infectious mother to her infant is an important route for HBV infection, accounting for 35–50% of carriers in Asian countries and other endemic areas. Transmission can occur in utero, at the time of delivery, or after birth. Children of HBsAg-positive mothers, who escaped HBV infection at the neonatal period, remain at high risk of infection during early childhood. Less than 5% of neonates born to HBsAg-positive, HBeAg-negative mothers will become infected with HBV, compared to more than 90% of those born to both HBsAg- and HBeAg-positive mothers (Table 18.4).
The e antigen is a small viral secretory protein which can cross the placenta barrier from the mother to the infant. HBeAg and HBcAg are highly cross-reactive in terms of helper T-cell recognition. Thus transplacental HBeAg may induce a specific unresponsiveness of helper T-cells to HBeAg and HBcAg in the neonates born to HBeAg-positive, HBsAg-positive mothers [17]. This may explain the high rate of chronic infection and the long-term immune tolerance status to HBV.
It is widely accepted that most perinatal HBV transmission occurs at or near the time of birth, since neonatal vaccination prevents newborn infection in 80–95% of cases. Theoretical risks for HBV transmission at delivery include exposure to cervical secretions and maternal blood. One study described a lower (9.7%) transmission rate to infants from highly infectious mothers when the infants were delivered by cesarean section than when the delivery was vaginal (24.9%) [18]. Other studies have not shown an effect of mode of delivery on the likelihood of HBV transmission and so routine cesarean section is not recommended.
Intrauterine Transmission
Intrauterine HBV infection occurs rarely, in <5% of the infants of HBeAg and HBsAg positive mothers. In a study in Taiwan, 2.4% of the 665 infants born to HBeAg and HBsAg positive mothers were seropositive for HBsAg at birth and remained HBsAg-positive at beyond 12 months of age, suggesting intrauterine infection [19].
Maternal HBV DNA load is strongly associated with HBV intrauterine transmission. The possibility of HBV intrauterine HBV infection increases if maternal blood contains HBV DNA >108 copies/mL. Possible mechanisms of intrauterine infection include transplacental leakage (which can occur at any gestational age), placental infection, transmission through peripheral blood mononuclear cells (PBMCs) and amniocentesis [20]. Although threatened abortion and/or threatened pre-term labor appeared to increase the risk of HBV transmission in several reports, others failed to confirm this association.
Both HBV DNA and HBeAg are detectable in breast milk from HBeAg-positive, HBsAg-positive mothers, with lower levels of HBV in the breast milk than in serum. However, the risk of perinatal transmission does not appear to be increased in breastfed infants [21]. Breast feeding is, therefore, permitted for the infants of mothers who are infected with HBV. If the mother has bleeding nipple lesions, caution is suggested if the mother has high levels of viremia. The American Academy of Pediatrics (AAP) recommends that chronic HBV infection of the mother is not a contraindication to breastfeeding of infants who receive the HBIG and HBV vaccine as scheduled [22].
Natural History of Hepatitis B Virus Infection
Hepatitis B virus infection in children may follow an acute, self-limited course, a fulminant course to hepatic failure with high mortality rate, or may persist for more than six months and become a chronic infection. Most infected children remain asymptomatic and only few present with acute or fulminant hepatitis. The interaction between the virus and host determines the outcome of HBV infection.
Acute Hepatitis B Virus Infection
Acute HBV infection in children can be either symptomatic or asymptomatic; the latter is more common, especially in infants and young children. Acute infection runs a self-limited course and recovery is marked by anti-HBs seroconversion. In symptomatic patients, the prodromal symptoms, including general malaise, anorexia, nausea, vomiting and fever, may persist for several days to weeks. Some cases present with jaundice with or without light colored stools. Hepatomegaly with right upper quadrant tenderness is common.
An incubation period of six weeks to six months is required for virus specific cytotoxic T lymphocytes to develop against HBV infected hepatocytes. During this early phase, serum alanine aminotransferase (ALT) levels rise and HBsAg and HBV DNA are detectable. The pre-icteric phase lasts from a few days to as long as a week and is followed by onset of jaundice or dark urine. The icteric phase of acute hepatitis B lasts for a variable period, averaging one to two weeks, during which viral levels decrease. In convalescence, jaundice resolves but constitutional symptoms may last for weeks or even months. During this phase, HBsAg is cleared followed by the disappearance of detectable HBV DNA from serum.
Patients with acute hepatitis B usually recover completely from the liver damage with the development of long-lasting immunity. However, persistent HBV infection may still develop in infants of HBV carrier mothers after acute hepatitis B.
Fulminant Hepatitis B
Acute liver failure occurs in less than 1% of patients with acute hepatitis B. The onset of fulminant hepatitis is typically marked by the sudden appearance of fever, abdominal pain, vomiting, and jaundice, followed by disorientation, confusion, and coma. Fulminant hepatitis B is relatively prevalent in infants below six months old, particularly in endemic areas. It typically occurs in infants born to HBeAg-negative, HBsAg-positive mothers. Fulminant hepatitis B can occur as early as two months of age. As the diagnosis of hepatic encephalopathy is difficult to establish in infants younger than one year, the presence of hepatic encephalopathy is not an absolute requisite for fulminant hepatic failure in this age group [23].
Children with fulminant hepatitis B present signs of liver failure, including coagulopathy, increasing bilirubin levels with declining aminotransferase levels, and a decreasing liver size, with or without hepatic encephalopathy, within eight weeks after the initial symptoms of HBV infection. HBsAg and HBV DNA levels generally fall rapidly as liver failure develops, and some patients are HBsAg-negative by the time of onset of hepatic failure. In this setting, positive anti-HBs or IgM anti-HBc is an important marker for diagnosis. The mortality rate for infants with fulminant hepatitis B is high; 67% of affected infants die without liver transplantation [24]. Careful monitoring and management are required for children with acute liver failure due to hepatitis B; they should be referred rapidly to a tertiary medical center with the availability of liver transplantation.
Pre-core gene mutation at nucleotide position 1896 can lead to a stop codon for HBeAg, which causes the HBV to cease production of HBeAg. Although pre-core mutation of HBV has been correlated with fulminant hepatitis B in adults, this could not be demonstrated in children. Pre-core mutation was found in 36% of children with fulminant hepatitis B and 30% of acute hepatitis B in a study in Taiwan [25].
Chronic Hepatitis B Virus Infection
Chronic HBV infection is defined as persistence of HBsAg for more than six months. Young children with chronic HBV infection are usually HBeAg seropositive with high HBV DNA and normal aminotransferase levels. Children may gradually clear HBV DNA and HBeAg with age, and enter the HBeAg seroconversion phase [26]. This usually occurs during adolescence, or when they enter young adulthood.
HBeAg is an important marker during the natural history of chronic HBV infection. HBeAg seropositivity indicates active HBV viral replication and high infectivity. HBeAg seroconversion (to anti-HBe status) is an important event during the natural history of chronic HBV infection. During the process of HBeAg seroconversion, the host immune system clears large amounts of HBV. This is accompanied by liver injury, manifested as a rise of ALT level.
The natural history of chronic HBV infection can be divided into the following phases according to the status of HBeAg, HBV replication, and liver injury [27] (Table 18.2).
Initial Immune Tolerance Phase
During the early phase of infection, the host is immune tolerant to HBV, highly infectious, with high viral DNA titers and positive HBeAg. The patients are usually asymptomatic, with normal, borderline, or mildly elevated ALT levels. This phase starts from infancy or early childhood, particularly in hyperendemic areas. Despite high levels of HBV DNA and HBeAg, liver damage in this phase is absent or minimal, as a consequence of T cell immune tolerance to HBeAg and HBcAg [28]. This high replication phase of HBV can persist for years to decades after primary infection.
Inflammatory (Immune Active) Phase
When the host immune system becomes more mature to recognize HBV-related epitopes on hepatocytes, immune-mediated viral clearance and hepatocyte damage begins. This phase, which typically lasts from two to seven years, is characterized by HBeAg positivity, high levels of HBV DNA and serum ALT levels, and active necroinflammation in the liver [26].
When children enter the inflammatory phase, most of them remain asymptomatic, or with mild nonspecific symptoms such as general malaise, or poor appetite. The ALT levels elevate; the peak ALT levels may fluctuate from below 100 IU/L to more than 1,000 IU/L. Severe and permanent liver damage with bridging hepatic necrosis which may progress into liver cirrhosis, though rare, does occur during childhood. Liver cirrhosis was reported in 3.4% of 292 long-term followed Italian HBsAg carrier children with elevated ALT activity [29].
The natural course of HBV infection in children varies in different individuals. The HBeAg seroconversion rate is affected by age and maternal HBsAg status. Before three years of age, the annual HBeAg seroconversion rate is very low (less than 2% per year). After age three, the annual HBeAg seroconversion rate increases gradually to 3–5% [30]. Children born to HBsAg carrier mothers have a lower HBeAg seroconversion rate, whereas those without maternal HBsAg positivity tend to clear HBeAg earlier.
In patients with perinatal or early childhood infection, transition from the immune tolerance to the immune clearance phase occurs mostly during the second or third decade of life. Serial ALT levels in chronic HBV-infected subjects offer a predictive effect on the occurrence of spontaneous HBeAg seroconversion. In a long-term follow-up study in children with chronic HBV infection, the median remaining times to spontaneous HBeAg seroconversion were observed to be 8.4, 5.1, 4.3, 4.0, and 2.8 years after the ALT levels crossed 20, 30, 40, 60, and 150 IU/L, respectively. The incidence rate of spontaneous HBeAg seroconversion within six months when a subject entered the phase of ALT between 60 and 150 IU/L was 5.57 times that of the phase with ALT < 60 IU/L. The incidence rate of HBeAg seroconversion once ALT levels were above 150 IU/L was 9.87 times that of the phase of ALT < 60 IU/L. The ALT levels above 30 IU/L were suggested to serve as a cut-off of the inflammatory phase in chronic genotype B and C HBV-infected patients [31].
Low Replicative Phase
After HBeAg seroconversion, ALT levels gradually return to normal. The liver histological change in anti-HBe-positive children with chronic HBV infection is usually mild or nonspecific if examined beyond six months after HBeAg seroconversion. HBeAg seroconversion to anti-HBe status indicates reduction of viral replication, and is generally considered to be beneficial for the patients with chronic HBV infection. After HBe seroconversion, acute exacerbation with reactivation of HBV and re-elevation of ALT is uncommon in children compared with adults. Most children who undergo HBeAg seroconversion have decreased viral loads, normal serum ALT, and uneventful courses [32]. In a prospective follow-up study of children with chronic hepatitis B, only six of 140 (4.3%) patients had elevated serum ALT after HBeAg seroconversion and normalization of ALT levels. However, if severe and permanent liver damage develops during the process of HBeAg seroconversion, early HBeAg seroconversion may not reflect a good prognosis [26]. In ten (14%) of the 72 infants with chronic HBV infection who had HBeAg seroconversion before three years of age, two developed HCC. Each had severe liver damage, with serum ALT level elevated to >500 IU/L during infancy or the second year of life, and returned to normal after two years of age. Serum ALT remained normal afterward but severe liver damage persisted, and HCC developed at 10 to 15 years of age.
After HBeAg seroconversion, HBV DNA can be detectable in sera, usually at <2 × 103 IU/mL or become undetectable by the polymerase chain reaction [33]. Histologically minimal or mild hepatitis may be observed in children after HBeAg seroconversion.
Reactivation Phase (HBeAg-Negative Chronic Hepatitis)
Reactivation of HBV replication and a rise in ALT levels are not common after HBeAg seroconversion in children; however, permanent liver damage and integration of the HBV genome may develop insidiously and gradually despite clearance of HBeAg. Subsequent development of liver cirrhosis or HCC is rarely observed but does occur during childhood. Notably, approximately 80% of childhood HCC occurs in children with anti-HBe. In an Italian long-term (29 years) follow-up study, 2% of the horizontally infected children showed progression to HCC after HBeAg seroconversion, and 6% had HBeAg-negative hepatitis [34]. In a group of long-term followed Taiwanese patients who were mainly infected in the perinatal period, the annual incidence of HBeAg-negative hepatitis was 0.37% among spontaneous HBeAg to anti-HBe seroconverters. HBeAg seroconversion before 18 years of age predicts a low risk of HBeAg-negative hepatitis in later life [35].
However, HBeAg-negative hepatitis is an important cause of liver injury after HBeAg seroconversion in adults. Liver injury occurs in up to 30% of inactive adult HBV carriers during long-term follow-up without reversion of HBeAg. This phase is characterized by negative HBeAg, positive anti-HBe, detectable HBV DNA levels (>2 × 103 IU/mL), serum ALT elevation and continuous necroinflammation of the liver, possibly due to active replication of HBV pre-core or basal core promoter mutants that cannot express HBeAg [36].
Spontaneous Clearance of Hepatitis B Surface Antigen
Spontaneous loss of serum HBsAg and appearance of its antibody is generally considered to indicate the possibility of HBV eradication and reflects a favorable event. Clearance of HBsAg is a rare event in children with chronic HBV infection; and anti-HBs seroconversion is very uncommon. Among children with chronic HBV infection in Taiwan, the annual HBsAg clearance rate is 0.58% [37]. Children with an initial low HBsAg serum level (<1,000 IU/mL) or children who were born to noncarrier mothers are more likely to develop HBsAg clearance [37]. However, in adult patients, HCC may still develop in those with cirrhosis who had HBsAg seroclearance at an older age [38]. After HBsAg seroclearance, some patients still have detectable HBV DNA in sera, owing to persistence of low level HBV cccDNA in the liver. These patients are considered to have occult HBV infection (OBI).
Occult Hepatitis B Virus Infection
The majority of OBI is attributed to low-level viremia in resolved phase of overt acute or chronic HBV infection. OBI has also been found in healthy vaccinated children, children with serologic non-A to E viral hepatitis, chronic HCV infection, and multiple transfusions [39]. Subjects with OBI may transmit HBV via blood or organ donation and develop hepatitis B reactivation when they receive chemotherapy or immunosuppressive therapy.
Liver Histologic Changes in Children with Acute or Chronic Hepatitis B Virus Infection
Liver biopsy is rarely performed in patients with acute HBV infection, particularly in children. However, as in adults, the main liver histological findings in children with acute hepatitis B include lobular disarray, focal necrosis with acidophilic bodies (necrotic hepatocytes), and portal mononuclear cell infiltration (Figure 18.4).
Liver histological findings in children with chronic hepatitis B in the immune tolerance phase generally reveal minimal or mild histologic changes with or without focal necrosis, reflecting the asymptomatic clinical manifestation and minimal ALT elevations. Immunohistochemical studies reveal striking expression patterns of HBV antigens in hepatocytes, with exclusive nuclear expression of HBcAg and homogeneous cytoplasmic expression of HBsAg (ground-glass cytoplasm) in isolated hepatocytes, which is in sharp contrast to the frequent clustered expression of HBsAg in adult patients (Figure 18.5). A liver histologic study was conducted in asymptomatic children aged four to nine years who had been born to HBeAg-positive HBsAg carrier mothers and who had chronic HBV infection and normal or minimal elevation of ALT [28]. Various, but mostly mild, degrees of histological abnormalities in the liver begin early in life and may progress to more significant liver damage with time [26].
Figure 18.5 (a) Liver histological features of chronic active hepatitis in a four-year-old asymptomatic, perinatally infected HBsAg carrier girl showing minimal focal necrosis. (b) Double immunohistochemical staining reveals exclusive nuclear expression of hepatitis B core antigen (HBcAg; blue) and homogeneous cytoplasmic expression of HBsAg (brown) in isolated hepatocytes.
During the process of HBeAg seroconversion, liver lobular changes develop with portal inflammation and various degrees of fibrosis, with or without piecemeal necrosis [40]. The inflammation is mild to moderate in most occasions. Although uncommon in children, bridging hepatic necrosis (inflammation connecting portal tracts to one another or to central veins) may occur during an acute exacerbation [40]. Within six months after HBeAg seroconversion, the inflammation is less active and, beyond six months, becomes inactive with mild to minimal inflammation and/or fibrosis in most children.
Liver specimens from a study of 30 children during the anti-HBe positive stage showed inactive cirrhosis in two (including one with HCC), chronic hepatitis with marked fibrosis in one, mild activity and moderate fibrosis in two, mild activity with mild fibrosis in nine, and minimal histologic changes in the remaining 16 [26].
Factors Affecting the Natural Course of Hepatitis B Virus Infection
Interactions between the virus and host may determine the natural course of HBV infection in an individual (Table 18.5). Maternal factors may also affect the disease process in children who acquire HBV infection perinatally, leading to a high rate of persistent infection. Host and viral factors may also influence the timing of HBeAg seroconversion.
| Factors | Viral Factors | Host Factors |
|---|---|---|
| Favorable factors |
|
|
| Unfavorable factors |
|
|
IL= interleukin
Maternal Factors
As mentioned above, children born to HBeAg and HBsAg double positive mothers have higher rates of chronic infection and lower rates of HBeAg seroconversion during long-term follow-up. This is due to the fact that exposure to transplacental maternal HBeAg in utero may generate specific T-cell unresponsiveness to HBeAg and to HBcAg, resulting in immune tolerance to HBV [17]. In contrast, infants of HBeAg-negative, HBsAg-positive mothers are prone to develop acute hepatitis B followed by recovery, or occasionally fulminant hepatitis [41].
Host Factors
Host Age
The clinical course and outcome of HBV infection is closely related to the age at infection and duration after chronic infection as discussed above (see “Chronic Hepatitis B Virus Infection”).
Host Immune Response
In order to maintain persistent infection in the host, HBV uses two possible mechanisms to influence the host immune system: induction of host immune tolerance and evasion of host immune surveillance with suppression of the host immune response.
After HBV infection in infancy and early childhood, an immune tolerance to HBV is induced, HBeAg being an important tolerogen. Transplacental transmission of HBeAg may reduce the immune recognition signals by the infants’ immune system and induce the immune tolerance status [17]. Subsequently active production of HBeAg by hepatocytes in the infected children may interfere with the cytokine production and function of cytokine, and apoptosis of the cytotoxic T cells.
Cytokines also play roles in directly inhibiting viral replication and indirectly determining the patterns of the host immune response. Higher levels of serum interleukin (IL)-12 (>45 ng/L) and IL-10 (>70 ng/L) have been associated with early spontaneous HBeAg seroconversion in children. Variations in host cytokine genes may influence HBeAg seroconversion individually. The IL-10–1082 G/G and IL-12 beta-10993C/G genotypes help to predict early spontaneous HBeAg seroconversion [42]. Additional determinant host factors need to be examined.
Viral Factors
Genotypes and Viral Titers
Ten different HBV genotypes (from A to J) are distributed in different geographic areas. Chronic infection with each genotype may have a different clinical course and outcome. Genotypes B and C are prevalent in Asia, while genotype A and D are more common in Europe, the Middle East, and India. Compared with genotypes A and B, patients with genotypes C and D have lower rates of spontaneous HBeAg seroconversion [43]. A study in children with chronic HBV infection revealed a lower HBeAg seroconversion rate in those with genotype C than with genotype B [44].
A spontaneous decline in serum HBV DNA levels reflects a reduction in viral replication. During the natural history of chronic HBV infection, HBV DNA levels may decline to low or undetectable levels with loss of HBeAg and appearance of anti-HBe. This generally suggests a favorable course with inactive disease [32]. Persistently high levels of HBV DNA into later adult life are associated with prolonged liver injury and higher risk of complication, such as liver cirrhosis or HCC [45].
Development of Hepatitis B Virus Mutations during Chronic Hepatitis B Virus Infection
In order to evade the immune surveillance, HBV may mutate during the natural course of chronic infection. In the later stage of chronic HBV infection, HBV replication is gradually reduced, forming a status of latent infection, to avoid the host immune surveillance. The HBV pre-core stop codon mutation, basal core promoter mutation, and core gene deletion mutation may influence HBeAg seroconversion in children.
Pre-core and Core Promoter Mutants
Wild-type HBV is the dominant strain during the long-term course of chronic HBV infection during childhood. An important G1896A mutation of the HBV pre-core gene may lead to production of a stop codon resulting in failure of HBeAg production. A long-term follow-up of 80 HBV-infected children revealed an increased proportion of the pre-core stop codon mutation (G1896A) from 10% during the early HBeAg-positive status to approximately 50% after HBeAg seroconversion [46]. Unlike adults, the HBV core promoter nucleotide 1762/1764 mutation does not play a major role in HBeAg seroconversion in children with chronic HBV infection in an age-matched, case-control study [47].
Core Gene Mutations
Because HBcAg is the target for the cytotoxic T-cell-mediated lysis of HBV-infected hepatocytes, it is predisposed to mutate during the chronic infection. Mutations of the core gene may change the conformation of the core protein and allow HBV to escape or modify the immune response via loss or change of immunodominant epitopes. Mutations of HBV core gene is more frequently seen in children with hepatocellular carcinoma. The pattern of mutation differs from that in children with chronic HBV infection. Core gene mutations at codons 74, 87, and 159 are frequently seen in HBV-infected children with HCC [48].
Treatment of Hepatitis B in Children
Children with chronic HBV infection may develop active liver inflammation and damage at any age in the presence of variable degrees of ALT elevation. Severe liver injury and complications, including bridging hepatic necrosis, cirrhosis, and even liver cancer, though rare, may occur in children [26]. With a long life expectancy, the risk increases over time. Whenever an ideal antiviral agent is available, treatment should be given as early as possible to eliminate the virus and prevent liver damage during chronic infection. Unfortunately, current treatment regimens are unable to eliminate HBV cccDNA in the liver, and are far from effective in eradicating HBV, particularly in children with immune tolerance.
Most children with chronic HBV infection are in an immune tolerant status with high viral load and normal serum ALT levels. In such children, current antiviral therapy does not result in a higher rate of HBeAg seroconversion compared with no treatment [49]. Suppression of viral replication and prevention of active liver damage and related consequences is more feasible in children who have active viral replication and elevated serum ALT. Currently available antiviral agents, approved by The US Food and Drug Administration (FDA) for use in children with chronic hepatitis B (CHB), are listed in Table 18.6.
Related posts:
Chapter 5 – Cirrhosis and Chronic Liver Failure in Children
Chapter 13 – Familial Hepatocellular Cholestasis
Chapter 16 – Diseases of the Gallbladder in Infancy, Childhood, and Adolescence
Chapter 26 – Cystic Fibrosis Liver Disease in Children
Chapter 32 – Lysosomal Storage Disorders in Children
Chapter 43 – Liver Transplantation in Children: Indications and Surgical Aspects
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