Viral Hepatitis

Viral Hepatitis: Introduction


Infectious hepatitis is a syndrome characterized by injury (inflammation or death) to hepatocytes. The process may be self-limiting or may lead to fibrosis, cirrhosis, and neoplastic changes. Clinically, the hepatocellular insult is manifested by elevation of serum aminotransferases (alanine aminotransferase (ALT) and aspartate transaminase (AST)). Typically, the alphabetically designated hepatitis viruses (A–G) and, in particular, hepatitis viruses A, B, and C are those generally considered by the clinician when evaluating a child with hepatitis (Table 24–1). However, many other viral agents such as Epstein–Barr virus (EBV), cytomegalovirus (CMV), coxsackieviruses, echoviruses, West Nile virus, etc., have the potential to infect the liver and cause clinical or subclinical hepatitis (Table 24–1). This chapter will focus on the hepatitis A, B, and C viruses, the major causes of viral hepatitis in children.

Table 24–1. Viruses Associated with Hepatitis

Definitions and Epidemiology


Hepatitis A Virus

Hepatitis A virus (HAV) is a small nonenveloped RNA virus in the genus Hepatovirus within the Picornaviridae family.1 Transmission of HAV occurs predominantly via a fecal–oral route. Because the majority of HAV infections in children result in subclinical disease, children play a major role in the transmission of the virus within communities. Outbreaks of hepatitis A occurring in child care centers are well known to occur. Common-source outbreaks through the ingestion of contaminated food or water have also been well documented. Transmission of HAV via transfusion of blood or blood products occurs occasionally when donors are sampled during the viremic phase of the infection. High-risk groups for the acquisition of HAV infection include travelers to developing countries, men who have sex with men, users of injection and noninjection drugs, and individuals working with nonhuman primates.

With the advent of recommendations for vaccination of high-risk individuals and children residing in states with a high prevalence of HAV infection, followed by the more recent recommendation of routine vaccination of all children 1 year of age, the incidence of hepatitis A infections in the United States has decreased significantly.2 In 2007, the reported incidence of hepatitis A infection was 1 case per 100,000 persons in the United States. During that year, the lowest rates of infection occurred among children <5 years of age. Taking into account asymptomatic infections and underreporting, it was estimated that 25,000 new cases of hepatitis A occurred that year.3 This represented the lowest incidence ever recorded.

Hepatitis B Virus

Hepatitis B virus (HBV) is a DNA virus in the Hepadnaviridae family.4 Replication of HBV occurs in an asymmetric manner, using an RNA intermediate and subsequent reverse transcription to give rise to the viral DNA genome.5 Error-prone replication occurs due to the lack of proofreading activity of the viral polymerase and gives rise to genetic heterogeneity in HBV. Phylogenetic analysis of HBV isolates indicates the existence of eight HBV genotypes, designated A–H (Table 24–2).4,6,7 The eight HBV genotypes exhibit a characteristic geographic distribution, and have a correlation with clinical and, in adults, therapeutic outcomes (Figure 24–1).6

Table 24–2. Hepatitis B Genotypes


Global distribution of chronic Hepatitis B infection.

Transmission of HBV may occur via mucosal or percutaneous exposure to infected blood or body fluids through injection drug use, blood or blood product transfusion, sexual contact, or during delivery. Today, transfusion-associated transmission is a rare event as a result of screening of blood donors and blood products. Nonsexual transmission may occur in settings of extended interpersonal contact such as those in households of individuals with chronic hepatitis B infection.3

Geographic areas of high endemicity (i.e., ≥8%) for HBV infection are shown in Table 24–3.8 In endemic regions of the world, maternal–fetal transmission is the principal mode of acquisition of HBV. Maternal HBe antigenemia has been shown to be a risk factor for vertical transmission of HBV.9 Approximately 90% of infants born to mothers who are hepatitis Be antigen (HBeAg) positive will become chronically infected.8 Approximately 5–15% of maternal–fetal transmission occurs as a result of transplacental (congenital) infection with remaining 85–95% occurring at the time of delivery.10

Table 24–3. Geographic Regions of High Hepatitis B Endemicity

In the U.S. recommendations for HBV vaccination of high-risk individuals, universal vaccination of all children and adolescents coupled with screening of pregnant women for HBV infection and prophylaxis of high-risk newborns has contributed to a significant reduction in the incidence of HBV infection. In 2007 the overall incidence of hepatitis B infections in the United States was 1.5 cases per 100,000 persons, the lowest ever recorded. The rate of hepatitis B infection among children and adolescents <15 years was 0.02 cases per 100,000 persons. After correction for asymptomatic cases and underreporting, it was estimated that 43,000 new infections occurred in 2007. That same year, only 83 cases of perinatal HBV transmission were reported. The Centers for Disease Control and Prevention estimate that, although perinatal HBV infection is a reportable disease, the number of actual reported cases represented <10% of the true number of cases.

Hepatitis C Virus

Hepatitis C virus (HCV) is an RNA virus in the family Flaviviridae.11 Error-prone replication of the RNA genome by the viral polymerase gives rise to significant viral heterogeneity in the form of viral quasispecies as well as genotypic diversity. Phylogenetic analysis has identified six genotypes of HCV (Table 24–4).12 The genomic heterogeneity of HCV displays a geographic distribution and plays a role in the pathogenesis of infection, response to therapy, and host immune evasion (Figure 24–2).

Table 24–4. Hepatitis C Genotypes


Global prevalence of Hepatitic C infection.

Transmission of HCV occurs primarily through percutaneous exposure. However, in some cases, mucosal exposure has also been shown to lead to infection. Transmission via blood and blood product transfusion has been significantly reduced by screening of blood donors and HCV inactivation of plasma-derived products.

HCV infection is the most common blood-borne infection in the United States. Previous studies of the seroprevalence of HCV infection in American children 6–11 years of age documented it to be 0.2% and for those aged 12–19 years 0.4%.13 In 2007, HCV infections among children continued to be rare.3 The incidence of HCV infection in older individuals was 0.5 cases per 100,000 persons for persons 25–39 years and for those ≥40 years 0.3 cases per 100,000 persons.

Unlike HBV maternal–fetal transmission occurs in only 5% of cases. However, rates of vertical transmission may be as high as 19% in women co-infected with the human immunodeficiency virus (HIV) (reviewed in14). This increased rate of transmission may be due to higher levels of hepatitis C viremia seen in HIV co-infected women. Although conflicting data regarding the level of viremia necessary for perinatal transmission of HIV exist, ample evidence suggests that in non-HIV-infected women viremia should be considered a risk factor for vertical transmission. Additional risk factors favoring vertical transmission include infant of female gender, prolonged rupture of membranes, obstetrical procedures (amniocentesis and fetal scalp monitoring), and exposure to maternal blood (maternal vaginal or perineal lacerations).14

Breastfeeding, in the absence of cracked or bleeding nipples, does not increase the rate of perinatal transmission of HCV. As such, recommendations for the avoidance of breastfeeding by HCV-infected women are unwarranted. Lastly, the mode of delivery and HCV genotype have not been shown to be correlated with increased maternal–fetal transmission rates.14



Hepatitis A

HAV is a single-stranded, positive-sense RNA virus in the genus Hepatovirus.1 It is transmitted via the fecal–oral route. The virus replicates within the cytoplasm of the hepatocytes and is excreted in bile resulting in fecal shedding. Virus may be found in blood (viremia) soon after infection. This viremia persists throughout the period of hepatic enzyme elevation. HAV is cleared via host humoral immune response.

Infected individuals are most contagious during the 2-week period prior to the onset of jaundice or, in anicteric children, the elevation of liver enzymes. Shedding in children is significantly longer than in adults and may last for up to 10 weeks after the onset of clinical illness. Infants may be prolific shedders of HAV, with virus present in their stool for up to 6 months after infection. Chronic infection with HAV does not occur.

Hepatitis B

HBV is an enveloped, 40–45 nm in diameter, virus containing a loosely coiled, partially double-stranded DNA genome15,16 (Figure 24–3). The viral genome measures approximately 3.2 kb and codes for three structural and four nonstructural viral proteins: S, L, and M, and polymerase, core, e, and X, respectively (Table 24–5).


Structure of the Hepatitis B virus.

Table 24–5. Hepatitis B Virus Proteins

The envelope of the virion is derived from the hepatocyte membrane and contains three virally derived surface proteins: S, also known as the hepatitis B surface antigen (HBsAg), L, and M. The viral membrane surrounds the viral nucleocapsid that is composed of the hepatitis B core protein or hepatitis Bc antigen (HBcAg). The nucleocapsid, in turn, encloses the partially double-stranded circular DNA viral genome as well as the viral DNA polymerase and several host cell proteins.

The viral replication cycle begins with binding of the virion, presumably via the L protein, to an, as of yet, unidentified host cell protein on the hepatocyte membrane. Subsequent fusion of HBV envelope and host cell membrane results in entry of the viral nucleocapsid core to the cell cytoplasm. The viral cores are transported to the cell nucleus where the HBV DNA genome is released, repair of the single-stranded gap is performed by host cell enzymes, and the genome is converted to a covalently closed circular DNA molecule (cccDNA). Viral genome then serves as a template for the generation of pregenomic and subgenomic RNA transcripts by the host cell’s RNA polymerase II.

HBV RNA transcripts are transported from the nucleus to the cytoplasm where subgenomic-length transcripts are translated to yield the viral proteins essential to the HBV life cycle (Table 24–5). Core proteins assemble to form the nucleocapsid in the cytoplasm and a single molecule of pregenomic RNA is incorporated within the nascent core. The HBV reverse polymerase transcribes the nucleocapsid-associated pregenomic RNA to DNA. However, generation of cccDNA is not completed until the virus infects another cell or nascent nucleocapsid containing partially double-stranded DNA and is transported back to the nucleus of the cell to maintain the pool intranuclear DNA template. The majority of mature cores bud into the ER membrane, which is studded with HBV surface proteins (S (HBsAg), L, and M), thus forming the mature virion’s envelope. Fully formed virions are then exported from the cell. Viral replication does not result in lysis of the host cell.

The host immune response to HBV infection is age-related and mediates the clinical presentation and outcome of infection. In immunocompetent adults, a robust CD8+ cytotoxic T-lymphocyte-mediated response results in clearance of the viral infection in >95% of all patients.17 Following a period of unchecked replication, during which HBV serum titers exceed 109 copies/µL (>1012 copies/mL), a rapid fall in viral titer occurs. The fall in serum viral concentration occurs prior to the occurrence of hepatic injury or cellular infiltration of the liver. This phase of noncytolytic clearance is believed to be the result of cytokine-mediated inhibition of HBV replication without associated hepatocellular injury. In simian and murine models, HBV-specific CD8+ cytotoxic T-lymphocytes are important during this phase of the immune response to HBV. Important cytokines mediating this phase of the host immune response are interferon-gamma, tumor necrosis factor-alpha, and interferon alpha/beta: which are all produced by CD8+ cytotoxic T-lymphocytes.

The development of clinical hepatitis, manifested by an increase in serum aminotransferases, follows the noncytolytic clearance of HBV for the serum. This period is characterized by cytolytic clearance of HBV accompanied by maximal CD4+ and CD8+ T-lymphocyte responses. Hepatic infiltration by HBV-specific and nonspecific T-lymphocytes, neutrophils, natural killer cells, monocytes, and macrophages occurs as a result of chemokine recruitment to the liver. During this phase of acute hepatitis, it is believed that much of the hepatocellular damage is due to nonantigen-specific inflammatory responses. The ultimate outcome of the combination of noncytolytic and cytolytic responses is the prevention of infection of hepatocytes and the elimination of those already infected. In addition to the host’s cell-mediated immune response, the immune system’s humoral arm also plays a role in clearing HBV. Antibodies to HBsAg aid in viral clearance and prevention of infection of hepatocytes.

In stark contrast to the vigorous response to HBV exhibited by the adult immune system, intrauterine or immediate postnatal exposure to HBV proteins produces a state of immunologic tolerance that prevents clearance of the infection in the majority of infants. Hepatitis B-specific CD4+ and CD8+ T-lymphocyte responses are diminished in comparison to those seen during the adult response. In animal models of chronic HBV infection, the persistence of viral antigens leads to a functional decline of HBV-specific cytotoxic T cell responses and, ultimately, T-cell elimination.17 The clinical outcome of this immunotolerant state is chronic HBV infection, so much so that 90% of prenatally infected infants develop chronic hepatitis.

Several HBV proteins have been associated with the development of chronic infection.17,18 HBeAg, which is derived from the nucleocapsid protein, is essential in the development of chronic infection. In the transgenic murine model of HBV, HBeAg contributes to the poor T-lymphocyte and antibody response to the core protein. Additionally, in the same model, HBeAg can cross the placenta and induce neonatal tolerance.18 Toll-like receptor 2 expression and function on monocytes, Kupffer cells, and hepatocytes is down-regulated in patients with HBeAg-positive chronic hepatitis.17 In contrast, patients with HBeAg-negative chronic hepatitis exhibit up-regulation of Toll-like receptor 2.

HBsAg is present in noninfectious filamentous and spherical particles produced during viral replication. These viral particles serve to bind anti-HBs antibodies, thus diverting them from neutralization of infectious HBV virions.17 Additionally, HBsAg may contribute to low CD8+ T-lymphocyte response and CD8+ T-lymphocyte depletion.18

Lastly, HBV X protein can inhibit cellular proteasome activity when it is over-expressed. As such, it has the potential to inhibit antigen processing and presentation.18

Hepatitis C

HCV is an enveloped, single-stranded, positive-sense RNA virus classified within the Flaviviridae family.11 The virion is approximately 50 nm in diameter (Figure 24–4). The RNA is 9.6 kb in length and codes for four structural proteins (core (C), E1, and E2) as well as seven nonstructural proteins (p7, NS2, NS4A, NS4B, NS5A, NS5B, and F/ARFP) (Table 24–6).11,19 Immediately preceding and following the single open reading frame of the viral genome are long untranslated regions (UTR), designated 5′ UTR and 3′ UTR, respectively. These regions are essential for viral translation and replication.

Jan 21, 2019 | Posted by in GASTROENTEROLOGY | Comments Off on Viral Hepatitis
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