Biology and Pathogenesis

The virus responsible for hepatitis A (hepatitis A virus [HAV]) is a 27-nm, non-enveloped, spherical virus with a single-stranded RNA genome, a member of the Picornaviridae family. Humans are the only natural host, although some primates can be experimentally infected. Hepatitis is the result of direct cytolytic and immune-mediated effects of HAV.

Epidemiology

Hepatitis A is widespread and can be found throughout the world. The reported incidence of hepatitis A in the United States has been steadily declining, with only 1398 symptomatic cases reported in 2011. However, if underreporting and asymptomatic infection were taken into account, an estimated 2800 new infections occurred in 2011. HAV is spread primarily by the fecal-oral route. The disease may be acquired from direct fecal contact (e.g., daycare centers) or indirectly through ingestion of contaminated water or food. There is no carrier state or chronic infection.

High rates of HAV infection have been associated with low socioeconomic status, both in the United States and other countries. In developing nations, under poor living conditions, HAV infection, like other enteroviral infections, is a childhood disease. In these countries, 92% to 100% of 18-year-olds have serologic evidence of past infection. In developed countries, the disease is acquired at a later age (20% by age 20, 50% by age 50 in the United States). Because the disease is more severe in older patients, it poses a greater health problem in developed countries.

Favorable conditions for endemic infections include crowding, poor sanitation, and poor personal hygienic practices. Specific risk factors reported to the Centers for Disease Control and Prevention (CDC) in 2007 included contact with an infected person (8% of cases), homosexual activity (6%), foreign travel (18%), contact with children attending a daycare center (5%), and illicit drug use (1%). In 50% of cases, no risk factor was reported. Recognized high-risk locales include households with infected individuals, prisons, military camps, residential facilities for the disabled, and daycare centers.

Daycare centers are likely settings for transmission, especially if they have a large proportion of young children with orocentric behaviors or those not yet toilet trained. Under these conditions, the disease usually comes to medical attention from an infected adult staff member or an infected older household contact rather than the asymptomatic daycare vector.

Historically there were geographic variations in the incidence of HAV infection in the United States. However, over the last decade, with widespread childhood vaccination, the rates in the West have been approximately equal to those in other regions of the United States.

Clinical Course and Outcomes

The clinical and serologic course of a typical HAV infection is shown in Figure 75-1 . The average incubation period is 28 days (range 14 to 49 days). Fecal shedding may occur for 2 to 3 weeks before and for 1 week after the onset of jaundice. It is during this period and while the patient is asymptomatic, that viral transmission is most likely. Serum aminotransferase elevations may persist for several months and rarely for as long as a year.

Typical clinical and serologic course of symptomatic hepatitis A.

(From Hoofnagle JH, Di Bisceglie AM. Serologic diagnosis of acute and chronic viral hepatitis. Semin Liver Dis 1991; 11 :73–83, with permission. )

The clinical expression of HAV infection is age dependent, and there are no pathognomonic clinical signs that allow differentiation from other forms of acute hepatitis. Examination may be remarkable for jaundice, evidence of dehydration, and a mildly enlarged, tender liver. Occasionally splenomegaly is noted. Serum aminotransferase values usually peak around the time that jaundice occurs. These values are often 20 to 100 times the upper limit of normal, and decrease rapidly within the first 2 to 3 weeks, although minor elevations may persist for months. Hyperbilirubinemia most often resolves within 4 weeks. Infants and toddlers are more likely to be asymptomatic (“anicteric hepatitis”), whereas the majority of adults will develop clinically evident hepatitis. Only one of 12 young children develops jaundice, and children are more likely than adults (60% vs. 20%) to have diarrhea, often leading to the mistaken diagnosis of infectious gastroenteritis. Asymptomatic HAV infection among children facilitates transmission to adult contacts, who are more likely to experience symptomatic and severe infection. The outcome of HAV infection in general is excellent. There are no reported cases of chronic infection. Most complications are rare, and the fatality rate from fulminant hepatitis in children younger than 14 years of age is 0.1%, as compared with 1% in adults older than 40. The complications and extrahepatic manifestations of HAV infection are outlined in Table 75-1 .

Diagnosis

The diagnosis of HAV infection is confirmed by specific serologic markers. A positive anti-HAV test indicates acute infection, immunity from past infection, passive antibody acquisition (e.g., transfusion, serum immune globulin infusion), or vaccination. The diagnosis of acute or recent HAV infection in the presence of a positive anti-HAV requires determination of anti-HAV immunoglobulin M (IgM). Anti-HAV IgM is present at the onset of disease but persists for only 3 to 12 months. Tests for the detection of HAV antigen in stool or HAV-RNA in stool, liver, and sera, are not commercially available but are rarely required for the diagnosis. Serologic markers of HAV infection are described in Table 75-2 .

Passive Immunoprophylaxis

Serum immunoglobulin can be given before exposure (e.g., travelers to endemic areas) or after exposure to an index case. The most frequent example of the latter occurs in the daycare setting or in household contacts. The recommended dose is 0.02 mL/kg body weight given as soon as possible but no more than 2 weeks after exposure. Exact dosing and administration regimens are provided elsewhere.

Active Immunoprophylaxis

In 1995, the United States became the 41st country to license a vaccine for HAV. Two preparations are currently available, both made from formalin-inactivated virus grown in culture. Dosages are prescribed in proprietary unit measurements for pediatric and adult formulations. The recommended schedule is two injections 6 to 12 months apart, and 99% of children develop protective levels of antibody. The vaccine is safe, with no serious complications having been reported. The most frequent side effects reported in children are pain and tenderness at the injection site. Routine HAV immunization is currently recommended for all children 1 year of age and older. Persons traveling to regions of endemic infection and those who belong to groups at high risk of acquiring HAV (see epidemiology of HAV) should also be immunized. Vaccines should replace serum immunoglobulin for use in preexposure cases and may be active in interrupting epidemics. It may be reasonable in such situations to use both active and passive immunization. The impact of this vaccination strategy has been dramatic. The incidence of hepatitis A has been falling since 1998, commensurate with the increasing use of widespread vaccination.

Biology and Pathogenesis

Despite a reduction in newly acquired hepatitis B virus (HBV) infections since the mid-1980s, HBV remains an important cause of liver disease in the United States. HBV is a 42-nm diameter spherical virus and is a member of the Hepadnavirus family (hepatotropic DNA viruses). It is the only member of this family capable of infecting humans and nonhuman primates.

The structure of the intact virus (the Dane particle) is double-shelled. The external shell, or envelope, expresses “the Australia antigen,” the hepatitis B surface antigen (HBsAg). An inner shell termed the core or nucleocapsid expresses a second antigen, hepatitis B core antigen (HBcAg). The presence of a viral shell has been associated with the development of chronicity and carcinoma. Inside the core resides the viral genome, a reverse transcriptase (DNA polymerase), and a third antigen, hepatitis B e antigen (HBeAg). The significance of these antigens is described in Table 75-3 .

The HBV genome is a double-stranded DNA circle with a unique single-stranded area. It is 3200 nucleotide bases in length. Viral replication, in a fashion similar to retroviruses, involves reverse transcription of an intermediate RNA template. Although there is only one serotype, there are eight genotypes, A through H, that vary by 8% at the nucleotide level over the entire genome, and multiple subtypes. Genotype predominance varies with geographic location. There are important pathogenic and therapeutic differences among the genotypes. Genotype C is associated with more severe liver disease than genotype B, and genotype D with more severe liver disease than genotype A. Genotypes C and D are less responsive to interferon therapy than are types A and B. Mutations of the HBV genome have been described and may determine outcomes such as the development of a fulminant course, latency, or response to treatment. Several types of mutants have been described: pre-core and core promoter mutants that have abnormal expression of the core protein and pre-S/S mutants.

Pre-core mutant HBV results from a single point mutation causing a premature stop codon. This typically develops at a late stage of chronic HBV infection, after natural HBeAg seroconversion. This variant is responsible for “e-antigen negative” HBV infection in which HBeAg is absent, anti-HBe is found, and hepatitis B viral DNA (HBV-DNA) remains detectable. HBeAg-negative infections are associated with a more severe course and outbreaks of fulminant hepatitis. The pre -S1, S2 , and S genes are responsible for envelope protein synthesis, including HBsAg. Mutations in these genes have been found in chronically HBV-infected persons who are HBsAg negative. This has raised concerns regarding safety and screening of blood supplies. These individuals have detectable HBV-DNA, HBeAg, and anti-HBs antibody. The clinical significance of HBV mutations in pediatric liver disease is unclear because pediatric reports are rare. It is likely that these mutations do not appear commonly in childhood, since they represent a late stage of HBV, often seen after decades of infection.

Although HBV can infect other organs, such as the spleen, kidneys, or pancreas, its replication has been demonstrated only in the liver. Replication produces not only complete viruses but also smaller 22-nm spherical and variable-length (50 to 1,000 nm) filamentous particles. These latter particles are rich in HBsAg and are thought to be incomplete viral coats. All three forms can be detected in the blood.

Clinical expression of HBV is polymorphic and thought to be determined by the body’s immune response to infection rather than a direct cytotoxic effect of the virus. The factors that determine a specific response, whether it is viral eradication, chronic persistent infection, or fulminant hepatitis, are incompletely defined.

Study of the pathogenesis of chronically acquired HBV infection is ongoing. It is thought that neonates are predisposed to chronic HBV infection because of their immature immune systems. This is supported by the observation that these children most often demonstrate little, if any, hepatic inflammatory injury. It has been shown that the passive transplacental transfer of anti-HBc IgG may interfere with the recognition of HBcAg on the hepatocyte surface by cytotoxic T cells. In addition, two studies have shown that in both humans and transgenic mice, HBeAg crosses the placental barrier and may induce immune tolerance. This tolerance is achieved through neonatal T-cell unresponsiveness to HBeAg and HBcAg, since these antigens share amino acid sequences.

Epidemiology

HBV infection is a major health problem throughout the world: According to the World Health Organization (WHO), an estimated 240 million people are chronically infected, with 600,000 deaths annually attributed to acute or chronic consequences of this virus. In the United States, however, the incidence has declined steadily since 1985. The true incidence of childhood infection is unknown because 85% to 90% of infections in this age group are asymptomatic. In addition, surveillance is done for new infections, but does not detect asymptomatic perinatally acquired infections, the most common scenario in children.

The development of chronic infection is the most important consequence of HBV acquisition in childhood. Ten percent of acute infections across all age groups will become chronically infected. However, although children younger than age 5 represent only 1% to 3% of all new HBV infections in the United States, they account for 30% of all chronic infections. The epidemiology of hepatitis B is strongly influenced by age, geographic location, and mode of transmission.

A 1985 study by McMahon and associates followed 1280 seronegative Eskimos in an endemic area of Alaska for 5 years. The results show that age of infection is inversely related to likelihood of asymptomatic infection and to the development of chronicity. These results have been confirmed by others and underscore the significant influence of age on the epidemiology of HBV infections. Age at the time of initial infection is believed to be the most important factor affecting prevalence. In areas where prevalence rates are high, the disease is acquired perinatally or at a very young age. Chronically infected individuals represent a persistent reservoir for infection and contribute significantly over their life spans to the maintenance of high endemicity. In areas of low endemicity, the infection is acquired in adulthood and is less likely to become chronic and generate high prevalence rates.

HBV infection has a worldwide distribution, but prevalence rates vary significantly from areas of high endemicity, mainly in developing countries, to areas of low endemicity in developed countries ( Figure 75-2 ). Small pockets of high prevalence exist and may be associated with ethnic minorities (e.g., Alaskan Yupik Eskimos). In a mobile society, it is important to recognize these geographic differences because it is not unusual to care for patients emigrating from areas of high endemicity. In the United States, chronic HBV infection is predominantly seen in immigrants from endemic parts of the world. It is likely that targeted screening of high-risk populations will be effective in identifying subjects who are at risk for complications of long-term HBV infection such as hepatocellular carcinoma (HCC), as well as susceptible individuals who are at risk of acquisition and thus most likely to benefit from vaccination. Furthermore, prevalence of HBV genotypes varies in different regions of the United States. There is a strong correlation between HBV genotypes and ethnicity. These genotypes may account for the heterogeneity in disease manifestations among patients with chronic HBV.

Geographic distribution of hepatitis B.

(Adapted from Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis 1991; 11 :84–92, with permission. )

There are no environmental reservoirs (e.g., food, water) for HBV. There are no natural animal reservoirs, and humans are the principal source of HBV infection. The traditional route of transmission is parenteral, through contaminated transfused blood products or needles for intravenous drug use. Transmission may also occur percutaneously or transmucosally from exposure to blood or other contaminated body fluids. Although HBsAg has been found in virtually every body fluid (e.g., feces, bile, breast milk, sweat, tears, vaginal secretions, and urine), only blood, semen, and saliva have been shown to contain infectious HBV particles. Transmission from infected human bites has been documented whereas transmission from feces has not. The lack of fecal-oral transmission and the types of close contact required for transmission probably explain the infrequent appearance of epidemics.

The route of acquisition within the pediatric population can be divided into three relevant age groups: perinatal, infancy-childhood, and adolescent–young adult.

Each year in the United States, 25,000 HBsAg-positive mothers give birth. Selective prenatal testing, based on the identification of known risk factors, is difficult and has shown an unacceptably low sensitivity (<50%). The failure of selective prenatal screening prompted recommendations for universal HBV screening of all pregnant women to identify at-risk newborns. The risk of perinatal or vertical transmission can be further defined by the mother’s full serologic profile: Mothers who are HBeAg positive have the highest rates of transmission (70% to 90%), whereas infants of mothers who are HBsAg positive but HBeAg negative are at lower risk (10% to 67%). The presence of anti-HBe antibody in an HBsAg-positive mother does not always confer safety to her child: although in most instances it signifies resolving disease, it may in rare cases predispose the newborn to fulminant hepatitis. Acute maternal infection during the third trimester carries the highest risk of perinatal transmission. In utero infections are rare but have been described. Perinatal acquisition is thought to occur during the birthing process because infection in newborns cannot be detected serologically for the first 1 to 3 months. It is postulated that during birth, the infant comes into contact with infected maternal body fluids, although whether the virus crosses through the infant’s mucosal membranes, intestinal tract, or minor skin abrasions is still not known.

Infants and children who do not become infected perinatally remain at high risk of infection during the first 5 years of life. This risk has been estimated in Asian children at 60% if the mother is HBeAg positive and 40% if she is HBeAg negative. Transmission in these instances was found to occur horizontally between children within the family. HBsAg can be detected in breast milk, but whether infection can be transmitted through ingested breast milk or from swallowed maternal blood from injured nipples is unclear.

Available data suggest that the risk of HBV transmission within the daycare setting, either between children or between caregivers and children, is low. Current recommendations are that HBV-infected children be allowed to attend daycare unless they have other medical conditions or behaviors that would increase the risk of transmission.

In 2007, the incidence of acute HBV in children was the lowest ever recorded since 1966 at 0.02 per 100,000 population in children younger than 15 years of age and 0.9 per 100,000 in people 15 to 24 years of age. In 52% of the cases, no data were available. However, among the 48% with a reported exposure, 55% were from sexual contact and 15% from intravenous drug use. The male-to-female ratio in adolescents is equal, but in adults, there is a slight male predominance.

The epidemiology of HBV infection allows the identification of high-risk groups, which are listed in Table 75-4 .

Acute HBV Infection

Clinical Course.

The clinical expression of acute HBV infection depends on the age at acquisition. The clinical course of a typical icteric, self-limited, acute HBV infection is portrayed in Figure 75-3 . The incubation period ranges from 28 to 180 days (mean 80 days), after which the patient may develop a prodrome consisting of fever, anorexia, fatigue, malaise, and nausea. Also during this period the child may present with immune-mediated extrahepatic manifestations, including migratory arthritis, angioedema, or a maculopapular or urticarial rash. Papular acrodermatitis of childhood, or Gianotti-Crosti syndrome, may become evident during this period. The syndrome includes a characteristic “lenticular, flat, erythematopapular” rash of the extremities, face, and buttocks, and lymphadenitis associated with hepatitis. It can be associated with other viral infections and is reported rarely in North America. This syndrome is thought to be the result of circulating immune complexes.

Typical clinical and serologic course of symptomatic acute hepatitis B.

(From Hoofnagle JH, Di Bisceglie AM. Serologic diagnosis of acute and chronic viral hepatitis. Semin Liver Dis 1991; 11 :73–83, with permission. )

After 1 to 2 weeks, most of the prodromal symptoms subside and clinically evident hepatitis develops, including, in many cases, jaundice, hepatosplenomegaly, and pruritus. Intense fatigue is a common complaint during this period. Symptoms may persist for 1 to 2 months, and longer in a minority of patients.

Outcomes.

The potential outcomes of an acute HBV infection are outlined in Figure 75-4 . The complications that may result from acute infection with HBV include fulminant hepatitis or development of chronic infection. Any child with an acute fulminant HBV infection or a biphasic course should be investigated for concomitant HDV coinfection.

Potential outcomes of hepatitis B across all age groups.

Chronic HBV Infection

Chronic infection with HBV is defined as the presence of HBsAg in the serum for at least 6 months. It should be characterized as HBeAg positive or negative, with or without detectable HBV-DNA, and with normal or elevated levels of alanine aminotransferase (ALT). The inflammatory activity and degree of fibrosis are important histopathologic descriptors.

Terms such as “asymptomatic” or “healthy carrier state” are discouraged. “Inactive carrier state” refers to a patient who is HBsAg+, HBeAg−, has a normal ALT and circulating HBV-DNA less than 2000 IU/mL (10,000 copies/mL). Resolved HBV is indicated by normal ALT level, HBV-DNA undetectable, absence of HBsAg, and the presence of anti-HBc (with or without anti-HBs) in serum.

Hepatocellular Carcinoma

Hepatocellular carcinoma (or HCC) is the sixth most common neoplasm worldwide, but its very poor prognosis makes it the third leading cause of cancer-related mortality, responsible for ~600,000 deaths annually. It is generally believed that the incidence is increasing. The majority of the cases are associated with chronic HBV infection. This is an important sequela from the pediatric perspective, not only because it is a major cause of childhood malignancy in certain parts of the world such as Asia but also because the initial HBV infection in most patients with HCC occurred in childhood. Risk factors for the development of HCC include chronic infection with HBV, long duration of infection, male gender, the presence of cirrhosis, and family history of HBV-associated HCC.

The higher incidence of HBsAg positivity in the mothers than in the fathers of patients with HCC suggests that primary infection occurs perinatally or in early infancy. This and other observations imply that the mean duration from primary infection to the development of HCC is 35 years. However, reported cases in children, some as young as 8 months, raise the issue of different oncogenic mechanisms. A study following 426 children with chronic HBV infection revealed that in 6250 person-years, 2 boys developed HCC. Both had e antigen seroconversion in early childhood and cirrhosis. Early e antigen seroconversion and/or cirrhosis may be risk factors for the development of HCC.

Extrahepatic Manifestations

Circulating immune complexes including HBsAg/anti-HBs complexes are reported to be responsible for extrahepatic manifestations of chronic HBV infection. Essential mixed cryoglobulinemia, polyarteritis nodosa, and glomerulonephritis have been described in association with chronic infection and may even be the presenting signs of HBV.

Diagnosis of Acute and Chronic Hepatitis B

HBsAg is the first serologic marker to appear and may be detected within 1 to 2 weeks after exposure. It precedes the development of symptoms by an average of 4 weeks. The presence of HBsAg indicates ongoing infection. Qualitative but not quantitative methods are used by most clinical laboratories because the amount of antigen does not correlate with disease activity or with the presence of an acute or chronic infection. Some symptomatic patients may have self-limited, acute HBV infection without detectable HBsAg. These patients, up to 9% in some studies, have other detectable markers of infection. HBeAg appears virtually simultaneously, peaks, and then declines in parallel with HBsAg. It usually disappears before HBsAg does. Adult patients who remain persistently positive for HBeAg for more than 10 weeks are likely to become chronically infected. HBeAg indicates a high level of viral replication and infectivity. Most patients with nondetectable HBeAg have resolving, minimal, or no active liver disease. Pre-core mutants of HBV do not express HBeAg; they may be responsible for a more severe course and, in some cases, fulminant disease. Serum aminotransferase levels become elevated but are nonspecific. They begin to increase just before the development of symptoms and then peak (sometimes 20 or more times higher than normal) with the development of jaundice.

The diagnosis of chronic HBV infection is based on the persistence of appropriate markers for at least 6 months or on detection of these markers in a child who on initial presentation has historic or physical evidence of long-standing infection. This information is summarized in Figures 75-3 and 75-5 and Tables 75-3 and 75-5 .

Typical clinical and serologic course of chronic hepatitis B.

(From Hoofnagle JH, Di Bisceglie AM. Serologic diagnosis of acute and chronic viral hepatitis. Semin Liver Dis 1991; 11 :73–83, with permission. )

The third marker of infection is HBV-DNA, which appears with HBsAg, peaks with the onset of symptoms, and then declines. Anti-HBc is the last serologic marker to appear. It can usually be detected 3 to 5 weeks after the appearance of HBsAg but before the onset of symptoms, and it persists for life. The presence of anti-HBc indicates ongoing or past infection. Anti-HBc does not appear after HBV vaccination and, in the presence of anti-HBs, is therefore helpful in distinguishing immunity due to vaccination from that due to natural infection.

Anti-HBs indicates resolving or past infection or successful immunization with vaccine, and confers protective immunity. In the majority of patients with self-limited infection, it can be detected only after HBsAg becomes undetectable. In a minority of patients with serum sickness–like symptoms, anti-HBs may appear before the onset of clinical symptoms. A “window” of variable duration has been described in some patients, during which HBsAg has disappeared and anti-HBs cannot yet be detected. The determination of anti-HBc may be helpful in these instances.

Antibody to HBeAg (anti-HBe) appears after HBeAg becomes undetectable and persists for 1 to 2 years after the resolution of hepatitis. The markers of HBV and their interpretation are summarized in Table 75-3 .

Treatment

Passive Prophylaxis

A detailed discussion of HBV immunoprophylaxis was provided by the CDC. Hepatitis B serum immunoglobulin (HBIg) is prepared from pooled plasma. It has a high titer of anti-HBs (>1 : 100,000). Its protective value is excellent when given as soon as possible after exposure, and persists for 3 to 6 months. Its benefit is doubtful, however, when given more than 7 days after exposure. HBIg is indicated for single instances of exposure, such as needle-stick accidents, sexual contact, and perinatal exposure. It has also proved valuable in the prevention of HBV infection recurrence after liver transplantation. HBIg should be given with HBV vaccine in cases of repeated or prolonged exposure, such as in health care employees, intimate household contacts, and neonates of infected mothers.

Active Prophylaxis

The first vaccine against hepatitis B virus was prepared from human plasma of chronic HBV carriers and released in the United States in 1982. It has since been replaced by recombinant vaccines prepared by introducing an HBsAg gene containing plasmid into baker’s yeast (Saccharomyces cerevisiae) . Recommended schedules involve three intra-deltoid injections over a 6-month period. HBV vaccine is also found in combination with a vaccine for Haemophilus influenzae type b. HBV vaccine is considered very safe; rare complications include anaphylaxis and Guillain-Barré syndrome. The vaccine induces the production of anti-HBs, and the vaccine manufacturers report protective titers in 95% to 99% of healthy children who receive the full schedule of injections.

Initial immunization policies in the United States targeted individuals at high risk, such as newborns of seropositive mothers, illicit drug abusers, and homosexual males. However, it became apparent that this strategy was ineffective in reducing the incidence of hepatitis B, and in 1991, the CDC issued new recommendations. This three-part strategy recommends prevention of mother-to-infant transmission through prenatal testing of all pregnant women, universal vaccination of all infants and children by age 11, and immunization of adolescents and adults in high-risk groups such as teenagers with multiple sexual partners and homosexual males. The long-term effectiveness of HBV vaccine, even in those who have lost detectable anti-HBs, does not support the administration of late booster doses.

A mass HBV vaccination program, conducted by the government of Taiwan, was started in 1984. The success of this program has led to a decline in HBV carrier rates among children in Taiwan from 10% to less than 1%. Furthermore, the mortality rate of fulminant hepatitis in infants and the annual incidence of childhood HCC have also decreased significantly. This is considered a remarkable success story in public health.

Biology and Pathogenesis

HCV is a 55-nm diameter lipid-enveloped virus with a 33-nm inner nucleocapsid. The genome is a linear, single-stranded, positive-sense RNA approximately 9400 nucleotides in length. Translation of the genome results in three structural and four nonstructural proteins. HCV belongs to the family Flaviviridae.

The HCV genome is highly susceptible to mutations, and comparison of different isolates has shown nucleotide sequence variation confined to specific areas. This has led to the identification of six major genotypes and a number of subtypes based on major and minor genomic differences. Genotype determination is relevant for epidemiology and response to therapy. Mapping of the geographic distribution of the known genotypes shows that genotypes 1 (a and b) and 2 are the most prevalent genotypes in North America and Western Europe. This may have clinical significance for the development of effective vaccines. More than 80% of infected individuals develop chronic HCV infection. Chronic HCV infection is not the consequence of the direct destruction of hepatocytes by the virus. Rather, it results from an intermediate immune response that is sufficiently vigorous to induce hepatic cell destruction and fibrosis but not enough so to eradicate the virus.

Epidemiology

The distribution of HCV is worldwide, and the prevalence rates appear to be evenly distributed, ranging from 0.3% to 1.5% when assessed among adult volunteer blood donors. In the United States, HCV is associated with 40% of cases of chronic liver disease. Approximately 12,000 deaths each year in the United States are attributed to hepatitis C. Only a small proportion of HCV-infected individuals are children, and there are few, if any, manifestations of this infection during childhood. The incidence of HCV-associated disease has been declining since 1989, corresponding to the development of the first serologic screening tools. Although the incidence in children is unknown, it is an estimated that 7000 to 17,000 new HCV cases occur annually in the United States after adjusting for asymptomatic infections and underreporting.

The prevalence of anti-HCV in children was much higher in those who received blood products for con­ditions such as thalassemia or hemophilia before 1990 to 1992, when enzyme-linked immunosorbent assay (ELISA) became available. Bortolotti and coworkers have shown that anti-HCV prevalence rates in children with NANB hepatitis were 60% to 65% in children with thalassemia, 59% to 95% in those with hemophilia, and 52% to 72% in survivors of leukemia. All of these children are now adults. The transmission of HCV via transfusion of blood and blood products has been virtually eliminated. Perinatal transmission has become the major route of HCV acquisition in childhood. Approximately 20% of infants spontaneously clear the virus after perinatal acquisition.

Although infection with HCV is far less common on a worldwide basis than infection with HAV or HBV, its propensity to become chronic has resulted in HCV becoming a major cause of chronic hepatitis. In the United States, it is responsible for most cases of chronic viral hepatitis and a large proportion of cases of chronic liver disease and cirrhosis. Most HCV-infected children develop chronic hepatitis, and although rare, cirrhosis and end-stage liver disease can occur during childhood.

There does not appear to be an epidemiologically relevant reservoir for HCV other than humans. The typical route of transmission is parenteral. Transmission may be divided into percutaneous (e.g., blood transfusions, intravenous drug use), and nonpercutaneous (e.g., intrafamilial and sexual routes).

The proportion of cases attributable to intravenous drug use has been increasing and may be as high as 60% of new HCV infections. This is due in part to the declining risk of transmission from blood products but also to the increasing frequency of drug abuse. The prevalence of anti-HCV among intravenous drug abusers ranges from 60% to 90%. Intravenous drug abuse in mothers also imposes a significant risk to their children: in one study this association was found in 6% of pediatric hepatitis C cases.

Occupational exposure in health care professionals occurs from percutaneous transmission of contaminated blood in instances of accidental needle stick. The risk of infection from a single needle stick from an HCV-RNA–positive patient ranges from 0.2% to 10%, and the disease is usually symptomatic. Skin tattooing has become increasingly popular among adolescents and has been associated with the transmission of HCV.

Nonpercutaneous transmission is the term used to describe cases that cannot be attributed to percutaneous transfer of HCV, such as perinatal and sexual transmission, intrafamilial and occupational spread, and sporadic infections in which no mode of transmission can be found. Transmission of HCV through body fluids other than blood has not been confirmed. Several studies have failed to detect the presence of HCV-RNA in the semen, saliva, urine, stool, or vaginal secretions of patients with chronic HCV infection, leaving uncertainty surrounding the mechanism of transmission in cases of nonpercutaneously transmitted infection.

Acute HCV Infection

Chronic HCV

Diagnosis of Acute and Chronic HCV Infection

Virus-specific serology is required for the accurate diagnosis of HCV infection. The serologic course of HCV disease is shown in Figure 75-6 . Serum aminotransferase levels begin to rise with the development of symptoms and jaundice. They rise rapidly and then decline in a fashion that may be either monophasic and rapid or multiphasic with wide fluctuations and a more protracted course. The multiphasic pattern may portend more severe disease or progression to a chronic state. Assays for the detection of HCV antigens are not available, owing to the low concentrations of virus in the blood; diagnosis depends on the detection of antibodies to viral proteins (anti-HCV) and the viral genome (HCV-RNA) ( Table 75-6 ).

Typical clinical and serologic course of symptomatic acute hepatitis C.

(From Hoofnagle JH, Di Bisceglie AM. Serologic diagnosis of acute and chronic viral hepatitis. Semin Liver Dis 1991; 11 :73–83, with permission. )

A third-generation ELISA detects antibodies to multiple, immunodominant, structural, and nonstructural proteins of HCV. A positive anti-HCV result indicates current or past infection. A negative anti-HCV result neither excludes infection in its early stages nor excludes past infection because it may disappear in patients whose disease has resolved. False-positive results are seen in patients with autoimmune disorders. HCV-RNA is the earliest detectable marker in the blood of patients with hepatitis C. It can be detected during the incubation period, before the development of symptoms. It is detected by the polymerase chain reaction (PCR), which can detect as few as 1 to 10 molecules of nucleic acid. PCR testing for HCV-RNA is the primary method available for direct assay of the presence of HCV, which is the most reliable measure of active infection; this may be the only test to detect early acute hepatitis C or infection in individuals who cannot mount an antibody response (e.g., immunocompromised patients). Persistence of HCV-RNA beyond 6 months indicates chronic infection, and its loss correlates with resolved disease. Quantification of HCV-RNA is helpful primarily in determining response to therapy.

Histologic features of chronic hepatitis C in children are similar to those reported in adults, and include portal inflammation with formation of lymphoid nodules, bile duct injury, and varying degrees of steatosis ( Figure 75-7 ). Necrosis and inflammation are usually mild, but fibrosis is common and appears to progress with increasing age and duration of infection.

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