CHAPTER 127

Viral Hepatitis

ChrisAnna M. Mink, MD, FAAP

Hepatitis is an inflammation of the liver that can occur as the result of an exposure to a toxin, such as a chemical or drug, or an infectious agent. In the United States, viruses are the most common cause of hepatitis in children and adolescents, including hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). With the advent of routine immunization for pediatric age groups against HAV and HBV, the prevalence of both infections, as well as complications and long-term consequences, have dramatically decreased. All 3 of these unrelated viruses can produce an acute illness characterized by nausea, malaise, abdominal pain, and jaundice. Hepatitis B virus and HCV also can produce chronic infections, which are generally asymptomatic but are associated with an increased risk for chronic liver disease and hepatocellular carcinoma.

Other common viruses that can cause hepatitis in children in the United States are Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), adenovirus, enteroviruses, and human herpesvirus; however, their contribution to the overall morbidity and mortality associated with infectious hepatitis is minimal. Hepatitis D (as coinfection with hepatitis B) and hepatitis E occur more commonly in other parts of the world.

Epidemiology

In 2017, more than 8,000 cases of viral hepatitis were passively reported from the 50 states and the District of Columbia to the Centers for Disease Control and Prevention (CDC). From 2011 to 2017, the number of HAV cases increased, primarily related to large, food-associated outbreaks and person-to-person transmission in communities of homeless individuals. In the past 10 years, the reported number of HBV cases has stayed relatively stable at approximately 3,000 annually. Over the same period, reported HCV cases increased more than 3-fold, with 3,186 new cases reported in 2017. The CDC notes under ascertainment and under-reporting and estimates that 44,300 acute hepatitis C cases occurred in 2017. The rise in HCV cases is related to an increase in injection-drug use, in part due to the opioid epidemic. There has also been an increase in case ascertainment of HCV, although most infections go undetected. Most new cases are reported in young adults, many with a history of drug use. The CDC states that the total number of acute and chronic hepatitis cases caused by these 3 viruses is probably underestimated because of under-recognition and underreporting but likely exceeds 50,000.

Since initiation of universal immunizations, the incidence of HAV and HBV infections in children and teenagers has significantly declined in the United States. For HAV, the rate of infections has declined from 12 per 100,000 in 1995 (before vaccinations) to a nadir of 0.4 per 100,000 in 2011, where it has remained, other than during outbreaks. Certain situations are associated with increased risk of HAV infection, including crowded living conditions, chronic care facilities, homelessness, military institutions, prisons, child care centers, traveling to endemic areas, outbreak exposure, use of illicit drugs, and high-risk sexual practices (eg, commercial sex workers, men who have sex with men). Poor personal hygiene and inadequate sanitation are also risk factors. In approximately 50% of HAV cases, however, the source of infection is unknown. Hepatitis A is found worldwide, but specific locations have an increased incidence of infections, including Central and South America, Africa, the Mediterranean region, and Asia.

For HBV, groups at increased risk of infection include individuals who use illicit parenteral drugs, commercial sex workers, men who have sex with men or who have multiple sexual partners, health care workers, neonates born to infected mothers, recipients of hemodialysis, household contacts of carriers of HBV, and immigrants from HBV-endemic areas. Individuals who live in crowded environments with poor hygienic standards, such as institutions for the developmentally disabled or correctional facilities, are also at risk for HBV infection. However, no risk factors are identified in 40% of cases. Worldwide, approximately 5% of the population (ie, 350 million people) is chronically infected with HBV. Individuals with chronic hepatitis B are the primary reservoirs for infection. Areas with the highest incidence of hepatitis B include Southeast Asia, China, the Pacific Islands, most of Africa, and parts of the Middle East.

Approximately 10% to 15% of primary infections with HBV result in a chronic carrier state. The younger children are when they are infected with HBV, the more likely they are to become chronic carriers. Without preventive measures, 70% to 90% of neonates born to infected mothers become carriers, and at least 50% of children infected before the age of 5 years become carriers. Boys have a greater risk of becoming chronic carriers than girls, although the reason for this disparity is not known.

Hepatitis C virus accounts for 20% to 40% of all viral hepatitis in adults. The prevalence in the pediatric age group is estimated to be 0.1%. Individuals at high risk for HCV infection are those who use intravenous (IV) drugs, recipients of transfusions of blood or blood products (especially before 1992), recipients of organ or tissue transplants, health care workers with blood exposure, hemodialysis patients, and, infrequently, sexual or household contacts of infected persons. No identifiable source can be found in at least 35% of cases. In the pediatric population, dialysis patients, institutionalized children, and high-risk newborns (ie, maternal history of IV drug abuse, sexually transmitted infections [STIs], HIV coinfection) are more at risk.

Because hepatitis D only occurs as a coinfection with HBV, high-risk groups are the same, with the exception of health care workers and men who have sex with men. High prevalence rates occur in Eastern Europe, Central Africa, southern Italy, and the Middle East.

Hepatitis E virus (HEV) infection is endemic in low-income countries such as Mexico, Central and Southeast Asia, North Africa, China, and India. No cases of HEV infection acquired in the United States have been reported. In endemic regions, HEV is the most common cause of symptomatic hepatitis in children. Young and middle-aged adults are most commonly affected, and HEV infection is especially severe for pregnant women.

Clinical Presentation

Children with acute hepatitis generally present with symptoms suggestive of a flu-like illness, including fever, malaise, decreased appetite, nausea, and vomiting. They may also report diffuse abdominal pain. Unlike adults, in whom jaundice is a common finding, pediatric patients, particularly infants and young children, are frequently anicteric. Hepatomegaly is often found on physical examination, although not universally, and there may be varying degrees of right upper quadrant discomfort (Box 127.1). A nonspecific macular rash, papulovesicular acrodermatitis (Gianotti-Crosti syndrome), and arthralgia can also occur in the course of HBV infection.

Pathophysiology

Hepatitis A

Hepatitis A virus is a picornavirus composed of single-stranded RNA with only 1 serotype. The most common modes of transmission are through close personal contact and contaminated food and water. This generally occurs by fecal contamination and oral ingestion. Shellfish, such as raw oysters, clams, and mussels, are a frequent source of infection. Infected food handlers may also transmit the disease. With universal immunization of children, most cases now occur in adults 20 years and older.

The average incubation period for hepatitis A is 28 to 30 days (range: 15–50 days). Peak viral secretion occurs before the onset of jaundice. The virus is shed in the stool 2 to 3 weeks before the onset of jaundice and up to 1 week after its appearance. However, most young children with HAV infection are anicteric, so infections often go unnoticed during this highly contagious period (Figure 127.1). The duration of illness is usually 2 to 4 weeks. A prolonged course or relapse occurs in 10% to 20% of adult cases. A chronic carrier state for HAV does not exist, although fulminant infections can occur. Lifelong immunity is conferred after a single infection. Mortality is rare, especially in children.

Hepatitis B

Hepatitis B virus is a double-stranded DNA virus in the Hepadnaviridae family. The disease is usually spread by contact with infected blood or blood products, but it can also occur through close interpersonal contact. Although hepatitis B surface antigen (HBsAg) is found in numerous body secretions (eg, blood and blood products, feces, urine, tears, saliva, semen, human milk, vaginal secretions, cerebrospinal fluid, synovial fluid), only serum, semen, vaginal secretions, and saliva have been proven contagious. No fecal-oral transmission occurs. Transmission is facilitated through percutaneous inoculation (eg, tattooing, IV drug use) and exposure of cuts in the skin and mucous membranes to HBV-infected fluids on objects such as razors. Sexual transmission occurs via semen, vaginal secretions, and saliva. Perinatal vertical transmission occurs in neonates whose mothers are acutely infected or chronic carriers and usually occurs from blood exposure perinatally. Postnatal infection from household exposure has been reported, although the exact mode of transmission is unclear. Hepatitis B virus can survive in the environment for longer than 7 days but can be inactivated with household disinfectants, such as bleach diluted 1:10 with water.

Figure 127.1. Course of acute hepatitis A infection.

Abbreviations: ALT, alanine aminotransferase; HAV, hepatitis A virus; Ig, immunoglobulin. Reproduced with permission from Tabor E. Etiology, diagnosis and treatment of viral hepatitis in children. In: Aronoff SC, Hughes WT, Kohl S, Speck WT, Wald ER, eds. Advances in Pediatric Infectious Diseases. Chicago, IL: Year Book Medical Publishers; 1988.

The average incubation period for HBV infection is 2 months (range: 1–6 months). Figure 127.2 depicts the typical course of acute hepatitis B infection, along with the course of the chronic carrier state.

Hepatitis C

Hepatitis C virus is a single-stranded RNA virus in the Flavivirus family; it is able to mutate rapidly, thus escaping detection by the host’s immune system. Like HBV, HCV can be spread through contact with contaminated blood and blood products. Previously, children with frequent exposure to blood products had increased risk, but currently the risk of HCV infection after transfusion is less than 1 per 2 million units of blood transfused. Most acute cases reported to public health occur in individuals who use drugs who have shared needles or paraphernalia. About one-third of young adult (aged 18–30 years) individuals who engage in injection drug use in the United States have HCV infection. For children, maternalfetal transmission is the most common route of infection, and the rate of vertical transmission is about 5% to 6%. Transmission of infection via household and sexual contact has been demonstrated but is uncommon.

The incubation period is variable, ranging from 2 weeks to 6 months, and averages 6 to 7 weeks. Most affected children are anicteric and asymptomatic. If symptomatic infection is present, it is usually mild, insidious, and indistinguishable from infections caused by HAV or HBV. Jaundice occurs in approximately 25% of patients. Fulminant hepatitis is extremely uncommon.

Figure 127.2. Course of hepatitis B infection. A, Acute hepatitis B infection. B, Chronic hepatitis B infection.

Abbreviations: ALT, alanine aminotransferase; HBc, hepatitis B core; HBe, hepatitis B e; HBeAg, hepatitis B e antigen; HBs, hepatitis B surface; HBsAg, hepatitis B surface antigen.

Reproduced with permission from Tabor E. Etiology, diagnosis and treatment of viral hepatitis in children. In: Aronoff SC, Hughes WT, Kohl S, Speck WT, Wald ER, eds. Advances in Pediatric Infectious Diseases. Chicago, IL: Year Book Medical Publishers; 1988.

Hepatitis D

Acute hepatitis D infection is caused by a distinct single-stranded RNA virus that requires HBsAg for replication. The virus and a delta antigen are enclosed in an envelope of HBsAg. Transmission is similar to HBV, but vertical transmission is uncommon. Hepatitis D infection occurs as a coinfection with HBV or a superinfection in a chronic carrier of HBV. Acute disease is usually more severe and carries a higher risk of fulminant hepatitis than HBV infection alone.

Hepatitis E

Hepatitis E virus is caused by an enterically transmitted RNA virus. There are 7 genotypes in its genus, Orthohepevirus, and the viruses can infect humans and multiple animal species. Transmission is primarily through contaminated drinking water and fecal-oral spread, especially during rainy or monsoon seasons in endemic areas. Hepatitis E virus is the most common viral hepatitis worldwide, and sporadic infection is common in Africa and the Indian subcontinent. Nearly all HEV infections in the United States have been reported in travelers returning from endemic areas.

The incubation period ranges from 2 to 6 weeks, with most cases of acute infection being self-limited. Mortality is low in endemic populations, except in pregnant women. Mother-to-neonate transmission is common and contributes to fetal loss and perinatal mortality. Hepatitis E virus can cause chronic infection, but this usually occurs in individuals who are severely immunocompromised.

Differential Diagnosis

The differential diagnosis of hepatitis depends on the patient’s demographics (eg, age), possible exposures, and immunization history. Possible infectious causes in neonates include overwhelming bacterial sepsis, VZV, and congenital infections (TORCHES [toxoplasmosis, other agents (syphilis, hepatitis B, varicellazoster virus [VZV], human immunodeficiency virus [HIV], parvovirus B19, enteroviruses, lymphocytic choriomeningitic virus), rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV)]), in addition to HBV infection. Perinatal transmission of HAV is rare. Genetic disorders and anatomical abnormalities causing biliary obstruction (eg, biliary atresia) should also be considered (see Chapter 126).

In older infants and children, in addition to HAV, HBV, and HCV, other viral etiologies include EBV, CMV, enteroviruses (including coxsackieviruses), adenovirus, VZV, human herpesvirus, and, uncommonly, rubella, rubeola, and HIV. In the United States, bacterial, parasitic, and fungal causes of liver infections are uncommon. Bacterial processes include pyogenic abscesses and sepsis. Parasitic agents include Plasmodium species (causes of malaria), Trypanosoma cruzi, and amoebic abscesses, among others, and these should be considered in individuals from endemic areas and returning travelers. Acute or chronic anemias, such as sickle cell disease, can also cause hepatomegaly and jaundice. Noninfectious conditions to consider include drug-induced hepatitis (eg, prescribed medications such as isoniazid or phenytoin and illicit drugs), toxin ingestion (eg, acetaminophen, herbal remedies), and conditions such as cystic fibrosis, α₁-antitrypsin deficiency, Wilson disease, and other congenital disorders such as Caroli disease (dilatation of the intrahepatic bile ducts).

In adolescents, viral etiologies to consider are similar to those listed for children. Other infectious processes to consider in the adolescent age group include biliary tract infections, bacterial sepsis, and Fitz-Hugh–Curtis syndrome (ie, liver inflammation associated with pelvic infections, especially with Chlamydia trachomatis or Neisseria gonorrhoeae). The list of prescribed and illicit drugs that may cause liver toxicity is extensive and includes oral contraceptives, seizure medications, alcohol, inhalants, acetaminophen, and tetracycline.

Evaluation

History

A comprehensive history should be obtained in children of all ages (Box 127.2). A dietary and travel history is essential, especially when considering HAV and HEV infection.

For neonates and young infants, a complete maternal and obstetric history should be obtained and include the following questions: Does the mother have any history of IV drug use? Does the mother come from an area in which hepatitis is endemic, such as Southeast Asia? Did the mother receive prenatal care? Was hepatitis B screening performed prenatally or at delivery? Did the mother have any known STIs or sexual contacts with hepatitis B-infected individuals?

History in adolescents should also include queries about sexual activity, history or symptoms of STIs, the number of sexual partners, parenteral drug use, and tattoos.

Physical Examination

Most children with viral hepatitis are asymptomatic and generally do not present for medical evaluation. For symptomatic children, there are no clues on the examination to aid in differentiating the causes. However, a complete physical examination should be performed to help rule out other etiologies. All vital signs should be recorded, including temperature to monitor for fever. In children who are vomiting, signs of dehydration (eg, tachycardia, evidence of orthostatic hypotension, dry mucous membranes, tenting of the skin, sunken eyes, lethargy) should be noted. Growth parameters, particularly weight, should be obtained and compared with previous measurements, if available.

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