Chapter 350 Viral Hepatitis

Viral hepatitis continues to be is a major health problem in both developing and developed countries. This disorder is caused by at least 5 pathogenic hepatotropic viruses recognized to date: hepatitis A, B, C, D, and E viruses (Table 350-1). Many other viruses (and diseases) can cause hepatitis, usually as 1 component of a multisystem disease. These include herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus, HIV, rubella, adenoviruses, enteroviruses, parvovirus B19, and arboviruses (Table 350-2).

Table 350-1 FEATURES OF THE HEPATOTROPIC VIRUSES

The hepatotropic viruses are a heterogeneous group of infectious agents that cause similar acute clinical illness. In most pediatric patients, the acute phase causes no or mild clinical disease. Morbidity is related to rare cases of acute liver failure (ALF) triggered in susceptible patients and to the chronic disease state and attendant complications that three of these viruses (hepatides B, C, and D) can cause.

Hepatitis A

Hepatitis A virus (HAV) infection is the most prevalent of the 5. This virus is also responsible for most forms of acute and benign hepatitis; although fulminant hepatic failure can occur, it is rare and occurs more often in adults than in children.

Etiology

HAV is an RNA virus, a member of the picornavirus family. It is heat stable and has limited host range—namely, the human and other primates.

Epidemiology

HAV infection occurs throughout the world but is most prevalent in developing countries. In the United States, 30-40% of the adult population has evidence of previous HAV infection. Hepatitis A is thought to account for ∼50% of all clinically apparent acute viral hepatitis in the United States. As a result of aggressive implementation of a childhood vaccination strategy, the prevalence of symptomatic HAV cases in the United States has declined significantly. However, outbreaks in daycare centers (where the spread from young, nonicteric, infected children can occur easily) as well as multiple foodborne and waterborne outbreaks have justified the implementation of a universal vaccination program.

HAV is highly contagious. Transmission is almost always by person-to-person contact through the fecal-oral route. Perinatal transmission occurs rarely. No other form of transmission is recognized. HAV infection during pregnancy or at the time of delivery does not appear to result in increased complications of pregnancy or clinical disease in the newborn. In the USA, increased risk of infection is found in contacts with infected persons, child-care centers, and household contacts. Infection has also been associated with contact with contaminated food or water and after travel to endemic areas. Common source foodborne and waterborne outbreaks have occurred, including several due to contaminated shellfish, frozen berries, and raw vegetables; no known source is found in about half of the cases. The mean incubation period for HAV is ∼3 wk. Fecal excretion of the virus starts late in the incubation period, reaches its peak just before the onset of symptoms, and resolves by 2 wk after the onset of jaundice in older subjects. The duration of viral excretion is prolonged in infants. The patient is therefore contagious before clinical symptoms are apparent and remains so until viral shedding ceases.

Clinical Manifestations

HAV is responsible for acute hepatitis only. Often, this is an anicteric illness, with clinical symptoms indistinguishable from other forms of viral gastroenteritis, particularly in young children.

The illness is much more likely to be symptomatic in older adolescents or adults, in patients with underlying liver disorders, and in those who are immunocompromised. It is characteristically an acute febrile illness with an abrupt onset of anorexia, nausea, malaise, vomiting, and jaundice. The typical duration of illness is 7-14 days (Fig. 350-1).

Figure 350-1 The serologic course of acute hepatitis A. ALT, alanine aminotransferase; HAV, hepatitis A virus.

(From Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, p 913.)

Other organ systems can be affected during acute HAV infection. Regional lymph nodes and the spleen may be enlarged. The bone marrow may be moderately hypoplastic, and aplastic anemia has been reported. Tissue in the small intestine might show changes in villous structure, and ulceration of the gastrointestinal tract can occur, especially in fatal cases. Acute pancreatitis and myocarditis have been reported, though rarely, and nephritis, arthritis, vasculitis, and cryoglobulinemia can result from circulating immune complexes.

Diagnosis

Acute HAV infection is diagnosed by detecting antibodies to HAV, specifically, anti-HAV (IgM) by radioimmunoassay or, rarely, by identifying viral particles in stool. A viral polymerase chain reaction (PCR) assay is available for research use (Table 350-3). Anti-HAV is detectable when the symptoms are clinically apparent, and it remains positive for 4-6 mo after the acute infection. A neutralizing anti-HAV (IgG) is usually detected within 8 wk of symptom onset and is measured as part of a total anti-HAV in the serum. Anti-HAV (IgG) confers long-term protection.

Table 350-3 DIAGNOSTIC BLOOD TESTS:

SEROLOGY AND VIRAL PCR

Rises in serum levels of ALT, AST, bilirubin, ALP, 5′-nucleotidase, and GGT are almost universally found and do not help to differentiate the cause of hepatitis.

Complications

Although most patients achieve full recovery, two distinct complications can occur.

ALF from HAV infection is a rare but not infrequent complication of HAV. Those at risk for this complication are adolescents and adults, but also patients with underlying liver disorders or those who are immunocompromised. The height of HAV viremia may be linked to the severity of hepatitis. Whereas in the United States, HAV represents <0.5% of pediatric-aged ALF, it is responsible for up to 3% mortality in the adult population with ALF. In endemic areas of the world, HAV constitutes up to 40% of all cases of pediatric ALF.

HAV can progress to a prolonged cholestatic syndrome that waxes and wanes over several months. Pruritus and fat malabsorption are problematic and require symptomatic support with antipruritic medications and fat-soluble vitamins. This syndrome occurs in the absence of any liver synthetic dysfunction and resolves with no sequelae.

Treatment

There is no specific treatment for hepatitis A. Supportive treatment consists of intravenous hydration as needed and antipruritic agents and fat-soluble vitamins for the prolonged cholestatic form of disease. Serial monitoring for signs of ALF and, if ALF is diagnosed, a prompt referral to a transplantation center can be lifesaving.

Prevention

Patients infected with HAV are contagious for 2 wk before and ~7 days after the onset of jaundice and should be excluded from school, child care, or work during this period. Careful handwashing is necessary, particularly after changing diapers and before preparing or serving food. In hospital settings, contact and standard precautions are recommended for 1 wk after onset of symptoms.

Immunoglobulin

Indications for intramuscular administration of immunoglobulin (IG) (0.02 mL/kg) include pre-exposure and postexposure prophylaxis (Table 350-4).

Table 350-4 HEPATITIS A VIRUS PROPHYLAXIS

PRE-EXPOSURE PROPHYLAXIS (TRAVELERS TO ENDEMIC REGIONS)
Age	Exposure	Dose
<1 yr of age	Expected <3 mo	Ig 0.02 mL/kg
	Expected 3-5 mo	Ig 0.06 mL/kg
	Expected long term	Ig 0.06 mL/kg at departure and every 5 mo thereafter
≥1 yr of age	Healthy host	HAV vaccine
	Immunocompromised host, or one with chronic liver disease or chronic health problems	HAV vaccine and Ig 0.02 mL/kg

POSTEXPOSURE PROPHYLAXIS*
Exposure	Recommendations
≤2 wk since exposure	< 1 y of age: IG 0.02 mL/kg Immunocompromised host, or host with chronic liver disease or chronic health problems: IG 0.02 mL/kg and HAV vaccine >1 yr and healthy host: HAV vaccine, IG remains optional Sporadic non-household or close contact exposure: prophylaxis not indicated*
>2 wk since exposure	None

Ig, immunoglobulin.

* Decision for prophylaxis in non-household contacts should be tailored to individual exposure and risk.

IG is recommended for pre-exposure prophylaxis for susceptible travelers to countries where HAV is endemic, and it provides effective protection for up to 3 mo. HAV vaccine given any time before travel is preferred for pre-exposure prophylaxis in healthy persons, but IG ensures an appropriate prophylaxis in children <1 yr of age, patients allergic to a vaccine component, or those who elect not to receive the vaccine. If travel is planned in <2 wk, older patients, immunocompromised hosts, and those with chronic liver disease or other medical conditions should receive both IG and the HAV vaccine.

IG as prophylaxis in postexposure situations should be used as soon as possible (not effective >2 wk after exposure). It is exclusively used for children <12 mo of age, immunocompromised hosts, those with chronic liver disease or in whom vaccine is contraindicated; IG is preferably used in patients > 40 yr of age. IG is optional in healthy persons 12 mo-40 yr, in whom HAV vaccine is preferred. An alternative approach is to immunize previously unvaccinated patients who are ≥12 mo at the age-appropriate vaccine dosage as soon as possible. IG is not routinely recommended for sporadic nonhousehold exposure (e.g., protection of hospital personnel or schoolmates).

Vaccine

The availability of two inactivated, highly immunogenic, and safe HAV vaccines has had a major impact on the prevention of HAV infection. Both vaccines are approved for children >1 yr of age. They are administered intramuscularly in a 2-dose schedule, with the 2nd dose given 6-12 mo after the 1st dose. Seroconversion rates in children exceed 90% after an initial dose and approach 100% after the 2nd dose; protective antibody titer persists at least for 10 yr. The immune response in immunocompromised persons, older patients, and those with chronic illnesses may be suboptimal; in those patients, combining the vaccine with IG for pre- and postexposure prophylaxis is indicated. HAV vaccine may be administered simultaneously with other vaccines. A combination HAV and HBV vaccine is currently undergoing trials in adults. For healthy persons >1 yr of age, vaccine is preferable to immunoglobulin for pre-exposure and postexposure prophylaxis (see Table 350-3).

In the USA and some other countries, universal vaccination is now recommended for all children >1 yr of age. Prior to implementing universal HAV vaccination, mass immunization of school children has been used when epidemics have been school centered. The vaccine is effective in curbing outbreaks of hepatitis A due to rapid seroconversion and the long incubation period of the disease.

Prognosis

The prognosis for the patient with hepatitis A is excellent, with no long-term sequelae. The only feared complication is ALF. HAV infection remains a cause of major morbidity, however, and has a high socioeconomic impact during epidemics and in endemic areas.

Hepatitis B

Etiology

HBV is a member of the Hepadnaviridae family. HBV has a circular, partially double-stranded DNA genome composed of ∼3,200 nucleotides. Four genes have been identified: the S (surface), C (core), X, and P (polymer) genes. The surface of the virus includes particles designated hepatitis B surface antigen (HBsAg), which is a 22 nm diameter spherical particle and a 22 nm wide tubular particle with a variable length of up to 200 nm. The inner portion of the virion contains hepatitis B core antigen (HBcAg), the nucleocapsid that encodes the viral DNA, and a nonstructural antigen called hepatitis B e antigen (HBeAg), a nonparticulate soluble antigen derived from HBcAg by proteolytic self-cleavage. HBeAg serves as a marker of active viral replication and usually correlates with HBV DNA levels. Replication of HBV occurs predominantly in the liver but also occurs in the lymphocytes, spleen, kidney, and pancreas.

Epidemiology

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