Hepatitis
Hepatitis: Excerpt from Pediatric Infectious Disease
Basic Considerations
Although there are many causes of hepatitis in childhood, including toxins and
metabolic processes, the most common cause is viral infection. The purpose of
this chapter is to review the common viruses that cause hepatitis in childhood
and discuss appropriate methods of diagnosis.
Hepatitis A
Epidemiology and Etiology
Hepatitis A is the most common viral etiology of pediatric hepatitis. The mode
of transmission is person to person, resulting from fecal contamination of
food. Sexual contact and nosocomial transmission have also been documented.
Presentation
Hepatitis A is an RNA virus that usually causes a self-limited illness
associated with fever, jaundice, and anorexia. In children younger than 5 years
of age, cases are often anicteric and frequently misdiagnosed as
gastroenteritis. Rarely, hepatitis A leads to a fulminant disease, which can be
fatal. Chronic infection does not occur, although prolonged disease causing
relapsing jaundice has been described.
Diagnosis
The diagnosis of hepatitis A is made by serology. Serum immunoglobulin M (IgM)
to hepatitis A is usually present at the onset of illness. The presence of
hepatitis A IgG without IgM indicates past infection and immunity.
Management
Currently, there is no specific therapy for hepatitis infection. Treatment is
supportive.
Hepatitis B
Epidemiology and Etiology
Hepatitis B is transmitted through blood or body fluids. Transmission by the
shared use of nonsterile needles or sexual contact is common in adults.
Presentation
A wide spectrum of clinical presentations is possible, ranging from nonspecific
symptoms of gastroenteritis to fulminant fatal hepatitis.
Diagnosis
There is often considerable confusion regarding the interpretation of hepatitis
B serology. The hepatitis B virus (HBV), termed the
Dane particle, is divided into two basic components: the surface and the core. The core
itself has two parts: the core antigen and the e antigen. The presence of high
levels of hepatitis B e antigen is correlated with increased levels of
circulating levels of HBV DNA and is thought to be a marker for disease
activity. Patients who develop antibodies to the hepatitis B e antigen often
have a reduction in circulating levels of HBV DNA and improvements in their
serum aminotransferase levels. During hepatitis B infection, all persons make
antibodies to the core antigen. Subsequent production of antibodies to the
surface antigen confers immunity. Failure to produce surface antibodies results
in the patient being chronically hepatitis B surface antigen positive; the
patient is then diagnosed as a chronic carrier of hepatitis B. The diagnosis of
acute or recent hepatitis B infection therefore rests on the presence of IgM
antibody to the core antigen because this is the antibody response that
all patients will make regardless of their ultimate carrier status.
Failure to make hepatitis B surface antibody and development of chronic
hepatitis B status are related to the age at the time of infection. Perinatally
infected children have a 90% chance of developing chronic infection; children
who acquire their infection at 1 through 5 years of age have a 20% to 50%
chance of developing chronic infection.
Chronic Infection
Chronic hepatitis B infection progresses to cirrhosis in 15% to 20% of cases.
Chronic hepatitis B is also associated with a higher incidence of
hepatocellular carcinoma. Protocols in adults suggest that chronic carriers of
hepatitis B should be screened yearly for hepatocellular carcinoma using
ultrasound examinations and serum
α-fetoprotein assays.
Prognosis of chronic hepatitis B infection is based on a variety of factors,
including alcohol consumption, prolonged replicative phase, persistent e
antigen, and the clearance of hepatitis B surface antigen. Various genotypes of
hepatitis B may have an increased likelihood of progressing to chronic disease.
Ongoing viral replication and inflammation are thought ultimately to increase
the incidence of cirrhosis and hepatocellular carcinoma in patients with
chronic hepatitis B infection. The goal of therapy is thus suppression of
ongoing viral replication and prevention of these end-stage conditions.
Treatment of Chronic Infection
There has been great interest in identifying patients with chronic infection who
will possibly benefit from preemptive therapy. A National Institutes of Health
Consensus Workshop on the management of hepatitis B recommended that treatment
be considered in patients who are hepatitis B surface antigen positive with an
accompanying a viral load of greater than 10
5/mL. This number is somewhat arbitrary; the precise DNA level associated with progressive disease is not
known.
Aminotransferase levels have been shown to be the best noninvasive marker for the presence of chronic active hepatitis, although up to 40% of patients with histologically confirmed chronic active hepatitis have normal aminotransferase levels. Many specialists consider liver biopsy the best method to determine the
need for therapy.
Response to therapy is usually defined as undetectable HBV DNA, loss of
hepatitis B antigen, and improvement in liver disease as determined by
normalization of aminotransferase levels or by biopsy.
Currently, there are two drugs used for the treatment of hepatitis B infection.
Interferon-
α has been shown to suppress HBV replication in 30% of adults as compared with
10% of controls. The dose for children is 6 million units/m
2 three times weekly, with a maximum of 10 million units. The recommended
duration of treatment is 24 weeks for patients who are hepatitis e antigen
positive. Long-term follow-up in adults has suggested that the 5-year
cumulative rate of hepatitis B e antigen clearance is similar in untreated
patients. The main role of interferon-
α may be to hasten viral clearance and thus reduce duration of active liver
disease. Patients with high pretreatment aminotransferase levels and low
baseline HBV DNA levels appear to have the best response to interferon.
Lamivudine is a nucleotide analog that is frequently used in the treatment of
human immunodeficiency virus (HIV) infection. There is increasing use of this
drug in patients with chronic hepatitis B infection. Treatment with 3 mg/kg per
day (up to 100 mg/day) leads to a significantly higher proportion of children
losing hepatitis B e antigen as compared with controls. A major concern in
treatment of hepatitis B with lamivudine is the development of the YMDD
mutation (thyroxine [y], methionine [m], aspartate [D], and aspartate [D]).
These mutations replicate less efficiently than wild-type strains; the
long-term implications of the development of these resistant strains are not
clear.
Guidelines for Adoption
As international adoption becomes more common, there will be an increasing
number of hepatitis B surface antigen
–positive children residing in the United States. The primary mode of
transmission is blood and body secretions; household and day care transmission
of hepatitis B is rare. Parents and caretakers should be instructed regarding
the following:
• Use thick disposable towels to attend to any bleeding wounds.
• Household items, such as toothbrushes and nail clippers, should not be shared.
• Household contacts should all receive the standard hepatitis B vaccination so
that they are protected.
Hepatitis C
Epidemiology and Etiology
Hepatitis C virus is transmitted in similar fashion to hepatitis B, through
exposure to blood and blood products.
Between 2% and 4% of women of childbearing age are antibody positive for
hepatitis C. The vertical transmission rate has been reported to be about 5%,
although this increases if the mother is also HIV positive. Most studies have
not shown a role in transmission based on the method of delivery. Mothers who
are infected with hepatitis C virus may breast-feed their children because
transmission through breast milk has not been proved. Transmission from a
single needle-stick accident is about 1%.
Presentation
The clinical presentation of hepatitis C infection is similar to that of
hepatitis A or B: acute disease is often mild and maybe asymptomatic. Only 20%
of patients with acute infection become jaundiced.
Diagnosis
Most acute hepatitis C infections are associated with few or no symptoms, making
clinical diagnosis difficult. The two available antibody assays are the enzyme
immunoassay (EIA) and recombinant immunoblot assay (RIBA). These assays are
greater than 95% sensitive and specific, although they can be falsely negative
early in disease onset. Viral load or polymerase chain reaction (PCR) assays,
similar to those used in detecting HIV, have been developed for hepatitis C.
Hepatitis C virus can be detected within 1 to 2 weeks after exposure and weeks
before abnormalities in liver enzyme tests are seen.
Hepatitis C antibodies cross the placenta and cannot be used for diagnosis in
the neonatal period. The evaluation of the hepatitis C
–exposed infant is a hepatitis C PCR at 6 to 8 weeks and again at 6 months of
age. Because of the persistence of maternal antibodies in exposed infants,
evaluation for hepatitis C antibodies should not be performed until the patient
is 1 year of age.
Chronic Infection
Like hepatitis B, hepatitis C infection is associated with a chronic state. The
chronic infection is defined by detection of hepatitis C virus by PCR in the
blood 6 months after infection. About 60% to 85% of patients infected with
hepatitis C develop a chronic infection. The proportion of chronically infected
patients who develop the sequelae of hepatitis C is not known. Estimates of 2%
to 4% of infected children progressing to cirrhosis and hepatocellular
carcinoma have been made. Although viral genotype and baseline viral load do
not appear to influence the risk for progression, host factors, including older
age at time of infection, alcohol consumption, and coinfection with HIV, may
play a role.
Treatment of Chronic Infection
There are evolving treatment options for patients with chronic hepatitis C
infection. Because many patients with infection do not have progressive
disease, there is great interest in defining patients who will most benefit
from therapy. Liver enzymes have shown little value in predicting the degree of
fibrosis or cirrhosis in a particular patient. Although hepatitis C RNA (viral
load) levels are available by PCR, the situation differs from HIV. In the
latter, the viral load is a major factor determining progression of disease and
is often involved in the decision to initiate treatment. In the case of
hepatitis C, viral load levels do not correlate with either the grade or stage
of disease on liver biopsy. There are no currently available noninvasive tests
that can reliably predict the level of inflammation or fibrosis of hepatitis C.
The decision to initiate treatment at the present time is usually guided by
liver biopsy. Liver biopsy results are evaluated in terms of grade and stage.
The grade refers to the level of inflammatory activity and is a measure of
ongoing disease. The stage of the liver biopsy refers to the degree of fibrosis
and is a measure of disease progression. Patients who have a certain grade of
inflammation or fibrosis become candidates for treatment.
Pegylated interferon plus oral ribavirin is currently the standard treatment of
hepatitis C. Effective treatment, or sustained viral response (SVR), is defined
as the absence of detectable hepatitis C RNA 24 weeks after the end of therapy.
Early viral response (EVR) is defined as a minimum 2-log decrease in the viral
load during the first 12 weeks of treatment. This is considered highly
predictive of SVR. Patients who fail to achieve EVR at week 12 have only a
small chance of achieving an SVR, and treatment is often not extended beyond 12
weeks in these patients.
Epstein-Barr Virus
Epidemiology and Etiology
EBV is a ubiquitous virus that is frequently the cause of infectious
mononucleosis.
Presentation
Adolescents and young adults with infectious mononucleosis typically have fever,
severe pharyngitis, rash, and mild to moderate hepatitis. Patients with
underlying immunodeficiencies can present with a wider spectrum of disease,
including disseminated disease and lymphoproliferative disorders.
Diagnosis
The diagnosis of EBV is also subject to considerable confusion. The monospot
test is frequently used to screen for EBV infection. However, children younger
than 5 years of age often do not produce the heterophile antibodies measured by
this test. EBV-specific serology is often indicated, although interpretation
can be difficult.
A variety of antigens have been identified in EBV. The presence of IgM and IgG
antibodies to specific antigens is used to diagnose acute or past EBV
infection. Viral capsid (VCA) antigens are detected in cells undergoing active
EBV infection. Anticapsid antibodies appear at the onset of acute infection and
persist for life. IgM to viral capsid antigens is the hallmark of acute EBV
infection. Early antigens (EA) are a group of proteins that become positive
later in acute infection. EBV nuclear antigen (EBNA) antibodies appear during
convalescence and persist for life; anti-EBNA titers indicate
old EBV infection.
Management
Treatment is generally supportive. Patients with extreme tonsillar hypertrophy
who are at risk for airway obstruction can be treated with a brief of course of
prednisone, usually 1 mg/kg per day for 5 to 7 days. Because of the potential
risk for splenic rupture, contact sports such as martial arts or football
should be avoided until the patient has recovered.
Cytomegalovirus
Epidemiology
Cytomegalovirus (CMV) is a DNA virus that is also ubiquitous and transmitted
person to person and through body fluids such as blood, breast milk, and urine.
Presentation
CMV is another herpesvirus infection that causes a variety of clinical
syndromes, the most common being an infectious mononucleosis-like syndrome with
prolonged fever and hepatitis. The disease is usually self-limited in
immunocompetent individuals, although severe illness can be seen in oncology
patients, organ transplant recipients, and patients infected with HIV.
Diagnosis
The diagnosis of acute CMV infection can be complex; diagnosis is difficult
because of the large number of asymptomatic persons shedding the virus at any
given time. IgM antibody is produced with primary infection, yet can also be
produced with reactivated infections. PCR technology can be used, although
typically this test is used only in patients with underlying
immunodeficiencies. In an immunocompetent patient with a mononucleosis-like
syndrome and negative studies for EBV, the diagnosis of CMV is often presumed.
Management
In the immunocompetent patient, care is usually supportive. In certain patient
populations such as organ transplant recipients and patients with HIV
infection, antiviral therapy with ganciclovir is given.
Selected Readings
Conjeevaram HS, Lok AS. Management of chronic hepatitis B. J Hepatol 2003;38[Suppl 1]:S90–103.
Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337(24):1733–1745.
Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD
variants during lamivudine therapy for patients with chronic hepatitis B.
Clin Infect Dis 2003;36(6):687–696.
Seef CB, Hoofnagle JH. Appendix: National Institute of Health Consensus
Development Conference. Management of hepatitis C.
Clin Liver Dis 2003;7(1):261–287.
Pictures
Book Source Details
- Book Title: Pediatric Infectious Disease
- Author(s): Donald Janner MD
- Year of Publication: 2004
- Copyright Details: Pediatric Infectious Disease, Copyright © 2004 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: Pediatric Infectious Disease
Authors: Donald Janner MD
Publisher: Lippincott Williams & Wilkins
Copyright: 2004
ISBN: 0-7817-5584-0
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