Pediatric Hepatitis B: Practice Essentials, Background, Pathophysiology (original) (raw)

Practice Essentials

Hepatitis B virus (HBV) infection in infants and children is associated with few or no symptoms but poses a high risk of becoming chronic. Although a limited number of medications can be used to treat chronic hepatitis B, vaccination is a safe and effective prevention strategy. [1]

Signs and symptoms

The clinical manifestations of hepatitis B depend on the age at infection, the level of HBV replication, and the host's immune status.

Clinical signs and symptoms of acute HBV infection include the following:

Abdominal pain
Anorexia
Arthralgias
Clay-colored or light stools
Coryza
Cough
Dark urine
Headache
Jaundice
Malaise
Myalgias
Nausea
Pharyngitis
Photophobia
Vomiting

Common symptoms of chronic hepatitis include fatigue, loss of appetite, and occasional bouts of mild jaundice. Fulminant hepatitis may present as jaundice, encephalopathy, and fetor hepaticus.

See Presentation for more detail.

Diagnosis

Because the symptoms of acute HBV infection and the laboratory indicators of hepatocellular dysfunction are indistinguishable from those of other forms of viral hepatitis, definitive diagnosis depends on serologic testing for HBV infection.

All patients with chronic HBV infection should have laboratory tests to assess liver diseases (complete blood cell counts with platelet count, hepatic panel, and prothrombin time), serologic markers of HBV replication, and tests for coinfection with hepatitis C virus (HCV), hepatitis D virus (HDV) in persons from countries where HDV infection is common and in those with a history of injection drug use, and human immunodeficiency virus (HIV) in those at risk. Patients should be screened for hepatocellular carcinoma–alpha fetoprotein (HCC-AFP) at baseline, and ultrasonography should be performed in high-risk patients.

Liver biopsy may be required in patients with signs of chronic disease to assess the extent of histologic involvement and the response to therapy.

See Workup for more detail.

Management

Optimal management of HBV infection requires a lifetime of routine monitoring, even when patients are asymptomatic. The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. Children with HBV infection may not need treatment until well into their adolescent years or adulthood.

See Treatment for more detail.

Background

The hepatitis B virus (HBV), discovered in 1966, infects more than 350 million people worldwide. [2] HBV can cause acute and chronic liver disease. The clinical presentation ranges from subclinical hepatitis to symptomatic hepatitis and, in rare instances, fulminant hepatitis. Long-term complications of hepatitis B include cirrhosis and hepatocellular carcinoma. [3]

Perinatal or childhood infection is associated with few or no symptoms but has a high risk of becoming chronic. A limited number of medications can be used to effectively treat chronic hepatitis B; a safe and effective vaccine is available to prevent hepatitis B infection caused by HBV. [4]

The public health burden of HBV infection is almost entirely due to its long-term effects on liver function. Chronic HBV infection is a major cause of cirrhosis and hepatocellular carcinoma.

In addition to the human suffering that these diseases cause, the social and economic costs are large. More than $1 billion is spent each year for hepatitis B–related hospitalizations. The indirect costs of chronic HBV infection are harder to measure but include reduced physical and emotional quality of life, reduced economic productivity, long-term disability, and premature death.

Pathophysiology

HBV is a DNA virus in the Hepadnaviridae family. The virus is responsible for 40% of hepatitis cases in the United States. Seven major genotypes of HBV are recognized, with different geographic distributions. The genotypes are thought to affect disease progression, but their role in response to treatment is not as clear as in hepatitis C. The genome of HBV is a partially double-stranded, circular DNA molecule of 3200 nucleotides that encodes the following:

The precore/core region of a nucleocapsid core protein (hepatitis B core antigen [HBcAg]) and a precore protein (hepatitis B e antigen [HBeAg]: HBcAg is retained in the infected hepatocyte; HBeAg is secreted into blood and is essential for the establishment of persistent infection
Envelope glycoprotein (ie, hepatitis B surface antigen [HBsAg]), which may be produced and secreted into the blood in massive amounts: Blood HBsAg is immunogenic and can be visualized as spheres or tubules
A DNA polymerase with reverse transcriptase activity: Genomic replication takes place through an intermediate RNA known as pregenomic RNA. In this process, mutant viral genomes are frequently generated
HBV-X protein: This acts as a transcriptional transactivator for many viral and host genes through interaction with various transcription factors. HBV-X is required for viral infectivity and may have a role in the causation of hepatocellular carcinoma by regulating p53 degradation and expression

HBV is a double-stranded DNA virus of the Hepadnaviridae family. HBV is a hepatotropic virus that replicates in the liver and causes hepatic damage and dysfunction. HBV is transmitted by percutaneous or permucosal exposure to infectious body fluids, by sexual contact with an infected person, and by perinatal transmission from an infected mother to her infant. Persons with chronic HBV infection are predisposed to chronic liver disease and have a greater than 200-fold increased risk of hepatocellular carcinoma.

Fulminant hepatic failure occurs in approximately 0.1-0.5% of patients and is believed to be caused by massive immune-mediated lysis of infected hepatocytes. Various extrahepatic manifestations (eg, urticarial rashes, arthralgia, arthritis) are associated with acute clinical and subclinical HBV infection, as well as multiple immune-complex disorders such as Gianotti-Crosti syndrome (papular acrodermatitis), necrotizing vasculitis, and hypocomplementemic glomerulonephritis.

HBV is associated with 20% of membranous nephropathy cases in children. Essential mixed cryoglobulinemia, pulmonary hemorrhage related to vasculitis, acute pericarditis, polyserositis, and Henoch-Schönlein purpura have been reported in association with HBV infection.

The adaptive immune response is thought to be responsible for viral clearance and disease pathogenesis during HBV infection. The humoral antibody response contributes to the clearance of circulating virus particles and the prevention of viral spread within the host while the cellular immune response eliminates infected cells.

Persistent HBV infection is characterized by a weak immune response due to inefficient CD4+ T cell (helper T cell) priming early in the infection and subsequent development of a quantitatively and qualitatively ineffective CD8+ T (cytotoxic T cell) cell response. [5]

Etiology

HBV is transmitted by percutaneous or permucosal exposure to infectious body fluids, by sexual contact with an infected person. It is also transmitted by perinatal transmission from an infected mother to her infant.

The virus is present in all body fluids, except stool. Blood and body fluids are the primary vehicles of transmission; the virus may also spread by contact with body secretions, such as saliva, sweat, tears, breast milk, semen, and pathologic effusions.

Modes of transmission are the same as for the human immunodeficiency virus (HIV), but HBV is 50-100 times more infectious. Unlike HIV, HBV can survive outside the body for at least 7 days. During that time, the virus can still cause infection if it enters the body of a person who is not infected.

Common modes of transmission in developing countries are as follows:

Perinatal (from mother to baby at birth)
Early childhood infections (inapparent infection through close interpersonal contact with infected household contacts)
Unsafe injection practices
Blood transfusions
Sexual contact

In many developed countries (eg, those in Western Europe and North America), patterns of transmission are different from those mentioned above. Today, most infections in these countries are transmitted during young adulthood by sexual activity and injecting drug use. HBV is a major infectious occupational hazard of health workers.

HBV is not spread by contaminated food or water and cannot be spread casually in the workplace.

Patients who are hepatitis B surface antigen (HBsAg) carriers should be educated about safe-sex practices and universal vaccination benefits. For patient education information, see Hepatitis B, Hepatitis A and B Vaccinations: Why You Need Them, and Hepatitis B Resource Center.

Epidemiology

United States statistics

The incidence (rate of new cases) of acute HBV infection has decreased dramatically in the United States since the mid 1980s. Reported acute clinical cases declined from 8,064 in 2002 to 4,519 in 2007. Many HBV infections are either asymptomatic or never reported, however; consequently, the US Centers for Disease Control and Prevention (CDC) estimates that 43,000 new infections occurred in the US in 2007. [6]

The reduction in incidence can be attributed to the availability of an effective vaccine and widespread immunization of infants and high-risk populations. However, the number of people who have chronic HBV infection remains high because of the long duration of infection and influx of immigrants who have chronic infection. National surveys have estimated that more than 1 million US residents (that 0.3-0.5% of the population) have chronic infection, which contributes to an estimated 2,000-4,000 deaths each year. Of these persons, 47-70% were born outside the United States.

More than 10,000 affected individuals require hospitalization, and 250 die of fulminant disease. In addition, 22,000 women with HBV infection give birth each year.

A study by Schillie et al found that perinatal HBV infection occurred among 1% of infants, most of whom received recommended immunoprophylaxis. Infants at greatest risk of infection were those born to women who were younger, hepatitis B e-antigen positive, or who had a high viral load or those infants who received < 3 HepB vaccine doses. [7]

International statistics

HBV infects more than 350 million people worldwide. Approximately 5% of the world's population has chronic HBV infection and it is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. Each year, an estimated 500,000 people die of cirrhosis and hepatocellular carcinoma caused by chronic infection and an additional 40,000 people die of acute hepatitis B. An estimated 500,000-1,000,000 persons die annually from HBV-related liver disease.

The distribution of HBV infection widely varies throughout the world. In some regions, over 10% of the population is positive for hepatitis B surface antigen (HBsAg), which indicates active infection. Countries are classified as having low endemic rates (< 2% of the population has the antibody to HBsAg), intermediate endemic rates (2-8% positive for HBsAg), or high endemic rates (>8% positive for HBsAg).

Hepatitis B is endemic in China, Southeast Asia, and Africa. Most people in the region become infected with HBV during childhood. In these regions, 8-10% of the adult population is chronically infected, which is the result of either neonatal transmission (vertical) or transmission from one individual to another (horizontal). In the Middle East and Indian subcontinent, an estimated 2-5% of the general population is chronically infected. High rates of chronic infections are also found in the Amazon region of South America and the southern parts of eastern and central Europe. Less than 1% of the population in Western Europe and North America is chronically infected, mostly as a result of horizontal transmission among young adults.

The prevalence of HBV infection is higher among black populations than among white populations. According to the CDC, approximately 20% of new reported cases each year in the United States occur in African Americans.

Exacerbations of chronic HBV infection are observed more often in men than in women. Although the reason for this sex difference is not clear, the higher frequency of exacerbations in men may account, in part, for the higher incidence of HBV-related cirrhosis and hepatocellular carcinoma among men.

Most acute HBV infections in the United States occur among young adults, although about one third of patients acquire chronic infections through perinatal and early childhood exposures. The prevalence increases with age. The age at infection primarily determines the rate of progression from acute infection to chronic infection, which is approximately 90% in the perinatal period, 20-50% in children aged 1-5 years, and less than 5% in adults.

Prognosis

Morbidity/mortality

Among patients with acute hepatitis B, 90% have a favorable course and recover completely. Patients of advanced age and those with serious underlying medical disorders, such as congestive heart failure, severe anemia, and diabetes mellitus, may have a prolonged course and are more likely to have severe hepatitis.

Although fatality rates for most cases of hepatitis B are low, patients ill enough to be hospitalized for acute hepatitis B have a 1% fatality rate.

In patients with persistent infection, 10-30% develop chronic hepatitis. Of patients with chronic hepatitis, 20-50% of patients progress to cirrhosis, and approximately 10% of those who progress to cirrhosis may develop hepatocellular carcinoma.

Approximately 2,000-4,000 persons in the United States die each year of HBV-related conditions. Most deaths are attributed to cirrhosis and primary hepatocellular carcinoma, and a smaller proportion of patients die of fulminant hepatitis. HBV-infected individuals are also at increased risk of death from nonliver causes such as non-Hodgkin lymphoma and circulatory diseases.

Complications

Rare complications of viral hepatitis are as follows:

Pancreatitis
Transverse myelitis
Peripheral neuropathy

Author

Coauthor(s)

Poonam Sharma, MD Assistant Professor, Department of Pathology, Creighton University Medical Center and Veterans Affairs Medical Center; Director of Pathology Course, School of Pharmacy and Health Professions, Creighton University Medical Center

Poonam Sharma, MD is a member of the following medical societies: College of American Pathologists, United States and Canadian Academy of Pathology