AUTHOR INFORMATION

Section 1 of 11

Authored by Alexander T Kessler, MD, Consulting Staff, Northside Medical Specialties, LLC

Coauthored by Athena P Kourtis, MD, PhD, Assistant Professor, Department of Pediatrics, Divisions of Infectious Diseases and Epidemiology, Emory University School of Medicine

Edited by David Jaimovich, MD, Section Chief, Division of Critical Care, Hope Children's Hospital, Assistant Professor Pediatrics, Assistant Professor, Department of Pediatrics, University of Illinois at Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine; Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center

Author's Email:	Alexander T Kessler, MD
Editor's Email:	David Jaimovich, MD

eMedicine Journal, February 5 2007, VOLUME 8, Number 2

INTRODUCTION

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Background: Hepatitis B is a viral disease with a high incidence and prevalence worldwide. Hepatitis B 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. Perinatal or childhood infection is associated with few or no symptoms, but it 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 the hepatitis B virus (HBV).

Pathophysiology: HBV is a double-stranded DNA virus of the Hepadnaviridae family. HBV is a hepatotropic virus that replicates in the liver and causes hepatic 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, including urticarial rashes, arthralgia, and 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 the cases of membranous nephropathy 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.

Frequency:

• In the US: Each year in the United States, an estimated 200,000-300,000 persons become infected with HBV. More than 10,000 require hospitalization, and 250 die of fulminant disease. In addition, 22,000 HBV-infected women give birth each year. The prevalence of chronic HBV infection in the United States is 0.35%. Although the reported incidence of acute hepatitis B increased by 37% from 1979-1985, the incidence since 1986 has declined to 1979 levels.

• Internationally: Approximately 5% of the world’s population has chronic HBV infection; it is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. An estimated 500,000-1,000,000 persons die annually from HBV-related liver disease. Countries are classified as those with low endemic rates (<2% of the general population has the antibody to the hepatitis B surface antigen [HBsAg]), intermediate endemic rates (2-8% positive for HBsAg), or high endemic rates (>8% positive for HBsAg).

Mortality/Morbidity: Of the 5000 persons in the United States who die each year from HBV-related conditions, 300 die from fulminant hepatitis; 3000-4000, from cirrhosis; and 600-1000, from primary hepatocellular carcinoma.

Race: The prevalence of HBV infection is higher among black populations than among white populations.

Sex: 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.

Age: 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.

CLINICAL

Section 3 of 11

History: The incubation period for hepatitis B virus (HBV) infection ranges from 6 weeks to 6 months, and the clinical manifestations depend on the age at infection, level of HBV replication, and host's immune status.

• Perinatally infected infants generally have no clinical signs or symptoms, and infection produces typical illness in only 5-15% of children aged 1-5 years.



• Older children and adults are symptomatic in 33-50% of infections.



• Clinical signs and symptoms of acute HBV infection include anorexia, nausea, malaise, vomiting, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, coryza, jaundice, dark urine, clay-colored or light stools, and abdominal pain.



• Fulminant hepatitis occurs in 1-2% of persons with acute disease and has a case/fatality ratio of 63-93%.

Physical:

• On physical examination, with the onset of clinical jaundice, the liver becomes enlarged and tender, and the patient may have right upper quadrant pain and discomfort.



• Splenomegaly and cervical adenopathy are present in 10-20% of patients with acute hepatitis.



• A few spider angiomas may appear during the icteric phase and disappear during convalescence, although angiomas are rare.

Causes:

• HBV, a DNA virus in the Hepadnaviridae family, causes hepatitis B. Seven major genotypes of HBV exist, with different geographic distributions. The genotypes are thought to affect disease progression, but their role in response to treatment is not as clear cut as for hepatitis C.



• Several well-characterized groups in the United States have an increased risk of hepatitis B infection, including injecting-drug users, homosexual men, persons who have heterosexual contact with multiple partners, household contacts of persons with chronic hepatitis B infection, hemophiliacs, hemodialysis patients and staff, and persons with occupational exposure to blood and infectious body fluids.

DIFFERENTIALS

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Autoimmune Chronic Active Hepatitis
Cytomegalovirus Infection
Hepatitis A
Hepatitis C
Herpes Simplex Virus Infection

Other Problems to be Considered:

Viral hepatitis shares certain clinical features with other viral diseases such as infectious mononucleosis; diseases caused by cytomegalovirus, herpes simplex, and coxsackieviruses; and toxoplasmosis. These diseases elevate serum aminotransferase levels and, less commonly, serum bilirubin levels. A complete drug history is particularly important because many drug and some anesthetic agents can produce a picture of acute hepatitis. Alcoholic hepatitis also must be considered. Acute hepatitis often is confused with acute cholecystitis, common duct stone, or ascending cholangitis.

WORKUP

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Lab Studies:

• Elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are hallmarks of acute hepatitis. Values as high as 1000-2000 IU/L are typical, with ALT values higher than AST values. In patients with hepatitis, increases in bilirubin levels often lag behind increases in aminotransferase levels. The prothrombin time is the best indicator of prognosis. Alpha-fetoprotein levels as high as 8000 ng/mL may also be seen.



• Because the symptoms of acute hepatitis B virus (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.


• • Acute HBV infection is characterized by the presence of HBsAg in the serum. This appears before the onset of symptoms and the elevation of ALT values, with the development of immunoglobulin M (IgM)–class antibody to hepatitis B core antigen (HBcAg).
  
  
  
  • Hepatitis B antigen (HBeAg), HBV DNA, and DNA polymerase also are detectable during acute infection. Measuring HBV DNA with quantitative DNA PCR is ideal for monitoring disease progression and effect of treatment.
  
  
  
  • During convalescence, HBsAg and HBeAg are cleared, and immunoglobulin G (IgG) antibodies to HBsAg, HBcAg, and HBeAg develop.
  
  
  
  • Hepatitis B surface antibody (HBsAb) is a protective antibody that neutralizes the virus, although the coexistence of HBsAg and HBsAb has been reported in approximately 25% of HBsAg-positive individuals. HBsAb, but not hepatitis B core antibody (HBcAb), is detected in persons who have received the hepatitis B vaccine.
  
  
  
  • Total HBcAb, including IgM and IgG, indicates exposure to the virus and viral replication. HBcAb appears shortly after HBsAg in acute disease and persists for life; therefore, HBcAb is not a good marker for acute disease.
  
  
  
  • Detection of IgM HBcAb is diagnostic of acute HBV infection. The carrier state is defined by the presence of HBsAg in the serum for 6 months or longer after its initial detection.
  
  
  
  • The presence of HBsAg alone does not necessarily indicate replication of complete virions, and patients may not have symptoms or liver damage.
  
  
  
  • In contrast, chronic replication of HBV virions is characterized by the persistence of circulating HBsAg, HBeAg, and HBV DNA, usually with HBcAb.
  
  
  
• The major clinical role of serum HBV DNA assays is the assessment of the candidacy of patients with chronic HBV infection for antiviral therapy and their response to it. Tests for HBV DNA in serum rarely help in identifying HBV as the cause of liver disease in HBsAg-negative patients; knowledge of this fact is especially important in patients with fulminant hepatitis B in whom HBsAg may have cleared by the time they seek care.

Procedures:

• Patients with signs of chronic disease may require a liver biopsy to assess the extent of histologic involvement and response to therapeutic protocols.

With acute hepatitis, hepatocyte injury takes the form of diffuse swelling. An inconstant finding is cholestasis. Two patterns of hepatocyte cell death are observed: cytolysis and apoptosis. In severe cases, confluent necrosis of hepatocytes may lead to bridging necrosis. Inflammation is a prominent feature of acute hepatitis. Kupffer cells undergo hypertrophy and hyperplasia. Usually, the portal tracts are infiltrated with a mixture of inflammatory cells.

Histologic features of chronic hepatitis range from exceedingly mild to severe. In the mildest forms, significant inflammation is limited to the portal tracts. Continued interface hepatitis and bridging necrosis are harbingers of progressive liver damage. Deposition of fibrous tissue is the hallmark of irreversible liver damage. Continued loss of hepatocytes and fibrosis results in cirrhosis, with fibrous septa and hepatocyte regenerative nodules, called postnecrotic cirrhosis.

TREATMENT

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Medical Care: Until recently, no specific treatment has been available for persons with acute hepatitis B virus (HBV) infection. Supportive and symptomatic care used to be the mainstay of therapy for most patients. However, the recent advent of nucleoside analogues such as lamivudine and adefovir dipivoxil has had a major impact on treatment of chronic hepatitis B. Nucleoside analogues achieve viral suppression (as measured by loss of HbeAg and suppression of HBV DNA), and interferon alpha (IFN-a) aims at immunomodulation.

New nucleoside analogues that are not yet FDA approved are tenofovir, emtricitabine, clevudine, and entecavir. The latter has the advantage of developing very little resistance and is effective against mutants resistant to lamivudine. Telbuvidine is an L-nucleoside with specific anti-HBV activity that was approved by the FDA in 2006. It seems to achieve significantly better viral suppression than lamivudine monotherapy, although resistance and cross-resistance is common. Combination therapy in the future may have additive or synergistic effects, reduction of adverse effects, and reduction of resistance with achievement of better viral suppression.

Surgical Care:

• Liver transplantation for decompensated liver disease



• Surgical resection of hepatocellular carcinoma

Consultations:

• Infectious-disease specialists for placement in therapeutic protocols



• Gastroenterologist for biopsy assessment and therapy

Diet: A high-energy diet is desirable, and because many patients may have nausea late in the day, they best tolerate their major caloric intake in the morning. Intravenous feeding is necessary in the acute stage if the patient has persistent vomiting and cannot eat.

Activity: Although forced and prolonged bed rest is not essential for full recovery, many patients feel better with restricted physical activity.

MEDICATION

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IFN-a has been the mainstay of treatment for chronic hepatitis B since its introduction in the mid-1980s, although only 30-40% of patients respond to this therapy. Lamivudine and the newer nucleoside analogues famciclovir, lobucavir, and adefovir dipivoxil directly block the replication of hepatitis B virus (HBV); they are highly effective, bioavailable, and extremely well tolerated. To date, only IFN-a, lamivudine, adefovir, and telbivudine are FDA approved for this indication. For more information, see Guidelines from the American Association for the Study of Liver Diseases (AASLD) for Chronic Hepatitis B.

Drug Category: Antiviral agents -- Interferon may prevent the progression of acute hepatitis to the chronic stage and promote more rapid resolution of viremia and normalization of serum aminotransferase levels. Several nucleoside analogues are active against HBV. The most widely used and studied is lamivudine, which has produced promising responses. However, relapse rates tend to be high after treatment is discontinued.

Drug Name	Interferon alfa-2b (Intron A) -- Interferons (IFNs) are proteins produced by host cells in response to viral infection. Three interferons have been identified, and each has antiviral and immunoregulatory actions: IFN-a is produced by B lymphocytes and monocytes; IFN-b, by fibroblasts; and IFN-g, by T helper and NK cells. Immunomodulatory effects of IFNs are mediated by an increase in HLA class I antigen and FC receptor expression, an increased CD4/CD8 ratio, and activation of NK cell pathways. Ideally, candidates for IFN therapy have evidence of ongoing viral replication (presence of HBeAg or HBV DNA) for at least 6 mo and either persistently increased serum aminotransferase activity or evidence of chronic hepatitis B infection at liver biopsy. Before IFN therapy, screening patients for at least 4-6 mo to identify those who may be entering a period of spontaneous seroconversion to HBeAb is often beneficial. Clinical variables associated with a favorable response to therapy are high pretherapy aminotransferase levels, low HBV DNA levels, and active disease at liver biopsy. Other less useful variables include female sex, acquisition of infection in adulthood, heterosexuality, HIV antibody negativity, and history of acute hepatitis. Responses to IFN-a-2b, is defined as a sustained loss of HBeAg and HBV DNA with a normalization or near normalization of ALT levels for at least 6 mo after therapy, is observed in 25-40% of patients. Controlled studies of IFN in children reveal comparable responses in primary non-Asian children. Chinese children respond poorly to IFN therapy. Safety and effectiveness in patients aged from 1-17 years have been established.
Adult Dose	5 million U SC qd or 10 million U SC 3 times per wk
Pediatric Dose	<1 year: Not established 1-17 years: High dose: 7.5-10 million U/m2 SC 3 times per wk Low dose: 3-6 million U/m2 SC 3 times per wk; studies with both showed that the high dose was more effective
Contraindications	Documented hypersensitivity; decompensation (cirrhosis)
Interactions	Interactions with other medications have not been evaluated fully; use caution with potentially myelosuppressive agents such as zidovudine; combination with theophylline decreases theophylline clearance, increasing theophylline levels by 100%
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	IFN does not appear to protect against hepatocellular carcinoma; treatment is associated with frequent adverse events; dose reduction is required in at least 20% of patients treated with recommended regimen; discontinuation of treatment is necessary in <5% of instances; most patients have influenza-like illness with fever, chills, myalgia, and headaches 6-8 hours after first injection; symptoms improve or disappear with subsequent injections; patients benefit from premedication with acetaminophen or NSAIDs Psychiatric adverse effects, especially depression, occur in about 15% of patients; frank delirium and suicidal ideation have been reported IFN decreases the platelet count by 30-50%, total white cell count by 20-40%, and hematocrit level slightly; changes are clinically insignificant and often return to normal after treatment is discontinued; can induce an autoimmune diathesis; associated with clinically significant worsening or unmasking of autoimmune conditions; autoantibodies, such as antinuclear, anti–smooth muscle, antithyroid, and insulin antibodies, develop in >50% of patients treated for 4 mo; thyroid abnormalities infrequent; evaluate serum TSH levels prior to therapy Acute, serious, hypersensitivity reactions (rare) require immediate discontinuation; transient rashes have occurred after injection but have not required treatment interruption; may exacerbate preexisting psoriasis

Drug Name	Lamivudine (Epivir-HBV) -- Only one of two nucleoside analogues approved by the FDA for chronic HBV treatment. It inhibits HBV DNA polymerase. Use should be considered in patients with ongoing HBV replication, elevated aminotransferase activity, and histologic evidence of liver injury. Lamivudine is now considered first-line therapy, eclipsing interferon. Consider lamivudine for cases that fail or are unlikely to respond to interferon or patients who cannot tolerate interferon. Discontinue lamivudine only when repeated assays demonstrate HBeAg loss or seroconversion to HbeAb; the time for stopping treatment, however, is controversial. Results of a histologic study showed that lamivudine treatment for 3 y reduced necroinflammatory activity and reversed fibrosis (including cirrhosis) in most patients. Emergence of resistance is the major drawback of nucleoside analogue monotherapy (incidence of resistance rises from 15-32% in the first year to 67-69% by the fifth year of treatment). The proper management of viral breakthrough in patients treated with lamivudine is not yet defined. Continuation of lamivudine appears to be warranted in most cases because the resistant strains of HBV seem to be attenuated and are associated with only mild liver injury. Combination therapy with 2 or 3 nucleoside analogues may delay or prevent emergence of viral resistance, but clinical trials are needed. Safe and effective in children aged 2-17 y. Note that the available dosage forms differ between Epivir and Epivir-HBV (formula specific for hepatitis B virus). Epivir-HVB is available as a 100 mg tab or oral solution 5 mg/mL, whereas Epivir contains 150 mg/tab or 10 mg/mL in oral solution.
Adult Dose	Epivir HBV: 100 mg PO qd
Pediatric Dose	<2 years: Not established 2-17 years: 3 mg/kg/d PO; not to exceed 100 mg daily >17 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Trimethoprim/sulfamethoxazole increases bioavailability of lamivudine; lamivudine increases concentration of zidovudine when administered concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in pediatric patients with history of prior antiretroviral nucleoside exposure, pancreatitis, or other significant risk factors for pancreatitis; new-generation nucleoside analogues appear to be remarkably free of adverse effects; mild constitutional symptoms (eg, malaise, fatigue, headache, nausea, abdominal discomfort) have been reported; aminotransferase levels increase in 30-40% of patients; lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, have been reported (mostly in women); obesity and prolonged exposure to nucleosides may be risk factors; physician experienced in managing chronic hepatitis B should assess patients before treatment; safety and efficacy is not established in patients with decompensated liver disease or organ transplants, in pediatric patients, and in patients dually infected with HBV, HCV, hepatitis delta, or HIV; reduced dose recommended in impaired renal function

Drug Name	Adefovir dipivoxil (Hepsera) -- Second nucleoside analogue FDA approved for chronic hepatitis B. An acyclic analogue of deoxyadenoside monophosphate and inhibits amplification of circular DNA in HBV-infected hepatocytes. When given daily for 48 wk, was associated with significant improvement of histologic results, higher rate of HbeAg seroconversion, reduction of HBV DNA by 3 logs, and higher normalization rate of ALT when compared with placebo. Has low chance of adefovir resistance development; however, a new adefovir-resistant mutant has been detected in 1.6% of patients at 96 weeks follow-up.
Adult Dose	CrCl >50 mL/min: 10 mg PO qd CrCl 20-49 mL/min: 10 mg PO q48h CrCl 10-19 mL/min: 10 mg PO q72h Hemodialysis: 10 mg PO qwk following hemodialysis
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with drugs excreted renally or known to affect renal function may affect adefovir renal elimination; ibuprofen 800 mg PO tid increased adefovir exposure by approximately 23%; however, the clinical significance of this is unknown
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Overall, a safe medication; no renal toxic effects recorded in clinical trials with the dose used for chronic hepatitis B, but renal function must be monitored closely; higher doses may have renal adverse effects, including renal tubular dysfunction

Drug Name	Entecavir (Baraclude) -- Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic hepatitis B infection. Available as tab and oral solution (0.05 mg/mL; 0.5 mg = 10 mL).
Adult Dose	Treatment for nucleoside naive: 0.5 mg PO qd 2 h ac or 2 h pc CrCl 30-49 mL/min: 0.25 mg PO qd CrCl 10-29 mL/min: 0.15 mg PO qd CrCl <10 mL/min: 0.05 mg PO qd Receiving lamivudine or lamivudine resistance: 1 mg PO qd 2 h ac or 2 h pc CrCl 30-49 mL/min: 0.5 mg PO qd CrCl 10-29 mL/min: 0.3 mg PO qd CrCl <10 mL/min: 0.1 mg PO qd
Pediatric Dose	<16 years: Not established >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Not a substrate, inhibitor, or inducer of cytochrome P450; coadministration with drugs that reduce renal function (eg, aminoglycosides, cidofovir, cyclosporine) or that compete for active tubular secretion (eg, probenecid, salicylates) may increase serum concentration of either entecavir or coadministered drug
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Reduce dose with renal impairment; if on hemodialysis, administer afterwards; common adverse effects include headache, tiredness, dizziness, and nausea; may elevate liver enzyme levels; may cause lactic acidosis; severe acute exacerbations of hepatitis B may occur in patients who discontinue antihepatitis B therapy

Drug Name	Telbivudine (Tyzeka) -- Nucleoside analogue approved by FDA for chronic hepatitis B treatment. Inhibits hepatitis B viral DNA polymerase. Indicated in patients with evidence of ongoing hepatitis B viral replication and either persistent elevated aminotransferase activity or histologic evidence of active liver disease. Consider in patients who did not or are unlikely to respond to interferon or for patients who cannot tolerate interferon. Emergence of resistance is major drawback of nucleoside analogue monotherapy.
Adult Dose	CrCl >50 mL/min: 600 mg PO qd CrCl 30-49 mL/min: 600 mg PO q48h or 400 mg PO qd CrCl <30 mL/min (not requiring dialysis): 600 mg PO q72h or 200 mg PO qd ESRD: 600 mg PO q96h Optimal treatment duration not established
Pediatric Dose	<16 years: Not established >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Toxicity may increase when concurrently administered with drugs that decrease renal excretion (eg, acyclovir, aminoglycosides, amphotericin B, cisplatin, cyclosporine, metformin, tacrolimus); may increase risk of myopathy when coadministered with HMG-CoA reductase inhibitors (statins)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with use of nucleoside analogs alone or in combination with antiretrovirals; severe acute hepatitis B exacerbations reported when anti–hepatitis B therapy (including telbivudine) is discontinued (closely monitor hepatic function with both clinical and laboratory follow-up for at least several months following discontinuation of anti–hepatitis B therapy and resume therapy if necessary); myopathy has been reported; common adverse effects include upper respiratory tract infection, fatigue, malaise, abdominal pain, nasopharyngitis, headache, increased CK level, cough, nausea, vomiting, flulike symptoms, diarrhea, pyrexia, arthralgia, rash, back pain, dizziness, and dyspepsia

FOLLOW-UP

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Further Inpatient Care:

• Most patients do not require hospital care. Patients with clinically severe illness may require hospitalization.



• A prolonged prothrombin time, low serum albumin level, hypoglycemia, and very high serum bilirubin values suggest severe hepatocellular disease; patients with these findings require prompt hospital admission.

Further Outpatient Care:

• Each vaccinated infant born to an HBsAg-positive mother should be tested for HBsAg during routine follow-up when he or she is aged 6 months.


• • An HBsAg positive finding in an infant, which is rare, indicates failure of immunoprophylaxis, and the third vaccine dose is not necessary.
  
  
  
  • Breastfeeding is acceptable and does not pose a risk of transmitting hepatitis B virus (HBV) to infants who have begun prophylaxis.
  
  
  
• Reserve routine screening of chronic HBV-infected patients with ultrasonography and alpha-fetoprotein determination for patients with severe chronic active hepatitis, cirrhosis, or both.

Deterrence/Prevention:

• Hepatitis B is one of the major diseases of mankind that can be prevented with vaccination. Two types of recombinant hepatitis B vaccines are licensed for use in the United States; both are effective and safe.



• Universal vaccination refers to the administration of HBV vaccine to all infants as a part of the routine childhood immunization schedule and to all children younger than 11 or 12 years who have not previously received a vaccine. Rapid (0-, 1-, and 2-mo) and standard (0-, 1-, 6-mo) schedules have identical efficacy.



• Passive immunization refers to the administration of preformed human or animal antibody, in the form of hepatitis B immunoglobulin (HBIG), to patients after or just before exposure.


• • The current recommendation for neonates of HBsAg-positive mothers is to administer HBIG 0.5 mL intramuscularly with the first dose of recombinant HBV vaccine within 12 hours of birth.
  
  
  
  • In infants of infected mothers, combined treatment with the vaccine and HBIG has 79-98% efficacy in preventing chronic HBV infection.
  
  
  

Complications:

• Fulminant hepatitis is the most feared complication of viral hepatitis. Fulminant hepatitis is observed primarily in hepatitis B (>50% of fulminant hepatitis cases) and in delta hepatitis. Patients typically present with signs and symptoms of hepatic encephalopathy that may evolve to deep coma. Usually, the liver is small, and the prothrombin time is excessively prolonged.



• The most severe complications of chronic hepatitis B infection are cirrhosis and hepatocellular carcinoma.



• Rare complications of viral hepatitis are as follows:


• • Pancreatitis
  
  
  
  • Myocarditis
  
  
  
  • Atypical pneumonia
  
  
  
  • Aplastic anemia
  
  
  
  • Transverse myelitis
  
  
  
  • Peripheral neuropathy
  
  
  

Prognosis:

• In acute hepatitis B, 90% of patients have a favorable course and recover completely.



• Patients of advanced ages and those with serious underlying medical disorders, such as congestive heart failure (CHF), severe anemia, and diabetes mellitus, may have a prolonged course and are more likely to have severe hepatitis.



• The prothrombin time is the best indicator of the prognosis in patients with acute 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.

Patient Education:

• Educate patients who are HBsAg carriers about safe-sex practices and universal vaccination benefits.



• For excellent patient education resources, visit eMedicine's Hepatitis Center and Children's Health Center. Also, see eMedicine's patient education articles Hepatitis B and Immunization Schedule, Children.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to screen a pregnant mother or a mother who presents in labor without having received prenatal care and whose hepatitis B status, therefore, is unknown could lead to physician liability, because the baby may not have received optimal prophylaxis and is at risk for chronic hepatitis B.



• Failure of the physician to either notify an infected person identified with blood screening or other tests or provide appropriate counsel regarding transmission (eg, sexual contact, needle sharing) may lead to the exposure of additional people to hepatitis B.

TEST QUESTIONS

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CME Question 1: A patient with hepatitis B surface antigen (HBsAg), immunoglobulin G (IgG) hepatitis B core antibody (HBcAb), hepatitis B antigen (HBeAg), and hepatitis B virus (HBV) DNA most likely has which of the following?

A: Nonreplicative phase of chronic hepatitis B
B: Immunity to hepatitis B after HBV immunization
C: Replicative phase of chronic hepatitis B
D: Window period of acute hepatitis B
E: Recovery of acute hepatitis B

The correct answer is C: Presence of HBeAg in the serum and of HBV DNA is an indicator of HBV replication and infectivity. Immunity to hepatitis B is conferred by HBsAb. The window period of acute hepatitis is characterized by the isolated detection of immunoglobulin M (IgM) HBcAb.

CME Question 2: Which of the following is the major determinant of the risk of chronic hepatitis B virus (HBV) infection?

A: Percutaneous transmission of HBV
B: Age at the time of infection
C: Excessively prolonged prothrombin time
D: Detection of immunoglobulin G (IgG) hepatitis B core antibody (HBcAb) in the serum
E: Detection of HBV DNA in the serum

The correct answer is B: Risk of chronic infection with HBV is inversely related to the patient`s age at the time of infection. 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.

Pearl Question 1 (T/F): Liver cirrhosis and hepatocellular carcinoma are the most serious complications of hepatitis B virus (HBV) infection.

The correct answer is True: Liver cirrhosis and hepatocellular carcinoma are the most serious complications of hepatitis B infection. Approximately 5% of the world’s population has chronic HBV infection; it is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. An estimated 500,000-1,000,000 persons die annually from HBV-related liver disease. Of the 5000 persons in the United States who die each year from HBV-related conditions, 300 die from fulminant hepatitis; 3000-4000, from cirrhosis; and 600-1000, from primary hepatocellular carcinoma.

Pearl Question 2 (T/F): The hepatitis B surface antibody (HBsAb) test is the best screening test for hepatitis B infection.

The correct answer is False: Hepatitis B surface antigen (HBsAg) in the serum is the best screening test for hepatitis B infection. Acute HBV infection is characterized by the presence of HBsAg in the serum. This appears before the onset of symptoms and the elevation of ALT values, with the development of immunoglobulin M (IgM)–class antibody to hepatitis B core antigen (HBcAg).

Pearl Question 3 (T/F): Interferon alpha is a currently approved agent for the treatment of chronic hepatitis B virus (HBV) infection.

The correct answer is True: Interferon alpha and lamivudine (3-TC) are both approved for the treatment of chronic hepatitis B. Alpha interferon (IFN-a) has been the mainstay of treatment for chronic hepatitis B since its introduction in the mid-1980s, although only 30-40% of patients respond to this therapy. Lamivudine and the newer nucleoside analogues famciclovir, lobucavir, and adefovir dipivoxil directly block the replication of HBV; they are highly effective, bioavailable, and extremely well tolerated. To date, only IFN-a and lamivudine are FDA approved for this indication.

Pearl Question 4 (T/F): The recommended preventive strategy for perinatal exposure to hepatitis B virus (HBV) involved the initiation of hepatitis B vaccination at birth.

The correct answer is False: Initiate hepatitis B immunoglobulin (HBIG) within 12 hours of birth and with concurrent initiation of the hepatitis B vaccine series. The current recommendation for neonates of HBsAg-positive mothers is to administer HBIG 0.5 mL intramuscularly with the first dose of recombinant HBV vaccine within 12 hours of birth. In infants of infected mothers, combined treatment with the vaccine and HBIG has 79-98% efficacy in preventing chronic HBV infection.

BIBLIOGRAPHY

Section 11 of 11

• Bhimma R, Coovadia HM, Adhikari M, Connolly CA: The impact of the hepatitis B virus vaccine on the incidence of hepatitis B virus-associated membranous nephropathy. Arch Pediatr Adolesc Med 2003 Oct; 157(10): 1025-30[Medline].
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