Harrison's Practice: Hepatitis B, Acute

Harrison's Practice

Hepatitis B, Acute

Definition

An acute systemic infection caused by the hepatitis B virus (HBV)
Liver is the primary target, but extrahepatic complications are common.
Transmitted by percutaneous, perinatal, and sexual routes
After acute infection, complete recovery with lifetime immunity occurs in ~95% of patients.
- Possible long-term complications
  - Chronic infection
  - Chronic liver disease
  - Liver failure
  - Hepatocellular carcinoma

Epidemiology

Incidence
- In the U.S.: 2.8 per 100,000 persons
- Causes ~25% of cases of acute viral hepatitis in the U.S.
  - Responsible for ~15% of cases of chronic viral hepatitis in the U.S.
Prevalence
- 4519 total cases reported in U.S. in 2007[1]
- 80% reduction in number of cases and number of deaths in U.S. between 1985 and 2006 due to vaccine and widespread immunization[2]
- 40,000 deaths yearly worldwide
Age
- Far East and Africa: disease of newborn and young children
- North America and western Europe: disease of adolescence and early adulthood
Sex
- In the U.S.: more men than women

Risk Factors

Spouse of an acutely infected person
Individuals who have unprotected sex with multiple partners (especially men who have sex with men)
Health care workers exposed to blood
Drug abusers who share needles
Individuals who snort cocaine
Recipients of repeated transfusions, especially of pooled blood concentrates (e.g., hemophiliacs)
Residents and staff of custodial institutions for developmentally handicapped persons
Incarcerated persons
Family members of chronically infected persons
Patients on hemodialysis
Recipients of a transplanted organ
Children born to an infected mother

Etiology

Caused by HBV
- DNA virus
- Genus: Orthohepadnavirus
- Family: Hepadnavirus
Transmission
- Through infected blood or body fluids
- Percutaneous: needle sharing
- Perinatal
  - Uncommon in North America and western Europe
  - Important mode of transmission in Far East and developing countries
  - Likelihood of perinatal transmission correlates with presence of hepatitis B e antigen (HBeAg).
  - Rate of transmission to offspring
    - 90% if mother is HBeAg-positive
    - 10–15% if mother is anti–HBe-positive
- Sexual
- Oral (rare)
Pathogenesis
- Nucleocapsid proteins (hepatitis B core antigen and possibly HBeAg), which are present on the cell membrane in minute quantities, together with host antigens, invite cytolytic T cells to destroy HBV-infected hepatocytes.
- Differences in cytolytic T cell responsiveness and in the elaboration of antiviral cytokines by T cells may account for differences in outcomes between:
  - Those who recover after acute hepatitis and those who progress to chronic hepatitis
  - Those with mild and those with severe (fulminant) acute HBV infection
- The occasional prodromal serum sickness–like syndrome appears to be related to:
  - Deposition in blood vessel walls of HBsAg-anti-HBs circulating immune complexes
  - Activation of the complement system and an inflammatory response

Symptoms & Signs

Incubation period: 30–180 days, typically about 3 months
Most infections are asymptomatic.
More likely to be severe in patients co-infected with hepatitis C or D
Constitutional symptoms may precede the onset of jaundice by 1–2 weeks (prodromal symptoms).
- Anorexia
- Nausea
- Vomiting
- Fatigue
- Malaise
- Arthralgias
- Myalgias
- Headache
- Photophobia
- Pharyngitis
- Cough
- Coryza
- Low-grade fever
Symptoms and signs related to liver dysfunction
- Jaundice
- Dark urine
- Clay-colored stools
- Tender hepatomegaly
- Right upper-quadrant pain
Uncommon symptoms and signs
- Splenomegaly (10–20% of patients with acute hepatitis)
- Cervical adenopathy (10–20% of patients with acute hepatitis)
- Spider angiomata
Extrahepatic manifestations
- Signs of extensive acute immune reactivity: arthritis, urticaria, angioedema
- Hematuria
- Proteinuria
Rare presentation in childhood
- Papular acrodermatitis of childhood or Gianotti–Crosti syndrome
  - Anicteric hepatitis
  - Non-pruritic papular rash of the face, buttocks, and limbs
  - Lymphadenopathy

Differential Diagnosis

Other hepatitis viruses
Other viral illnesses that frequently involve the liver
Toxoplasmosis
Rare causes of liver injury confused with viral hepatitis
- Leptospira species
- Candida species
- Brucella species
- Mycobacteria species
- Pneumocystis species
Many drugs and certain anesthetic agents
Alcoholic hepatitis
Acute cholecystitis
Common duct stone
Ascending cholangitis
Carcinoma of the pancreas
Other clinical constellations that may mimic acute hepatitis
- Right ventricular failure with passive hepatic congestion
- Hypoperfusion syndromes
  - Shock
  - Severe hypotension
  - Severe left ventricular failure
- Any disorder that interferes with venous return to the heart
  - Right-atrial myxoma
  - Constrictive pericarditis
  - Hepatic vein occlusion (Budd–Chiari syndrome)
  - Veno-occlusive disease
Disorders in pregnancy that may be confused with viral hepatitis
- Acute fatty liver of pregnancy
- Cholestasis of pregnancy
- Eclampsia
- HELLP syndrome (hemolysis, elevated liver enzyme levels, and low platelet count)
Genetic or metabolic liver disorders
- Wilson disease
- α₁–Antitrypsin deficiency
- Hemochromatosis
Nonalcoholic fatty liver disease
Cancers that metastasize to the liver (rarely present similarly to acute viral hepatitis)

Diagnostic Approach

All patients with acute hepatitis should undergo 4 serologic tests.
- HBsAg
- IgM anti-HBc
- IgM anti–hepatitis A virus (HAV)
- Anti–hepatitis C virus (HCV)
The presence of HBsAg, with or without IgM anti-HBc, confirms HBV infection.
If IgM anti-HBc is present, HBV infection is considered acute.

Laboratory Tests

Diagnostic tests for acute HBV infection

Serum HBsAg
- Indicative of acute or chronic HBV infection
- Infrequently, levels of HBsAg are too low to be detected during acute HBV infection.
Serum IgM anti-HBc
- Indicative of acute HBV infection
Serum IgG anti-HBc
- Indicative of chronic HBV infection
HBeAg
- Presence of HBeAg is associated with high infectivity.
- Because HBeAg is invariably present during early acute hepatitis B, HBeAg testing is indicated primarily during follow-up of acute infection as it progresses to a chronic state.
Serum anti-HBs
- Immunization with HBsAg (after vaccination)
- Hepatitis B in the remote past
- False-positive result
Quantitative HBV DNA [3]
- Typically < 0.5 pg/mL in acute infection
- Levels > 0.5 pg mL associated with chronic infection
- Useful in chronic disease to assess viral activity
- Serum
- Liver

Diagnostic tests for acute hepatitis due to other viruses

IgM anti-HAV
- Indicative of acute hepatitis A virus infection
- False positive: rheumatoid factor
Anti-HCV
- Indicative of acute or chronic hepatitis C virus infection

Laboratory abnormalities in acute viral hepatitis

Serum alanine aminotransferase and aspartate aminotransferase levels
- Variable increase during the prodromal phase of acute viral hepatitis
  - Precedes the increase in bilirubin level
- Acute levels of these enzymes do not correlate well with the degree of liver-cell damage.
- Peak levels vary from 400–4000 IU.
Serum bilirubin
- Jaundice is usually visible in the sclera or skin when the serum bilirubin value exceeds 43 μmol/L (2.5 mg/dL).
- In most instances, the total bilirubin is equally divided between the conjugated and unconjugated fractions.
- Bilirubin levels > 340 μmol/L (20 mg/dL) that increase and persist late into the course of viral hepatitis are more likely to be associated with severe disease.
  - In patients with underlying hemolytic anemia, such as glucose-6-phosphate dehydrogenase deficiency and sickle-cell anemia, a high serum bilirubin level is common (due to superimposed hemolysis).
  - Bilirubin levels > 513 μmol/L (30 mg/dL) have been observed and are not necessarily associated with a poor prognosis.
Prothrombin time
- Prolonged value may:
  - Reflect a severe hepatic synthetic defect
  - Signify extensive hepatocellular necrosis
  - Indicate a worse prognosis
Serum alkaline phosphatase level
- May be normal or only mildly elevated
Albumin level
- Decrease is uncommon in uncomplicated cases.

Imaging

There are no specific imaging tests for the diagnosis of hepatitis B.
In patients with significant cholestasis, imaging of the biliary tree may be necessary to rule out obstruction from stone or neoplasm.

Diagnostic Procedures

Liver biopsy is rarely necessary or indicated in acute viral hepatitis.
- Exceptions
  - Question about the diagnosis
  - Clinical evidence suggesting a diagnosis of chronic hepatitis

Treatment Approach

Mainstay of therapy is supportive care.
In rare instances of severe acute hepatitis B, antiviral therapy has been attempted.
- This is in contrast to the widespread use of antiviral therapy in chronic hepatitis B.
Liver transplantation is indicated for patients with fulminant hepatic failure and severe encephalopathy.

Specific Treatments

Supportive care

Activity as tolerated
High-calorie diet (often tolerated best in morning)
Intravenous hydration and parenteral nutrition
- Patients with severe vomiting
- Patients unable to maintain oral intake
Avoidance of alcohol and drugs metabolized by the liver
Avoidance of drugs that may produce adverse reactions (e.g., cholestasis)
Bile-salt sequestrant resins, if severe pruritus
- Cholestyramine: up to 4 g PO 4 times daily
No role for glucocorticoids

Antiviral therapy

Nucleoside analogues
- In rare instances of severe acute hepatitis B, treatment with a nucleoside analogue has been successful (see caveats below).
  - Lamivudine: 100 mg/d PO
- Caveats
  - Severe acute hepatitis B is not an approved indication for therapy.
  - Efficacy has not been established with clinical trials.
  - Duration of therapy has not been determined.

Liver transplantation

Liver transplantation is indicated in the rare cases of fulminant hepatic failure and grade III or IV encephalopathy.

Monitoring

Some patients require inpatient monitoring.
- Elderly
- Those with serious underlying medical disorders
- Those with any of the following presenting features:
  - Ascites
  - Peripheral edema
  - Hepatic encephalopathy
  - Prolonged prothrombin time
  - Low serum albumin level
  - Hypoglycemia
  - Very high serum bilirubin or aminotransferase levels
Monitor for clinical and biochemical recovery.
- It is particularly important to document the disappearance of HBsAg after apparent clinical recovery from acute hepatitis B.
- Patients who fail to convert to HBsAg-negative status may:
  - Be inactive carriers
  - Have low-grade, mild chronic hepatitis
  - Have moderate to severe chronic hepatitis, with or without cirrhosis
- The likelihood of becoming an HBsAg carrier after acute HBV infection is especially high among:
  - Neonates
  - Persons with Down syndrome
  - Patients receiving chronic hemodialysis
  - Immunosuppressed patients, including persons with HIV infection
Monitor for complications.

Complications

Serum sickness–like syndrome (5–10% of cases)
- Characterized by:
  - Arthralgia or arthritis
  - Rash
  - Angioedema
  - Rarely hematuria and proteinuria
- Syndrome occurs before the onset of clinical jaundice.
Glomerulonephritis with nephrotic syndrome
Polyarteritis nodosa–like systemic vasculitis (< 1% of patients with chronic hepatitis B)
Fulminant hepatitis (massive hepatic necrosis)
- Occurs in 1% of infections
- HBV accounts for > 50% of fulminant hepatitis cases.
- Consider possibility of co-infection with hepatitis D.
  - Co-infection of HBV with hepatitis D virus produces a more fulminant hepatitis than HBV alone.
Chronic hepatitis B (See Chronic Hepatitis B.)
- Occurs in 1–10% (90% of neonates)
- More common in patients who present with chronic infection without having experienced an acute illness
- Certain clinical and laboratory features suggest progression of acute hepatitis to chronic hepatitis.
  - Lack of complete resolution of clinical symptoms of anorexia, weight loss, and fatigue, and persistence of hepatomegaly
  - Presence of bridging or multilobular hepatic necrosis on liver biopsy during protracted, severe acute viral hepatitis
  - Failure of the serum aminotransferase, bilirubin, and globulin levels to return to normal within 6–12 months after the acute illness
  - Persistence of HBeAg beyond 3 months or HBsAg beyond 6 months after acute hepatitis
Rare complications
- Pancreatitis
- Myocarditis
- Atypical pneumonia
- Aplastic anemia
- Transverse myelitis
- Peripheral neuropathy
Hepatocellular carcinoma
- Increased risk in patients with chronic hepatitis B, particularly:
  - Those infected in infancy or early childhood
  - Chronic carriers of HBeAg
- Patients who have both hepatitis B and hepatitis C infection are at particularly high risk.

Prognosis

95–99% of previously healthy adults have a favorable course and recover completely.
- Complete clinical and biochemical recovery can be expected 3–4 months after the onset of jaundice in three-quarters of uncomplicated cases.
  - In the remainder, biochemical recovery may be delayed.
Fulminant hepatitis: 0.1–1%
- Fatality rate
  - Among patients ill enough to be hospitalized for acute hepatitis B: 1%
Indications of poorer prognosis
- Advanced age
- Serious underlying medical disorders
- Initial presenting features, such as ascites, peripheral edema, and symptoms of hepatic encephalopathy
- Prolonged prothrombin time
- Low serum albumin level
- Hypoglycemia
- Very high serum bilirubin values
Progression to chronicity
- Adults: 1–10%
- Neonates: 90%
Carrier state: 0.1–30%

Prevention

Screening
- The United States Preventive Services Task Force
  - Provides a strong recommendation for screening women during their first prenatal visit
  - Recommends against screening the general asymptomatic population
    - Cites lack of evidence that such screening improves health outcomes and could possibly cause harm from stigmatizing patients in whom screening is being performed
- The American Association for the Study of Liver Diseases
  - Recommends screening certain high-risk groups and vaccinating those who are not already immune or infected
    - Pregnant women
    - Persons born in hyperendemic areas
    - Men who have sex with men
    - Injection drugs users
    - Patients on dialysis
    - HIV-infected patients
    - Family and household contacts of HBV-infected persons
Vaccination
- Recombinant hepatitis B vaccine
  - Vaccine components and administration
    - 2 available vaccines: 10 µg IM (Recombivax-HB) or 20 µg IM (Engerix-B)
    - Half dose for children
    - 40-µg dose for patients receiving hemodialysis and immunocompromised adults
    - Given at 0, 1, and 6 months
    - Deltoid, not gluteal, injection
- Recommendations
  - Universal vaccination of all children regardless of maternal HBsAg status
    - Vaccination of neonates of HBsAg-positive mothers is a critical step toward the eradication of chronic HBV infection.
  - Adults in high-risk groups
    - Health care workers
    - Individuals who have unprotected sex with multiple partners
    - Intravenous drug users
    - Patients receiving hemodialysis
    - Hemophiliac patients
    - Household and sexual contacts of HBsAg carriers
    - Patients with chronic liver disease
- Duration of protection
  - At least 5 years in ~80–90% of immunocompetent vaccine recipients
  - At least 10 years in ~60–80% of immunocompetent vaccine recipients
  - Booster vaccinations are only indicated for:
    - Immunosuppressed individuals who no longer have detectable anti-HBs
    - Immunocompetent persons who sustain percutaneous HBsAg-positive inoculations after losing detectable anti-HBs
    - Dialysis patients whose anti-HBs antibody levels fall below 10 mIU/mL
Postexposure prophylaxis
- Hepatitis B immune globulin: 0.06 mL/kg IM
  - Immediately after needlestick, followed by a complete course of hepatitis B vaccine to begin within the first week
  - Within 14 days of sexual exposure followed by a complete course of hepatitis B vaccine to begin within the first week
  - For perinatal exposure of infants born to an HBsAg-positive mother, a single 0.5-mL IM dose should be given immediately after birth in combination with a complete course of 3 injections of hepatitis B vaccine to be started within the first 12 hours of life.

ICD-9-CM

070.20 Viral hepatitis B with hepatic coma, acute or unspecified, without mention of hepatitis delta
070.21 Viral hepatitis B with hepatic coma, acute or unspecified, with hepatitis delta
070.30 Viral hepatitis B without mention of hepatic coma, acute or unspecified, without mention of hepatitis delta
070.31 Viral hepatitis B without mention of hepatic coma, acute or unspecified, with hepatitis delta