BASICSDaniel J. Stein, MD, MPH • Stephen K. Lane, MD, FAAFP
BASICS
DESCRIPTION
One of the world’s most common diseases, hepatitis A is an infection with the hepatitis A virus (HAV) primarily involving the liver.
EPIDEMIOLOGY
Pediatric Considerations
• Often, milder or asymptomatic in children; severity increases with age.
• Infections asymptomatic in 70% of children age <6 years
• In 2009, <50% of 13- to 17-year-olds in the United States had been vaccinated.
Pregnancy Considerations
• Pregnant women with HAV have increased risk of complications including preterm labor.
• Vertical transmission has been reported; fecal–oral transmission during birth is possible.
• Breastfeeding is not contraindicated.
Incidence
• HAV causes ~50% of reported cases of viral hepatitis in the United States.
• 1.4 million cases globally each year
• Since the hepatitis A vaccine has been in routine use (1995), the incidence of HAV has decreased by 95%.
• Approximately 2,500 HAV infections in 2014, lowest ever recorded in the United States
• Incidence in the United States: 0.4/100,000
• No difference based on sex
• As many as 1/2 of current HAV infections in the United States are acquired from travel to endemic countries.
• Incubation period averages 28 days but can be as long as 50 days.
Prevalence
Serologic evidence of prior HAV infection is present in ~1/3 of U.S. population. Anti-HAV prevalence related to age, ranging from 9% in children ages 6 to 11 years to 75% of those >70 years. Related inversely to income
ETIOLOGY AND PATHOPHYSIOLOGY
• HAV is a single-stranded linear RNA enterovirus of the Picornaviridae family.
• Infection is limited to hepatocytes and macrophages.
• HAV is excreted into the bile and then stool, providing major route of spread.
• Primary transmission is fecal–oral.
• Humans are the only natural host.
• Incubation is 2 to 6 weeks (mean 4 weeks).
• Greatest infectivity is the 2 weeks before and 1 week after onset of clinical illness.
• Infection occurs primarily after consuming food or water contaminated with HAV or via direct contact.
• Outbreaks occur through exposure to a common food or water source.
• Virus is stable in water and on surfaces but is easily killed with high heat or cleaning agents.
• Shellfish (clams and oysters) may be contaminated if harvested from waters contaminated with HAV.
• Blood-borne transmission is rare.
• HAV is not a chronic disease but can last for months.
Genetics
Autoimmune hepatitis is rarely associated with human leukocyte antigen class II; DR3 and DR4 after active infection with HAV.
RISK FACTORS
• Travel to developing countries accounts for >50% of cases in North America and Europe.
• Employment in health care
• Household exposure
• Intimate exposure, especially men who have sex with men
• Injection of illicit drugs
• Child care centers, schools
• Institutionalized individuals
• Clotting factor disorders, such as hemophilia
• Blood exposure/transfusion (rare)
• No identifiable risk factor in 50%
GENERAL PREVENTION
• Proper sanitation and personal hygiene (hand washing), especially for food handlers, health care, and daycare workers
• Active immunization: HAV vaccines: Havrix and Vaqta; Twinrix-combination HAV and HBV
• Vaccine lasts ~25 years or more.
– All children aged 12 to 23 months, with catch-up administration until 18 years old
– All travelers to countries with a high endemic rate of hepatitis A
– Men who have sex with men
– Illicit IV drug users
– Anyone with chronic liver disease (including pre- and postliver transplant)
– Individuals with a clotting factor disorder
– Household members and close contacts of children adopted from countries with a high HAV prevalence (prior to arrival)
– Anyone exposed during an outbreak
• Routine vaccination is no longer routinely recommended for food service, child care, or health care workers (1)[C].
• HIV-infected patients who are negative for HAV IgG should receive HAV vaccine series, preferably early in course of HIV infection.
– If CD4 count is <200 cells/mm3 or the patient has symptomatic HIV disease, defer vaccination until several months after initiation of antiretroviral (ARV) therapy to maximize the antibody response to the vaccine.
• HAV is not killed by freezing.
• HAV is killed by
– Heating to 185°F for 60 seconds
– Chlorine
– Iodine
DIAGNOSIS
HISTORY
• Onset is often abrupt. Common symptoms include nausea, emesis and diarrhea, and headache.
• Symptom severity increases with age.
• Pediatric cases (<6 years) frequently asymptomatic
• Other symptoms:
– Fever, malaise, fatigue, myalgias, anorexia
– Dark urine (bilirubinuria)
– Right upper abdominal pain
– Pruritus (can suggest cholestasis)
PHYSICAL EXAM
• Fever (variable)
• Jaundice and icterus present in >70% of adults and older children
• Hepatomegaly is also common; splenomegaly is less common.
• Right upper quadrant abdominal tenderness
• Rarely can have lymphadenopathy (cervical), arthritis, or rash
• Asterixis indicates acute hepatic failure.
DIFFERENTIAL DIAGNOSIS
• Hepatitis B, C, D, E. Not clinically distinguishable from other forms of viral hepatitis; diagnosis may be suspected with typical symptoms during an outbreak.
• Drug-induced hepatitis; toxin-induced hepatitis
• Alcoholic hepatitis
• Hemochromatosis (adults) or Wilson disease
• Autoimmune hepatitis
• Malaria
• Epstein-Barr virus (EBV), cytomegalovirus (CMV)
• Primary or secondary hepatic malignancy
• Ischemic hepatitis or Budd-Chiari syndrome
• Nonhepatobiliary disease (elevated AST/ALT): celiac disease, congestive heart failure, thyroid disease
• Bacterial infections (Q fever, leptospirosis, syphilis, Rocky Mountain spotted fever)
• Parasites (liver flukes or toxocariasis)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• Anti-HAV IgM: positive at time of onset of symptoms sensitivity and specificity >95%. Primary test used to diagnose acute infection
• Anti-HAV IgG: appears soon after IgM and generally persists from years to lifetime
• AST and ALT elevated ~500 to 5,000: ALT usually > AST
• Alkaline phosphatase: mildly elevated
• Bilirubin: conjugated and unconjugated fractions usually increased. Bilirubin rises typically follow rise in ALT/AST, consistent with hepatocellular injury pattern.
• Prothrombin time and partial thromboplastin time usually remain normal or near normal.
– Significant rises should raise concern for acute hepatic failure or coexisting chronic liver disease.
• CBC: mild leukocytosis; aplasia and pancytopenia
– Thrombocytopenia may predict illness severity.
– Autoimmune hemolytic anemia (rare)
• Albumin, electrolytes, and glucose to evaluate for hepatic and renal function (rare renal failure)
• Urinalysis (not clinically necessary): bilirubinuria
• Consider ultrasound (US) to rule out biliary obstruction only if lab pattern is cholestatic.
Follow-Up Tests & Special Considerations
Illness usually resolves within 4 weeks of symptom onset. Repeat labs are not indicated unless symptoms persist or new symptoms develop.
Liver biopsy is usually not necessary. US can evaluate other causes (e.g., thrombosis or concurrent cirrhosis).
Test Interpretation
• Positive serum markers in hepatitis A
– Acute disease: anti-HAV IgM only
– Recent disease (last 6 months): anti-HAV IgM and IgG positive
– Previous disease: anti-HAV IgM negative and IgG positive
• If liver biopsy obtained, shows portal inflammation; immunofluorescent stains for HAV antigen positive
TREATMENT
GENERAL MEASURES
• Maintain appropriate nutrition/hydration.
• Avoid alcohol.
• Universal precautions to prevent spread
• Monitor coagulation defects, fluid, electrolytes, acid–base imbalance, hypoglycemia, and renal function.
• Report cases to local public health department.
• Laboratory evaluation including coagulation factors is important to rule out fulminant hepatic failure.
• Referral to liver transplant center for fulminant failure (rare)
MEDICATION
• Preexposure vaccination should be given according to recommended guidelines. Both hepatitis A vaccines the US (Havrix, Vaqta) require two doses.
• For travelers, the ACIP recommends administering the first dose as soon as possible with any planned travel to endemic areas (1)[C].
– For healthy individuals 40 years or younger, vaccination is sufficient up to the day or departure (1)[C].
– Immunoglobulin (0.02 mL/kg) should also be given to anyone >40 years or with chronic medical conditions if less than 2 weeks from planned departure (1)[C].
• Give postexposure prophylaxis to persons who have not previously received HAV vaccine within 2 weeks of exposure to HAV (3)[A],(4)[C].
– Administer hepatitis A vaccine to healthy persons between the ages of 1 and 40 years at age-appropriate dose (5)[A].
– Administer immunoglobulin (0.02 mL/kg) to persons <1 or >40 years of age or to patients with significant comorbidities (immunosuppression, liver disease) who are at risk for poor immune response (3)[A],(4)[C].
• Use immunoglobulin for passive preexposure prophylaxis in those not eligible for the vaccine (3)[A],(4)[C].
– 0.02 mL/kg provides 1 to 2 months of coverage; 0.06 mL/kg provides 3 to 5 months of coverage
– Long-term prophylaxis should be with 0.06 mL/kg every 5 months for sustained risk (e.g., travelers).
– Use immunoglobulin alone in children <1 year old and unvaccinated pregnant women who will be traveling.
– Do not give immunoglobulin with the MMR or varicella vaccines.
First Line
• No antiviral medications indicated; spontaneous resolution occurs in almost all patients.
• Limit acetaminophen use to 2 g/day or less.
• Avoid hepatotoxic agents.
Second Line
• Antiemetics (e.g., ondansetron)
• IV fluids
• Pruritus: diphenhydramine 50 mg PO IM q6h, consider cholestyramine 4 g BID if cholestasis
ISSUES FOR REFERRAL
• Dictated by severity of illness
• Hepatic failure, refer to a high-volume liver transplant program
SURGERY/OTHER PROCEDURES
Liver transplant in fulminant hepatic failure—rare
COMPLEMENTARY & ALTERNATIVE MEDICINE
Avoid potentially hepatotoxic botanicals including barberry, comfrey, golden ragwort, groundsel, huang qin, kava kava, pennyroyal, sassafras, senna, valerian, wall germander, and wood sage.
ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS
• Treatment is usually outpatient unless signs of liver failure; dictated by severity of illness
• Treat dehydration and electrolyte imbalances.
• Enteric isolation. Private rooms, gowns, and masks are not necessary. Frequent hand washing. Use gloves when handling potentially contaminated material.
• 1:100 bleach dilution can be used to clean surfaces.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Return to work/school 10 to 14 days after onset of symptoms with diligence to hygiene (patients remain infectious for up to 4 weeks from symptom onset).
Patient Monitoring
Monitor coagulation defects, fluid and electrolytes, acid–base imbalance, hypoglycemia, and renal function.
DIET
• Adequate balanced nutrition
• Avoid alcohol.
PATIENT EDUCATION
• Segregate food handlers with HAV.
• HAV immunity persists after infection
• CDC Hepatitis A FAQs Link: http://www.cdc.gov/hepatitis/hav/afaq.htm
PROGNOSIS
• Excellent; mortality is 0.3%.
• Risk increased with underlying chronic liver disease and in the elderly (1.8% mortality age >50 years)
COMPLICATIONS
• Coagulopathy, encephalopathy, and renal failure
• Relapsing HAV: usually milder than the initial case
• Positive anti-HAV IgM. Total duration is usually <9 months.
• Prolonged cholestasis: characterized by protracted periods of jaundice and pruritus (>3 months), resolves without intervention (supportive care only)
• Autoimmune hepatitis: can be seen after HAV infection; good response to steroids
• Hepatic failure: rare (1–2%)
• Postviral encephalitis, Guillain-Barré syndrome, pancreatitis, aplastic or hemolytic anemia, agranulocytosis, thrombocytopenic purpura, pancytopenia, arthritis, vasculitis, and cryoglobulinemia (all rare)
REFERENCES
1. Centers for Disease Control and Prevention. Hepatitis A questions and answers for health professionals. http://www.cdc.gov/hepatitis/hav/havfaq.htm. Accessed August 8, 2016.
2. Irving GJ, Holden J, Yang R, et al. Hepatitis A immunisation in persons not previously exposed to hepatitis A. Cochrane Database Syst Rev. 2012;(7):CD009051.
3. Liu JP, Nikolova D, Fei Y. Immunoglobulins for preventing hepatitis A. Cochrane Database Syst Rev. 2009;(2):CD004181.
4. Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1–23.
5. Victor JC, Monto AS, Surdina TY, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med. 2007;357(17):1685–1694.
SEE ALSO
• Algorithm: Hyperbilirubinemia, Cirrhosis, and Jaundice
CODES
ICD10
B15.9 Hepatitis A without hepatic coma
CLINICAL PEARLS
• HAV vaccine is indicated for all children, travelers, those at elevated risk of disease, and anyone with liver impairment.
• Check HAV IgG in all HIV-positive patients; provide HAV vaccine to those who are negative.
• HAV disease severity directly correlates with age; children are often asymptomatic.
• Treatment of acute disease is supportive.
• Give postexposure prophylaxis to eligible patients within 14 days of exposure.