HEPATITIS A
Edward Feller, MD
BASICS
DESCRIPTION
Infection with the hepatitis A virus (HAV) primarily
involving the liver.
One of the world’s most common viral diseases.
EPIDEMIOLOGY
Pediatric Considerations
Disease is often milder or asymptomatic in pediatric
population,
severity increases with age.
Infections are asymptomatic in 70% of children age <6
years.
In 2009, <1/2 of 13–17-year-olds (in the US) had been
vaccinated (1).
As many as ½ of current HAV infections in the US acquired
from travel
to endemic countries.
Pregnancy Considerations
Pregnant women with HAV have increased gestational
complications,
pre-term labor.
Incidence
World-wide problem: 1.4 million cases globally.
Since the hepatitis A vaccine has been in use (1995),
incidence of HAV
has decreased by >90% (2).
Estimated cases: 22,000 HAV infections in 2009 (lowest ever
recorded in
the US)
Incidence in the US: 0.6/100,000
Predominant sex: Male = Female
Prevalence
Serologic evidence of prior HAV infection: 1/3 of US
population. Anti-
HAV prevalence related to age, ranging from 9% in children
ages 6–11 to
75% of those >70. Related inversely to income
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ETIOLOGY AND PATHOPHYSIOLOGY
Hepatitis A is a single-stranded linear RNA enterovirus and
a member of
the Picornaviridae family.
Humans are the only natural host.
Incubation is 2–6 weeks:
Mean of 4 weeks
Greatest infectivity is during the 2 weeks before the onset
of clinical
illness.
Infection occurs after eating food or drinking water
contaminated with
HAV or direct contact with infected person who has poor
personal
hygiene.
Food can become contaminated if handled by an infected
individual
with poor personal hygiene.
Shellfish, such as clams and oysters, may be contaminated if
harvested
from waters contaminated with HAV.
Bloodborne transmission occurs, but is rare.
No chronicity in HAV
Genetics
Autoimmune hepatitis is associated with human leukocyte
antigen class
II; DR3 and DR4 after active infection with HAV, although
rare.
RISK FACTORS
Foreign 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
Childcare centers, schools
Institutionalized individuals
Clotting factor disorders, such as hemophilia
Blood exposure/transfusion rare
No identifiable risk factor in 50%
GENERAL PREVENTION
HAV vaccines: Havrix and Vaqta; Twinrix- combination HAV and
HBV
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vaccine for active immunization only
Separate syringe site from immunoglobulin
For travelers, daycare staff/children, custodial facility
employees,
sewage workers, military, men who have sex with men (MSM),
food
handlers, IVDUs
For close contacts of children adopted from countries with
HAV
infection. Ideally ≥2 weeks before arrival
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, it is preferable to defer vaccination until several
months after
initiation of antiretroviral (ARV) therapy to maximize the
antibody
response to the vaccine (2)[A].
Coadministration of the HAV vaccine with
measles-mumps-rubella
(MMR) and varicella vaccines had no impact on the
immunogenicity
of any of the vaccines and was well tolerated (3)[B].
Passive immunization: Immunoglobulin is
effective for both pre- and postexposure prophylaxis of
hepatitis A (4)
[A]:
0.02–0.06 mL/kg IM given within 2 weeks after exposure
prevents
illness in 80–90%.
HAV vaccine has similar efficacy to immunoglobulin in
postexposure
prophylaxis if given within 2 weeks.
Use immunoglobulin in cases where travelers need immediate
protection, children age <1 year, and pregnant women who
will be
traveling.
Use 0.06 mL/kg q5mo for long-term travelers if they are unable
to
receive the vaccine.
Do not give immunoglobulin with MMR or varicella vaccines.
Good sanitation; good hygiene, including handwashing,
especially for
food handlers, healthcare, and daycare workers
HAV is not killed by freezing.
HAV is killed by:
Heating to 185°F for 60 seconds
Chlorine
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Iodine
DIAGNOSIS
HISTORY
Fever
Malaise
Nausea and vomiting, headache
Anorexia
Dark urine:
Right upper abdominal pain
Fatigue; myalgias
Pruritus; a sign of cholestasis
Symptom severity has direct correlation to age.
Pediatric cases frequently asymptomatic
Incubation: 15–50 days (mean of 28 days)
PHYSICAL EXAM
Hepatomegaly or splenomegaly are possible
Fever
Jaundice
Right upper quadrant abdominal tenderness
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.
Infectious mononucleosis, CMV
Primary or secondary hepatic malignancy
Ischemic hepatitis
Drug-induced hepatitis
Alcoholic hepatitis
Hemochromatosis in adults
Autoimmune hepatitis; Wilson disease
Nonhepatobiliary disease (elevated AST/ALT): Celiac disease,
congestive
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heart failure, thyroid disease
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
AST and ALT elevated: ALT usually > AST
Hepatocellular injury pattern
Anti-HAV IgM: Positive at time of onset of symptoms with
sensitivity
and specificity > 95%
Anti-HAV IgG: Appears soon after IgM and generally persists
for years
Alkaline phosphatase: Mildly elevated
Bilirubin: Conjugated and unconjugated fractions usually
increased.
Usually follows rises in ALT/AST.
Prothrombin time and partial thromboplastin time: Usually
remain
normal or near normal:
Significant rises should raise concern.
CBC: Mild leukocytosis; aplasia and pancytopenia are rare:
Thrombocytopenia may predict illness severity.
Albumin, electrolytes, and glucose
Urinalysis: Bilirubinuria
Usually not needed
Consider US to rule out biliary obstruction only if lab
pattern is
cholestatic.
Follow-Up Tests & Special Considerations
Illness usually resolves within 4 weeks from onset of
symptoms. Usually
can be managed as outpatient
Diagnostic Procedures/Other
Liver biopsy usually not necessary
Test Interpretation
Portal inflammation
Immunofluorescent stains for HAV-antigen positive
Positive serum markers in hepatitis A:
Acute disease: Anti-HAV IgM
Recent disease: Anti-HAV IgM and IgG positive
Previous disease: Anti-HAV IgM negative and IgG positive
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TREATMENT
GENERAL MEASURES
Monitor coagulation defects, fluid and electrolytes,
acid–base
imbalance, hypoglycemia, and impairment of renal function
(5).
Report acute cases to local public health department.
Maintain bed rest and appropriate nutrition/hydration.
MEDICATION
Postexposure prophylaxis to persons within 2 weeks of
exposure to HAV:
Administer hepatitis A vaccine to persons between the ages
of 1 and 40.
Administer immunoglobulin to persons <1 and >40 years
of age.
First Line
No antiviral medications indicated; spontaneous resolution
occurs in
almost all patients
Steroids not indicated unless patient has autoimmune
hepatitis
Second Line
Antiemetics
IV fluids
Pruritus: Diphenhydramine 50 mg PO/IM q6h and cholestyramine
4 g
b.i.d.
ISSUES FOR REFERRAL
Dictated by severity of illness
Hepatic failure
SURGERY/OTHER PROCEDURES
Liver transplant in fulminant hepatic failure
COMPLEMENTARY AND ALTERNATIVE MEDICINE
Avoid botanicals with hepatotoxicity potential, including
barberry,
comfrey, golden ragwort, groundsel, huang qin, kava kava,
pennyroyal,
sassafras, senna, valerian, wall germander, wood sage.
IN-PATIENT CONSIDERATIONS
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Admission Criteria/Initial Stabilization
Treatment is usually outpatient; dictated by severity of
illness.
IV Fluids
Treat dehydration and electrolyte imbalances.
Nursing
Enteric isolation. Private rooms, gowns, and masks are not
necessary.
Frequent handwashing. Use gloves when handling material
potentially
contaminated with feces.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Return to work/school 10–14 days after onset of symptoms
with diligence
to hygiene
Patient Monitoring
Monitor coagulation defects, fluid and electrolytes,
acid–base
imbalance, hypoglycemia, and impairment of renal function.
Report acute cases to local public health department.
Usually infectious 4 weeks from initial symptoms
DIET
Adequate balanced nutrition
Avoid alcohol.
Avoid medications that may accumulate in the liver.
PATIENT EDUCATION
Segregate food handlers with HAV.
HAV immunity after infection
CDC Hepatitis A Fact Sheet Link:
http://www.cdc.gov/hepatitis/A/PDFs/HepAGeneralFactSheet_BW.pdf
PROGNOSIS
Excellent; mortality is 0.2%.
Risk increased with underlying chronic liver disease and in
the elderly
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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
Autoimmune hepatitis: Good response to steroids
Hepatic failure: Rare (1–2%)
Postviral encephalitis, Guillain-Barré syndrome, aplastic or
hemolytic
anemia, agranulocytosis, thrombocytopenic purpura,
pancytopenia,
arthritis, vasculitis, and cryoglobulinemia (all rare)
HEPATITIS B
Michael P. Curry, MD
BASICS
DESCRIPTION
Systemic viral infection that may cause acute and chronic
liver disease
and hepatocellular carcinoma (HCC)
EPIDEMIOLOGY
Incidence
Predominant age: All ages
Predominant sex: Fulminant hepatitis B virus (HBV): Male
> Female
(2:1)
In the US, estimated 38,000 new infections in 2009, 70% due
to IV drug
use
African Americans: Highest rate of acute HBV infection in
the US
Overall rate of new infections down 82% since 1991 (due to
national
immunization strategy)
US vaccine coverage increased from 68.6% in 2011 to 71.6% in
2012 for
the birth dose of HepB (1)[A]
Prevalence
In the US, 800,000–1.4 million people have chronic hepatitis
B virus
(HBV).
Asia and the Pacific Islands have the largest populations at
risk for HBV.
Chronic HBV worldwide: 350–400 million persons:
Per year: 1 million deaths:
2nd most important carcinogen (behind tobacco)
Of chronic carriers, 25% die of cirrhosis or HCC
Of chronic carriers, 75% are Asian
ETIOLOGY AND PATHOPHYSIOLOGY
HBV is a DNA virus of the family Hepadnaviridae.
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Genetics
Family history of HBV and/or HCC to determine exposure and
future
HCC risk
RISK FACTORS
Screen high-risk groups with HBsAg/sAb (1)[A]:
Persons born in endemic areas (45% of world)
Hemodialysis patients
IV drug users (IVDU), past or present
Men who have sex with men (MSM)
HIV- and HCV-positive patients
Household members of HBsAg carriers
Sexual contacts of HBsAg carriers
Inmates of correctional facilities
Patients with chronically elevated aspartate
aminotransferase/alanine
aminotransferase (ALT/AST)
Vaccinate all above groups if negative.
Additional risk factors:
Needle stick/occupational exposure
Recipients of blood/products; transplanted organ recipients
Intranasal drug users
Body piercing/tattoos
Pediatric Considerations
Shorter acute course; fewer complications
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90% of vertical/perinatal infections become chronic
Pregnancy Considerations
Screen all pregnant women for HBsAg (2)[A].
High viral load at 28 weeks should prompt consideration for
treatment
with oral nucleos(t)ide medicines from 32 weeks to reduce perinatal
transmission.
Infant of HBV-infected mother needs HB immune globulin
(HBIg) (0.5
mL) plus HBV vaccine within 12 hours of birth and HBV series
at 0, 1,
and 6 months (2)[A].
Breastfeeding is safe if HBIg and HBV vaccine are
administered and
nipples are without fissures. Oral nucleos(t)ide medications
are not
recommended in lactating mothers. Risk and benefits must be
assessed.
HIV coinfection significantly increases risk of vertical
transmission.
Continue medications if pregnancy occurs while on an oral
antiviral
therapy to prevent acute flare.
GENERAL PREVENTION
Most effective: HBV vaccination series (3 doses):
Vaccinate:
All infants at birth
All at-risk patients (see “Risk Factors”)
Health care and public safety workers
Sexual contacts of HBsAg carriers
Household contacts of HBsAg carriers
Proper hygiene/sanitation by health care workers, IVDU, and
tattoo/piercing artists:
Barrier precautions, needle disposal, sterilization of
equipment, cover
open cuts
Do not share personal items exposed to blood (e.g., nail
clipper, razor,
toothbrush).
Safe sexual practices (condoms)
HBsAg carriers cannot donate blood or tissue.
Postexposure (e.g., needle stick): HBIg 0.06 mL/kg in <24
hours and
vaccination
COMMONLY ASSOCIATED CONDITIONS
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Arthritis, polyarteritis nodosa, membranous glomerulopathy,
anemia
(including aplastic anemia), dermatitis, cardiomyopathy,
hepatitis D
virus infection, metabolic syndrome
DIAGNOSIS
HISTORY
Exposure: Detailed family and social history
Acute HBV:
Fever, malaise, fatigue, arthralgias, myalgias
Anorexia, nausea, vomiting
Jaundice, scleral icterus
Dark urine, pale stools
Right upper quadrant (RUQ) abdominal pain
Chronic HBV: Typically asymptomatic
PHYSICAL EXAM
Acute: Ill; jaundice/scleral icterus; RUQ tenderness,
hepatomegaly
DIFFERENTIAL DIAGNOSIS
Epstein–Barr virus (EBV); cytomegalovirus (CMV); hepatitis
A, C, or E
Drug-induced, alcoholic, or autoimmune hepatitis
Wilson disease or rheumatologic/immunologic disorders
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
AST/ALT: Marked elevation in acute HBV, particularly of ALT,
400 to
several thousand IU/mL (may be normal or mildly elevated in
chronic
HBV):
Elevated before bilirubin elevates
Bilirubin: Normal to markedly elevated in acute HBV,
conjugated/unconjugated:
Last test to normalize as acute infection resolves
Alkaline phosphatase: Mild elevation
HBcAb IgM may be the only early finding (“window period,”
when
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HBsAg/sAb–).
For acute hepatitis:
Monitor PT, albumin, electrolytes, glucose, CBC
If severe acute HBV, check for superinfection with hepatitis
D (HDV Ag
and HBDV Ab)
Hepatitis B serologic markers
Hepatitis Be antigen (HBeAg+) indicates high
replication/infectivity;
confirmed with high HBV DNA (≥105 copies/mL); these patients
benefit
from medical therapy.
HBV precore mutants have undetectable HBeAg despite active
viral
replication (confirm with HBV DNA level), as well as
antibody to e
antigen (HBeAb+).
Screen for HDV, HIV, HCV, and immunity to hepatitis A virus
(HAV Ab
total/IgG).
US to demonstrate ascites, splenomegaly, portal
hypertension, rule out
obstruction, screen for HCC
Contrast CT or MRI if abnormal US or elevated α-fetoprotein
(AFP)
Follow-Up Tests & Special Considerations
HBsAg+ persistence >6 months defines chronic HBV:
Measure HBV DNA level and ALT every 3–6 months.
If age >40 and ALT borderline or mildly elevated,
consider liver biopsy.
Measure baseline AFP
Follow HBeAg for loss (every 6–12 months).
Lifetime monitoring for progression, need for treatment, and
screening
for HCC
Diagnostic Procedures/Other
Liver biopsy, serum markers of fibrosis (Hepascore, Fibro
test) or
measurement of elastography (Fibroscan) determines extent of
injury and
excludes other liver disease.
Test Interpretation
Liver biopsy in chronic HBV may show interface hepatitis and
inflammation, necrosis, cholestasis, fibrosis, cirrhosis, or
chronic active
hepatitis.
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TREATMENT
GENERAL MEASURES
Vaccinate for HAV if seronegative.
Monitor CBC, coagulation, electrolytes, glucose, renal
function,
phosphate.
Monitor ALT and HBV DNA; increased ALT and reduced DNA
implies
response to therapy.
Screen for HCC even in those without cirrhosis.
MEDICATION
First Line
Acute HBV:
Supportive care; antiviral therapy not indicated;
spontaneously
resolves in 95% of immunocompetent adults. Treatment for
acute HBV
resulting in acute liver failure.
Chronic HBV: Treatment based on HBeAg status:
FDA-approved drugs: Lamivudine 100 mg, adefovir 10 mg,
entecavir
0.5–1 mg, telbivudine 600 mg, or tenofovir 300 mg, all given
PO
every day (dose based on renal function); pegylated
interferon (peg-
IFN) α2a SC weekly (2,3)[A]
Lamivudine is no longer recommended as first-line therapy
due to high
rates of resistance.
Entecavir, tenofovir, peg-IFN are preferred first-line
agents (2)[A].
Oral agents given for extended period:
If HBeAg+, treat 6–12 months postloss of HBeAg and gain of
HBeAb,
and monitor after cessation (2)[A].
If HBeAg–, treat indefinitely or until HBsAg clearance and
HBsAb
development (2)[A].
Change/Add drug based on development of resistance:
Confirm patient compliance with medications before assuming
resistance
Adherence to therapy lowers rate of resistance
Dose adjustment made for elevated creatinine
Standard interferon (Intron A) no longer used in favor of
peg-IFN:
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Peg-IFN (Pegasys) injections given weekly for 48 weeks
Best efficacy in genotype A
Contraindicated if decompensated cirrhosis
Goals of therapy: Undetectable HBV DNA, normal ALT, loss of
HBeAg,
gain of HBeAb; loss of HBsAg and gain of HBsAb
Precautions:
Oral drugs: Renal insufficiency
Peg-IFN: Coagulopathy, myelosuppression, depression/suicidal
ideation
Second Line
Emtricitabine effective; pending FDA approval
ISSUES FOR REFERRAL
Refer all HBsAg+ patients for consideration of antiviral
therapy.
Refer to liver transplant program ASAP if fulminant acute
hepatitis,
end-stage liver disease, or HCC.
SURGERY/OTHER PROCEDURES
Liver transplantation, operative resection, radiofrequency
ablation
IN-PATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Worsening course (marked increase in bilirubin,
transaminases, or
symptoms)
Hepatic failure (high PT, low albumin)
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ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Vaccinate for HAV if seronegative (2)[B].
Monitor serial ALT and HBV DNA:
High ALT + low HBV DNA associated with favorable response to
therapy
Serologic markers: See chart
Metabolic complications and renal function
WBC/platelets with interferon therapy
Monitor HBV DNA q3–6 mo during therapy:
Undetectable DNA at week 24 of oral drug therapy associated
with low
resistance at year 2.
Monitor for complications (ascites, encephalopathy, variceal
bleed) in
cirrhosis.
DIET
Avoid alcohol
PATIENT EDUCATION
Acute HBV:
Review transmission precautions (2)[A].
Chronic HBV:
Alcohol/Smoking accelerates progression of liver disease.
Strict compliance with oral medication is critical to
prevent flare.
Patient education materials in English and Spanish available
at
www.cdc.gov/hepatitis/Resources/PatientEdMaterials.htm
PROGNOSIS
Acute infection: 95% of adults recover
Severity of encephalopathy predicts survival in fulminant
hepatic
failure.
Acute HBV: Mortality 1%
Acute HBV + HDV: Mortality 2–20%
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Chronic HBV:
Spontaneous resolution: 0.5% per year
Premature death from cirrhosis or HCC: 25%
Risk of HCC rises with rate of viral replication, even if no
cirrhosis
US and AFP q6–12 mo for screening (patient-specific
guidelines) (2,4)
[B]
COMPLICATIONS
Acute or subacute hepatic necrosis; cirrhosis; hepatic
failure
HCC (all chronic HBV patients are at risk)
Severe flare of chronic HBV with corticosteroids: Avoid
corticosteroids if
possible.
Reactivation of resolved infection if immunosuppressed
(e.g.,
chemotherapy): Prophylactic premedication recommended if
HBsAg+
(2,4) or if HBcAb+ and received systemic chemotherapy.
