HEPATITIS A & B

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.