Hepatitis B

Afsha Rais Kaisani, MD, FAAFP and Niyomi DeSilva, MD Reviewed 05/2023

BASICS

DESCRIPTION

Hepatitis B infection(HBV), caused by a DNA virus, is often transmitted by body fluids (blood, semen and vaginal secretions). HBV is a serious global healthcare concern due to the spectrum of liver disease it can cause ranging from acute hepatitis to cirrhosis and/or hepatocellular carcinoma (HCC).

EPIDEMIOLOGY

Incidence

Infects patients of all ages; 80% of cases are in persons aged 30-59 (1)
Predominant sex: fulminant HBV: male > female (2:1)
~60,000 new cases annually in the U.S. (2)
Lower incidence in the U.S. compared to Asia and Africa due to: better access to healthcare, use of vaccinations and preventive measure.

Prevalence

In the U.S., 1.59 million persons (range 1.25-2.49 million) with chronic HBV (3)
Asia, the Pacific Islands, and people born in Africa have the largest populations at risk
Chronic HBV worldwide: 350 to 400 million persons
- Second most important carcinogen (behind tobacco)
- Of chronic carriers with active disease, 25% die due to complications of cirrhosis or HCC

ETIOLOGY AND PATHOPHYSIOLOGY

HBV is a DNA virus of the Hepadnaviridae family. Two modes of transmission:

Horizontal: mucosal surface contact with infectious bodily fluids
Vertical: maternal-to-newborn perinatal

Genetics

Family history of HBV and/or HCC

RISK FACTORS

Screen the following high-risk groups for HBV with HBsAg. If positive, test for antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc) to distinguish between infection and immunity. Vaccinate if seronegative (4)

Household or sexual contacts with hepatitis B. Persons born in regions with increase prevalence (Asia, Africa, Eastern Europe). HIV- and HCV-positive patients
Persons born in the U.S. who were not vaccinated as infants or whose parents are from regions of high prevalence
Individuals with chronic liver disease. Pregnant women. Residents in carceral facilities

Additional risk factors:

Donors and recipients of blood/products. Persons on hemodialysis or immunosuppressive therapy. Needle stick/occupational exposure. Intranasal drug use; body piercing/tattoos. Survivors of sexual assault. Infants born to mothers positive for Hepatitis B surface antigen

Pediatric Considerations

Shorter acute course; fewer complications
90% of vertical/perinatal infections become chronic.

Pregnancy Considerations

Screen for HBsAg at first prenatal visit (4)[A].
If HBsAg (+), obtain HBV DNA.
Consider treating patients with high viral load at 28 weeks or history of previous HBV (+) infant with oral nucleos(t)ide medication beginning at 32 weeks to reduce perinatal transmission . Infants born to HBV-infected mothers require hepatitis B immune globulin (HBIG) and HBV vaccine within 12 hours of birth, completing the vaccine series and serologic testing for infection and immunity by 9 to 12 months.
Breastfeeding is safe if HBIG and HBV vaccines are administered and the areolar complex is without fissures or open sores. Avoid oral nucleos(t)ide medications during lactation.
HIV increases risk of vertical transmission. Continue medications if pregnancy occurs while on an oral antiviral therapy to prevent acute flare.

GENERAL PREVENTION

Vaccination

Three IM injections at 0, 1, and 6 months in infants or healthy adults
Indicated for: all medically stable infant weighing 2,000 g (4 lb, 6 oz) or more within 24 hours of birth, unvaccinated infants and children and adults, all at-risk patients, healthcare and public safety workers, sexual contacts and household contacts of HBsAg carriers
CDC does not recommend administration of more than 2 complete hepatitis B series except for certain cases related to patients on hemodialysis

Other preventive measures

Proper hygiene/sanitation by health care workers, IVDUs, and tattoo/piercing artists. Barrier precautions, needle disposal, sterilize 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 in addition to vaccination (no more than 7 days after exposure)
- Second dose of HBIG should be administered 30 days after exposure

COMMONLY ASSOCIATED CONDITIONS

HIV, hepatitis C coinfection
Extrahepatic manifestations include:
- Serum sickness-like syndrome (fever, erythematous rash, myalgias, arthralgias, fatigue). Glomerulonephritis (membranous or membranoproliferative glomerulonephritis, IgA-mediated nephropathy)
- Polyarteritis nodosa (Primary systemic necrotizing vasculitis, high fever, weakness, malaise, loss of weight and appetite). Dermatologic conditions (bullous pemphigoid, lichen planus, Gianotti-Crosti syndrome). Cryoglobulinemia (Raynaud phenomenon, arthritis, sicca syndrome)
- Neurologic/psychological condition (Guillain-Barré syndrome, altered mental status, depression/psychosis)

DIAGNOSIS

HISTORY

Exposure: detailed family history, such as HBV infection and liver disease, vaccinations status and social history including alcohol use, drug use, and sexual history

Acute HBV
- Fever, fatigue, arthralgias, myalgias, anorexia, nausea, vomiting, right upper quadrant (RUQ) abdominal pain
- Jaundice/scleral icterus, dark urine, pale stools
Chronic HBV: typically asymptomatic

PHYSICAL EXAM

Evaluate for stigmata of chronic liver disease: jaundice/scleral icterus, RUQ tenderness, hepatomegaly, palmar erythema, ascites, spider nevi, hepatic encephalopathy.

DIFFERENTIAL DIAGNOSIS

Epstein-Barr virus (EBV); cytomegalovirus (CMV); hepatitis A, C, Dor E
Drug-induced, alcoholic, or autoimmune hepatitis
Wilson's disease; Hemochromatosis; HIV

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

AST/ALT: Markedly elevated in acute HBV, ALT typically higher than AST
- Transaminases may be normal or mildly elevated in chronic HBV; may increase before bilirubin
Bilirubin (conjugated/unconjugated): normal to markedly elevated in acute HBV; last test to normalize as acute infection resolves
Alkaline phosphatase: mild elevation
HBcAb IgM may be the only early finding (“window period” before HBsAg is positive).
For acute hepatitis:
- PT/INR, albumin, electrolytes, glucose, CBC. If severe acute HBV, check for superinfection with hepatitis D (HDV Ag and HDV Ab). Hepatitis B serologic markers
Hepatitis B e-antigen (HBeAg+) indicates high replication/infectivity; confirmed with high HBV DNA (≥10⁵ copies/mL); benefit from medical therapy
Screen for HDV, HIV, HCV, and immunity to hepatitis A virus (HAV Ab total/IgG).
- Acute HBV and HDV coinfection tends to be more severe than acute HBV infection alone.
- 10% of patients with HIV have co-infection/chronic HBV, making treatment of each more complex
Ultrasound to document ascites, organomegaly, signs of portal hypertension, hepatic or portal obstruction, and screen for HCC

Follow-Up Tests & Special Considerations

Chronic HBV: HBsAg+ persistence >6 months; has five distinct phases based on HBsAg, HBeAg, HBV DNA, ALT, liver inflammation: immune tolerant, immune reactive HBeAg positive, inactive carrier, HBeAg negative and Occult hepatitis B.

Measure HBV DNA level and ALT q3–6 mo.
If age >40 years and ALT borderline or mildly elevated, consider liver biopsy.
Measure baseline AFP.
Follow HBeAg for elimination every 6–12 mo.

Screening for HCC (4)

HCC surveillance recommended for all patients with viral load >100,000 copies/mL
Abdominal ultrasound and alpha fetoprotein testing every 6 months as screening for HCC; if ultrasound is abnormal, CT or MRI of the liver is recommended.
Continue surveillance even after treatment.

Diagnostic Procedures/Other

Liver biopsy is diagnostic
Noninvasive tests (Hepascore™, FibroTest™) or elastography (FibroScan™) can be used to assess fibrosis

Test Interpretation

Liver biopsy in chronic HBV may show interface hepatitis and inflammation, necrosis, cholestasis, fibrosis, cirrhosis, or chronic active hepatitis.

TREATMENT

GENERAL MEASURES

Vaccinate for HBV if seronegative.
Monitor CBC, coagulation, electrolytes, glucose, renal function. Monitor ALT and HBV DNA; increased ALT and reduced DNA imply response to therapy. Screen for HCC if HBsAg+.
High risk for developing HCC with chronic HBV infection—needs routine monitoring

MEDICATION

Goals of therapy: loss of HBsAg with sustained HBV DNA suppression, improvement in patient-oriented outcomes, HBeAg loss/seroconversion and ALT normalization.

First Line

Acute HBV

Supportive care; spontaneously resolves in 95% of immunocompetent adults
Antiviral therapy not indicated except: fulminant liver failure or immunosuppressed
Treat patients with severe or protracted course and those with acute liver failure.
Treatment options include monotherapy with tenofovir or entecavir.

Marker	Acute Infection	Chronic Infection	Inactive Carrier	Resolved Infection	Susceptible to Infection	Vaccinated
HBsAg	+	+	+	−	−	−
Anti-HBs	−	−	−	+	−	+
Anti-HBc	+IgM	−IgM; +total/IgG	+	+	−	−
HBeAg	+	±	−	−	−	−
Anti-HBe	−	±	+	±	−	−
HBV DNA	Present	Present	Low negative	−	−	−
ALT	Marked elevation	Normal to mildly elevated	Normal	Normal	Normal	Normal

Chronic HBV: treatment per HBeAg status.
- FDA-approved drugs: lamivudine 100 mg, adefovir 10 mg, entecavir* 0.5 to 1 mg, telbivudine 600 mg, or tenofovir alafenamide* 25 mg, all given PO every day (dose based on renal function and age); pegylated interferon (peg-IFN) α2a (Pegasys)*, α2b SC weekly for 48 weeks (4)[A]
- *Recommended as first-line treatment options for chronic hepatitis B
Extended oral regimens are indicated (4)[A]
- HBeAg+, treat 6 to 12 months post disappearance of antigen and gain of antibody.
- HBeAg−, treat indefinitely or until clearance of antigen with antibody development.
Change/add drug based on resistance; confirm medication adherence prior to assuming drug resistance.
Precautions:
- Oral drugs: renal insufficiency
- Peg-IFN: coagulopathy, myelosuppression, depression/suicidal ideation

ISSUES FOR REFERRAL

Referral to hepatology and transplant for all persistent HBsAg+, fulminant acute hepatitis, end-stage liver disease or HCC.

Chronic Hepatitis B Therapy (4)

HBeAg	HBV DNA Viral Load	ALT*	Recommend
+	≥20,000 IU/mL	Elevated	Treat with antiviral or interferon.
+	≥20,000 IU/mL	Elevated but <2x ULN	Monitor every 3–6 months; treat if biopsy shows moderate fibrosis
+	≥20,000 IU/mL	Normal	Observe every 6 months, consider treatment if ALT elevated. Biopsy if age >40 years or ALT is high normal to mild elevation.
−	≥2,000 IU/mL	Elevated	Treatment indicated
−	≥2,000 IU/mL	Elevated but <2x ULN	Consider biopsy or serum fibrosis marker, treatment if findings concerning.
−	≥2,000 IU/mL	Normal	Monitor every 3 months
−	≤2,000 IU/mL	Normal	Monitor every 3–6 months.
Cirrhosis	Any	Any	Treat with mono or combination treatment.
Liver failure	Any	Any	Treat and refer for transplant.
*ALT elevated if >2 X ULN; ULN for male = 30 IU/mL and for female = 19 IU/mL

SURGERY/OTHER PROCEDURES

Liver transplantation, operative resection, radiofrequency ablation for HCC

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

Worsening course (marked increase in bilirubin, transaminases, or symptoms); Hepatic failure (high PT, encephalopathy)

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Serial ALT and HBV DNA: High ALT + low HBV DNA associated with favorable therapy response.
WBC and platelets if on interferon therapy
Monitor HBV DNA q3–6mo during therapy:
- Undetectable DNA at week 24 of oral therapy associated with low resistance at year 2
Monitor for complications (ascites, encephalopathy, variceal bleed) in cirrhosis.
Vaccination status.
Ultrasound q6–12mo to screen for HCC starting at age 40 years in men and 50 in women (4)[B]

DIET

Alcohol increases risk of cirrhosis or HCC.

PATIENT EDUCATION

Acute HBV: Review transmission precautions.
Chronic HBV, alcohol and tobacco use accelerate progression. Emphasize medication compliance to prevent flare.
Counsel chronic HBV carriers regarding risk of transmission to others.
Immunizations, especially against hepatitis A
http://www.cdc.gov/hepatitis/Resources/PatientEdMaterials.htm

PROGNOSIS

Chronic hepatitis B

Once HBV diagnosed, the 5-year cumulative incidence of developing cirrhosis is ~8-20% in those with untreated chronic HBV. Of patients with chronic HBV, 2-5% will progress to HCC with or without presence of cirrhosis.

COMPLICATIONS

Hepatic necrosis; cirrhosis; hepatic failure. HCC (all chronic HBV are at risk)
Severe flare of chronic HBV with corticosteroids and other immunosuppressants
Reactivation of infection if immunosuppressed. Premedicate prophylactically if HBsAg+ or if HBcAb+ and receiving systemic chemotherapy.

REFERENCES

Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67(No. RR-1):1–31.

Centers for Disease Control and Prevention. 2019 Viral Hepatitis Surveillance Report. https://www.cdc.gov/hepatitis/statistics/SurveillanceRpts.htm. Accessed November 4, 2021.

Lim JK, Nguyen MH, Kim WR, et al. Prevalence of Chronic Hepatitis B Virus Infection in the United States. Am J Gastroenterol. 2020;115(9):1429-1438.

Wilkins T, Sams R, Carpenter M. Hepatitis B: Screening, Prevention, Diagnosis, and Treatment. Am Fam Physician. 2019;99(5):314-323.

CODES

ICD10

B19.10 Unspecified viral hepatitis B without hepatic coma
B16.9 Acute hepatitis B w/o delta-agent and without hepatic coma
B18.1 Chronic viral hepatitis B without delta-agent
Z22.51 Carrier of viral hepatitis B

SNOMED

66071002 Type B viral hepatitis (disorder)
76795007 acute type B viral hepatitis (disorder)
61977001 chronic type B viral hepatitis (disorder)
235871004 hepatitis B carrier (finding)

CLINICAL PEARLS

Screen all patients born in countries with endemic disease for HBV infection using HBsAg.
Chronic HBV is present if HBsAg persists > 6 months. Patients with chronic HBV need lifetime monitoring for disease progression and HCC.
Acute HBV is diagnosed with HBsAg and IgM anti-HBc; treatment is supportive.
Antiviral therapy is based on the presence or absence of cirrhosis, the ALT level and HBV DNA levels.

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