Hepatitis BHepatitis B

Patricia D. Jones, M.D. Patricia D. Jones, M.D.

November 13, 2009November 13, 2009

Hepatitis BHepatitis B Prototype member of the Prototype member of the

Hepadnaviridae familyHepadnaviridae family

DNA virusDNA virus

Outer lipoprotein envelope Outer lipoprotein envelope with 3 glycoproteins – Hep B with 3 glycoproteins – Hep B surface antigens (HBsAg)surface antigens (HBsAg)

Viral nucleocapsid protein - Viral nucleocapsid protein - Hep B core antigen (HBcAg)Hep B core antigen (HBcAg)

Soluble nucleocapsid Soluble nucleocapsid protein-Hepatitis B e antigen protein-Hepatitis B e antigen (HBeAg)(HBeAg) http://pathmicro.med.sc.edu/virol/hep-b5.jpg

EpidemiologyEpidemiology Worldwide:Worldwide:

Affects 350-400 million Affects 350-400 million personspersons

Endemic areas: Asia, AfricaEndemic areas: Asia, Africa 1 million worldwide deaths 1 million worldwide deaths

per yearper year Acquired perinatally and in Acquired perinatally and in

childhoodchildhood

United States: United States: Affects 1.25 million Affects 1.25 million

personspersons 4000-5000 deaths per year4000-5000 deaths per year Acquired via sexual Acquired via sexual

activity, then IVDU and activity, then IVDU and occupational exposureoccupational exposure

http://liver.stanford.edu/images/education/world_incidence.jpg

Primary InfectionPrimary Infection Incubation Period 4-10 weeksIncubation Period 4-10 weeks During the prodromal period, patient may During the prodromal period, patient may

have a serum sickness-like syndrome. have a serum sickness-like syndrome. Constitutional symptoms, anorexia, nausea, Constitutional symptoms, anorexia, nausea,

RUQ discomfort and jaundice.RUQ discomfort and jaundice. 30 % develop icteric hepatitis.30 % develop icteric hepatitis. 70% develop anicteric or subclinical 70% develop anicteric or subclinical

hepatitis.hepatitis. 0.5-1% develop fulminant liver failure. 0.5-1% develop fulminant liver failure. Symptoms and jaundice disappear in 1-3 Symptoms and jaundice disappear in 1-3

months, though fatigue may persist. months, though fatigue may persist.

Infection in Children vs. Infection in Children vs. AdultsAdults

ChildrenChildren In neonates, the immature immune system does In neonates, the immature immune system does

not recognize a difference between the virus and not recognize a difference between the virus and the host. the host.

Cellular immune responses to hepatocyte-Cellular immune responses to hepatocyte-membrane HBV proteins do not occur.membrane HBV proteins do not occur.

Risk of developing chronic HBV infection is 90% in Risk of developing chronic HBV infection is 90% in infants born to HBeAg positive mothers. In infants born to HBeAg positive mothers. In children under 5, risk is 25-30%. children under 5, risk is 25-30%.

Adults:Adults: Tend to have a more vigorous immune response.Tend to have a more vigorous immune response. Less than 5% of those infected develop continual Less than 5% of those infected develop continual

viremia and persistent infection.viremia and persistent infection.

Serologic DiagnosisSerologic DiagnosisHBsAHBsA

ggHBeAgHBeAg Anti-HBc Anti-HBc

IgMIgMAnti-HBc Anti-HBc

IgGIgGAnti-HBeAnti-HBe HBsAbHBsAb HBV HBV

DNADNA

ACUTEACUTE

EarlyEarly ++ ++ ++ ++++++

WindowWindow ++ ++

RecoveryRecovery ++ ++ ++ +/-+/-

CHRONICCHRONIC

Replicative Replicative ++ ++ ++ ++++++

NonreplicatiNonreplicativeve

++ ++ ++ +/-+/-

FlareFlare ++ +/-+/- ++ ++ ++

Precore/Precore/core core

promoter promoter mutantsmutants

++ ++ ++ ++++

http://www.haps.nsw.gov.au/userData/img//hepB1.jpg

Chronic Hepatitis B Chronic Hepatitis B InfectionInfection

Early Replicative Phase: Immune ToleranceEarly Replicative Phase: Immune Tolerance Perinatally acquired infectionPerinatally acquired infection High levels of HBV DNA, HBeAg presentHigh levels of HBV DNA, HBeAg present No liver disease—normal ALT, asymptomatic, Stage 0-1 fibrosisNo liver disease—normal ALT, asymptomatic, Stage 0-1 fibrosis Lasts 10-30 yearsLasts 10-30 years

Replicative Phase: Immune ClearanceReplicative Phase: Immune Clearance Spontaneous clearance of HBeAgSpontaneous clearance of HBeAg Often characterized by periods of increased HBV DNA and Often characterized by periods of increased HBV DNA and

increased ALT due to immune-mediated lysis of infected increased ALT due to immune-mediated lysis of infected hepatocytes, i.e. flareshepatocytes, i.e. flares

Nonreplication Phase: Inactive Carrier StateNonreplication Phase: Inactive Carrier State HBeAg negative, anti-Hep B e positive, HBV DNA undetectableHBeAg negative, anti-Hep B e positive, HBV DNA undetectable ALT levels normalize, however some patients may have active ALT levels normalize, however some patients may have active

inflammationinflammation

Chronic Hepatitis B Chronic Hepatitis B InfectionInfection

HBeAg-negative Chronic HepatitisHBeAg-negative Chronic Hepatitis Precore/Core Promoter MutationsPrecore/Core Promoter Mutations Moderate levels HBV DNAModerate levels HBV DNA Active liver disease and elevated ALTActive liver disease and elevated ALT Older patients Older patients

ResolutionResolution Hallmark is the clearance of HbSAgHallmark is the clearance of HbSAg Does not preclude development of cirrhosis, Does not preclude development of cirrhosis,

HCC or failure.HCC or failure. Patients may still produce HBV DNA, which has Patients may still produce HBV DNA, which has

implications in the immunosuppressedimplications in the immunosuppressed

Sequelae of Chronic HBV Sequelae of Chronic HBV InfectionInfection

CirrhosisCirrhosis Hepatocellular CarcinomaHepatocellular Carcinoma Hepatic DecompensationHepatic Decompensation Extrahepatic Extrahepatic

ManifestationsManifestations DeathDeath Prognosis is worse in Prognosis is worse in

endemic areas:endemic areas: Prolonged replicative phaseProlonged replicative phase Clearance of HBeAg causes Clearance of HBeAg causes

a 2 fold decrease in death a 2 fold decrease in death rate.rate.

Patients who reactivate Patients who reactivate have worse prognosis. have worse prognosis.

http://pathmicro.med.sc.edu/lecture/images/hepato-b.jpghttp://pathmicro.med.sc.edu/lecture/images/hepato-b.jpg

Extrahepatic Extrahepatic ManifestationsManifestations

Occur in 10-20% of Occur in 10-20% of patients with patients with Chronic Hep B.Chronic Hep B.

Serum SicknessSerum Sickness Polyarteritis NodosaPolyarteritis Nodosa Membranous and Membranous and

MembranoproliferatMembranoproliferative ive GlomerulonephritisGlomerulonephritis

GenotypesGenotypes

Genotype B associated with HBeAg seroconversion at an earlier Genotype B associated with HBeAg seroconversion at an earlier age, more sustained remission, less active hepatic age, more sustained remission, less active hepatic necroinflammation, a slower rate of progression to cirrhosis and necroinflammation, a slower rate of progression to cirrhosis and lower rate of HCC development when compared with Genotype lower rate of HCC development when compared with Genotype C. C.

Genotypes A and B are associated with higher rates of Genotypes A and B are associated with higher rates of seroconversion with pegIFN-alpha than C and D.seroconversion with pegIFN-alpha than C and D.

Indications for TherapyIndications for Therapy

Acute HepatitisAcute Hepatitis One trial demonstrated no biochemical or One trial demonstrated no biochemical or

clinical benefit in patients treated with clinical benefit in patients treated with Lamivudine vs. placebo in 12 months.Lamivudine vs. placebo in 12 months.

General Rule: General Rule: Coagulopathy INR>1.5 Coagulopathy INR>1.5 Persistent symptoms or marked jaundice (bilirubin Persistent symptoms or marked jaundice (bilirubin

>10 mg/dl) for more than 4 weeks after presentation>10 mg/dl) for more than 4 weeks after presentation Fulminant Hepatic FailureFulminant Hepatic Failure Concomitant infection with Hep C or DConcomitant infection with Hep C or D

Indications for TherapyIndications for TherapyHBeAg-positive patients: HBeAg-positive patients with

persistently normal ALT should be tested for ALT at 3-6 month intervals

HBeAg status should be checked every 6-12 months.

HBeAg positive with HBV DNA levels >20,000 IU/mL after a 3-6 month and ALT 1-2 x ULN OR are >40 years liver biopsy w/ treatment if biopsy shows moderate/severe inflammation or significant fibrosis.

Patients who remain HBeAg positive with HBV DNAlevels>20,000 IU/mL after a 3-6month period of elevated ALT levels >2 ULN should be considered for treatment.

HBeAg-negative patients: HBeAg-negative patients with

normal ALT and HBV DNA <2,000 IU/mL: Tested ALT q 3months during the first year to verify true “inactive carrier state” and then every 6-12 months.

http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdfhttp://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdf

http://knol.google.com/k/-/-/1w026jckgcwg2/18ad7q/slide4%20(1).jpghttp://knol.google.com/k/-/-/1w026jckgcwg2/18ad7q/slide4%20(1).jpg

References:References: Dienstag JL. Hepatitis B Virus Infection. N Dienstag JL. Hepatitis B Virus Infection. N

Eng J Med 2008;359: 1486-500.Eng J Med 2008;359: 1486-500. Ganem D, Prince AM. Hepatitis B Virus Ganem D, Prince AM. Hepatitis B Virus

Infection—Natural History and Clinical Infection—Natural History and Clinical Consequences. N Eng J Med 2004; 350: Consequences. N Eng J Med 2004; 350: 1118-29.1118-29.

Liaw YF, Chu CM. Hepatitis B Virus Infection. Liaw YF, Chu CM. Hepatitis B Virus Infection. Lancet 2009;373:582-592.Lancet 2009;373:582-592.

Lok ASF, McMahon BJ. Chronic Hepatitis B: Lok ASF, McMahon BJ. Chronic Hepatitis B: Update 2009. Hepatology 2009; 3: 1-36.Update 2009. Hepatology 2009; 3: 1-36.

Lok ASF. Clinical manifestations and natural Lok ASF. Clinical manifestations and natural history of hepatitis B virus infection. history of hepatitis B virus infection. UpToDateUpToDate

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