HEPATITIS B

Dr. james

ACUTE HEPATITIS B

An acute systemic infection caused by the hepatitis B virus (HBV) Liver is the primary target, but extrahepatic complications are common. After acute infection, complete recovery with lifetime immunity occurs in ~95% of patients.

Definition

Possible long-term complications

Chronic infection Chronic liver disease Liver failure Hepatocellular carcinoma

Epidemiology

PEAK INCIDENCE: 30 to 45 yr of age,

at rates of 5% to 20% 40,000 deaths yearly worldwide Predominant in males because of increased intravenous drug abuse, homosexuality Females more commonly terminate in chronic carrier state

Caused by HBV (DNA virus) Transmission through infected blood or body fluids Percutaneous: needle sharing Perinatal

Etiology

Important mode of transmission in Far East and developing countries Likelihood of perinatal transmission correlates with presence of hepatitis B e antigen (HBeAg). Rate of transmission to offspring

90% if mother is HBeAg-positive 1015% if mother is antiHBe-positive

Sexual Oral (rare)

Symptoms & Signs

Most infections are asymptomatic. More likely to be severe in patients coinfected with hepatitis C or D Constitutional symptoms may precede the onset of jaundice by 12 weeks (prodromal symptoms). Long incubation

Uncommon symptoms and signs

Splenomegaly (1020% ) Cervical adenopathy (1020%) Spider angiomata

Extrahepatic manifestations
Signs of extensive acute immune reactivity: arthritis, urticaria, angioedema Hematuria Proteinuria

Diagnostic Approach

All patients with acute hepatitis should undergo 4 serologic tests.

HBsAg IgM anti-HBc IgM antihepatitis A virus (HAV) Antihepatitis C virus (HCV)

The presence of HBsAg, with or without IgM anti-HBc, confirms HBV infection. If IgM anti-HBc is present, HBV infection is considered acute.

Laboratory Tests

Serum HBsAg
infection

chronic HBV infection

-Indicative of acute or

Serum IgM anti-HBc -Indicative of acute HBV Serum IgG anti-HBc -Indicative of chronic
HBV infection

HBeAg
Presence of HBeAg is associated with high infectivity.

Because HBeAg is invariably present during early acute hepatitis B, HBeAg testing is indicated primarily during follow-up of acute infection as it progresses to a chronic state.

Laboratory Tests

Serum anti-HBs

Immunization with HBsAg (after vaccination) Hepatitis B in the remote past False-positive result Typically < 0.5 pg/mL in acute infection Levels > 0.5 pg mL associated with chronic infection Useful in chronic disease to assess viral activity

Quantitative HBV DNA

Serum ALT & AST

Variable increase during the prodromal phase Precedes the increase in bilirubin level Acute levels of these enzymes do not correlate well with the degree of liver-cell damage. 4000 IU.

. Peak levels vary from 400

Serum bilirubin

Jaundice is usually visible in the sclera or skin when > 43 mol/L (2.5 mg/dL). Bilirubin levels > 340 mol/L (20 mg/dL) that increase and persist late into the course of viral hepatitis are more likely to be associated with severe disease.

Prothrombin time Serum alkaline phosphatase level Albumin level

Treatment

Mainstay of therapy is supportive care. In rare instances of severe acute hepatitis B, antiviral therapy has been attempted. Lamivudine: 100 mg/d PO (not

approved, Efficacy, & Duration of therapy has not been determined.)

Liver Transplantation is indicated

Supportive care

Activity as tolerated High-calorie diet (often tolerated best in

morning)

Intravenous hydration and parenteral nutrition Avoidance of alcohol and drugs metabolized by the liver. Bile-salt sequestrant resins, if severe pruritus

Cholestyramine: up to 4 g PO 4 times daily

Monitoring
(inpatient)

Elderly Those with serious underlying medical disorders.

Those with any of the following presenting features: Ascites , Peripheral edema Hepatic encephalopathy Prolonged prothrombin time Low serum albumin level Hypoglycemia

Monitoring

It is particularly important to document the disappearance of HBsAg after apparent clinical recovery from acute hepatitis B.

Patients who fail to convert to HBsAg-negative status may:

Be inactive carriers Have low-grade, mild chronic hepatitis Have moderate to severe chronic hepatitis, with or without cirrhosis

The likelihood of becoming an HBsAg carrier after acute HBV infection is especially high among:
Neonates Persons with Down syndrome Patients receiving chronic hemodialysis Immunosuppressed patients, including persons with HIV infection

Complications

Serum sicknesslike syndrome

of cases)

(510%

Glomerulonephritis with nephrotic syndrome Polyarteritis nodosalike systemic vasculitis Fulminant hepatitis (massive hepatic
necrosis)

Chronic hepatitis B Hepatocellular carcinoma

Prognosis

9599% of previously healthy adults have a favorable course and recover completely. Fulminant hepatitis: 0.11% Progression to chronicity
Adults: 110% Neonates: 90%

Carrier state: 0.130%

Prevention

Vaccination

(Recombinant

hepatitis B vaccine) 2 available vaccines: 10 g IM (Recombivax-HB) or 20 g IM (Engerix-B) Half dose for children 40-g dose for patients receiving hemodialysis and immunocompromised adults Given at 0, 1, and 6 months Deltoid, not gluteal, injection

Duration of protection: At least 5 years in ~8090% of immunocompetent vaccine

Booster vaccinations are only indicated for:

Immunosuppressed individuals who no longer have detectable anti-HBs Immunocompetent persons who sustain percutaneous HBsAg-positive inoculations after losing detectable antiHBs Dialysis patients whose anti-HBs antibody levels fall below 10 mIU/mL

Hepatitis B immune globulin: 0.06 mL/kg IM

Postexposure prophylaxis

Immediately after needlestick, followed by a complete course of hepatitis B vaccine to begin within the first week Within 14 days of sexual exposure followed by a complete course of hepatitis B vaccine to begin within the first week

For perinatal exposure of infants born to an HBsAg-positive mother, a single 0.5-mL IM dose should be given immediately after birth in combination with a complete

CHRONIC HEPATITIS B

Chronic Hepatitis B,

A viral disorder of the liver of varying severity in which hepatic inflammation and necrosis continue for 6 months. Mild forms are nonprogressive or only slowly progressive. Severe forms may be associated with scarring and architectural reorganization, which can ultimately lead to cirrhosis.

Epidemiology

Worldwide: >350 million hepatitis B surface antigen (HBsAg) carriers

More in men than women Prevalence is higher among:

African Americans Hispanics Persons of Asian origin

Risk Factors

Spouse of an acutely infected person Unprotected sex with multiple partners Health care workers exposed to blood Injection drug users, Cocaine users (snort) Patients receiving hemodialysis, transplanted organs Patients with defects in cellular immune competence Down syndrome & Chronic hemodialysis Immunosuppressed patients, including HIV infection Persons who require repeated transfusions

Risk of chronicity after acute hepatitis B varies as a function of age.

Infection at birth is associated with a clinically silent acute infection, but a 90% chance of chronic infection. Infection in young adulthood in immunocompetent persons is typically associated with clinically apparent acute hepatitis, but a risk of chronicity of only approximately 1%.

Etiology

Hepatitis B virus (HBV) Transmission

- DNA virus

Perinatal Percutaneous (intravenous drug users, tattooing, body piercing, household contacts through sharing of razors or toothbrushes) Sexual Transfusion Nosocomial (needlestick injuries to health care workers) Organ transplantation

Symptoms & Signs

Many patients are asymptomatic Onset tends to be insidious Nonspecific symptoms may dominate

Fatigue Malaise Anorexia

Jaundice may be persistent or intermittent. Other stigmata of chronic liver disease may include: Hepatomegaly, Palmar erythema, Spider angiomas Occasionally, patients present with

Diagnostic Approach

Establish diagnosis with serologic markers of chronic HBV infection. Then determine degree of HBV replication.

Based on hepatitis B e antigen (HBeAg) status and HBV DNA levels

These tests have both prognostic and therapeutic implications.

Liver biopsy can determine the severity of the disease and guide further interventions.

Liver biopsy should be considered for patients

HBsAg positive for >6 months Serum HBV DNA >10(5) copies/mL Persistent or intermittent elevation in ALT/ AST

Liver biopsy is most important for patients who do not meet current criteria for treatment but have:
Serum HBV DNA 10(4) to 10(5) copies/mL ALT/AST levels that are normal or mildly

Diagnostic tests

HBsAg : present except in patients without ongoing viral activity (i.e.,inactive carrier state) IgG anti-HBc : present IgM anti-HBc :

Present with acute or recent infection Useful for distinguishing acute from chronic infection in patients found to be HBsAg positive for unknown duration (e.g., blood donors) Usually undetectable or at low levels in chronic disease After immunization with HBV vaccine, which consists of HBsAg alone, anti-HBs is the only serologic marker to appear. May indicate HBV infection in the remote past

Anti-HBs:

Diagnostic tests

HBeAg :

Qualitative marker for active HBV replication

HBV DNA :
Quantitative marker for active HBV replication Correlates with the level of liver injury and risk of progression

Active HBV replication is usually indicated by presence of:

HBeAg HBV DNA HBcAg

HBeAg-negative chronic hepatitis is a subgroup with active virus replication, but with the following profile
HBV DNA present HBeAg absent Anti-HBe present

LABS

LFT
ALT & AST level: elevated Alkaline phosphatase : normal or marginally elevated Serum bilirubin level: moderately elevated Hypoalbuminemia

PT INR : prolonged Imaging

Abdominal U/S or CT

Diagnostic Procedures

Liver biopsy, may be indicated

To assess severity of disease, Predict response to therapy, To rule out hepatocellular carcinoma

Classification of Chronic Hepatitis

By cause:

Hepatitis B, C , D ; Autoimmune hepatitis, Drugassociated hepatitis, Cryptogenic cirrhosis. Histologic assessment of necroinflammatory activity based on liver biopsy. e.g. Histologic Activity Index (HAI) & METAVIR Level of progression of disease based on fibrosis

By grade:

By stage:

Treatment Approach

Management is directed at suppressing the level of HBV viral replication. Disease progression occurs primarily in patients with active HBV replication. Among patients with chronic hepatitis B who are at risk for hepatocellular carcinoma, the risk is highest for those with continued, high-level HBV replication. Goal should be HBV DNA < 10(4) copies/mL, preferably lower. Patients should be tested for anti-HIV prior to therapy.

Drugs

Drugs approved for treatment.

Interferon Pegylated interferon (PEG IFN) Lamivudine Adefovir dipivoxil Entecavir

Drugs being tested in clinical trials

Telbivudine Emtricitabine Pradefovir Tenofovir Oral anti-viral combination therapy

Recommendations for Treatment of Chronic Hepatitis B

HBeAg Clinical Status HBV DNA ALT (copies /mL) Recommendation

HBeAgreacti ve

<105

Normal (2 ULN) b No treatment; monitor Normal (2 ULN) b, cNo treatment; current treatment of limited benefit (Some suggest liver biopsy and treating if abnormal) Elevated (>2 ULN) Treat d
b

Chronic hepatitis 105

Chronic hepatitis 105 Cirrhosis + or e compensated Cirrhosis + or e decompensat ed

Normal or elevated

Treat e with oral agents, f not PEG IFN Treat e with oral agents, g not PEG IFN; refer for liver transplantation

Normal or elevated

Recommendations for Treatment of Chronic Hepatitis B

HBeAg- a <104 or 105 h Normal (2 negat ULN) b ive Chronic 104 or 105 h Normal hepatitis Chronic 104 or 105 h Elevated hepatitis (>2 ULN) b Cirrhosis + or compen sated Elevated or normal Inactive carrier; treatment not necessary Consider liver biopsy; treat if biopsy abnormal Treat i

Treat with oral agents, j not PEG IFN (some authorites recommend either following or treating for HBV DNA <104 copies/mL) Treat with oral agents, j not PEG IFN (some authorities would follow without therapy for undetectable HBV DNA; refer for liver transplantation)

Cirrhosis + or decomp ensated

Elevated or normal

Comparison of Interferon (PEG IFN), Lamivudine, Adefovir, and Entecavir Therapy for Chronic Hepatitis B
Feature Route of administration PEG IFN b Subcutaneous injection Lamivudine Oral 52 weeks Adefovir Oral 48 weeks Entecavir Oral 48 weeks

Duration of therapy c 4852 weeks

Tolerability

Poorly tolerated

Well tolerated

Well tolerated; creatinine monitoring recommended 23%

Well tolerate d 22%

HBeAg loss 1 year HBeAg seroconversion 1 year Rx >1 year Rx

2930%

2033%

1820% NA

1621%

12%

21% 31% @ 2 years

Up to 50% @ 5 years 43% @ 3 years d

Choice of therapies

Among the 5 available drugs for hepatitis B, PEG IFN has supplanted standard IFN. Because entecavir has been proved superior to lamivudine in clinical trials. PEG IFN, lamivudine, adefovir, and entecavir can each be used as first-

PEG IFN

Benefits
Requires finite-duration of therapy Achieves the highest rate of HBeAg responses after a year of therapy Does not readily induce viral mutations

Disadvantages
Requires subcutaneous injections Associated with inconvenience and intolerability Not safe in patients with cirrhosis

Oral antiviral

Benefits
Does not require injections Very well tolerated Leads to improved histology in 5090% of patients suppresses HBV DNA more profoundly than does PEG IFN Effective even in patients who fail to respond to IFN-based therapy

Oral antiviral

Disadvantages
Duration of therapy remains unclear. Requires long-term therapy in most patients

Resistance
High with lamivudine monotherapy Adefovir much less so Entecavir rarely at all

Interferon

Indications:
Serum HBeAg/HBV DNApositive patients with symptoms, elevated aminotransferase levels, and biopsy evidence of chronic hepatitis

Dose: 5 million U SC once daily, or 10 million U SC 3

times weekly

Duration: 16-week course Best predictors of response:

Lower levels of HBV DNA Substantially elevated aminotransferase levels

Interferon

Ineffective response for:

Patients positive for antihepatitis D virus or HIV Adult carriers infected in childhood Immunocompromised patients Asian patients with minimal to mild ALT elevations Persons infected with HBeAg-negative "pre-core" mutant

Interferon

Side effects Flu-like reaction (common) Depression Bone marrow depression Precipitation of autoimmune diseases, including thyroid disease Emotional lability Central nervous system symptoms Anorexia Sleep disturbance Alopecia Rashes Diarrhea Numbness and tingling of extremities Side effects are reversible by dose lowering or cessation of therapy, with the possible exception of autoimmune thyroiditis.

Lamivudine

First-line therapy in patients with evidence of active hepatitis and viral replication who:

Have contraindicatons to interferon(especialy decompensated cirrhosis)or Have pre-core mutations or Have chronic immunosuppression or Do not respond to interferon

Dose: 100 mg PO once daily Duration: 52 weeks (duration in clinical trials) In practice, at least a year and continued indefinitely or until at least 6 months after HBeAg seroconversion Side effects: minimal , very safe. Post-treatment flares occur in 2030% of lamivudine-treated patients.

Adefovir dipivoxil

Dose: 10 mg PO once daily In lamivudine-resistant patients:

Adding adefovir (i.e., maintaining lamivudine to preempt the emergence of adefovir resistance) appears to be the favored approach.

Duration: 48 weeks or until HBeAg response HBeAg-negative chronic hepatitis B:

Reactivation is the rule when therapy is discontinued

Entecavir

Most potent of the HBV antivirals Just as well tolerated as lamivudine Dose: 0.5 mg daily Also effective against lamivudineresistant HBV infection

Pegylated interferon 2a

More effective than the more frequently administered, standard IFN Dose: 180 g once weekly Duration: 48 weeks (used in clinical trials)

In practice, at least a year and continued indefinitely or until at least 6 months after HBeAg seroconversion

Likelihood of HBeAg loss in PEG IFN treated HBeAg-reactive patients is

Pegylated interferon 2a

Superior to lamivudine on the basis of:

HBeAg seroconversion HBsAg seroconversion

No benefit of combination therapy with lamivudine 6 months after treatment

Treatment of chronic HBV in pregnancy Lamivudine:No teratogenicity during pregnancy. Adefovir: may be an increased risk of spontaneous abortion. In general, except perhaps for lamivudine and until additional data become available, the other antivirals for hepatitis B should be avoided or used with extreme

HBV-HIV co-infection

Lamivudine should never be used as monotherapy Adefovir and entecavir have been used successfully to treat chronic hepatitis B in HBV-HIV co-infected patients. Tenofovir and the combination of tenofovir and emtricitabine in 1 pill are approved therapies for HBV-HIV

Monitoring

Side effects of medications Seroconversion from HBeAg to anti-HBe

Viable stopping point in therapy for HBeAgpositive chronic hepatitis B Cannot be used for HBeAg-negative chronic hepatitis B

Loss of HBsAg HBV DNA levels Aminotransferase levels Healthy carriers should have annual blood tests to check aminotransferase levels.

Complications

Hepatic complications

Extrahepatic complications

Complications of cirrhosis (end-stage chronic hepatitis) Hepatocellular carcinoma

Arthralgias Arthritis Immune-complex glomerulonephritis Purpuric cutaneous lesions Generalized vasculitis (PAN-like)

Prognosis

Histologic features are of prognostic importance Mild chronic hepatitis

5-year survival rate: 97% 15-year survival rate: 77% 5-year survival rate: 86% 15-year survival rate: 66%

Moderate to severe chronic hepatitis

Chronic hepatitis and postnecrotic cirrhosis

5-year survival rate: 55% 15-year survival rate: 40%

Prognosis

A more important prognostic factor than histologic findings alone in patients with HBV is the degree of hepatitis B replication. Higher HBV DNA concentration associated with higher likelihood of hepatocellular carcinoma, cirrhosis and death from liver disease HBeAg status and ALT not correlated with outcome

Glossary of Clinical Terms Used in HBV Infection

Chronic hepatitis B Chronic necroinflammatory disease of the liver caused by persistent infectionwith hepatitis B virus. Chronic hepatitis B can be subdivided into HBeAg positive and HBeAg negative chronic hepatitis B. Inactive HBsAg carrier state Persistent HBV infection of the liver without significant, ongoing necroinflammatory disease Resolved hepatitis B Previous HBV infection without further virologic, biochemical or histological evidence of active virus infection or disease Acute exacerbation or flare of hepatitis B Intermittent elevations of aminotransferase activity to more than 10 times the upper limit of normal and more than twice the baseline value Reactivation of hepatitis B Reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B HBeAg clearance Loss of HBeAg in a person who was previously HBeAg positive HBeAg seroconversion Loss of HBeAg and detection of anti-HBe in a person who was previously HBeAg positive and anti-HBe negative HBeAg reversion Reappearance of HBeAg in a person who was previously HBeAg negative, anti-HBe positive