Viral Hepatitis in Children

DR. HOSSAIN IBRAHIM AGEEL PEDIATRIC GASTROENTEROLOGIST

PEDIATRIC DEPARTMENT KFCH – JAZAN

General Concepts

• Hepatitis = 'inflammation of the liver'.

• Virus causes:

Hepatotropic and non-hepatotropic

• Hepatotropic viruses:

HAV, HBV, HCV, HDV, HEV, HGV

ENVELOPE DNA or RNA FAMILY VIRUS

No RNA* Picornaviridae HAV

Yes DNA** Hepadnaviridae HBV

Yes RNA* Flaviviridae HCV

Yes RNA* Deltaviridae HDV

No RNA* Hepeviridae HEV

Yes RNA* Flaviviridae HGV

Classification of Hepatitis Viruses

*Single strand ** Double strand

Worldwide infection

Transmission of hepatitis A virus:

Fecal-oral route

• Close personal contact

• Contaminated water and food

Parentral (rare)

Incubation: 15-50 days (mean 28)

Hepatitis A Virus Infection

Pathogenesis

HAV infection is biphasic process:

• Non-cytopathic stage

• Cytopathic stage

Hepatocellular damage is immune mediated

process and not direct cytopathic effect by

hepatitis A virus.

Clinical manifestations

HAV infection is an acute self-limited illness

• General nonspecific symptoms (fever, malaise, anorexia,

vomiting, nausea, abdominal pain and diarrhea)

• Jaundice

• Choluria (bilirubin in urine)

• Mild hepatomegaly

Symptomatic hepatitis:

30% of infected children younger than six years.

70 – 80% in older children and adults infected with HAV

Atypical presentations

Hepatic manifestations: • Relapsing hepatitis (3-20%)

• Acute liver failure (<1%)

• Cholestasic hepatitis (30% of adult).

• Autoimmune hepatitis.

Extra-hepatic manifestations (common)

• An evanescent rash (11%)

• Arthralgias (14%)

Atypical presentations

Extra-hepatic manifestations (rare)

• Vasculitis

• Arthritis

• Optic neuritis

• Transverse myelitis

• Encephalitis

• Bone marrow suppression

Diagnosis

Serologic tests:

• Anti HAV IgM : indicates an acute infections

• Anti HAV IgG : indicates resolved infections or

vaccine induced immunity.

Other techniques:

• HAV detection in stool and body fluids by electron

microscopy.

• HAV RNA detection in stool, body fluids, serum and

liver tissues by PCR.

Treatment

Self-limited disease, rarely requires hospitalization

Only supportive measures in uncomplicated cases:

• Bed rest.

• Control fever.

• Increased fluid intake versus intravenous fluids.

• No particular diet is needed.

• Limit hepatotoxic medications, be cautious with

acetaminophen.

Children with HAV infection should be away for 1 wk.

Identify the index case for preventive measures

If complicated with acute liver failure:

• Hospitalization

• Aggressive supportive therapy

• Early transfer to liver transplantation center.

If HAV triggered secondary disorders

• Treat the specific disease

Treatment

Prevention and Prophylaxis

General measures:

• Adherence to sanitary practices (hand washing).

• Heating food appropriately.

• Avoidance of water or food from endemic areas.

Active immunization:

Two hepatitis A vaccines (inactivated vaccines)

• HAVRIX (in1995)

• VAQTA (in 1996)

Passive immunization:

• Polyclonal serum immunoglobulin (IgG)

Hepatitis A Vaccines

Inactivated whole virus vaccines

Pediatric and adult formulations :

• Pediatric formulations vaccines approved for persons 12 months through 18 years

• Adult formulations approved for persons 19 years and older

Hepatitis A Vaccines

• Adult

1 dose ( >95% seropositive )

booster dose 6-18 months after first dose ( 100% seropositive )

• Children and Adolescents

1 dose ( >97% seropositive )

booster dose 6-18 months after first dose ( 100% seropositive )

VAQTA HAVRIX Formulation

1–18 years

0.5 ml

1–18 years

0.5 ml

Pediatric:

Age

Dose

≥ 19 years

1.0 ml

≥ 19 years

1.0 ml

Adult:

Age

Dose

Hepatitis A Vaccines

• Available since 1940s

• Passive immunity lasts for up to six months

• Effective if administered within 2 weeks

post-exposure

• Dose is 0.02 ml per kg IM

Polyclonal serum immunoglobulin (IgG)

Structure of Hepatitis B Virus

Virion is 42 nm in diameter

Consists of :

An envelop contains viral

derived surface proteins also

known as HBsAg

Nucleocapsid contains

hepatitis core protein or

hepatitis Bc antigen(HBcAg)

Hepatitis Be protein (HBeAg)

Partially ds circular DNA

viral genome.

Viral DNA polymerase

Others

Hepatitis B genotypes

Geographic Regions Genotype

North America, Western Europe, Central Africa A

China, Indonesia, Vietnam, Taiwan B

East Asia, Korea, China, Japan, Taiwan,

Polynesia, Vietnam C

Mediterranean area, Middle East, India D

Nigeria, West Africa E

Alaska, Polynesia F

North America, France G

Central America H

Pathogenesis of HBV Infection

Two mechanisms:

• immune-mediated liver injury which is

related to cytotoxic T cell-mediated

lysis of infected hepatocytes.

• Direct cytotoxic liver injury may occur

when the viral load is very high

Rate Areas Categories

0.1–2% United States, Canada, Western

Europe, Australia, and New

Zealand

Low

3–5%

Mediterranean Countries, Japan,

Central Asia, Middle East, Latin

and South America

Intermediate

10–20% Southeast Asia, China, Sub-

Saharan Africa High

Epidemiology

Prevalence of hepatitis B virus infection

Concentration of Hepatitis B Virus

in Various Body Fluids

Concentration of Hepatitis B Virus

in Various Body Fluids

High ModerateLow/Not

Detectable

blood semen urine

serum vaginal fluid feces

wound exudates saliva sweat

tears

breastmilk

High Risk Groups Modes of

Transmission

Infants born to HBeAg-positive mothers Perinatal

Household Close Contacts Horizontal

Injection drug users, Health care

workers, Hemodialysis patients,

Recipients of blood products

Parentral

Heterosexuals and homosexuals Sexual

Transmissions and High Risk Groups

Incubation Period of HBV

• Average: 60–90 days

• Range: 45–180 days

Clinical manifestations

Acute Infection:

• Asymptomatic

• Symptomatic : Prodromal (serum sickness like syndrome, Constitutional (anorexia, nausea, jaundice, right upper quadrant pain, fatigue)

• Occasionally develops acute fulminant hepatitis and Gianotti-Crosti syndrome.

Clinical manifestations

Chronic Infection:

• Asymptomatic

• Vague right upper quadrant pain and fatigue

• Occasionally associated with extrahepatic manifestation including polyarteritis nodosa and glomerulonephropathy

Investigations

Laboratory tests: • Complete blood count with platelets

• Liver biochemical tests including AST, ALT, total bilirubin, alkaline phosphatase, albumin.

• Prothrombin time.

• Tests for HBV infectivity and immunity including HBsAg and HBsAb.

• Tests for HBV replication including HBeAg and HBeAb.

• Screen for hepatocellular carcinoma with abdominal ultrasound and serum alpha fetoprotein.

• Liver biopsy for patients who meet criteria of chronic hepatitis and who are considered for treatment

Serologic responses to hepatitis B Virus infection

90% if perinatal acquisition

20-50% if acquired between

1-5 years of age.

<5% if acquired in adult

Progression to chronic state

Interpretation Results Tests Susceptible Negative HBsAg

Negative Anti-HBc

Negative Anti-HBs

Immune due to natural

infection

Negative HBsAg

Positive Anti-HBc

Positive Anti-HBs

Immune due to hepatitis

B vaccination

Negative HBsAg

Negative Anti-HBc

Positive Anti-HBs

Acutely infected

Positive HBsAg

Positive Anti-HBc

Positive IgM anti-HBc

Negative Anti-HBs

Chronically infected Positive HBsAg

Positive Anti-HBc

Negative IgM anti-HBc

Negative Anti-HBs

Natural Course of Chronic Hepatitis B Infection

Lack of effective immune

response and exhibit

immune tolerance

Immune

Tolerance

State

Phase 1

Immune-mediated viral

clearance

Immune

Active

Phase 2

Low replication state Inactive

Carrier

Phase 3

Subsequent reactivation

of chronic hepatitis

Reactivation

State

Phase 4

Phases of Chronic Hepatitis B Infection

Labs and Histology Phase • Liver biopsy not indicated

• Antiviral Rx is ineffective.

• Risk of drug resistance if

treated with nucleoside.

• ALT Normal

• DNA > 20,000 IU/ml

• HBeAg +ve

• Minimal liver inflammation and fibrosis

Immune

Tolerant

• Liver biopsy is indicated.

• spontaneous conversion

• Resolution of infection.

•Treatment if there is no

spontaneous conversion

• ALT elevated

• DNA level >20,000 IU/ml

• HBeAg +ve

• Liver inflammation & fibrosis develops

Immune

Active

• Liver biopsy not indicated

• Treatment not indicated

• Up to 20% immune active

• 20-30% reactivate

• ALT normal

• DNA < 2,000 IU/ml or undetectable

• HBeAg -ve, Anti-HBe +ve

• No liver inflammation, Fibrosis regress

Inactive

Carrier

(latent)

• 20-30% of patients

• HBeAg-ve chronic HBV

• Usually 2nd to mutant virus

• Liver biopsy is indicated

• Antiviral therapy indicated

• ALT normal or elevated

• DNA levels increase (>2,000 IU/ml)

• HBeAg –ve

• HBeAb +ve or -ve

Reactiva-

tion

Monitoring of patients

Disease activity:

• ALT every 6-12 months

• HBeAg and HBeAb every 12 months

• If HBeAg is +ve, measure HBV DNA.

HCC surveillance:

• Ultrasound of liver every 12 months

• Alpha fetoprotein every 12 months

Treatment

Interferon alfa

• First line treatment choice.

• Six month course of interferon alfa-2b, six million units (MU) per m(2) (maximum 10MU) SC. three times a week for 24 weeks.

• Response rate in 30 – 40% of patients.

• Side effects: Flu like symptoms, Bone marrow suppression and changes in personality

Treatment

Lamivudine

• Second line treatment choice

• Nucleoside analog.

• Dose: 3 mg per kg of body weight (max. 100 mg)

• Limited efficacy.

• Drug resistance with long term use

Treatment

Newer agents

• Pegylated interferon therapy approved for ≥ 3 years of age.

• Adefovir : licensed for use in patient ≥ 12 years of age.

• Tenofovir : licensed for use in patient ≥ 12 years of age.

• Entecavir: licensed for use in patient ≥ 16 years of age.

Prevention HBV vaccine

• Universally recommended for all infants.

• Series of 3 doses over 6-9 months.

• Catch up immunizations for older unimmunized children.

• HBV-exposed family members or closed contacts.

HBV immune globulin indication for use

• Infants born to HBsAg positive mothers.

• Post exposure prophylaxis within 24 hours of exposure if no past vaccine.

Prevention

Other measures

• Household contacts:

Avoid sharing of tweezers, shavers, toothbrush, nail clippers.

• Universal precautions for handling abrasions, bleeding, etc.

Hepatitis C Virus

Hepatitis C genotypes Geographic Regions Genotype

United State, Europe 1

United State, Europe 2

India, Far East, Australia 3

Africa, Middle East 4

South Africa 5

Hong Kong, Vietnam, Australia 6

Mode of transmission

• Vertical

• Parentral

• Sexual

Perinatal transmission

• Perinatal transmission rates are 5%

• Rates are increased up to 15 – 20% if mother is coinfected with HIV.

• Risk factors:

Use of internal fetal monitoring devices

Prolonged rupture of membranes (>6 hours)

High viral load

HIV coinfection

• Breast feeding and vaginal delivery doesnot increase vertical transmission

Clinical Features

• Incubation period: 30-150 days

• Chronic infection will develop in 60-80% of exposed children.

• Majority of patients are asymptomatic in childhood.

• End-stage liver disease with decompensated cirrhosis has been described in children.

• Acute liver failure from HCV infection has not reported in immunocompetent patients.

• Comorbidities: Glomerulonephritis, Cryoglobulinemia and Autoimmune hepatitis

Diagnosis

• Check liver panel

• Screen with HCV IgG antibody after 18 month of age and HCV RNA after 2 month of age.

• HCV genotype analysis indicated if treatment is being considered.

Treatment

• Subcutaneous weekly pegylated interferon-alpha

injections for 48 weeks (genotypes 1 or 4) or 24 weeks (genotypes 2 or 3), plus oral ribavirin.

• Treatment response: nondetectable HCV RNA by 24 weeks.

• Pegylated interferon/ribavirin therapy approved for ≥ 3 years of age.

Prevention

• HCV vaccine: none available.

• HCV immunoglobulin: none available.

• Household contacts: avoid sharing of tweezers, shavers, toothbrush, nail clippers.

• Universal precautions for handling abrasions, bleeding, etc.

• Screening for hepatocellular carcinoma (HCC): increased risk for HCC in setting of chronic HCV hepatitis.

HEPATITIS D VIRUS

• Defective interfering virus, requires HBV co-infection

• Prevalent in Mediterranean basin, North Africa, and

South America

• 10% of HBV infected persons co-infected with HDV

• More severe infection

• Diagnosis: Co-infection with acute HBV showed

positive IgM anti-HDV while super-infection of

chronic HBV showed positive IgG & IgA anti-HDV in

addition to serological markers of HBV.

HEPATITIS E VIRUS

• Incubation period 15-60 days

• Enteric transmission via fecal-oral route.

• Endemic in Southeast & Central Asia; Middle East,

North and West Africa

• Acute, self-limited hepatitis

• Clinical features range from asymptomatic to mild

to fulminant picture with high mortality rate in

pregnant women in third trimester (20%)

• Diagnosis: Anti-HEV IgM positive for 2-3 months,

Anti-HEV IgG persists long term in haIf of patients.

• Immunoprophylaxis: none

HEPATITIS G VIRUS

• RNA virus

• Flaviviridae family with 25% homology with HCV.

• Parenterally transmitted agent ; can be transmitted

perinatally .

• Clinical significance is uncertain, majority of

infected patients without liver disease.