Viral Hepatitis

in
Infants and Children
Ricardo A. Caicedo, M.D.
Pediatric Gastroenterology and Nutrition
Wake Forest University Baptist Medical Center

Learning Objectives
Recognize the clinical manifestations of
viral hepatitis in the pediatric population
Understand the natural history of
hepatotropic viral infections in children

Become familiar with the diagnosis and

management of pediatric viral hepatitis

Topics

Hepatotropic Viruses
Acute vs. Fulminant vs. Chronic
Hepatitis A virus
Hepatitis B virus
Diagnosis
Natural history
Immunoprophylaxis/management

Hepatitis C virus
Diagnosis
Natural history
Management

Other viral agents

www.microscopyu.com

Hepatotropic Viruses
PRIMARY

Hepatitis A Virus (HAV)

Hepatitis B Virus (HBV)
Hepatitis C Virus (HCV)
Hepatitis D Virus (HDV)
Requires HBV co-infection

Hepatitis E Virus (HEV)

Hepatitis F Virus
(controversial)
Hepatitis G Virus
(pathogen?)

SYSTEMIC

Cytomegalovirus (CMV)
Epstein-Barr Virus (EBV)
HIV
Adenovirus
Parvovirus B19
Rubella
Coxsackievirus B
Enteroviruses
Human Herpes Viruses
Herpes Simplex Virus (HSV)
HHV-6
Varicella Zoster Virus (VZV)

Acute Viral Hepatitis

Acute hepatocellular injury/inflammation
Reflected by elevated transaminases (AST or SGOT,
ALT or SGPT)
Clinical manifestations often include fever, malaise,
jaundice, RUQ pain, nausea/vomiting

Typically self-limited and of short duration

Contrast with: chronic, fulminant

Causative agents
HAV (50% of cases in U.S.), HEV
CMV, EBV, VZV

Fulminant Hepatitis
Acute, massive hepatocellular necrosis
Impaired synthetic, excretory, and detoxifying
functions of the liver
Cholestasis, ascites, coagulopathy, encephalopathy,
multi-system failure
Initially very elevated transaminases
Falling transaminases and rising bilirubin ominous
Hyperammonemia, hypoalbuminemia, prolonged PT,
hypoglycemia

Viral agents (50% of cases)

Most cases of fulminant hepatic failure are caused by
unidentified agent, presumably viral
HAV, HBV+/-HDV, HCV, HEV
HSV, enteroviruses, EBV, CMV, HHV-6, VZV

Chronic Hepatitis
Prolonged necroinflammatory process
Elevated transaminases for > 4-6 months
Insidious clinical manifestations
Can include cholestasis (jaundice, pruritus),
ascites, hypoalbuminemia, coagulopathy,
encephalopathy
Can progress to fibrosis and then cirrhosis

Viral agents: HBV (+/- HDV), HCV

Other causes include autoimmune, metabolic
disorders (Wilsons, CF, alpha-1 antitrypsin deficiency),
drug/toxin-mediated, idiopathic

Chronic Viral Hepatitis

Risk Factors

Hochman J, Balistreri WF. Pediatr Rev. 2003; 24:399-410.

Hepatitis A Virus
Causes 33% of acute viral hepatitis in U.S.
NOT a cause of chronic hepatitis
rarely causes fulminant hepatitis (< 1% cases)
Can trigger autoimmune hepatitis in predisposed individuals

Epidemiologic factors

Fecal-oral transmission
Poor hygiene
High population density
Daycare centers and minor epidemics

HAV
Acute, self-limited illness
Fever, malaise, anorexia, vomiting, nausea, abdominal pain,
diarrhea
Elevated AST/ALT
Jaundice (conjugated hyperbilirubinemia) usually 1 wk after
onset of symptoms
Duration
Age < 6 y: typically, <2 wks
Older children and adults can have prolonged course and often
have hepatomegaly

Dx: serology
Anti-HAV IgM

Supportive care

HAV Course

Quiros-Tejeira RE. Up to Date v. 14.3, 2006.

HAV Vaccine
Prevents morbidity and mortality associated with
HAV infection
Incidence of HAV in U.S. has decreased by 75%
since vaccine introduced in 1997
Because humans are the only known reservoir for HAV,
universal immunization strategies could hypothetically
eradicate HAV

AAP Recommendation, 2006

All children age 12-23 months should be immunized
Extended safety data supports incorporation of HAV vaccine
into routine childhood immunization schedule

Recommended Standard Childhood

Immunization Schedule, 2006

www.cdc.gov/nip/recs/child-schedule.htm

Hepatitis B Virus
Hepadnavirus
Double-stranded DNA
A retrovirus in disguise

Multiple genotypes and serotypes

Replication factory
Significant mutation rate
Can escape serological detection and/or vaccine

Triggers host immune attack on liver cells

T-cell-mediated hepatocellular lysis
Chronic infection results from ineffective immune response

HBV Epidemiology
Worldwide
Persons infected: 2 billion
Persons with chronic HBV: 350 million
Annual deaths: 1 million

U.S.
Chronic HBV: 1.25 million
Annual deaths: 5000

HBV Transmission
Sexual
High risk: non-monogamous heterosexual and
all homosexual encounters

Vertical (maternal-fetal)
Intravenous drug use
Hemodialysis
Blood products
Risk of acquiring HBV from blood transfusion:
< 1:60000

HBV Manifestations
Incubation period: 45-160 d
Prodromal flu-like illness
Malaise, fatigue, anorexia, nausea, fever

Jaundice
Cholestasis

Elevated AST/ALT
Less common
Fulminant hepatitis: coagulopathy, encephalopathy
1-5% of HBV cases

Glomerulonephritis, arthritis
Papular acrodermatitis (Giannotti-Crosti)

Papular acrodermatitis

Screening for HBV

TESTS: HBsAg and anti-HBs
Adolescents who engage in high-risk behaviors
IV or intranasal drug abuse
unprotected sex with an infected partner or > 1 partner
Hx of STD

All internationally adopted children

Immigrants from high-prevalence areas
Africa, SE Asia, the Middle East except Israel, the interior
Amazon River basin, Haiti/D.R.

Children living in communities where HBV is endemic

Household contacts of individuals with HBV infection
Infants born to women with HBV infection
If infant got hepatitis B immune globulin and hepatitis B vaccine
at birth, followed by two additional immunizations, test at 9-15 m
Unimmunized should be tested as soon as identified

HBV Diagnosis

Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.

HBV Diagnosis
SEROLOGIC RESPONSES

Lok ASF. Up to Date v. 14.3, 2006.

HBV Serology

HBsAg: +
Anti-HBc: +
IgM anti-HBc: +
Anti-HBs: INTERPRETATION:
Acute HBV infection

HBsAg: +
Anti-HBc: +
IgM anti-HBc: Anti-HBs: INTERPRETATION:
Chronic HBV infection

HBV Serology
HBsAg: Anti-HBc: +
Anti-HBs: +
INTERPRETATION:
Immunity due to
natural infection

HBsAg: Anti-HBc: Anti-HBs: +

INTERPRETATION:
Immunity due to
HBV vaccination

HBV Course

Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.

HBV Sequelae
Risk of
Chronic HBV
95%

30%
5%

Occurs in 2050% by age 72

in absence of
prevention or tx

Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.

Evaluation of HBsAg+ Patients

AST/ALT, T/D bilirubin

PT/INR, albumin
HBV DNA
Anti-HBc, Anti-HBe, HBeAg
Serology for HAV, HCV, HDV
Test for HIV and other STDs
Test household and sexual contacts
If chronic
Ultrasound
Liver biopsy
Alpha feto-protein (AFP)
Lin KW, Kirchner JT. Am Fam Physician 2004; 69:75-82.

Management
Pediatric Chronic HBV
Prove chronic infection
> 2 HBsAg+ samples 6 months apart
OR anti-HBc+, IgM anti-HBc

Follow ALT q 6 months

If > 1.5-2X normal, liver biopsy and consider treatment

Yearly
HBeAg and anti-HBe (look for seroconversion)
Ultrasound and AFP

Immunize
HAV vaccine
All household contacts
Jonas MM, NASPGHAN Postgraduate Course, 2005.

HBV Treatment

Lin KW, Kirchner JT. Am Fam Physician 2004; 69:75-82.

GOALS of TREATMENT
- Suppress HBV replication
- Seroconversion from eAg to e Ab
- Prevent long-term sequelae

Interferon-alfa
Lamivudine
Adefovir

HBV Immunoprophylaxis
PASSIVE: HBIG
In conjunction with
vaccine
Perinatal exposure
Occupational exposure
(needle stick)
Household contact
exposed to blood

ACTIVE: HBV Vaccine

AAP recommends
immunizing all newborns
Started in 1991
By end of 1990s, rate of
acute HBV in children
reduced by 75%
Taiwan: vaccination program
reduced incidence of
HBsAg+, HCC, and
fulminant hepatitis

No objective evidence linking

vaccine to multiple sclerosis
or autism

HBV Prophylaxis
NEONATAL
Routine screening of all pregnant women for HBsAg is now
mandatory
HBsAg-negative mother: Infant vaccinated at birth; at 1-2 m;
at 6-18 m
Infants born to mothers with unknown or known positive HBsAg
status: HB immune globulin (HBIG) plus the 1st dose HB vaccine
within 12 h of birth, 2nd at 1-2 m; 3rd at 6 m

OTHER
Post-exposure (occupational): for nonvaccinated individuals or
absence of documented response
High risk groups

Healthcare workers
Chronic liver disease
Dialysis or chronic parenteral therapy recipients
High risk behaviors (IV drug use, unprotected sex)

Hepatitis C Virus
Discovered 1989
Post-transfusion non-A, non-B hepatitis

RNA flavivirus
Difficult to clear
Genetic heterogeneity
9 known genotypes
Rapid mutation rate
Exists as mixture of closely related mutants (quasispecies) within an individual host

HCV Epidemiology
Prevalence
Adults: 2%
Children: 0.2%, Adolescents: 0.4%

Transmission
Maternal-fetal
Mother HCV+: 5% risk
Mother co-infected with HIV: 15% risk
All infants born to HCV-infected mothers should be tested for
anti-HCV Ab after 12 m of age

Blood transfusion
Screening blood products has reduced risk to <1:100,000

Other risk factors

High risk sexual behavior
IV drug abuse
Tattooing, body piercing

HCV Sequelae
Mild systemic
illness; usually
without
jaundice

C = Chronic; chronic infection develops in

most patients with HCV

HCV Diagnosis

Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.

HCV Management
No immunoprophylaxis available
Screen for and vaccinate vs. HAV & HBV
Avoid hepatotoxins
Acetaminophen, alcohol

Follow-up at regular intervals

Follow LFT
AFP, ultrasound (screen for HCC)

Treatment in selected patients

Prevent progression to cirrhosis

If HCV identified during acute stage - eradication
Pegylated-interferon (choice in adults)
PEG-IFN + ribavirin (multicenter pediatric trial)
Liver transplantation: indicated for cirrhosis or HCC

Viral Hepatitis
Consultation with Pediatric GI

Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.

Breastfeeding
HBsAg+ mothers
can breastfeed as long as neonate has
received HBIG and vaccine within 12 h of
birth

HCV+ mother is not contraindication to

breastfeeding
Data re: transmission in human milk is limited

CMV
Usually acute self-limited hepatitis

Mononucleosis syndrome with fever

Typically anicteric
Transaminases peak at 200s at 2-3 wks
Dx: IgM, antigenemia, PCR
Rarely causes fulminant hepatitis
Can treat with ganciclovir or foscarnet

More severe cases

Immunocompromised
Chronic liver disease

EBV
Classic infectious mononucleosis
syndrome
Fever, sore throat, fatigue
Cerv. lymphadenopathy, splenomegaly

Liver insult secondary to infected T cells

Mild anicteric hepatitis in most cases

Dx = EBV serology, PCR

Fulminant course (1:3000 cases)
Severe hepatitis, bone marrow failure

North American Society for Pediatric Gastroenterology,

Hepatology and Nutrition
www.naspghan.org
www.cdhnf.org

www.hepb.org
www.aasld.org