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
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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
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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
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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 (Wilson’s, 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
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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
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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
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HBsAg: +
Anti-HBc: +
IgM anti-HBc: +
Anti-HBs: INTERPRETATION:
Acute HBV infection
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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
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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
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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
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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
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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