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

2. 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

3. Topics Hepatotropic Viruses Acute vs. Fulminant vs. Chronic
Hepatitis A virus
Hepatitis B virus
Diagnosis
Natural history
Immunoprophylaxis/management
Hepatitis C virus
Management
Other viral agents

4. Hepatotropic Viruses PRIMARY SYSTEMIC 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)

5. 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

6. 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

7. 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

8. Chronic Viral Hepatitis Risk Factors
Hochman J, Balistreri WF. Pediatr Rev. 2003; 24:

9. 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

10. HAV Acute, self-limited illness Dx: serology Supportive care
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

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

12. 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 months should be immunized
Extended safety data supports incorporation of HAV vaccine into routine childhood immunization schedule

13. Recommended Standard Childhood Immunization Schedule, 2006

14. Hepatitis B Virus Hepadnavirus Replication factory
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

15. HBV Epidemiology Worldwide U.S. Persons infected: 2 billion
Persons with chronic HBV: 350 million
Annual deaths: 1 million
U.S.
Chronic HBV: 1.25 million
Annual deaths: 5000

16. HBV Transmission Sexual Vertical (maternal-fetal) Intravenous drug use
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

17. 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)

18. Papular acrodermatitis

19. 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

20. HBV Diagnosis
Hochman J, Balistreri WF. Pediatr Rev. 2003; 24:

21. HBV Diagnosis
SEROLOGIC RESPONSES
Lok ASF. Up to Date v. 14.3, 2006.

22. HBV Serology HBsAg: + Anti-HBc: + IgM anti-HBc: + Anti-HBs: - HBsAg: +
INTERPRETATION: Acute HBV infection
INTERPRETATION: Chronic HBV infection

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

24. HBV Course
Hochman J, Balistreri WF. Pediatr Rev. 2003; 24:

25. Occurs in 20-50% by age 72 in absence of prevention or tx
HBV Sequelae
Risk of
Chronic HBV
95%
30% 5%
Occurs in 20-50% by age 72 in absence of prevention or tx
Hochman J, Balistreri WF. Pediatr Rev. 2003; 24:

26. 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.

27. 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.

28. Refer to Pediatric Gastroenterology
HBV Treatment
Refer to Pediatric Gastroenterology
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

29. 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

30. HBV Prophylaxis NEONATAL OTHER
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)

31. Hepatitis C Virus Discovered 1989 RNA flavivirus Difficult to clear
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 (quasi-species) within an individual host

32. HCV Epidemiology Prevalence Transmission Maternal-fetal
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

33. HCV Sequelae C = Chronic; chronic infection develops in
Mild systemic illness; usually without jaundice
C = Chronic; chronic infection develops in
most patients with HCV

34. HCV Diagnosis
Hochman J, Balistreri WF. Pediatr Rev. 2003; 24:

35. 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

36. Viral Hepatitis Consultation with Pediatric GI
Hochman J, Balistreri WF. Pediatr Rev. 2003; 24:

37. 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

38. 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

39. 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

40. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition