An overview of pediatric viral hepatitis; pathophysiology, diagnosis, management and prevention.. Hepatitis A, B, C, D and E.

1. VIRAL HEPATITIS
Dr Joyce Mwatonoka
3rd Year Resident
Pediatrics and Child Health
March 2021

2. Introduction
• Viral hepatitis s a systemic infection affecting
the liver predominantly with primary
inflammation of the liver by any of a
heterogeneous group of hepatotropic viruses
• At least 5 pathogenic hepatotropic viruses
recognized to date: hepatitides A (HAV), B
(HBV), C (HCV), D (HDV), and E (HEV) viruses

3. Cont…
• Many other viruses (and diseases) can cause
hepatitis, usually as 1 component of a
multisystem disease
• These include HSV, CMV, EBV, varicella-zoster
virus, HIV, rubella, adenoviruses,
enteroviruses, parvovirus B19, and
arboviruses

4. Cont…
• In most pediatric patients, the acute phase
causes no or mild clinical disease
• Morbidity is related to rare cases of ALF in
susceptible pts, and to the chronic disease
state and attendant complications that 3 of
these viruses (hepatitides B, C, and D) can
cause

5. ISSUES COMMON TO ALL FORMS
OF VIRAL HEPATITIS

6. Clinical presentation
• Jaundice
• Tender hepatomegally
• Splenomegaly and lymphadenopathy may be
present
• Extrahepatic sxs (rashes, arthritis) are more
readily seen in HBV and HCV infections
• Clinical signs of altered sensorium or hyper-
reflexia (onset of encephalopathy and ALF)

7. Differential Diagnoses
• Varies with age of presentation;
• In the newborn period;
Infection is a common cause of conjugated
hyperbilirubinemia; can be bacterial agent
(e.g., E coli, Listeria, syphilis) or a
nonhepatotropic virus (e.g.HSV, enteroviruses,
CMV)

8. Cont…
Metabolic (α1antitrypsin deficiency, cystic
fibrosis, tyrosinemia)
Anatomic causes (biliary atresia, choledochal
cysts) and inherited forms of intrahepatic
cholestasis should always be excluded

9. In later childhood;
• Extrahepatic obstruction
(gallstones, primary
sclerosing cholangitis,
pancreatic pathology),
• Inflammatory conditions
(autoimmune hepatitis,
juvenile rheumatoid
arthritis, Kawasaki
disease)
• Infection (EBV, varicella,
malaria, leptospirosis,
syphilis)
• Immune dysregulation
(hemophagocytic
lymphohistiocytosis),
• Infiltrative disorders
(malignancies)
• Toxins and medications,
metabolic disorders
(Wilson disease, cystic
fibrosis)

10. Common Biochemical Profiles in the
Acute Infectious Phase
1. Cytopathic injury to the hepatocytes; rise in
serum levels of alanine aminotransferase
(ALT) and aspartate aminotransferase (AST)
-Take weeks to return to normal unlike
bilirubin
NB; The magnitude of enzyme elevation does
not correlate with the extent of hepatocellular
necrosis and has little prognostic value

11. Cont…
2. Cholestasis, defined by elevated serum
conjugated bilirubin levels
• Markers of cholestasis;
-serum alkaline phosphatase (ALP)
-5′-nucleotidase
-γ-glutamyl transpeptidase
-urobilinogen

12. Cont…
• Improvement tends to parallel the acute
hepatitis phase
• Absence of cholestatic markers does not rule
out progression to chronicity in HCV or HBV
infections

13. Cont…
3. Synthetic dysfunction is reflected by a
combination of;
• Abnormal protein synthesis (prolonged PT,
high INR, low serum albumin levels)
• Metabolic disturbances (hypoglycemia, lactic
acidosis, hyperammonemia)
• Poor clearance of medications
• Hepatic encephalopathy

14. HEPATITIS A VIRUS (HAV)
• Member of picornavirus family, RNA virus
• Host; humans and other primates
• The most prevalent hepatotropic virus
• Responsible for most forms of acute and
benign hepatitis
• Fulminant hepatic failure can occur, but it is
rare (<1%) and occurs more often in adults
than in children

15. Cont…
• HAV is highly contagious
• Transmission is almost always by person-to-
person contact through the fecal–oral route
• Perinatal transmission occurs rarely
• Mean incubation period is approx 3 wk
• Fecal excretion of the virus starts late in the
incubation period, reaches its peak just before
the onset of sxs, and resolves by 2 wk after
the onset of jaundice in older subjects

17. Clinical Manifestations of HAV
• Often an anicteric illness, clinically
indistinguishable from other forms of viral
gastroenteritis, particularly in young children
• More likely to be symptomatic in adults, in pts
with liver disorders and immunocompromised
• An acute febrile illness with anorexia, nausea,
malaise, vomiting, and jaundice
• The typical duration of illness is 7-14 days

18. Cot…
• May have regional lymphadenopathy and
splenomegally
• Bone marrow may be moderately hypoplastic
(aplastic anemia)
• Ulceration of the GIT can occur, especially in
fatal cases
• Though rarely; acute pancreatitis, myocarditis,
nephritis, arthritis and vasculitis

19. Treatment
• HAV infection is usually self-limited
• Treatment consists of supportive care
• Full clinical and biochemical recovery is
observed within 3 months in 85% of pts, and
complete recovery is observed by 6mo in
nearly all patients

20. Prevention;Vaccine
• 2 inactivated vaccines (HAVRIX and VAQTA)
• Approved for children older than 12 mo
• Administered IM in a 2-dose schedule, with
the 2nd dose given 6-12 mo after the 1st dose
• Seroconversion rates in children exceed 90%
after an initial dose and approach 100% after
the 2nd dose; protective antibody titer
persists for >10 yr in the vast majority of pts

21. Cont…
• HAV vaccine may be administered
simultaneously with other vaccines
• A combination HAV and HBV vaccine is
approved in adults older than age 18 yr
• For healthy persons at least 12 mo old,
vaccine is preferable to Ig for preexposure and
postexposure prophylaxis

22. Prognosis
• Excellent Px, with no long-term sequelae
• The only feared complication is ALF

23. HEPATITIS B VIRUS (HBV)
• HBV is a member of the Hepadnaviridae
family, DNA virus
• HBV has 8 genotypes (A-H). A is pandemic, E
in Africa
• Four genes have been identified: the S
(surface), C (core), X, and P (polymer) genes
• The surface of the virus includes particles
designated hepatitis B surface antigen
(HBsAg)

24. Cont…
• The inner portion of the virion contains HBcAg,
the nucleocapsid that encodes the viral DNA, and
a nonstructural Ag called hepatitis B e antigen
(HBeAg), a nonparticulate soluble antigen
derived from HBcAg by proteolytic self-cleavage
• HBeAg serves as a marker of active viral
replication and usually correlates with HBV DNA
levels
• Replication of HBV occurs predominantly in the
liver but also occurs in the lymphocytes, spleen,
kidney, and pancreas

25. Epidemiology
• Areas of highest prevalence of HBV infection
are sub-Saharan Africa, China, parts of the
Middle East, the Amazon basin, and the Pacific
Islands

26. Acute infection
• The dx of acute HBV infection is based upon
the detection of HBsAg and IgM antibody to
hepatitis B core antigen (anti-HBc)
• Hepatitis B immune globulin and hepatitis B
vaccine should be administered to all
household and sexual contacts who are not
known to be immune

27. Cont…
• HBV is present in high concentrations in blood,
serum, and serous exudates and in moderate
concentrations in saliva, vaginal fluid, and
semen
• Efficient transmission occurs through blood
exposure and sexual contact

28. Risk factors for HBV infection and
modes of transmission;
• No risk factors are identified in approximately
40% of cases
• The most important risk factor for acquisition
of HBV remains perinatal exposure to an
HBsAg-positive mother

29. Mother-to-child transmission
• HBsAg-positive and HBeAg-positive and/or a
high HBV viral load, have greatest risk of
transmission
• Up to 90% of these infants become chronically
infected if untreated
• Transmission may occur in utero (2.5%) , at
the time of birth (commonest), or after birth

30. Cont…
• Immunoprophylaxis with hepatitis B
immunoglobulin (HBIG) and the HBV
immunization, given within 12 hr of delivery is
very effective in preventing infection and
protects > 95% of neonates born to HBsAg-
positve mothers

31. Cont…
• However, despite the proper use of
prophylaxis, transmission can still occur
• Among women with a high viral load, antiviral
therapy for the mother can further reduce the
risk of transmission

32. Cont…
• Breastfeeding; does not appear to increase the
risk of transmission
• Paternal transmission; In a study conducted in
Taiwan, the HBV infection rate was 65% among
neonates born to HBsAg-negative mothers and
HBsAg-positive fathers; believed to result from
close contact
Application of hepatitis B virus genotyping and phylogenetic analysis in intrafamilial
transmission of hepatitis B virus. Lin CL, Kao JH, Chen BF, Chen PJ, Lai MY, Chen DS Clin
Infect Dis. 2005;41(11):1576.

33. Cont…
• Transfusion; The WHO suggests screening
with both HBsAg and hepatitis B core antibody
(anti-HBc)
• In the US residual risk of HBV transmission
after screening for both ranged from approx 1
in 280,000 to 1 in 357,000 donations
• With addition of HBV DNA screening

34. Cont…
• In adolescents; IV drug use, contaminated
needles, sexual contact, institutional care, and
intimate contact with carriers

35. Cont…
• After infection, the incubation period ranges
from 45-160 days, with a mean of
approximately 120 days
• Sxs begin an average of 3months (range 2-
5mo) after exposure to HBV
• Sxs typically last for several weeks but can
persist for up to 6mo
• 70% subclinical (anicteric), <1% fulminant dse

36. Chronic HBV
• HBsAg positive for more than 6mo
• Approximately 30-50% of pts with chronic HBV
infection have a past history of acute hepatitis
• Many pts with chronic HBV are asymptomatic
(unless they have decompensated cirrhosis or
have extrahepatic manifestations)
• Nonspecific symptoms such as fatigue

37. Extrahepatic manifestations
• Are thought to be mediated by circulating
immune complexes
• The two major extrahepatic complications of
chronic HBV are polyarteritis nodosa and
glomerular disease
• HBV can induce both membranous
nephropathy and, less often,
membranoproliferative glomerulonephritis

38. Cont…
• The typical presentation is with nephrotic
range proteinuria
• Approximately 30-60% of children with HBV-
related membranous nephropathy undergo
spontaneous remission
• The efficacy of antiviral therapy is uncertain

41. Labs;

42. Treatment of HBV
• Rx of acute HBV is mainly supportive
• Indications for admission; coagulopathy, deep
jaundiced, hepatic encephalopathy
• Antiviral treatment; not required in acute
• Indications for Rx; fulminant hepatitis B,
fibrosis on liver biopsy, post-liver transplant,
immunocompromised, concomitant infection
with hepatitis C or D virus, preexisting liver
disease

43. Cont…
• Rx of chronic HBV infection is in evolution; no
one drug currently achieves consistent,
complete eradication of the virus
• Lack of reliable long-term outcome data on
which to base treatment recommendations
• The goal of Rx is to reduce viral replication
defined by having undetectable HBV DNA in
the serum and development of anti-HBe,
termed seroconversion

44. Cont…
• The development of anti-HBe transforms the
disease into an inactive form, thereby
decreasing infectivity, active liver injury and
inflammation, fibrosis progression, and the
risk of hepatocellular carcinoma
• Rx should be individualized and done under
the care of a experienced pediatric
gastroenterologist

45. Cont…
• Entecavir,tenofovir, lamivudine, adefovir or
telbivudine used in acute infection
• If unclear the pt has acute HBV or an acute
exacerbation of chronic HBV, entecavir or
tenofovir is preferred since these agents have
a higher barrier to resistance
• Treatment can be stopped after confirmation
(two consecutive tests 4 weeks apart) that the
patient has cleared HBsAg

46. Complications
• Acute liver failure with coagulopathy,
encephalopathy, and cerebral edema occurs
more commonly with HBV than the other
hepatotropic viruses
• Liver cirrhosis
• Primary hepatocellular carcinoma

47. HEPATITIS C VIRUS (HCV)
• HCV is a single-stranded RNA virus, classified
as a separate genus within the Flaviviridae
family, with marked genetic heterogeneity
• It has 6 major genotypes and numerous
subtypes
• Genotype 1b is the commonest genotype in
the US and is the least responsive to the
currently available medications

48. Epidemiology
• HCV infection is the most common cause of
chronic liver disease in adults and causes
• Approx 170 million people worldwide are
estimated to be infected with HCV
• Approx. 85% of infected adults remain
chronically infected
• In children, seroprevalence of HCV is 0.2% in
those < 11 yr and 0.4% in children age 11 yr or
older

49. Transmission
• The mechanisms underlying vertical
transmission of HCV are poorly understood
• Intrauterine transmission during pregnancy
and infection at the time of delivery are both
possible
• In most infants, HCV RNA levels only become
detectable several weeks after birth,
suggesting perinatal infection

50. Cont…
• A study involving 20 pregnant women (HCV
antibody and RNA positive), infants tested
atleast by 18months of age; The pooled
transmission rate was 5.8% among women
with HCV monoinfection and 10.8% among
those with HCV/HIV coinfection
Vertical transmission of hepatitis C virus: systematic review and meta-analysis. Benova L,
Mohamoud YA, Calvert C, Abu-Raddad LJ Clin Infect Dis. 2014;59(6):765. Epub 2014 Jun
13

51. Established risk factors
• Maternal HCV viremia during pregnancy or at
the time of delivery and with concomitant HIV
infection
• Maternal IV drug use
• Peripheral blood mononuclear cell infection
(serves as a vector for the HCV or because the
viral variant of HCV that infects PBMCs is able
to interact with and overcome the immune
cells of the placenta)

52. Possible risk factors for transmission
• Invasive prenatal testing
• Prolonged rupture of membranes
• Obstetric procedures

53. Clinical manifestations
• Newborns with HCV infection usually are
asymptomatic
• Although progression to chronicity occurs in
most infants with vertically acquired HCV, liver
disease usually is mild throughout childhood

54. Cont…
• One of the largest series with long-term follow-up
of children with perinatally acquired HCV
included 266 children who were followed for a
median of 4.2 years
• 20% cleared the infection at a median age of 15
months, whereas 80% had chronic infection
• Most children with chronic infection were
asymptomatic
Three broad modalities in the natural history of vertically acquired hepatitis C virus
infection. European Paediatric Hepatitis C Virus Network Clin Infect Dis.
2005;41(1):45.

57. Diagnosis
• Detection of antibodies to HCV antigens or
detection of viral RNA; neither can predict the
severity of liver disease
• Anti-HCV is not a protective antibody and
does not confer immunity
• In children born to infected mothers; check an
anti-HCV antibody test after 18 months of age

59. Treatment
• The natural history of HCV infection in
children is still being defined
• It is believed that children have a higher rate
of spontaneous clearance than adults (up to
45% by age 19 yr)
• Peginterferon (Schering), IFN-α2b, and
ribavirin are approved by the FDA for use in
children older than 3 yr of age with HCV
hepatitis

60. Cont…
• Treatment should be considered for all
children infected with genotypes 2 and 3,
because they have an 80-90% response rate to
therapy with peginterferon and ribavirin
• If the child has genotype 1b virus, the
treatment choice remains more controversial

61. Cont…
• Rx should be considered for pts with evidence
of advanced fibrosis or injury on liver biopsy
• The currently approved treatment consists of
48 wk of peginterferon and ribavirin (stop if
still detectable on viral PCR at 24 wk of
therapy)
• Rx of children with normal biochemical profile
and mild histologic inflammation should be
reserved to a clinical study context

62. Cont…
Factors associated with a higher likelihood of
response are;
• Age younger than 12 yr,
• Genotypes 2 and 3, and, in
• Pts with genotype 1b, an RNA titer of <2
million copies/mL of blood
• Viral response (PCR at weeks 4 and 12 of
treatment)

63. Prevention
• Identifying and treating HCV-infected women
prior to conception
• Antiviral therapy during pregnancy is not an
option since the safety and efficacy have not
been evaluated

64. HEPATITIS D VIRUS (HDV)
• Is the smallest known animal virus, is
considered defective because it cannot
produce infection without concurrent HBV
infection
• Its outer coat is composed of excess HBsAg
from HBV. The inner core of the virus is single-
stranded circular RNA that expresses the HDV
antigen

65. Epidemiology
• HDV can cause a coinfection, or superinfection
with HBV
• Transmission usually occurs by intrafamilial or
intimate contact in areas of high prevalence,
which are primarily developing countries
• The incubation period for HDV superinfection
is approximately 2-8 wk; with coinfection, it is
similar to that of HBV infection

66. Pathogenesis
• Liver pathology in HDV hepatitis has no
distinguishing features except that damage is
usually quite severe
• In contrast to HBV, HDV causes injury directly
by cytopathic mechanisms
• The most severe cases of HBV infection
appear to result from coinfection of HBV and
HDV

67. Clinical Manifestations
• The sxs are similar to, but usually more severe
than those of the other hepatotropic viruses
• In coinfection, acute hepatitis, which is much
more severe than for HBV alone, is common,
but low risk of developing chronic hepatitis
• In superinfection, acute illness is rare and
chronic hepatitis is common. Hihgest risk of
ALF. Hepatitis D should be considered in any
child with ALF

68. Diagnosis
• By detecting IgM antibody to HDV; the Abs to
HDV develop approximately 2-4 wk after
coinfection and approximately 10 wk after a
superinfection
• A test for anti-HDV antibody is commercially
available
• PCR assays for viral RNA are available as
research tools

69. Treatment
• Supportive
• The treatment is mostly based on controlling
and treating HBV infection, without which
HDV cannot induce hepatitis
• Pegylated interferon alfa (IFNa)
Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B
guidance. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr,
Bzowej NH, Wong JB Hepatology. 2018;67(4):1560.

70. HEPATITIS E VIRUS (HEV)
• RNA virus
• Transmission is fecal-oral
• The highest prevalence of HEV infection has
been reported in the Indian subcontinent, the
Middle East, Southeast Asia, and Mexico,
especially in areas with poor sanitation

71. Cont…
• The clinical illness associated with HEV
infection is similar to that of HAV but is often
more severe
• As with HAV, chronic illness does not occur
• Tends to affect older patients, with a peak age
between 15 and 34 yr
• HEV is a major pathogen in pregnant women,
in whom it causes ALF with a high fatality
incidence

72. Dx
• Antibodies to HEV particles
• IgM and IgG assays are available to
distinguish between acute and resolved
infections
• IgM antibody becomes positive after
approximately 1 wk of illness
• Viral RNA can be detected in stool and serum
by PCR.

73. Prevention
• A recombinant hepatitis E vaccine

74. Thank You For Your Attention!