This will cover viral hepatitis, drug induced and autoimmune hepatitis

1. Approach to a case of
Paediatric Hepatitis
Dr Raghav Kakar
M.D. Paediatrics

2. We will be covering:
Viral hepatitis – Aetiology
Pathogenesis
Clinical features
Diagnosis
Management
Autoimmune hepatitis
Drug induced hepatitis

3. HEPATITIS
• Inflammation of liver parenchyma
• 2 types
• Acute – duration < 6 months
• Chronic – duration ≥ 6 months
• It’s commonly caused by a viral infection, but there are other
possible causes of hepatitis. These include autoimmune hepatitis
and hepatitis that occurs as a secondary result of medications,
drugs, toxins, and alcohol.

4. Etiology
1. Viral
• Hepatotropic viruses – HAV, HBV (serum virus), HCV, HDV, HEV
• Non hepatotropic viruses – CMV, EBV, Adenovirus, HSV, Dengue virus etc.
2. Non viral – Leptospirosis, Enteric fever, TB, Histoplasmosis, Amebiasis.
3. Drug and toxin induced – Acetaminophen, Phenytoin, INH,
Nitrofurantoin, Methotrexate, Alcohol.
4. Autoimmune - Autoimmune hepatitis, SLE, JRA
5. Metabolic – Tyrosinemia, Wilson disease
6. Ischaemic hepatitis – Shock, CHF
7. Non alcoholic fatty liver disease – Reye syndrome

5. Viral hepatitis
• Most common cause worldwide
• Caused by 5 pathogenic hepatotropic viruses : Hepatitides A (HAV),
B(HBV), C(HCV), D(HDV) and E(HEV) viruses.
• HAV – most common in India , > 80% children
• Although the agents can be distinguished by their antigenic properties,
the 5 kinds of viruses may produce clinically similar illness.

6. Viruses Type Incubation
period (days)
Transmission Chronic
infection
Fulminant
disease
HAV RNA 15-19 Faeco-oral No Rare
HBV DNA 60-180 Parenteral, sexual,
perinatal
Yes Yes
HCV RNA 14-160 Parenteral, sexual,
perinatal
Yes Rare
HDV RNA 21-42 Parenteral, sexual,
perinatal
Yes Yes
HEV RNA 21-63 Faeco-oral No Yes

7. Pathogenesis
• The viruses do not directly cause apoptosis. Rather, infection of liver
cells activates the innate and adaptive immune system leading to an
inflammatory response which causes cellular damage and death.
• Depending on the strength of the immune response, the types of
immune cells involved and the ability of the virus to evade the body's
defense, infection can either lead to clearance (acute disease) or
persistence (chronic disease) of the virus.
• The acute response of the liver to hepatotropic viruses involves a direct
cytopathic and an immune mediated injury.

8. • The chronic presence of the virus within liver cells results in multiple
waves of inflammation, injury and wound healing that overtime lead
to scarring or fibrosis and culminate in HCC
• With recovery, the liver morphology returns to normal within 3
months.
• In chronic case, inflammatory infiltrate settles in periportal areas and
leads to progressive scarring – HBV, HCV

9. Biochemical Profiles in Acute Infectious Phase
1. As a reflection of Cytopathic injury
• Increased AST/ALT.
• Rapidly falling AST/ALT predict poor outcome.
2.Cholestasis
• Elevated conjugated billirubin
• Elevated ALP, 5’ nucleotidase, Urobilinogen, GGT
3.Altered Synthetic functions
• Hypoalbuminaemia, Prolonged PT/INR

10. Hepatitis A
• Most prevalent
• HAV – RNA virus, picornavirus family
• Host – human and other primates
• Transmission – Faeco oral route
• Faecal excretion of virus starts late in the incubation period and reaches
the peak just before the onset of symptoms and resolves within 2 weeks
after onset of jaundice

11. CLINICAL FEATURES:
• Illness is usually symptomatic in older children
• Acute febrile illness with abrupt onset of anorexia, malaise ,
vomiting, jaundice
• Duration is usually 7-14 days
• Hepatomegaly , regional lymph nodes and spleen may be enlarged
• Acute pancreatitis, gastrointestinal ulcers , myocarditis, nephritis,
arthritis – circulating immune complexes

12. DIAGNOSIS
• Detection of Anti-HAV Ig M antibodies – symptoms are apparent,
remains for 4-6 months
• Viral particles in faeces
• Ig G type is detected within 8 weeks of infection
• Rise in serum transaminases, bilirubin and alkaline phosphatase is
universal and hence cannot distinguish between other forms of
hepatitis

13. COMPLICATIONS:
• Most patients – full recovery
• Acute liver failure – rare. Seen in immunocompromised and those with
underlying liver disorders
• Prolonged cholestatic syndrome - persistent hyperbilirubinemia,
pruritus, and constitutional symptoms that last for 12-16 weeks in the
absence of biliary obstruction on sonograms.

14. Treatment
• No specific treatment
• Fat soluble vitamins for prolonged cholestatic form.
• Serial monitoring for signs of ALF.
• Patients contagious 2 weeks before and 7 days after onset of jaundice.
• Handwashing after toilet

15. • Intravenous immunoglobulin – ‘Pre exposure prophylaxis’ for travellers to
endemic regions. Provides protection upto 3 months
AGE EXPECTED EXPOSURE
DURATION
DOSE
< 1 year <3 months
3-5 months
> 5 months
0.02 ml/kg
0.06 ml/kg
0.06 ml/kg , repeated every
5 months
≥ 1 year Healthy
Immunocompromised /
chronic liver disease
HAV vaccine
HAV vaccine + 0.02 ml/kg

16. Post exposure prophylaxis with Ig –
• Not effective 2 weeks after exposure.
• For exposure less than 2 weeks:
< 1 y.o. child - 0.02 ml/kg. For immunocompromised host and those with
chronic liver disease – give HAV as well.
> 1 year – HAV vaccine. Ig is optional.
• Vaccine : - Inactivated vaccine ( Haverix) 0.5 ml I.M in deltoid, 2 doses > 1
year of age 6 months apart.
• Live vaccine is also available in India (Biovac A) – Single dose of H2 strain.

17. Hepatitis B
• DNA virus, Hepadnaviridae family.
• Discovered in 1966.
• Also known as Dane Particle.
• HBV is present in high concentrations in blood , serum and serous
exudates and moderate concentrations in semen, vaginal fluid and
saliva

19. Modes of Transmission:
• Perinatal – Vertical transmission from mother to baby
• Parentral – Transfusion of infected blood and its products,
using non sterile syringes,needles and medical instruments.
• Sexual
• Risk of transmission increases with the level of HBV DNA in
serum and HBeAg positive

20. • In children, most important mode is vertical transmission.
• 90% of these infants remain chronically infected if untreated
• Intrauterine infection occurs in 2.5 %
• HBsAg is inconsistently recovered from human milk of infected mothers.
• Breastfeeding of non immunized infant by an infected mother does not
confer a greater risk of hepatitis than formula feeding.

21. CLINICAL FEATURES:
• Clinicopathologic syndromes include the following:
1. Acute hepatitis with resolution:
2. Chronic hepatitis, with or without progression to cirrhosis
3. Fulminant hepatitis with massive liver necrosis
4. Coinfection/Superinfection with hepatitis D virus
• Acute symptomatic similar to HAV and HCV, but more severe
• In some, illness preceeded by serum sickness like prodrome – arthralgia,
skin lesions including urticarial, purpural or maculopapular rash.

22. • Dark urine, clay-colored or light stools, and abdominal pain
• Tender hepatomegaly
• Splenomegaly in 15 -20% cases
• A few spider angiomas may appear during the icteric phase and disappear
during convalescence
• Chronic carrier state – 10 %

24. Phases of HBV Infection
1. Replicative phase with Immune Tolerance : It represents the
incubation period and lasts several weeks..
2. Replicative phase with Immune Clearance : The immune
system of the host responds to the virus resulting in hepatic
inflammation and direct cell lysis. Lasts for 4-6 weeks. If the
immune response is ineffective it may persist for many years.

25. 3. Integrative phase with no replication : The immune response
of the host is successful and active viral replication ends. HBV
DNA becomes undectable and HBeAg becomes positive.
4. Integrative phase with viral clearance : Viral replication
completely stops and HBsAg becomes negative. Patients who
recover from acute hepatitis B will reach this phase but those
with chronic infection, never reach it.

26. DIAGNOSIS:
• LFT’s - Elevations of ALT and AST levels are hallmarks of acute hepatitis.
Values as high as 1000-2000 IU/L are typical, with ALT values higher than
AST values.
• The prothrombin time is the best indicator of prognosis
• HBsAg (also known as the Australia antigen) is the surface antigen of the
hepatitis B virus (HBV). Its presence indicates current hepatitis B infection.
• Definitive diagnosis depends on serologic testing for HBV infection.

27. Serological Diagnosis in Hepatitis B
HBsAg HBeAg Anti HBsAg Anti HBeAg Anti HBcAg
Acute Infection + + - - +
Chronic Infection + + - - +++
Recently Cured
HBV
- - ++ + ++
Past infection - - + - +
Healthy Carrier + - - + +++
Vaccinated - - ++ - -

29. • Patients with signs of chronic
disease may require a liver
biopsy - extent of histologic
involvement and response
to therapeutic protocols.
• Pathognomonic ground glass
hepatocyte inclusions (arrows)
distributed singly in a haphazard
fashion with no zoning preference.

30. COMPLICATIONS:
• Acute liver failure with coagulopathy, encephalopathy and cerebral
edema ( more in superinfection with HDV)
• Chronic hepatits may lead to cirrhosis and end stage liver disease
• Hepatocellular carcinoma
• Membrano – glomerular nephritis – deposition of complement and
HBeAg in the glomerulus

31. Age at infection
Acquire infection
perinatally:
Poor prognosis
30 % children, 5 %
neonates full recovery
Adults or older
children:
Good prognosis
95% full recovery
Older age:
Poor prognosis

32. Treatment
• Acute HBV – largely supportive, close monitoring for ALF
• Chronic HBV - Treatment indicated for those with immune active form:
1. Interferon alpha 2 b – immune modulatory agent, given s.c for 24 weeks
2. Lamivudine – oral nucleoside analogue that inhibits viral enzyme reverse
transcriptase. Used for more than 6 months
3. Other agents –Adefovir, tenofovir, entecavir.
4. Immune tolerant patients – those with normal ALT, AST, HbeAg positive
with positive viral load - monitor

33. PREVENTION:
• Screening of pregnant women
• Use of HBIG and HBV vaccine infants
• Mothers with HBV DNA load > 200,000 IU/ml – lamivudine or tenofovir
during 3rd trimester should be given.
• HBV is not spread by sharing utensils, breastfeeding, hugging
• Vaccine – Recombinant vaccine 0.5 ml given IM on anterolateral thigh
at birth, then 6 weeks, 6 months
• Infants born to HBsAg positive mothers – 0.5 ml HBIG within 12 hours
of birth along with 1st dose of HBV vaccine

34. • If mother’s status is not known, vaccine should be administered
regardless of birth weight within 12 hours of birth
-Infants < 2000g , HBIG and HBV should be given
-Mother’s HBsAg status should be identified and if she is positive
and the infant is > 2000g, HBIG should be given no later than 1 week
• Post vaccination testing for HbsAg – 9-18 months.
-If positive for anti HBs , then the child is immune to HBV
-If result is positive for HBs Ag only – paediatric gastroenterologist
-If negative for both – second complete HBV vaccine series
• Administration of 4 doses of vaccine is permissible when combination
vaccines are used after birth dose – does not increase vaccine response

35. • Exposure following intimate or identifiable blood exposure :
HBIG + HBV at exposure, then HBV at 1, 6 months
0-19 years – Recombivax vaccine 5 microgram
>19 years -10 microgram
• Household contancts – HBV vaccine at exposure, 1,6 months. Same dose as
above
• Immunocompromised – 40 microgram Recombivax at exposure, 1 , 6
months along with HBIG at exposure

36. Hepatitis C
• RNA, Flaviviridae
• 6 major phenotypes
• HCV is uncommon in the pediatric population
• Seroprevalence is 0.2 % in < 11 yrs and 0.4 % in ≥ 11 yrs
• Mode of transmission – Illegal drug abuse, sexual transmission. Blood
transfusion before 1992, occupational exposure
• Vertical transmission in children – main – 20 %
• Incubation period= 7-9 weeks.

37. CLINICAL FEATURES:
Acute HCV:
• Mild, insidious onset
• Nausea
• Vomitting
• Pain abdomen
• Icterus
• Dark urine
Chronic HCV :
Most likely to progress to chronic infection

39. DIAGNOSIS
• Detection of antibodies to HCV antigen by EIA ( enzyme immune assay)
• Detection of Viral RNA by PCR. Usually detectable within 1-2 weeks of
exposure.
• Anti HCV is not a protective antibody and therefore does not confer
immunity
• Acute infection - The peak serum ALT level is less than 2000 IU/mL in most
patients with acute HCV infection, and 50% have a peak serum ALT level
of less than 800 IU/mL. Overall, this peak is generally less than that seen
in hepatitis A or B infections.
• Liver biopsy – assess presence and extent of hepatic fibrosis

40. Treatment
• Children has a higher spontaneous clearance rate than adults ( 45% till 19
yrs).
• Peginterferon has been approved by FDA for those > 3 yrs
• Treatment considered for those with evidence of advanced fibrosis or
injury on liver biopsy
• Current recommendation – 48 weeks of peginterferon and ribavirin
• Those with normal biochemical profile and mild histological change – no
specific treatment
• Screen yearly with liver ultrasound and alpha fetoprotein for HCC
• No vaccine yet available

41. Hepatitis D
• RNA virus
• Defective – only can cause infection along with HBV as it is incapable of
making its own coat proteins
• Co-infection or superinfection, uncommon in children
CLINICAL MANIFESTATIONS –
• Symptoms similar to infection with other hepatitis viruses, but more
severe.
• In co infection, acute hepatitis is much more severe than for HBV alone

42. • In super infection, acute illness is rare, but chronic hepatitis is common.
Risk of acute liver failure is highest
DIAGNOSIS
• HDV – not yet isolated
• IgM antibody to HDV – 2-4 weeks after co infection, 10 weeks after super
infection
COMPLICATIONS
• HDV to be considered in all cases of acute liver failure

43. Hepatitis E
• RNA virus
• Epidemic form of what was formerly called as non A non B hepatitis
• Transmission – faecal-oral route
CLINICAL FEATURES:
• Similar to that of HAV but more severe. Chronic illness does not occur
• Major pathogen in pregnant women – acute liver failure with higher
fatality incidence

44. DIAGNOSIS:
• HEV-RNA can be detected in stool from 1 week prior to the onset of
symptoms and for more than 2 weeks after the onset.
• Detection of IgM antibody 1 week after illness

45. Treatment
• No specific HDV or HEV targeted treatments yet
• Control and treat HBV infection without which HDV cannot induce
hepatitis.
• Ongoing trials – Interferons
• No vaccine available for both
Once chronic infection is identified, close follow up and referral to
paediatric gastroenterologist is recommended.

47. Autoimmune hepatitis
• Chronic hepatic inflammatory process
• It is manifested by – Elevated AST/ALT, Liver associated serum auto antibodies,
hyper gammaglobulinemia – Antinuclear antibody(ANA), antibody against
liver kidney microsome( Anti LKM-1) and smooth muscle antibodies (SMA)
• It is a Clinical constellation s/o immune mediated process, responsive to
immunosuppresive therapy.
• Trigger factors – infection, drugs, toxins in a genetically susceptible host
• 25-30 % children – mimic viral hepatitis. Patients can be asymptomatic or
have fatigue, malaise, behavioural changes, anorexia.

48. • Mild to moderate jaundice with hepatomegaly and in some case,
splenomegaly and ascites
• Serum bilirubin may be normal in mild cases.
• Serum aminotransferases range between 100-300 IU/l.
• Hypoalbuminemia and Hypergammaglobulinemia are common.
• Prothrombin Time is prolonged mostly due to Vit K deficiency and
also as a reflection of impaired hepatocellular function.

49. TREATMENT:
• Prednisolone with or without azathioprine – improves clinical, biological and
histological features.
• Prednisolone 1-2 mg/kg/day till aminotransferases return to less than twice the
upper limit of normal, then decrease the dose.
• Azathioprine 1.5-2 mg/kg/day – with frequent monitoring for bone marrow
suppression
• Cyclosporine, Tacrolimus and Mycophenolate Mofetil have been used in
refractory cases.
• Steroid resistant hepatitis in some cases is seen and these may progress to
cirrhosis or end stage liver disease – liver transplantation.

50. Diagnostic approach to autoimmune hepatitis

51. Drug induced hepatitis
Paracetamol
• In Single large dose or in repeated doses it causes acute hepatitis.
• The pathways for paracetamol metabolism get saturated at high
doses, which leads to production of a toxic metabolite, NAPQI, which
leads to cell death.
• A single dose of 120-150mg/kg could be hepatotoxic.
• Rectal administration of acetaminophen can also cause hepatotoxixity.

52. • Nausea, persistent vomiting for 24 hours followed by tender
hepatomegaly, jaundice and coagulopathy is seen.
• N-Acetyl Cystiene is the most effective antidote.
• Mortality rate in well managed cases is <1%.
• The hypatic dysfunction resolves in 2-3 weeks.

53. Valproic Acid
• More common in young children.
• Children below 3 years, on multiple anticonvulsants, and
presence of associated medical problems like MR are more
likely to develop hepatotoxicity with valproate.
• Recent studies show that very early Carnitine supplementation
has a beneficial role

54. Phenytoin
• Phenytoin induced hepatitis is ‘drug hypersensitivity reaction’
• Fever, rash, Steven Johnson syndrome and lymphadenopathy
may be the presenting features.
• Elevation of ALT/AST with jaundice is seen.
• Concurrent administration of phenobarbitone aggravates the
hepatic injury.

55. • IV Methyl Prednisolone 2mg/kg/day has been effective in
some patients.
• IVIG has been benefitial in those wiith SJS.

56. Anti Tubercular drugs
• The risk of hepatic dysfunction is more in children who are
receiving Isoniazid along with Rifampicin and Pyrezinamide.
• INH hepatotoxicity is mainly due to a toxic metabolite,
Acetylisoniazid.

57. • Treatment is mainly supportive
• Withdraw the offending agent
• Corticosteroids may have a role in immune mediated disease
• Prognosis – Injury is usually completely reversible when the agent is
withdrawn

58. To summarise
• Aggressive perinatal, childhood and adolescent immunisation
strategies can reduce the disease burden due to viral hepatitis.
• Early detection and treatment of viral hepatitis can improve
outcome.
• Educating the community regarding the disease and its prevention
should be implemented.
• Drugs causing hepatitis should be used with caution.

59. THANK YOU