This document discusses chronic hepatitis in children. It begins by defining chronic hepatitis as ongoing liver inflammation persisting for more than six months that is detectable biochemically and histologically. Chronic hepatitis in children is often asymptomatic with mild illness and normal growth, though it can progress to cirrhosis or liver cancer at any age. The causes include hepatitis B, C, autoimmune hepatitis, and metabolic disorders. The document outlines approaches to diagnosing and classifying chronic hepatitis and reviews treatment options and goals in the pediatric population.

1. ‫الرحمن‬ ‫ا‬ ‫بسم‬‫الرحمن‬ ‫ا‬ ‫بسم‬
‫الرحيم‬‫الرحيم‬

2. LiverLiver
DiseasesDiseases

3. Chronic hepatitisChronic hepatitis
in childrenin children
Dr Tai Al AkawyDr Tai Al Akawy
Alexandria university children hospitalAlexandria university children hospital
Based on Nelson text book of pediatrics and many online articles that will be mentioned
on the slides

4. DEFINITIONDEFINITION
The term chronic hepatitis means ongoingThe term chronic hepatitis means ongoing
inflammation of the liver persisting forinflammation of the liver persisting for moremore
than six monthsthan six months that is detectable bythat is detectable by
biochemical and histologic means.biochemical and histologic means.

5. Clinical featuresClinical features
-Depend on pathology & aetiology-Depend on pathology & aetiology
--Mild illnessMild illness with dyspepsia & variablewith dyspepsia & variable
increase in liver enzymes without evidenceincrease in liver enzymes without evidence
of chronic liver diseaseof chronic liver disease
--Florid progressiveFlorid progressive illness withillness with
evidence of chronic liver disease.evidence of chronic liver disease.

6. DiagnosisDiagnosis
 Elevated transaminasesElevated transaminases
 Minimal elevation of alk. Phos.Minimal elevation of alk. Phos.
 Hepatic dysfunctionHepatic dysfunction
- serum bilirubin- serum bilirubin
- serum albumin- serum albumin
- P.T.- P.T.
 Liver biopsyLiver biopsy

7. Chronic hepatitisChronic hepatitis
 OLD CLASSIFICATIONOLD CLASSIFICATION
 Chronic persistant hepatitisChronic persistant hepatitis
 Chronic active hepatitisChronic active hepatitis
Based on histopathological distinctionBased on histopathological distinction

8. 1-Chronic persistent hepatitis1-Chronic persistent hepatitis
(CPH)(CPH)
-Chronic inflammatory infiltrate-Chronic inflammatory infiltrate
confined to portal tractconfined to portal tract
-Spotty necrosis-Spotty necrosis
-Normal liver architecture-Normal liver architecture
-Cirrhosis is rare-Cirrhosis is rare

9. 2- Chronic active hepatitis2- Chronic active hepatitis
(aggressive)(aggressive)
-Inflammatory infiltrate in portal tract &-Inflammatory infiltrate in portal tract &
parenchyma (piece meal necrosis)parenchyma (piece meal necrosis)
-Distorted lobular architecture-Distorted lobular architecture
-Septa linking portal tract-Septa linking portal tract
& C.V& C.V
-Subsequent Cirrhosis can-Subsequent Cirrhosis can
follow.follow.

11. PRESENT CLASSIFICATIONPRESENT CLASSIFICATION
of chronic hepatirisof chronic hepatiris
 CAUSECAUSE
 GRADEGRADE
 SEVERITYSEVERITY

12. CAUSECAUSE
 Chronic viral hepatitisChronic viral hepatitis
 Autoimmune hepatitisAutoimmune hepatitis
 Drug induced hepatitisDrug induced hepatitis
 Metabolic disorders associated with CLDMetabolic disorders associated with CLD

13. GRADEGRADE -Histological assessment of-Histological assessment of
necroinflammatory activitynecroinflammatory activity
 Portal inflammationPortal inflammation
 Periportal necrosisPeriportal necrosis
 Piecemeal necrosis orPiecemeal necrosis or
interface hepatitisinterface hepatitis
 Bridging necrosisBridging necrosis

15. SeveritySeverity
 Level of progression of the disease based onLevel of progression of the disease based on
the degree of fibrosis orthe degree of fibrosis or cirrhosiscirrhosis

16. CAUSESCAUSES
 Hepatitis B ,C , DHepatitis B ,C , D
 Autoimmune hepatitisAutoimmune hepatitis
 Drug-induced hepatitisDrug-induced hepatitis
 Metabolic :Wilson's disease ,A 1-antitrypsinMetabolic :Wilson's disease ,A 1-antitrypsin
deficiency ,haemochromatosis, glycogen storagedeficiency ,haemochromatosis, glycogen storage
disease type IVdisease type IV

17. Hepatitis B Virus
Hepatitis B (HBV) Hepadnaviridae (1970)

18. Hepatitis B Virus (HBV)Hepatitis B Virus (HBV)
1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936–962.
2. Lok AS, McMahon BJ. Hepatology. 2007;45:507–539.

19. 19
HBVHBV : Structure: Structure

20. 20
Hepatitis B VirusHepatitis B Virus

21. 21
Replication of HBV

22. Epidemiology of Hepatitis BEpidemiology of Hepatitis B
 Prevalent in Asia, Africa, SouthernPrevalent in Asia, Africa, Southern
Europe and South America (2-20%)Europe and South America (2-20%)
 Age of infectionAge of infection is important inis important in
determining the outcome of thedetermining the outcome of the
disease.disease.
Lok AS, et al. Hepatology. 2007;45:507-539.

23. Chronic Hepatitis B InfectionChronic Hepatitis B Infection
Infections acquired perinatally and in early childhood usually becomes chronic

24. Symptomatic Infection
Chronic Infection
Age at Infection
Chronic Infection (%)
SymptomaticInfection(%)
Birth 1-6 months 7-12 months 1-4 years Older Children
and Adults
0
20
40
60
80
100100
80
60
40
20
0
Outcome of Hepatitis B Virus Infection
by Age at Infection
ChronicInfection(%)

26.  Sexual - sex workers and homosexuals are
particular at risk.
 Parenteral - IVDA, Health Workers are at
increased risk.
 Perinatal - Mothers who are HBeAg positive
are much more likely to transmit to their
offspring than those who are not. Perinatal
transmission is the main means of
transmission in high prevalence populations.
Hepatitis B Virus
Modes of Transmission
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936–962.

27. Diagnostic Interpretations ofDiagnostic Interpretations of
Hepatitis B markersHepatitis B markers
HBsAgHBsAg
Non infectious component
of viral coat
Indicator of disease. If > 6
months: chronic HBV
Anti-HBsAnti-HBs
Antibody response to
HBsAg
Indicates recovery and/or
immunity
HBeAgHBeAg
Antigen that correlates
with replication and
infectivity
High level of infectivity and
replication
Anti-HBeAnti-HBe
Antibody response to
HBeAg
Decreasing level of
replication
Remission/resolution
Anti-HBc IgMAnti-HBc IgM
Non protective antibody to
the HBcAg
Recent HBV infection
Anti-HBc IgGAnti-HBc IgG
As above Remote exposure to HBV
HBV DNAHBV DNA
Replictative genetic
material of HBV; infectious
agent
Viral replication and
continues infection

28. Diagnostic Interpretations ofDiagnostic Interpretations of
Hepatitis B markersHepatitis B markers
HBsAgHBsAg
Non infectious component
of viral coat
Indicator of disease. If > 6
months: chronic HBV
Anti-HBsAnti-HBs
Antibody response to
HBsAg
Indicates recovery and/or
immunity
HBeAgHBeAg
Antigen that correlates
with replication and
infectivity
High level of infectivity and
replication
Anti-HBeAnti-HBe
Antibody response to
HBeAg
Decreasing level of
replication
Remission/resolution
Anti-HBc IgMAnti-HBc IgM
Non protective antibody to
the HBcAg
Recent HBV infection
Anti-HBc IgGAnti-HBc IgG
As above Acute or remote exposure
to HBV
HBV DNAHBV DNA
Replictative genetic
material of HBV; infectious
agent
Viral replication and
continues infection

29. Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBsHBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Acute Hepatitis B Virus Infection with
Recovery Typical
SerologicCourse
Weeks after Exposure
Titre

30. IgM anti-HBc
Total anti-HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after
Titr
e
Progression to Chronic Hepatitis B Virus
Infection Typical Serologic Course

31. HBV ScenariosHBV Scenarios
HBsAgHBsAg anti-HBsanti-HBs anti-HBcanti-HBc
IgMIgM
anti-HBcanti-HBc
IgGIgG
HBeAgHBeAg DXDX
++ -- ++ ++ ++
++ -- -- ++ ++
-- ++ -- -- --
-- ++ -- ++ --
-- -- ++ -- --
-- -- -- ++ --
Acute
infection
Carrier
Vaccinated
Exposed
Immune
Acute
Window
Exposed
Ab lost

32. 32
Possible Outcomes of HBV InfectionPossible Outcomes of HBV Infection
Acute hepatitis B infection
Chronic HBV infection
3-5% of adult-
acquired infections
95% of infant-
acquired infections
Cirrhosis
Chronic hepatitis
12-25% in 5 years
Liver failureHepatocellular
carcinoma
Liver transplant
6-15% in 5 years 20-23% in 5 years
DeathDeath

33. Chronic Hepatitis BChronic Hepatitis B
Infection in PediatricsInfection in Pediatrics
•Mostly asymptomaticMostly asymptomatic
•Normal growthNormal growth
•Liver damage is mild during childhoodLiver damage is mild during childhood
•Cirrhosis, hepatocellular carcinoma at any ageCirrhosis, hepatocellular carcinoma at any age
(rare)(rare)

34. Zacharakis G. J Pediat Gastr Nutr; 44:84-91.2006
Natural History of Chronic HBVNatural History of Chronic HBV
(in children)(in children)
•HBeAb seroconversion rate 55% inHBeAb seroconversion rate 55% in
12 years12 years
•Lower seroconversion in verticalLower seroconversion in vertical
transmision (38.5%) Vs. horizontaltransmision (38.5%) Vs. horizontal
(74%)(74%)
•Loss of HBsAg seen in 5%Loss of HBsAg seen in 5%

35. Courtesy of Jerrold R. Turner, M.D., Ph.D.
Hepatitis B Liver BiopsyHepatitis B Liver Biopsy
This patient has cirrhosis due to hepatitis B virus (HBV)

36. Courtesy of Jerrold R. Turner, M.D., Ph.D.
Hepatitis B Liver BiopsyHepatitis B Liver Biopsy
The portal area is expanded, and the regenerative nodule is encircled by collagen

39. Courtesy of Jerrold R. Turner, M.D., Ph.D.
Hepatitis B Liver BiopsyHepatitis B Liver Biopsy
Ground-glass hepatocytes represent cells with cytoplasm swollen by viral particles.

40. Courtesy of Jerrold R. Turner, M.D., Ph.D.
Hepatitis B Liver BiopsyHepatitis B Liver Biopsy
Immunoreactive HBsAg(stained red) is deposited in the cytoplasm

41. Who to treat?Who to treat?
 High ALTHigh ALT
 Inflammation in biopsyInflammation in biopsy
 Low HBV DNALow HBV DNA
 Late acquisition ofLate acquisition of
infectioninfection
BetterBetter
ResponseResponse
toto
treatmenttreatment
Mei-Hwei Chang. Pediatric Gastroint Dis. 2004
Children with chronic HBV (HBsAg > 6 months)Children with chronic HBV (HBsAg > 6 months)

42. Goals of treatment in PediatricGoals of treatment in Pediatric
populationpopulation
 Reducing the risk of HBV relatedReducing the risk of HBV related
cirrhosiscirrhosis andand HCCHCC
 Elimination ofElimination of HBeAgHBeAg maymay
considerably improve prognosisconsiderably improve prognosis

43. How to treat?How to treat?
PediatricsPediatrics
IFN-IFN-αα LamivudineLamivudine

44. How to treat?How to treat?
PediatricsPediatrics
IFN-IFN-αα LamivudineLamivudine
AdefovirAdefovir
EntecavirEntecavir
Successful response to treatment will result in the disappearance of HBsAg,
HBV-DNA, and seroconversion of HBeAg.

45. INF-INF-αα
 Approx 58% of patient showApprox 58% of patient show
responseresponse
 Advantage:Advantage:
 More durable responseMore durable response
 Lack of resistant mutantsLack of resistant mutants
 Disadvantage:Disadvantage:
 Weekly SC administrationWeekly SC administration
 Very expensiveVery expensive
 Adverse reactions:Adverse reactions: Flu-like symptoms, depression,Flu-like symptoms, depression,
anorexia, bone marrow suppressionanorexia, bone marrow suppression

46. LamivudineLamivudine
 Virologic response in children, 23%Virologic response in children, 23%
compared to 13% in placebocompared to 13% in placebo
 Ad:Ad:
 OralOral
 Well toleratedWell tolerated
 CheapCheap
 Dis:Dis:
 Less durability of responseLess durability of response
 Increased risk of drug resistant , 70% by 5 yearsIncreased risk of drug resistant , 70% by 5 years

47. HEPATITISHEPATITIS - C- C

48. Courtesy of the C. Everett Koop Institute at Dartmouth
Hepatitis C VirusHepatitis C Virus
(HCV)(HCV)

49. hypervariable
region
capsid envelope
protein
protease/helicas
e
RNA-
dependent
RNA
polymerase
c22
5’
core E1 E2 NS
2
NS
3
33c
NS
4
c-100
NS
5
3’
Hepatitis C Virus
Hepatitis C (HCV) Flaviviridae (1988)
Structural genes at the 5' end, the non-structural genes at the 3' end

50. 50
HCV replicates exclusively in the cytoplasm
via an RNA intermediate
Nucleus
Viral entry & uncoating
Translation & processing
(+)
(+)
(-)
(+)
HCV RNA
replicationVirus particle
assembly Replicative
intermediate

51. El-Kamary SS. J Pediatr. 143:54-9, 2003.
Jonas MM. J Pediatr. 131:314-6, 1997.
Yeung LT. Hepatology. 34:223-9, 2001.
Aletr MJ. N Engl J Med. 341; 556-62. 1999
Prevalence of HepatitisPrevalence of Hepatitis
CC
•1.8% prevalence in US1.8% prevalence in US
•10,000-60,000 newborn will be infected10,000-60,000 newborn will be infected
worldwide yearlyworldwide yearly

52. Prevalence of HepatitisPrevalence of Hepatitis
CC

53. Genotype Distribution ofGenotype Distribution of
Hepatitis CHepatitis C
Gower E, Estes C, Blach S, et al. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 2014.

54. Mode of TransmissionMode of Transmission
of Hepatitis Cof Hepatitis C
•Transfusion of blood or contaminatedTransfusion of blood or contaminated
products (prior to 1992)products (prior to 1992)
•Use of intravenous drugsUse of intravenous drugs
•SexualSexual
•VerticalVertical (most important among children)(most important among children)

55. Mast EE. J Infect Dis. 192:1880-1889, 2005
Perinatal TransmissionPerinatal Transmission
of Hepatitis Cof Hepatitis C
•3.7% of the infants(born to HCV infected3.7% of the infants(born to HCV infected
mothers) acquired HCV.mothers) acquired HCV.
•Infection rate in HIV positive mothers, 25%Infection rate in HIV positive mothers, 25%

56. Breast feeding andBreast feeding and
transmission of Hepatitis Ctransmission of Hepatitis C
• HCV detected in breast milk and colostrumHCV detected in breast milk and colostrum
• Rate of transmission is identical to bottle-fedRate of transmission is identical to bottle-fed
infantsinfants
• Safety based on the absence of traumatized,Safety based on the absence of traumatized,
cracked or bleeding nipplescracked or bleeding nipples
Yeung LT. Hepatology.34:223-9, 2001.

57. Risk Factors for VerticalRisk Factors for Vertical
Transmission of Hepatitis CTransmission of Hepatitis C
 Breast feedingBreast feeding
 Vaginal deliveryVaginal delivery
does not increasedoes not increase vertical transmissionvertical transmission
Mast EE. J Infect Dis. 192:1880-1889, 2005

58. Risk Factors for VerticalRisk Factors for Vertical
Transmission of Hepatitis CTransmission of Hepatitis C
Does increaseDoes increase vertical transmission:vertical transmission:
 Use of internal fetal monitoringUse of internal fetal monitoring
devicesdevices
 High viral loadsHigh viral loads
 Prolonged rupture of membranes (>6Prolonged rupture of membranes (>6
h)h)
 HIV co-infectionHIV co-infection
Mast EE. J Infect Dis. 192:1880-1889, 2005

59. Natural History of Hepatitis CNatural History of Hepatitis C
ExposureExposure
NoNo
infectioninfection
AcuteAcute
ChronicChronic
SpontaneouSpontaneou
s clearances clearance
(early)(early)
•CirrhosisCirrhosis
(20-40%)(20-40%)
•HCCHCC
(1-4%/year)(1-4%/year)
<75%<75%
>20%>20%

60. England K. J Pediatr. 147:227-32, 2005.
Clinical Features ofClinical Features of
Hepatitis C inHepatitis C in
PediatricsPediatrics•Normal growthNormal growth
•Mostly are asymptomaticMostly are asymptomatic
•HepatomegalyHepatomegaly
•Elevated liver enzymesElevated liver enzymes

61. Diagnosis of HepatitisDiagnosis of Hepatitis
CC
HCVHCV
antibodiesantibodies (IgG)(IgG)
HCV RNA PCRHCV RNA PCR
(quantitative/qualitative)(quantitative/qualitative)
Initial screeningInitial screening
DiagnosisDiagnosis
Confirmation of DiagnosisConfirmation of Diagnosis
(qualitative)(qualitative)
PretreatmentPretreatment
evaluationevaluation
Post treatment monitorPost treatment monitor
Fried MW, et al. N Eng J Med. 2002;347:975-982.
Manns MP, et al. Lancet 2001;358:958-965.

62. Kelly DA. Hepatology; 34:680A. 2001
Wirth S. Hepatology; 36:1280-4. 2002
Davis GL. N Engl J Med; 339:1493-9.1998
McHutchinson JG. N Engl J Med; 339:1485-92.1998
Antiviral Therapy for HepatitisAntiviral Therapy for Hepatitis
CC
•Combined PEGCombined PEG Interferon and RibavarinInterferon and Ribavarin
•45-62% sustained virological response45-62% sustained virological response
•Better responseBetter response
•Ribavirin Side effectsRibavirin Side effects
•Anemia/ThrombocytopeniaAnemia/Thrombocytopenia
•Fetal malformationsFetal malformations
(teratogenic)(teratogenic)
Genotype 2, 3Genotype 2, 3
Low pretreatment viral loadLow pretreatment viral load
Younger ageYounger age
Absence of cirrhosisAbsence of cirrhosis

63. Hepatitis C VirusHepatitis C Virus
Fate of Acute InfectionFate of Acute Infection
15%
Chronic
85%
Spontaneous
resolution
Alter MJ, et al. N Eng J Med. 1999;341:556-562.

64. 64
Symptoms
anti-
HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Hepatitis C Virus Infection
Typical Serologic Course
Titre
Months Years
Time after
Exposure

65. Hepatitis C Virus InfectionHepatitis C Virus Infection
Natural HistoryNatural History
Stable
80% (68%)
HCC
Liver failure
25% (4%)
Slowly
progressive
75% (13%)
Resolved
15% (15%)
Acute HCV
Cirrhosis
20% (17%)
Chronic HCV
85% (85%)
ver cancer and liver failure occur in 4% of patients who are exposed to HCV over a 20- to 25-year period.

66. Chronic Viral Hepatitis inChronic Viral Hepatitis in
PediatricsPediatrics
PreventionPrevention

67. The Good News: Hepatitis BThe Good News: Hepatitis B (HBV)(HBV)
VaccineVaccine
HBsAg recombinant DNA technologyHBsAg recombinant DNA technology
90%-95% efficacy (anti-HBs titers90%-95% efficacy (anti-HBs titers >> 10mIU/ml)10mIU/ml)
Long-term protectionLong-term protection
Post Exposure Prophylaxis(PEP)Post Exposure Prophylaxis(PEP)
Hep B Immunoglobulin(HBIG),passively acquired anti-HBsHep B Immunoglobulin(HBIG),passively acquired anti-HBs
Infants born to HBsAg+ mothersInfants born to HBsAg+ mothers
(HBIG & vaccine, efficacy 95% )(HBIG & vaccine, efficacy 95% )

68. HBV: ACIP 2005 RecommendationsHBV: ACIP 2005 Recommendations
Birth DoseBirth Dose
““For all medically stable infants weighing ≥2,000 gramsFor all medically stable infants weighing ≥2,000 grams
at birth and born to HBsAgat birth and born to HBsAg negativenegative mothers, the firstmothers, the first
dose of HB vaccine should be administered beforedose of HB vaccine should be administered before
hospital discharge.”hospital discharge.”
ACIP= Advisory committee of immunization practice

69. HepatitisHepatitis CC PreventionPrevention
The Less Good News:The Less Good News:
There is NO effective vaccineThere is NO effective vaccine
BUT;BUT;
Spontaneous clearance of HCV can occur inSpontaneous clearance of HCV can occur in
20-30% of acute infections20-30% of acute infections
Immunity against persistent HCV can be acquiredImmunity against persistent HCV can be acquired
England K. J Pediatr. 147:227-32, 2005.

70. Prevention HCVPrevention HCV
Immune Correlates of Viral ClearanceImmune Correlates of Viral Clearance
Humoral ImmunityHumoral Immunity
Neutralizing antibodies, in vitro, are not necessary forNeutralizing antibodies, in vitro, are not necessary for
resolution of HCV infection.resolution of HCV infection.
Cellular ImmunityCellular Immunity
Vigorous polyclonal CD4+ and CD8+ T-cell responsesVigorous polyclonal CD4+ and CD8+ T-cell responses
Weak and narrow in chronically infectedWeak and narrow in chronically infected

71. HCVHCV
Cellular Immune Response in AcuteCellular Immune Response in Acute
InfectionInfection
Bowen and Walker, Nature 2005

72. HCV Prevention StrategyHCV Prevention Strategy
Increased screening and knowledge of HCV statusIncreased screening and knowledge of HCV status
reduces HCV transmissionreduces HCV transmission
2/3 of people with chronic HCV are not2/3 of people with chronic HCV are not
diagnoseddiagnosed
10% of people with HCV infection have10% of people with HCV infection have
no recognized source for their infectionno recognized source for their infection
Hagan 2001 Am J Pub HealthHagan 2001 Am J Pub Health

73. 73
HBsAg
RNA
δ antigen
Hepatitis D (Delta)
Virus
Hepatitis D (HDV) ? (1977)

74. Hepatitis DHepatitis D
 Requires coexistent Hep BRequires coexistent Hep B
 CoinfectionCoinfection: does not worsen acute Hep B or: does not worsen acute Hep B or ⇑⇑
risk for chronic staterisk for chronic state
 SuperinfectionSuperinfection::
– usually develop chronic HDV infection.usually develop chronic HDV infection.
– high risk of severe chronic liver disease.high risk of severe chronic liver disease.
 Diagnosis: Anti-HDV IgMDiagnosis: Anti-HDV IgM

75. 75
Jaundice
Symptoms
ALT
Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
HBV – HDV
SuperinfectionTypical Serologic Course
Time after Exposure
Titre

76. 76
 HBV-HDV Coinfection
Pre or post exposure prophylaxis to prevent
HBV infection.
 HBV-HDV Superinfection
Education to reduce risk behaviors among
persons with chronic HBV infection.
Hepatitis D - Prevention

79. Immune disordersImmune disorders
Autoimmune disease can affect the hepatocyteAutoimmune disease can affect the hepatocyte
or bile ductor bile duct
And, is characterized byAnd, is characterized by
The presence ofThe presence of autoantibodiesautoantibodies
IncreasedIncreased IgIg levels.levels.

80. DefinitionDefinition
Autoimmune HepatitisAutoimmune Hepatitis
 Unresolving inflammation of the liver of unknownUnresolving inflammation of the liver of unknown
cause.cause.
Reflect a complex interaction betweenReflect a complex interaction between
 Triggering factorsTriggering factors :Infections, medications, toxins,:Infections, medications, toxins,
molecular mimicry?molecular mimicry?
 AutoantigensAutoantigens
 Genetic predisposition:Genetic predisposition:Antigen presentation/immunocyteAntigen presentation/immunocyte
activation, DRB1,activation, DRB1, TNF*2A,TNF*2A, HLA B14, HLA DR3,DR4HLA B14, HLA DR3,DR4
 Immunoregulatory mechanismsImmunoregulatory mechanisms
Krawitt. N Engl J Med 2006;354:54

81. Autoimmune HepatitisAutoimmune Hepatitis
 Characterized by the presence of interfaceCharacterized by the presence of interface
hepatitis & portal plasma cell infiltration inhepatitis & portal plasma cell infiltration in
histological examinationhistological examination
 hypergammaglobulinaemiahypergammaglobulinaemia
 auto antibodiesauto antibodies
Manns et al. Hepatology 2006;43:S132

82. epidemiologyepidemiology
In northern EuropeansIn northern Europeans
 Annual incidence 1.9/100,000Annual incidence 1.9/100,000
 Prevalence 16.9/100,000Prevalence 16.9/100,000
 2.6% of liver transplant2.6% of liver transplant
 Female affected more than malesFemale affected more than males
gender ratio 3.6:1gender ratio 3.6:1

83. classificationclassification
 3 main subtypes3 main subtypes
 Based on difference in theirBased on difference in their immunologicalimmunological
markersmarkers
Czaja et al. Hepatology 2002;36:479

84. Type 1 AIHType 1 AIH
 The most commonThe most common
form of the diseaseform of the disease
worldwideworldwide
 Associated withAssociated with
ANAANA and/orand/or SMASMA
 HLA DR3 & DR4HLA DR3 & DR4
 Over 70% areOver 70% are
female and overfemale and over
40%40% younger ageyounger age
groupgroup..
Czaja et al. Hepatology 2002;36:479

85. Type 2 AIHType 2 AIH
 More common inMore common in
Europe and southEurope and south
America.America.
 Associated withAssociated with
anti-LKManti-LKM
 Described inDescribed in
paediatrics patientpaediatrics patient
but in Europe 20%but in Europe 20%
are adultsare adults
Krawitt. N Engl J Med 2006;354:54
Czaja et al. Am J Gastroenterol 1995;90:1206

86. Type 3 AIHType 3 AIH
 Is the leastIs the least
established form ofestablished form of
the disease.the disease.
 Associated withAssociated with
anti-SLA/LPanti-SLA/LP
 ReclassificationReclassification::
Variant type 1 AIHVariant type 1 AIH
(soluble liver antigen/ liver-pancreas antigen)

87. Diagnostic criteriaDiagnostic criteria
 Diagnosis require presence ofDiagnosis require presence of
characteristics featurescharacteristics features && exclusion of otherexclusion of other
condition that resemble AIHcondition that resemble AIH
 All patients must be evaluated forAll patients must be evaluated for
hereditaryhereditary,, infectiousinfectious andand drugdrug inducedinduced
liver injury.liver injury.
 Interface hepatitisInterface hepatitis is the histologic hallis the histologic hall
mark of the syndrome &mark of the syndrome & portal plasmaportal plasma
infiltration typifies the disorder, butinfiltration typifies the disorder, but neitherneither
are specific.are specific.

88. Autoimmune Hepatitis
Clinical Manifestations
 Fatigue
 Fever
 Jaundice(+/-)
 RUQ pain
 Myalgia/arthralgia
 Anorexia
 Hepatosplenomegaly
 Spider angiomata
 Cushingoid features
 Hirsuitism
 Acne
 Portal hypertension
– Ascites
– Varices
– Encephalopathy
 FHF
 HCC
 Asymptomatic
Desmet et al. Hepatology 1994;19:1513

89. Autoimmune Hepatitis
Extrahepatic Autoimmune Diseases
 Autoimmune
thyroiditis
 Grave’s disease
 Connective tissue
diseases
 Inflammatory bowel
disease
 Celiac disease
 Adrenal insufficiency
 Autoimmune
hematologic disorders
 Type 1 DM
 Sjogren’s syndrome
 Fibrosing alveolitis
 Vitiligo
 Vasculitis
 Nephritis
Krawitt. N Engl J Med 2006;354:54
Czaja et al. Hepatology 2002;36:479

90. Interface hepatitis and bridging necrosis in severe type 1 autoimmune hepatitisInterface hepatitis and bridging necrosis in severe type 1 autoimmune hepatitis

91. Autoimmune Hepatitis
Histology
 Lymphoplasmacytic
infiltrate
 Interface hepatitis
Portal inflammation and invasion of
limiting plate

92. Plasma cell infiltration of the portal tracts in type 1 autoimmune hepatitisPlasma cell infiltration of the portal tracts in type 1 autoimmune hepatitis

93. Autoimmune Hepatitis
Cirrhosis to Hepatocellular Carcinoma
Netter’s Gastroenterology, 2nd
ed., Elsevier Inc., 2010, all rights reserved
HCC

94. The diagnosis of AIH requiresThe diagnosis of AIH requires
 Determination ofDetermination of elevated aminotransferaseelevated aminotransferase
andand gamma globulinsgamma globulins
 Detection ofDetection of ANAANA and/orand/or SMASMA or in theiror in their
absence,absence, anti-LKManti-LKM
 liver tissue examinationliver tissue examination

95. Indications for treatmentIndications for treatment
Czaja et al. Hepatology 2002;36:479

96. Treatment regimensTreatment regimens
Two regimens comparable with each otherTwo regimens comparable with each other
Prednisone alone orPrednisone alone or
lower dose of prednisone in conjunction withlower dose of prednisone in conjunction with
azathioprineazathioprine
All patients should be monitored for theAll patients should be monitored for the
development of drug side effectdevelopment of drug side effect
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54

97. Czaja et al. Hepatology 2002;36:479

98. Autoimmune HepatitisAutoimmune Hepatitis
Disease RemissionDisease Remission
 Disappearance of symptomsDisappearance of symptoms
 Normalization or near normalization of ASTNormalization or near normalization of AST
to < 2 x ULNto < 2 x ULN
 GG and bilirubin: normalGG and bilirubin: normal
 Minimal or no hepatic inflammationMinimal or no hepatic inflammation
10 year survival: 90%10 year survival: 90%
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54

99. relapserelapse
 Relapse is common after drug withdrawalRelapse is common after drug withdrawal
 PatientsPatients should be monitoredshould be monitored by serumby serum
aminotransferase ,bilirubin and gammaaminotransferase ,bilirubin and gamma
globulin levelglobulin level

100. 

102. IBD AS A CAUSE OF CHRONICIBD AS A CAUSE OF CHRONIC
LIVER DISEASESLIVER DISEASES

103. Primary sclerosing cholangitis
• PSC is an idiopathic inflammatory disease resulting in intra
and extra hepatic biliary strictures and cholestasis
cirrhosis;often assoc.with ulcerative cholitis
• It can occur in infancy and childhood
•This is a cholestatic disease whose etiology is unknown
• This disease differs from primary biliary cirrhosis in that the
large bile ducts, the extra hepatic biliary tree ,are affected

104. Symptoms:
Fatigue
Pruritis
Jaundice
Fever
Weight loss
Diagnosis:
 Liver function tests
 CT scan
 Ultrasound
 ERCP is the diagnostic tool of choice.
(Endoscopic retrograde cholangiopancreatography)
 Liver biopsy

106. Immunosuppressants and steroids
Ursodeoxycholic acid
Endoscopic dilation of dominant strictures, with or
without stenting
Treatment

107. Drug induced Chr. hepatitisDrug induced Chr. hepatitis
 (Medication-induced liver diseases)(Medication-induced liver diseases)
 History of medicines , herbals and alternateHistory of medicines , herbals and alternate
medicinesmedicines
 Mild to very severe hepatic dysfunctionMild to very severe hepatic dysfunction

108. Drug induced chr. Liver DiseaseDrug induced chr. Liver Disease
 Idiosyncratic reactionsIdiosyncratic reactions-- Isoniazid, sodiumIsoniazid, sodium
valproate, phenytoinvalproate, phenytoin
 Cholestatic reactionsCholestatic reactions-- Erythromycin,Erythromycin,
phenothiazinesphenothiazines
 Acute and chronic hepatitisAcute and chronic hepatitis ––
Amiodarone, HIV drugs,Amiodarone, HIV drugs, àà methyl dopamethyl dopa
Discontinuation of the offending drug is the main line of therapy

109.  Metabolic and genetic disorders:Metabolic and genetic disorders:
 (a) Haemochromatosis(a) Haemochromatosis
 (b) Wilson’s disease(b) Wilson’s disease
 (c)(c) αα- antitrypsin deficiency- antitrypsin deficiency
 (d) Glycogen storage disease type IV(d) Glycogen storage disease type IV

110. Thank youThank you