Moderator Speaker

PROF. A.K. RITWIZ

AUTOIMMUNE HEPATITIS
 Autoimmune hepatitis(AIH) is a
chronic, generally progressive self-
perpetuating hepatocellular
inflammation of unknown cause
 Characterized by
1. Interface hepatitis
2. Hypergammaglobuline
mia
3. Autoantibody in serum
EPIDEMIOLOGY

 Considerable geographical variation

 Among White Northern European
 Mean annual incidence = 1.9 per 100,000
 Prevalence = 16.9 per 100,000

 Accounts for 11-20% of all CLD cases

Boberg et.al. scand J gastroenterol

It accounts for
 40% of pts with untreated severe disease
die within 6 months of diagnosis
 Cirrhosis develops in 40% of survivours
 54% develop esophageal varices within 2
year after cirrhosis
 20% of individual with varices die from
hemorrhage

Albert J Czaja et.al. Hepatology vol

In India
 Over all prevalence is 1.5-6.1%
 Most of them have advance liver disease
 Type 1 AIH is present in 80-91% cases
 Mean age 36.3 yrs with female preponderance(4:1)

• Gourdas et. al. BMC

Gastroenterology 2005
• Gupta R et. al. J Gastroenterol
hepatol 2001
 Diagnostic criteria.

Requisites Definitive Probable

Lab features Predominant Predominant AST/ALT
AST/ALT abnormality,
abnormality hypergammaglobuline
Immunoglobulin mia of any degree
level >1.5 times
Autoantibodi ANA, SMA, or ANA, SMA, or
es antiLKM1 >1:80, antiLKM1 >1: 40 or
no AMA other antibody
Histology Interface hepatitis, Interface hepatitis, no
no biliary lesions, biliary lesions,
granulomas, or granulomas, or
prominent changes prominent changes of
ANA of other
=antinuclear ab;disease
SMA=anti other
smoothdisease
muscle
ab;
Exclusion Definitive Probable
of
Genetic Normal Partial
liver α 1 antitrypsin α 1 antitrypsin
disease phenotype phenotype
Normal Non specific
ceruloplsmin, Fe, ceruloplsmin, Fe,
and ferritin level and ferritin level

No active Absence of current Absence of

viral Hepatitis A, B, and current Hepatitis
infection C infection A, B, and C
infection
No toxic or Alcohol <25 g/d , Alcohol<50 g /d,
alcohol No recent use of No recent use of
 Scoring criteria
Category Factor Score Categor Factor Score
y
Gender Female +2 AMA Positive -4
AP/AST >3 -2 Viral Positive -3
<1.5 +2 marker Negative +3
IgG level >2 +3 Drug Yes -4
1.5-2 +2 No +1
1-1.5 +1 Alcohol <25g/d +2
ANA/SMA >1:80 +3 >60g/d -2
anti-LKM1 1:80 +2 HLA DR3/DR4 +1
1:40 +1 Immune Thyroiditis, +2
disease colitis, etc

Other ab Anti-SLA/LP, +2 histolog Interface +3

antiactin,etc y hepatitis
Tt complete +2 plasmacytic +1
Scoring criteria

 An aggregate score reflects the net

strength of diagnosis
 Pretreatment score >15 indicate
definitive diagnosis, and 10-15
indicates probable diagnosis
 Post treatment score >17 indicates
definitive and 12-17 indicates
probable
 Rarely needed for clinical diagnosis
IMMUNOPATHOGENESIS

 A cell-mediated immunologic attack

 Predisposition to autoimmunity is
inherited

 Injury is triggered by environmental

(e.g., chemical or viral) factors

 Humoral immune mechanisms have

been shown to play a role in the
extrahepatic manifestations of
Evidence to support an autoimmune
pathogenesis
 Presence of cytotoxic T cells and
plasma cells in histopathologic
lesions
 Circulating autoantibodies
 HLA-B1, -B8, -DR3, and -DR4
association
Autoantibodies described in
these patients are

Auto Type 1 Type 2 Type 3

antibodies
conventional Smooth Liver/kid none
muscle, ney
Nuclear microsom
e type 1

novel pANCA, Livercyto Soluble liver

Actin, sol type antigen/liver
1 pancreas
Asialoglyc
oprotein
receptor
putative unknown CYP2D6 Transfer
Antibodies contd

 Autoantibodies are neither

pathogenic nor disease specific

 Single low antibody titer never

excludes the diagnosis

 Levels do not reflect severity of

disease or response to treatment

 Need not to be monitored

Conventional antibodies
Antinuclear antibody(ANA)

 Marker of type 1 AIH

 Present in 67% of pts (13% alone &

with SMA 54%)

 React against diverse recombinant

nuclear antigen e.g.
centromere,RNP etc.
Anti smooth muscle antibodies

Directed against actin and non

actin components

Present in 87% of pts (alone 33% &

with ANA 54%)

Also standard marker of type 1 AIH

Anti liver kidney microsome
type1(antiLKM1)

 Typically occurs in absence of

ANA and SMA

 Reactivity against 50-kd

microsomal drug metabolizing
enzyme

 Only 4% of pts with AIH

 More common in pediatric age

group
Anti soluble liver antigen/liver-
pancreas

 Highly specific marker of AIH

 A 50 kd cytosolic protein(tRNP
complex) is target

 Antibody to soluble liver antigen

and antibody to liver/pancreas
have identical reactivity
Others

 pANCA: present in 90% of pts of AIH

type1
 Antibody to actin: have more
specificity than SMA for AIH type1
 Antibody to asialoglycoprotien
receptor: correlates with histological
activity and response to treatment.
 Antibody to liver cytosol type 1: have
Portal and interface hepatitis, with a mixed
inflammatory infiltrate composed of
lymphocytes, plasma cells, and eosinophils
Autoimmune hepatitis
Cirrhotic stage
SUBCLASSIFICATION

Clinical Type1 Type2 Type3

feature
Age bimodal pediatric adult
Women% 78 89 90
Gamma marked mild moderate
globulin
elevation
HLA B8,DR3,D B14,DR3, uncertain
R4 DR7
Glucocorticoi +++ ++ +++
d
responsiven
ess
Overlap syndrome

 Clinical & biochemical manifestation of AIH

 Plus another type of AI liver disease
 Behavior of disease and response to treatment
depend on component of disease that
predominates

 e.g.Overlap with primary biliary cirrhosis

Outier syndrome

Clinical & biochemical

manifestation of AIH

 Plus lack of characteristic

autoantibodies

 e.g. cryptogenic chronic

Distinctiv AIH +PBC AIH+PSC Autoimmune Cyptogenic
e feature cholangitis chronic
hepatitis
clinical AIH features AIH features ANA and/or SMA AIH features
present
AMA present CUC No CUC No
autoantibodies

AMA absent AMA absent HLA-B8 or DR3

Abn Normal
cholangiogram chplangiogram
histologic cholangitis cholangitis cholangitis Interface
al hepatitis
Cholestasis Cholestasis Cholestasis
treatment Prednisolone Prednisolone Prednisolone Conventional
tt for AIH
+/- + +/-
ursodeoxycholi ursodeoxycholic ursodeoxycholic
PBC =cprimary
acid acid
biliary cirrhosis acid= primary sclerosing
PSC
cholangitis
CUC = chronic ulcerative colitis AMA= antimitochondrial
CLINICAL FEATURES

 Onset of disease may be insidious or abrupt

 A history of recurrent bouts of hepatitis

 Complications of cirrhosis, such as ascites,

encephalopathy, hypersplenism, coagulopathy, or
variceal bleeding may bring the patient to initial
medical attention
Clinical feature contd

Symptoms Occurrence Findings Occurrence

Fatigue 85 Hepatomegal 78
y
Jaundice 77 Splenomegal 32
y
Abd 48 Spider 58
discomfort angioma
Pruritis 36 Ascites 20
Anorexia 30 Encephalopat 14
hy
Polymyalgia 30 Immune 48
disease
Fever 18
Other immune disease includes

Disease Percentage
Autoimmune 12%
thyroiditis
Graves disease 6%

Chronic ulcerative 6%
colitis
Rheumatoid arthritis <1%

Pernicious anemia <1%

Systemic sclerosis <1%

LABORATORY FEATURES

 Similar to those seen in chronic viral hepatitis

 Liver biochemical tests may not correlate with
the clinical severity or histopathologic features
 Hypergammaglobulinemia (>2.5 g/dL) is
common
 Circulating autoantibodies are also common
Laboratory features contd
Lab finding Occurrenc Markers Occurrenc
e e
AST elevation 100 SMA/ANA/anti 100
LKM
Hypergamma 92 pANCA 92
globulinemia Type1 only

Hyperbilirubin 83 Anti ASGPR 82

emia
Alkp >2 fold 33 Antiactin 74
Anti liver 32
cytosol 1 Type2 only

Anti soluble 11-17

POOR PROGNOSTIC FEATURES

 AST>10-fold of normal
 AST > 5 fold of normal with
gammaglobulin >2 fold of normal
 Bridging necrosis or multilobular
necrosis
 Cirrhosis
 Failure to treatment response
Diagnostic algorithm for autoimmune hepatitis
Abn AST & GG level
AST: Alkp > 3

AMA,ceruloplasmin normal
Alfa1 anti trypsin phenotype normal
Normal/non specific Fe level
HBsAg,AntiHCV,IgM antiHAV -ve

definite Interface probable

hepatitis
GG<1.5 normal
GG>1.5 normal ANA,SMA or LKM1>1:40
ANA,SMA or LKM1>1:80 No drugs or blood product
No drugs or blood product Alcohol <50g/d
Alcohol <25g/d Other autoantibody

type1 type2

LKM1
ANA &/or SMA
 TREATMENT

 The mainstay of management is

glucocorticoid therapy

 A therapeutic response can be expected in

up to 80% of patients

 Therapy leads to symptomatic, clinical,

biochemical, and histologic improvement
as well as increased survival

 Unfortunately, therapy has not been shown

to prevent ultimate progression to
The indications of treatment
Finding Absolute Relative None

Clinical Incapacitatin Mild Asymptomat

g symptoms symptoms ic
    Previous
Relentless
clinical intolerance to
progression therapy
Laboratory AST >10 fold AST 3-9 fold AST < 3 fold

  AST >5 fold AST <5 fold Severe

gamma gamma cytopenia
globulin > 2 globulin
Histologic fold
Bridging < 2 fold
Interface Inactive
necrosis hepatitis cirrhosis
   
Multilobular Portal
necrosis hepatitis
      Decompensa
ted liver
with variceal
bleed
Treatment contd

 Prednisone is just as effective and is

favored by most authorities
 An alternative but equally effective
approach is prednisone & azathioprine
 Azathioprine alone, however, is not
effective in achieving remission
 Efficacy of therapy in mild or
asymptomatic autoimmune hepatitis has
not been established
Combination therapy Single drug
therapy
Prednisone Azathioprine Prednisone
(mg/day) (mg/day) (mg/day)
30 mg x 1wk 50 mg until end 60 mg x 1wk
point
20 mg x 1wk   40 mg x 1 wk

15 mg x 2 wk   30 mg x 2 wk

10 mg until end   20 mg until end

point point
TREATMENT END POINTS
REMISSION

 The absence of symptoms,

 Resolution of inflammatory indices

(except for AST level < 2 fold),

 Histological improvement to
normal or minimal activity
TREATMENT FAILURE

 Deterioration during the therapy

1. Increase in the serum AST or bilirubin
levels by at least 67% of previous
values,
2. Progressive histological activity,
3. Onset of ascites or encephalopathy.
INCOMPLETE RESPONSE

 An improvement that is
insufficient to satisfy remission
criteria

 Require indefinite treatment

 Low dose immunosuppressant

is needed
 Treatment end points
Predisolone +azathioprine or
Prednisolone alone

Incomplete
remission Treatment failure Drug toxicity
response

No High dose Therapy

therapy therapy
relapse >3 yrs Drug
reductio
Repeat Stable n
Liver decompens Indefinite
therapy ation azathioprine Or
functio
n withdra
2and or prednisone
wal
remission
Chroni Liver
No therapy c transplanta
therap tion
relapse y
Indefinite
azathioprine or
prednisone
OTHER DRUGS
6-Mercaptopurine :

 Substituted for azathioprine in

combination therapy

 In adults (25–100 mg/day) and children

(0.75–1.0 mg/kg/day)

 C/I in thiopurine methyltransferase

deficiency; cancer, or cytopenia, and
 CYCLOSPORI
NE
 Sometimes used as monotherapy in
children
 Sometimes used as an alternative drug in
adults with treatment-refractory disease
Mycophenolate mofetil, Methotrexate,
Cyclophosphamide
 Role of mycophenolate mofetil,
methotrexate, and cyclophosphamide is
not established
LIVER TRANSPLANT

 Liver transplantation is required

1. Refractoryto or intolerant of
immunosuppressive therapy
2. End-stage liver disease develops
 The survival rate is approximately 80
to 90 percent
 Recurrence rate has been reported to
be as highas 42 percent.
TAKE HOME MASSAGE
 AIH is a rare cause of CLD
 It remains important to distinguish AIH
because
1. High % of pts respond to
therapy
2. Mx prolongs survival
3. Improves the quality of life