This document summarizes information about autoimmune hepatitis (AIH), including: - It is a T-cell mediated immune attack on the liver that causes progressive damage and can lead to cirrhosis. - Two main types (type 1 and type 2) are distinguished by their associated autoantibodies. - Women are affected more often than men. Treatment involves immunosuppression with glucocorticoids alone or in combination with azathioprine to induce remission. Response to treatment and long term outcomes depend on disease severity at presentation.

2.  Un resolving inflammation of liver of
unknown cause.
 Environmental triggers, failure of immune
tolerance, genetic predisposition.
 T-cell mediated immune attack upon liver
antigens.
 Progressive necro-inflammatory and fibrotic
process leading on to cirrhosis and liver
failure.

3.  Women are affected more frequently than
men(3.6:1).
 All ethnic groups and all age groups
affected.
 Mean Incidence is 1 to 2 per 100,000
persons per year in Norway, Sweden, North-
America.
 When untreated 6 month mortality is 40%,
while treated cases show a 10 year survival
of 80-90 %.

4.  Exact pathogenesis is unknown.
 Popular hypothesis- includes triggering agent
(infectious agent, drug, toxin), genetic
predisposition(HLA – B1,B8,DR3,DR4).
 Loss of immune tolerance and activation of cell
mediated immunity against liver antigens.
 Humoral immunity plays a role in extra-hepatic
manifestations of arthritis, vasculitis and
glomerulonephritis by immune complex deposition
and complement activation.

5. Symptoms
Fatigue
Jaundice
Upper abdominal discomfort
Pruritus
None(at presentation)
Anorexia
Myalgias
Diarrhoea
Cushingoid features
Fever( <=40 deg celsius)
Occurrence (%)
86
77
48
36
25-34
30
30
28
19
18

6. Physical Signs
Hepatomegaly
Jaundice
Spider Angiomata
Concurrent immune disease
Splenomegaly
None
Ascites
Encephalopathy
Occurrence
78
69
58
<38
>32
<25
20
14

7. Lab Feature
Elevated AST
Hypergammaglobulinemia
Increased immunoglobulin G level
Hyperbilirubinemia
ALP >2 fold normal
Immunoserologic Markers
SMA,ANA or Anti- LKM1
Atypical p-ANCA
Anti sialoglycoprotein receptor
Anti Actin
Anti Liver Cytosol 1
Anti Soluble Liver Antigen
Occurrence (%)
100
92
91
83
33
Occurrence
100
92(type 1 AIH only)
82
74
32(type 2 AIH only)
11-17

8.  AIH is a diagnosis of exclusion.
 Other causes of chronic hepatitis must be
ruled out.
 Viral hepatitis, Wilson’s disease, Drug
induced hepatitis, Alcoholic and Non
alcoholic Fatty liver disease, Primary Biliary
Cirrhosis and Primary Sclerosing
Cholangitis.

9. Category Variable Score
1) AUTO ANTIBODIES
ANA or SMA
Anti LKM-1
Anti SLA
1:40
>=1:40
>1:80
Positive
+1
+2
+2
+2
2) IMMUNOGLOBULIN-G
LEVEL
> Upper limit of normal
>1.5 times upper limit
+1
+2
3) HISTOLOGY Compatible with AIH
Typical of AIH
+1
+2
4) VIRAL DISEASE No viral markers +2
DEFINITE DIAGNOSIS >=7
PROBABLE DIAGNOSIS 6

10. Elevated serum AST & Gamma Globulin levels
AST:ALP >3
AMA negative
Ceruloplasmin normal
Normal Alpha 1 Antitrypsin phenotype
Normal or near normal serum iron
HBsAg, Anti HCV, IgM Anti HAV and Anti HEV
negative
LIVER BIOPSY
Interface Hepatitis +/- Lobular Hepatitis

11. Auto immune hepatitis
DEFINITE
Gamma globulin level >=1.5 normal
ANA, SMA, or ANTI LKM1 >=1:80
No exposure to drugs or blood products
Alcohol intake<25 g/day
PROBABLE
Gamma globulin level <1.5 normal
ANA, SMA, or ANTI LKM1<=1:40
Previous exposure to drugs or blood
products
Alcohol Use
Other liver related auto antibodies

12.  Two types of AIH (Type 1 and Type 2).
 Based on serological markers.
 A proposed third type (type 3) has been
abandoned and considered a more severe
form of type 1 AIH.
 Anti-SLA is found in both type 1 AIH and in
type 2 AIH and indicator of severe disease
and poor outcome.

13.  Characterized by the presence of ANA, SMA or
both, and constitutes 80% of AIH cases.
 70 % of patients are female, with a peak
incidence between ages 16 and 30 years.
 Associations with other autoimmune diseases
are common (15%-34%); these include
autoimmune thyroid disease, synovitis, celiac
disease and ulcerative colitis.

14.  Characterized by the presence of anti-LKM1
and/or anti-LC1 and/or anti-LKM-3.
 Most patients with type 2 AIH are children,
and serum immunoglobulin levels are usually
elevated except for IgA, which may be
reduced.

15. Antibody Target Antigen Liver Disease
ANA Chromatin,
ribonucleoproteins,
ribonucleoprotein complexes
Type1 AIH,PBC,PSC,
Drug-induced, Chronic
hepatitis B&C,NAFLD
SMA Microfilaments(filamentous
actin) & intermediate
filaments (vimentin,desmin)
Type1 AIH,PBC,PSC,
Drug-induced,Chronic
hepatitis B&C,NAFLD
LKM 1 Cytochrome P450 2D6
(CYP2D6)
Type 2 AIH
Chronic hepatitis C
LC 1 Formiminotransferase cyclo
deaminase (FTCD)
Type 2 AIH
Chronic hepatitis C
pANCA (atypical) Nuclear lamina proteins Type1 AIH
PSC
SLA tRNP(SER)Sec AIH,Chronic hepatitis C

16. Antibody Target Antigen Liver Disease
LKM 3 family 1 UDP glucuronosyl
transferases (UGT1A)
Type 2 AIH, Chronic
hepatitis D
ASGPR Asialoglycoprotein receptor AIH
PBC
Drug induced
hepatitis
Chronic hepatitis B,
C, D
LKM2 Cytochrome P450 2C9 Ticrynafen induced
hepatitis
LM Cytochrome P450 1A2 Dihydralazine
induced hepatitis
APECED hepatitis

17.  Recommended at presentation to establish the
diagnosis and to guide the treatment decision.
 Interface hepatitis is the histological hallmark and
plasma cell infiltration is typical.
 Neither histological finding is specific for AIH, and
the absence of plasma cells in the infiltrate does not
preclude the diagnosis.
 Eosinophils, lobular inflammation, bridging
necrosis, and multiacinar necrosis may be present.
 Portal lesions generally spare bile ducts.

18.  Hallmark of AIH.
 The limiting plate of the portal tract is
disrupted by a lympho plasmacytic infiltrate.

19. AIH+PBC AIH+PSC AIH+Cholestatic
features
Autoantibody
negative AIH
Clinical&
Lab
Features
Features
of AIH,
AMA +
AIH
Features
plus
Ulcerative
colitis, AMA
-,
Abnormal
cholangiogr
am
ANA and or SMA+
AMA -, No
ulcerative colitis,
Normal
cholangiogram
AIH
Features,No
Autoantibody,
HLA DR3 or
DR4 +
Histology Cholangiti
s,
cholestasi
s
Cholangitis
,
cholestasis
Cholangitis,
cholestasis
Interface
Hepatitis

20.  13% of chronic hepatitis of unknown cause
satisfy criteria for AIH but lack the
characteristic autoantibodies.
 Commonly called CRYPTOGENIC
CHRONIC HEPATITIS.
 Clinical, biochemical and histological
features are characteristic of AIH.
 They have the similar HLA types and
respond to steroids like AIH.

21.  Autoimmune thyroiditis, Graves’ disease,
synovitis and ulcerative colitis are the most
common immune-mediated disorders
associated with AIH in North American
adults.
 Type I diabetes mellitus, vitiligo, and
autoimmune thyroiditis are the most common
concurrent disorders in European anti-
LKM1+ AIH patients.

22.  In children with AIH, autoimmune sclerosing
cholangitis can be present, with or without IBD.
 Cholangiographic studies should be considered
to exclude PSC in adults if there has been no
response to corticosteroid therapy after 3
months.
 All children with AIH and all adults with both AIH
and IBD should undergo cholangiographic
studies to exclude PSC.

23.  Incapacitating symptoms and relentless
clinical progression.
 Serum AST or ALT levels are >=10 fold the
upper limit of normal.
 If AST or ALT levels are >=5 fold the upper
limit of normal with gamma globulin >=2 fold
the upper limit of normal.
 Bridging or Multi-lobular Necrosis on
histology

24.  Mild or no symptoms.
 Serum AST is 3-9.9 fold ULN.
 Serum AST is >=5 fold ULN BUT gamma
globulin is <2 fold ULN.
 Interface Hepatitis on histology

25.  Asymptomatic with minimal laboratory
changes.
 Serum AST <3 fold the ULN.
 Burned out or Inactive Cirrhosis – patients
do not benefit from therapy and have
increased drug induced side effects (Hypo-
albuminemia, hyper-bilirubinemia and porto-
systemic shunting affect protein binding and
increase free prednisone)

26.  Portal hepatitis and Decompensated Cirrhosis
with variceal bleeding.
 Severe pre treatment CYTOPENIA or known
deficiency of thiopurine methyltransferase
deficiency.
 Brittle diabetes, vertebral compression,
psychosis, osteoporosis and uncontrolled
hypertension where steroids can be harmful.
 Previous intolerances to azathioprine or
prednisone.

27.  Mainstay of management of AIH is
Glucocorticoid therapy.
 Although some advocate the use of
prednisolone, prednisone is just as effective
and favoured by most authorities.
 Two treatment regimens are used and are
equally effective but it is the combination
therapy which is preferred.

28.  It is usually preferred as over a span of 18
months it reduces the serious life threatening
side effects of steroids from 66% down to under
20 %.
 Begin with 30 mg/d of prednisone along with 50
mg/d(1-2mg/kg in europe) of azathioprine.
 With azathioprine maintained at 50mg/d the
prednisone dose is tapered over a month to a
maintainance level of 10mg/d.

29.  Preferred in patients in whom azathioprine
cant be given.
 Severe pre treatment cytopenia, known
thiopurine methyl transferase deficiency,
pregnancy, active malignancy and if
treatment is to be given for a short course <6
months.

30. Monotherapy Combination Therapy
Prednisone
only(mg/d)
Prednisone
(mg/d)
Azathioprine
U.S.A(mg/d)
Azathioprine
EU(mg/kg/d)
Week 1 60 30 50 1-2
Week 2 40 20 50 1-2
Week 3 30 15 50 1-2
Week 4 30 15 50 1-2
Maintaina
nce until
end point
20 10 50 1-2

31.  Cosmetic changes, including facial rounding,
dorsal hump formation.
 Striae, weight gain, acne, alopecia and facial
hirsuitism, occur in 80% of patients after 2 years
of corticosteroid treatment regardless of the
regimen.
 Severe side effects include osteopenia with
vertebral compression, brittle diabetes,
psychosis, pancreatitis, opportunistic infection,
labile hypertension, and malignancy.

32.  regular weight baring exercise program, vitamin
D and calcium supplementation and
administration of bisphosphonates wherever
needed.
 Patients on long-term corticosteroid treatment
should be monitored for bone disease by
baseline and annual bone mineral densitometry
of the lumbar spine and hip.
 Pre treatment vaccination against HAV and
HBV should be performed if there has been no
previous vaccination .

33.  include nausea, emesis, rash, opportunistic
infection, villous atrophy, malabsorption, bone
marrow suppression and malignancy.
 The principal side effect of azathioprine is
cytopenia and the most common cause of
cytopenia in these patients is hypersplenism
associated with cirrhosis.
 Patients undergoing azathioprine therapy
should have blood leukocyte and platelet counts
assessed at 6-month intervals.

34.  Patients with near-zero erythrocyte concentrations of its
activity are at risk for myelo-suppression during
azathioprine treatment.
 The rarity of severe azathioprine-induced myelo-
suppression, the low dose of azathioprine used in
conventional treatment (50 mg-150 mg daily), and the
inability to reliably predict risk by phenotypic and genotypic
assessments have not supported routine screening for
thiopurine methy-ltransferase activity in AIH.
 Pre treatment cytopenia, cytopenia developing during
therapy, or the administration of higher than conventional
doses of azathioprine (>150 mg daily) justifies
determination of enzyme activity.

35.  Autoimmune hepatitis can improve during
pregnancy and this improvement may allow
reductions in immunosuppressive therapy
during pregnancy.
 Pre-conceptional counselling is advised and
termination of immunosuppressive therapy
should be attempted where possible.

36.  Patients must be counselled regarding the uncertain risk of
azathioprine(CAT D) in pregnancy, and azathioprine
should be discontinued, if possible, in patients during
pregnancy.
 Postpartum exacerbation of AIH must be anticipated by
resuming standard therapy 2 weeks prior to anticipated
delivery and by closely monitoring serum AST or ALT
levels at 3-week intervals for at least 3 months after
delivery.
 Contraception should be advised in women with advanced
liver disease and features of portal hypertension because
they are at risk for variceal hemorrhage during pregnancy.

37.  Remission
 Treatment failure
 Incomplete response
 Relapse
 Drug toxicity

38.  Disappearance of symptoms, normal serum
aminotransferases, bilirubin and gamma globulin levels,
normal hepatic tissue or inactive cirrhosis is the ideal
treatment endpoint and the goal of initial therapy.
 Liver biopsy assessment prior to termination of treatment
is the only method by which to ensure full resolution of the
disease and an optimal endpoint of therapy.
 Interface hepatitis is found in 55% of patients with normal
serum AST and gamma-globulin levels and these
individuals typically relapse after cessation of treatment,
therefore, a liver biopsy is recommended before
termination of therapy.

39.  Termination of therapy should be considered after
at least 2-year treatment, when liver function tests
and immunoglobulin levels have been repeatedly
normal.
 Termination of therapy after induction of remission
requires a gradual, well-monitored dose reduction
over a 6-week period of close surveillance.
 Laboratory tests are performed at 3-week intervals
during drug withdrawal and for 3 months after
termination of therapy. Thereafter, they are
repeated at 3 months and then every 6 months for
1 year and then annually life-long.

40.  Treatment failure connotes clinical, laboratory and histological
worsening despite compliance with conventional treatment
schedules or development of jaundice, ascites or hepatic
encephalopathy.
 This demands institution of high dose therapy with prednisone
alone (60 mg daily) or prednisone(30 mg daily) in conjunction
with azathioprine(150 mg daily) for at least 1 month.
 Thereafter, dose reduction of prednisone is done by 10mg and
azathioprine by 50 mg for each month of improvement until
standard treatment doses are achieved.
 The development of hepatic encephalopathy, ascites, and/or
variceal bleed during therapy for treatment failure is an
indication for liver transplantation.

41.  If high dose therapy of steroids and
azathioprine fails to induce remission then
alternative drugs are used such as
cyclosporine, tacrolimus, or mycophenolate
mofetil.
 In treatment failure mycophenolate mofetil or
cyclosporine have had the most empiric use as
alternative medications. Mycophenolate mofetil
(2 g daily orally) is the most promising current
agent.

42.  Clinical, laboratory and histological
improvement which is insufficient to satisfy
criteria for a treatment endpoint after continuous
therapy for at least 36 months.
 Reduction in doses of prednisone by 2.5
mg/month until lowest level possible (10 mg
daily) to prevent worsening of serum AST or
ALT abnormalities.
 Indefinite azathioprine therapy (2 mg/kg daily)
as an alternative treatment if corticosteroid
intolerance.

43.  Relapse connotes recrudescence of disease activity after
induction of remission and termination of therapy.
 It is characterized by an increase in the serum AST level to
more than three-fold the ULN and/ or increase in the
serum gamma globulin level to more than 2g/dL.
 The first relapse after drug withdrawal should be retreated
with a combination of prednisone plus azathioprine at the
same treatment regimen as with the initial course of
therapy and then tapered to mono therapy with either
azathioprine (2 mg/kg daily) as a long-term maintenance
therapy or with indefinite low dose prednisone (10 mg
daily) in patients intolerant of azathioprine.

44.  Drug toxicity justifies premature
discontinuation or alteration of conventional
therapy.
 therapy with the tolerated agent (prednisone
or azathioprine) can be maintained in
adjusted dose to prevent worsening in the
clinical and laboratory features.

45.  occurs in 4% of patients with type 1 AIH, and the
10-year probability of developing this neoplasm is
2.9%.
 Risk factors include male sex, portal hypertension
manifested by ascites, oesophageal varices, or
thrombocytopenia, immunosuppressive treatment
for at least 3 years, and cirrhosis of at least 10
years duration.
 A focused surveillance strategy based on hepatic
ultrasonography at 6-month intervals is
recommended for these individuals

46.  AIH and acute liver failure
 Decompensated cirrhosis with a MELD score
>=15
 Hepatocellular carcinoma meeting criteria for
transplantation.

47.  40% of all patients develop cirrhosis.
 54% develop oesophageal varices in 2 years.
 Poor prognosis if ascites or hepatic encephalopathy
present.
 13-20% can have spontaneous resolution.
 Of patients who survive the early and active stage
of disease, approximately 41% of them develop
inactive cirrhosis.
 Of patients who have severe initial disease and
survive the first two years, typically survive long
term.

48.  Suspect AIH as a cause of acute or chronic hepatitis when
other causes such as viral, hereditary, metabolic,
cholestatic, and drug-induced diseases, have been
excluded.
 Two types based on the presence of ANA and SMA (type1
AIH) or anti-LKM1 and anti-LC1 (type 2 AIH).
 Immunosuppressive treatment should be instituted in
patients with serum AST or ALT levels greater than 10-fold
ULN, at least five-fold ULN in conjunction with a serum
gamma-globulin level at least 2-fold ULN, and/or
histological features of bridging necrosis or multi-lobular
necrosis.

49.  Immunosuppressive treatment should not be
instituted in patients with minimal or no disease
activity or inactive cirrhosis, but these patients
must continue to be followed closely, i.e., 3-6
months.
 Apart from alcoholic hepatitis (DF>32), it is the
only hepatitis for which STEROIDS should be
given.
 AIH must always be suspected because early
treatment can reduce the mortality and
progression to cirrhosis significantly.