This document provides information on autoimmune hepatitis, including: - It is a chronic hepatitis of unknown etiology that can progress to cirrhosis. It is characterized by the presence of autoimmune antibodies and evidence of hepatitis. - The two main types are type 1, associated with ANA/SMA positivity, and type 2, associated with LKM1 positivity. - Treatment involves immunosuppressive drugs like prednisone, either alone or in combination with azathioprine. The goal is to induce and maintain remission. - Remission is defined as resolution of symptoms and normalization of liver tests and histology. Treatment is then tapered slowly to maintain remission.

1. AUTOIMMUNE HEPATITIS
• CHAIRPERSON : DR.SANJEEV KUMAR
• SPEAKER: DR.RAJESH KUMAR GOYAL

2. AUTOIMMUNE HEPATITIS
• Chronic hepatitis of unknown etiology
• Can progress to cirrhosis
• Characteristics include:
– presence of autoimmune antibody
– evidence of hepatitis (interface being
characteristic)
– elevation of serum globulins
– Continuing/unresolving hepatocellular
inflammation and necrosis

3. OTHER NAMES
• Active chronic hepatitis or chronic active
hepatitis
• Chronic aggressive hepatitis
• Lupoid hepatitis
• Plasma cell hepatitis
• Autoimmune chronic active hepatitis

4. • Diagnosis of autoimmune hepatitis requires
the exclusion of other chronic liver diseases
that have similar features, including wilson
disease ,chronic viral hepatitis, drug induced
liver disease, non alcoholic fatty liver disease,
and the immune cholangiopathies of primary
biliary cirrhosis (PBC) and primary sclerosing
cholangitis (PSC)

5. BACKGROUND
• First described in 1950’s
• Accounts for 5.6% of liver transplants in the
US
• Affects women more than men (3.6:1)
• If untreated approximately 40% die within 6
months
• 40% develop cirrhosis

6. EPIDEMIOLOGY
• Frequency of AIH among patients with chronic
liver disease in North America is between
11%- 22%
• Accounts for 5.6% of liver transplants in the
US
• Prevalence greatest among northern
European white persons
• Japenese have a lower frequency

7. PATHOGENESIS
EVIDENCE SUPPORTING AUTOIMMUNE PATHOGENESIS
 Histopathological lesions composed of cytotoxic
Tcells and plama cells
 Circulating autoantibodies
 Hyperglobulinemia
 Other autoimmune disorders: thyroiditis, RA ,
autoimmune hemolytic anemia, ulcerative colitis,
membranoproliferative glomerulonephritis, diabetes
mellitus, celiac disease, sjogren’s syndrome
 Histocompatibility haplotypes associations
 Response to steroids and immunosuppression.

8. Pathogenesis
• Exact pathogenesis is unknown
• Predisposition to autoimmunity is inherited
,whereas the liver specificity of this injury is
triggered by environmental factors (chemical,
drugs like minocycline or viral)
• Genetic predisposition is also present (HLA –
B1, B8, DR3,DR4)

9. • Cell mediated immune attack is directed
against the liver cells
• CD4 T lymphocytes are capable of becoming
sensitized to hepatocyte membrane protein
and of destroying liver cells
• Humoral immunity plays a role in extra-
hepatic manifestations of arthritis,vasculitis
and glomerulonephritis by immune complex
deposition and complement activation.

10. CLINICAL FEATURES
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

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

12. LABORATORY FEATURES
• 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

13. ASSOCIATED CONDITIONS
• Hashimotos thyroiditis and other thyroid
abnormalities like myxoedema and
thyrotoxicosis.
• Endocrine changes like cushingoid appearance,
acne , hirsutism.
• Pulmonary changes like pleurisy,transitory
pulmonary infiltrates and collapse.
• Acute,recurrent and non- deforming polyarthrits
of large joints.
• Mild aneamia, leucopenia, thrombocytopenia can
occur.

14. DIAGNOSTIC
ALGORITHM
FOR AUTOIMMUNE
HEPATITIS

15. Simplified scoring system for diagnosis
of AIH
Category Variable Score
1) AUTO ANTIBODIES
ANA or SMA
Anti LKM-1
Anti SLA
1:40
>1:80
>1:40
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

16. Classification
• 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.

17. Type 1 Autoimmune Hepatitis
• Classically in young females
• ANA or Anti-Smooth Muscle antibody positive
• Titer usually > 1:100
• 10% will have an antibody to Soluble Liver antigens
(SLA)
• Other Antibodies: anti-DNA, pANCA, Anti-
mitochondrial, Anti-Actin (AAA), cytoskeletal
antibody, nuclear envelope proteins lamin A and C,
plasma membrane sulfatides
• Anti-actin antibodies have greater specificity

18. TYPE 1 AIH Contd.
 Bimodal Age distribution (ages 10-20 and 45-70)
 Female:male (3.6:1)
 HLA DR3 or DR4 assosciation
 Associated with extrahepatic manifestations(38%):
 Autoimmune thyroiditis(12%), Graves disease(6%),
Chronic UC(6%).
 Less commonly with RA, pernicious anemia, systemic
sclerosis, ITP, SLE,coombs positive hemolytic anemia,
leucocytoclastic vasculitis, erythema nodosum
 40% present with acute onset of symptoms similar to toxic
hepatitis or acute viral hepatitis

19. TYPE 2 AUTOIMMUNE HEPATITIS
• Seen in children (2-14 years).
• HLA DRB1 or DQB1 assosciation
• Presence of anti-Liver/Kidney Microsome
Antibodies (anti- LKM1 )directed against
cytochrome p450 2D6 {same as LKM seen in
patients with chronic hepatitis C}
• Anti-Liver Cytosol antibody (ALC-1)
• Concurrent autoimmune disease like autoimmune
thyroiditis,vitiligo and type 1 diabetes mellitus can
be present.
• Acute or fulminant presentation possible

20. TYPE 3 AUTOIMMUNE HEPATITIS
It is now considered as a more severe form of
type 1 AIH
• Antibodies to soluble liver antigen / liver
pancreas antigen
• Lack ANA and anti- LKM 1 antibodies
• More in women, part of spectrum of type 1
AIH

21. AUTOANTIBODIES IN AIH
• ANA : Present mainly in type 1 AIH. It is
targeted against chromatin and
ribonucleoproteins
• SMA: Present in type 1 AIH. It is targeted
against various microfilaments like actin ,
vimentin, desmin
• LKM 1 : Present in type 2 AIH and chronic
hepatitis c. it is directed against cytochrome
p450 2D6

22. • SLA : prsent in type 3 AIH. Directed against t
rnp
• LKM 2 : Present in drug induced hepatitis.
Directed against cytochrome p450 2c9
• LKM3: present in type 3 AIH and chronic
hepatitis D. directed against UDGT1A

23. VARIANT FORMS OF AIH
• AUTOIMMUNE HEPATITIS + PRIMARY BILIARY
CIRRHOSIS (PBC)
• AUTOIMMUNE HEPATITIS + PRIMARY
SCLEROSING CHOLANGITIS(PSC)
• AUTOIMMUNE HEPATITIS + CHOLESTATIC
FEATURES
• AUTOANTIBODY-NEGATIVE AUTOIMMUNE
HEPATITIS

24. AIH + PRIMARY BILIARY CIRRHOSIS
• Along with features of AIH pt also have
Antimitochondrial antibodies
• Histological features of cholangitis and bile
duct loss are present
• Treatment with prednisone is done if alkaline
phosphatase level is ≤2 × ULN
• Treatment with prednisone and UDCA is done
if AP >2 × ULN

25. AIH + PRIMARY SCLEROSING
CHOLANGITIS
• Along with features of AIH pt may have
abnormal cholangiographic changes
• Inflamatory bowel disease may be present
• Antimitochondrial antibodies are absent
• Histological features of cholangitis and
cholestasis may be present
• Treatment includes prednisone and UDCA

26. AIH + CHOLESTATIC FEATURES
• Along with features of AIH pt have antinuclear
antibodies or antismooth muscle antibodies
• Histological features of cholangitis and
cholestasis are present
• No inflamatory bowel disease is present
• Absence of antimitochondrial antibodies and
cholangiographic changes
• Treatment with prednisone and UDCA

27. Auto Antibody Negative AIH
• 13% of chronic hepatitis of unknown cause
satisfy criteria for AIH but lack the
characteristic autoantibodies.
• Commonly called CRYPTOGENIC CHRONIC
HEPATITIS.
• Age, female predominance, frequency of
immunologic diseases, histologic features and
lab findings are similar with classic AIH.
• Associated withHLA-B8, DR-3
• Respond to treatment with glucocorticoids.

28. HISTOLOGY
• Chronic hepatitis with marked piecemeal necrosis
and lobular involvement
• Numerous plasma cells
• Interface hepatitis: hallmark finding
• Necroinflammatory activity
• Evidence of hepatocellular regeneration (“rosette
formation” , regenerative “pseudolobules”)
• Bile duct injuries and granulomas are
uncommon

29. DIFFERENTIAL DIAGNOSIS
• Primary biliary cirrhosis
• Post-necrotic cryptogenic cirrhosis
• Primary sclerosing cholangitis
• Acute viral hepatitis
• Chronic viral hepatitis
• Wilsons disease
• Alcoholic hepatitis
• Non alcoholic fatty liver disease

30. TREATMENT OF AUTOIMMUNE
HEPATITIS

31. Absolute Indications For Treatment of
AIH
• 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

32. Relative Indications For Treatment of
AIH
• 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

33. Treatment NOT INDICATED
• 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)

34. Treatment NOT INDICATED
• 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.

35. Treatment Regimens for AIH in Adults
• 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.

36. PREDNISONE ONLY
• Prednisone 60mg PO daily which is tapered
down to 30mg at the 4th week of treatment
and then maintenance of 20mg daily til the
endpoint
• Reasons for Prednisone only:
Cytopenia
TPMT deficiency
Malignancy
Pregnancy
• Therapy response expected in upto 80% of
cases

37. Combination Immunosuppressive
Therapy
• 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.

38. Preferred treatment regimens
Combination therapy Single drug therapy
Prednisone (mg/day) Azathioprine (mg/d) Prednisone (mg/day)
30mg × 1 week 50 mg until the end
point
60mg × 1 week
20mg × 1 week 40mg × 1 week
15mg × 2 weeks 30mg × 2 weeks
10mg until the end
point
20mg until the end
point

39. CORTICOSTEROID SIDE EFFECTS
• Cosmetic side effects like alopecia, dorsal
hump, facial rounding,hirsutism,striae,weight
gain can occur in 80% of the pt. after 2 years
of treatment
• Severe side effects like cataract, diabetes
mellitus, emotional instability, hypertension,
osteopenia, vertebral compression can occur
• Rare side effects includes malignancy,
opportunistic infections and pancreatitis

40. Azathioprine-Related Side Effects
• The mc side effects of azathioprine is
cytopenia occuring in 46% of the pt.
associated with cirrhosis
• Other side effects include arthralgias, fever,
nausea, vomiting and rash and bone marrow
faliure
• Pt. undergoing azathioprine therapy should
have blood leucocyte and platelet counts
assessed at 6 months interval

41. AZATHIOPRINE IN PREGNANCY
• Placenta is only a partial barrier to the
metabolites of azathioprine and its use has been
associated with congenital malformations in
newborn
• Azathioprine is not an essential medication in the
treatment of autoimmune hepatitis and can be
discontinued during pregnancy.
• Pt with autoimmune hepatitis in pregnancy can
be successfully managed by adjustments in the
dose of prednisone.

42. TREATMENT ENDPOINTS
• Remission
• Treatment failure
• Incomplete response
• Relapse
• Drug toxicity

43. Remission
• Remission connotes absence of symptoms,
resolution of all lab indices of active
inflammation and histologic improvement to
normal liver tissue or inactive cirrhosis.
• Evaluation of the liver tissue before drug
withdrawl is essential to establish remission
because histologic activity may be present in
55% of pt. who satisfy other requirements of
remission.

44. Remisson contd.
• If a remission has ensued, judged clinically,
biochemically and by liver biopsy, the drug
should be tapered off slowly over about 2
months.
• If relapse occurs indefinite low dose
prednisone or indefinite azathioprine (50-
100mg) can be given.

45. Treatment Faliure
• Treatment faliure is characterised by worsening
of serum AST or bilirubin levels by at least 67%of
the previous values, progressive histologic activity
or onset of ascites or encephalopathy.
• High dose therapy with prednisone alone (60 mg
daily) or prednisone(30 mg daily) in conjunction
with azathioprine(150 mg daily) constitues the
standard treatment in this group.

46. Treatment faliure contd.
• Alternative management regimens include the
administration of cyclosporine,
mycophenolate mofetil, ursodeoxycholic acid,
budesonide, 6-mercaptopurine, methotrexate
and cyclophosphamide.
• If liver decompensation occurs despite the
high dose therapy liver transplantation should
be considered.

47. Incomplete Response
• Incomplete response connotes clinical
improvement that is insufficient to satisfy the
remission criteria.
• Faliure to achieve remissoin within three years
indicates that the remission is unlikely and
warrants discontinuation of conventional
treatment.
• The administration of azathioprine(2mg/kg daily)
as the sole drug or low dose predisone regimen
can be done

48. Drug toxicity
• Drug toxicity justifies premature withdrawl of
medication or a reduction in dose.
• Treatment can usually be continued with the
single tolerated drug (prednisone or
azathioprine) in an adjusted dose.
• Cyclosporine, 6-mercaptopurine and
cyclophosphamide also have been used
successfully

49. TAKE HOME MESSAGE
• 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.
• 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.
• AIH must always be suspected because early
treatment can reduce the mortality and
progression to cirrhosis significantly

50. THANK YOU