AUTOIMMUNE

HEPATITIS
 BACKGROUND
First described in the late 1940s by
Harold Percival Himsworth
Chronic active hepatitis described by
Waldenstrom in 1950
Lupoid hepatitis discussed in the
Lancet by Ian Mackay in 1956
Plasma cell hepatitis
Idiopathic chronic hepatitis
In 1992, the International Autoimmune
Hepatitis Group settled on the term
Autoimmune Hepatitis (AIH)
Developed probable vs. definite scoring
system
1. Mackay IR et al., Ann N Y Acad Sci 1965; 124: 767-780
2. Himsworth HP. Lectures on the Liver and its Diseases. Oxford: Blackwell, 1947: 158-161
3. Waldenstrom JL: Blutproteine und Nahrungseiweiss. Dtsch Ges Verdau Stoffwechselkr 1950: 15: 113-119
4. Mackay IR et al., Lupoid Hepatitis. Lancet, 1956: 271: 1323-1326
5. Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology 1993; 18: 998-1005
BACKGROUND

The incidence of autoimmune hepatitis (AIH) estimated

0.1-1.9 per 100,000 people
Accounts for 6% of liver transplantations in the U.S.
Accounts for 3% of liver transplantations in Europe
 BACKGROUND
OLD Definition: Chronic, unresolving inflammation of the
liver, due to unknown causes
NOW: Characteristics: plasmacytic necroinflammatory
liver dz, hypergammaglobulinemia and presence of one
or more autoantibodies
Women affected more than men (~ 70% of cases are
women) although both affected at all ages
 BACKGROUND
Increased coexistence of other autoimmune disease
Rheumatoid arthritis
Diabetes
Thyroiditis
Uveitis
Celiac Sprue
Ulcerative Colitis
Lupus
Psoriasis
Others
 WHY DOES AIH OCCUR?
Genetic susceptibility
HLA association
AIH type 1: B8, DR3, DR4
AIH type 2: B14, DR3, C4AQ0
AIH type 3: unknown

1. Pando M., et al. Hepatology 1999 Dec;30(6):1374-80

Pathophysiology
 PRESENTATION
History variable
Asymptomatic patients often discovered with
elevated liver enzymes
Can present with mild-moderate symptoms
(fatigue, arthralgia, abdominal discomfort, etc)
25% of cases present with acute hepatitis
Can also present with fulminant hepatitis or
with decompensated cirrhosis (~25%)
Physical Examination:
Variable
May present with no abnormalities
May present with hepatosplenomegaly,
jaundice and stigmata of chronic liver disease.
 DIAGNOSIS
First Step: exclusion of conditions that resemble AIH
Hereditary
Infectious
Drug induced liver injury
Next step: Laboratory abnormalities
Autoantibodies present
Elevated aminotransferase
AST/ALT (may be in the 30-40 range or as
high as 100-1,000)
Bili (above ULN: if 3-10mg/dL eval for severe
liver disease)
Elevated Gamma Globulins (>2.5g/dL)
May be manifest as elevation in total protein
DIAGNOSTIC CRITERIA SHOULD BE APPLIED TO ALL PATIENTS
IF THE DIAGNOSIS OF AIH IS NOT CLEAR, SCORING SYSTEM SHOULD BE USED
DIFFICULT DIAGNOSIS

Recently, attempts have been made to introduce a

newer, simplified scoring system geared for clinical
practices
Hennes et al. introduced a new scoring system
studied two cohorts of patients: a training set and a
validation set
The training set: 250 patients with definite AIH and 193
controls with other well-defined liver diseases
The validation set: 109 with AIH and 284 controls
Stepwise logistic regression identified the best
predictors for AIH to be ANA and SMA titers, IgG levels,
and liver histology
SIMPLIFIED METHOD
QUESTIONS OF THE NEW
SYSTEM
Remains somewhat arbitrary
Has not been compared to the existing
scoring system
Does emphasize the importance of
excluding viral hepatitis, HAV, HBV,
HCV, HEV
Does it help differentiate overlap syndromes?
Prevalence of Serological Autoimmune Markers
in Subjects With Selected Liver Diseases and
Controls
% positive (no positive/total)

Liver disease ANA SMA AMA

15% (62/413) 34% (126/366) 0.7% (2/269)
chronic HCV
chronic HBV 14% (7/48) 9% (4/47) 0% (0/270)
acute HBV 0% (0/10) 74% (63/85) 0% (0/406)
AIH 69% (154/223) 80% (174/217) 14% (41/298)
cryptogenic 36% (12/33) 33% (10/33) 18% (12/65)
cirrhosis
alcohol-induced 13% (215) 0% (0/16)
5% (1/19)
liver disease
Wilson disease
25% (5/20) 25% (5/20) ND
controls
(no liver disease) 6% (12/200) 3% (7/228) 3% (26/850)

Clifford et al., Hepatology 1995;21:617

Gregorio et al., Clin Exp Immunol 1998;112:472
 AUTOANTIBODIES
ANA (anti nucleic antibodies)
Homogeneous staining pattern
Titers of at least 1:80
ASMA (Anti-Smooth Muscle Antibodies)
Non specific
Titers of at least 1:320
AAA/F-actine (antiactin antibodies)
Generally much more specific
ALKM-1 (Anti Liver Kidney Microsome)
Directed against P450 IID6
Anti-SLA (Soluble Liver Antigen)
Directed against a UGA suppressor or tRNA-associated protein
Not widely available
p-ANCA
Atypical p-ANCA
ALC-1 (anti liver cytosol antibody)
Generally occur with ALKM
Not widely available
ROLE OF LIVER BIOPSY
Determines diagnosis, type of AIH and severity
Aminotransferase/gamma globulin do not
accurately predict the level of
necrosis/damage
Can also detect AIH overlap syndromes
(primary sclerosing cholangitis, Primary biliary
cirrhosis, etc.)
Biopsy can provide alternative diagnosis
(steatosis, iron overload, etc)
 HISTOLOGY

Interface hepatitis (piecemeal necrosis)

Portal plasma cell infiltration
Some degree of fibrosis usually present
Bile duct usually spared (to differentiate)
INTERFACE HEPATITIS AND BRIDGING NECROSIS IN SEVERE TYPE 1
AUTOIMMUNE HEPATITIS
PLASMA CELL INFILTRATION OF THE PORTAL TRACTS IN
TYPE 1 AUTOIMMUNE HEPATITIS
Mott Cell , a full engorged
Plasma cell
DX: AIH
 OFTEN UN REC OG NIZED FEATURES

Differential Diagnosis
Drug-induced Autoimmune Hepatitis
Minocycline Inflixamab
Nitrofurantoin INH
Orlistat Statins (unmask
Meloxicam AIH)
Allopurinol
Aldomet
 CLASSIFICATION
AIH is classified by the type of autoantibody present
Type 1 (classic): antibodies to nuclei (ANA) and/or smooth
muscle (ASMA) or antiactin antibodies (AAA)
Bimodal distribution
Occasionally, antimitochondrial antibodies present
Most common
Type 2: antibodies to liver/kidney microsomes (ALKM-1) and/or
antibodies to liver cytosol antigens (ALC-1)
Predominately younger women
More common in Europe and South America
Type 3?: Antibodies against soluble liver antigen (anti-SLA)
Predominately older patients
No longer considered an independent entity
10% of type 1 AIH have SLA

The clinical implications arising from this subclassification are

uncertain
AUTOIMMUNE OVERLAP/VARIANT SYNDROMES
AMA neg
PBC
polyarteritis
with
Granulomatous
normal ERCP Hepatitis
Microscopic Peri-
Cholangio- cholangitis PBC Mild
pathy idiopathic
IgG 4 ductopenia
2-8% ASC of adulthood
Autoimmune
cholangitis
10%
PSC MastCell
cholangiopathy
Classic 6-25%
Giant Cell Hepatitis
Drug induced AIH Vanishing Bile
AIH Duct Syndrome
hepatitis
11% 1-2%
Autoantibody Eosinophilic Hepatitis
Cryptogenic
negative HCV
hepatitis
Fatty Liver idiopathic HBV
with hepatitis
Central Venulitis
autoantibodies
 OVERLAP SYNDROMES
Patients with AIH may also have features of other
autoimmune liver disease
Primary Biliary Cholangitis
7-14% of PBCholangitis patients will have AIH
Primary sclerosing cholangitis (in children)
Autoimmune cholangitis
MCC or peri-cholangitis
Suspect it when a patient with AIH has:
Pruritus
UC
Bile duct abnormalities on biopsy
Marked elevation in alkaline phosphatase
Despite revisions of the criteria for the diagnosis,
remains difficult to correctly diagnose overlap
syndromes
Cholangiography?
NATURAL HISTORY OF
DISEASE
Morbidity and mortality are high:
Failure of Bilirubin to improve within 2 weeks is a poor
prognostic indicator
Without treatment, 40-50% of patients with severe AIH will
die within 5 years
Cirrhosis develops >40% of survivors who are untreated with
severe AIH
54% of those develop esophageal varices within two
years
20% of those with varices die from hemorrhage
Patients with milder AIH may still develop cirrhosis:
50% within 15 years if untreated
Death from hepatic failure in >10%
Risk of hepatocellular cancer is rare
(0.5% in one study), surveillance every 12 months advised
NATURAL HISTORY OF
DISEASE
Severity of symptoms vary but can include:
Fatigue
RUQ pain
Mild pruritus
Fluctuating course
Spontaneous exacerbations
Spontaneous remissions
 INDICATIONS FOR IMMUNOSUPPRESSIVE
TREATMENT
ABSOLUTE RELATIVE NONE
Serum AST >10 fold ULN Symptoms (fatigue,
arthralgia, jaundice)
Serum AST > 5 fold ULN & Serum AST and/or Gamma
Gamma globulin level > 2 globulin less than absolute
fold ULN criteria
Bridging necrosis or Interface hepatitis
multiacinar necrosis on
histological examination
Incapacitating symptoms Osteopenia, emotional
instability, hypertension,
diabetes,or cytopenia
(white blood cell counts
2.5 109/Lor platelet
counts 50 109/L)
Asymptomatic with normal
or near normal serum
AST and Gamma globulin
levels
Inactive cirrhosis or mild
portal inflammation
(portal hepatitis)
Severe cytopenia (white blood
cell counts <2.5 109/L or
platelet counts <50 109/L)
or known complete deficiency
of TPMT activity precludes
treatment with azathioprine
Vertebral compression,
psychosis, brittle diabetes,
uncontrolled hypertension,
known intolerances
to prednisone or
azathioprine
 CHOICE OF TREATMENT
AASLD recommends either treatment with
corticosteroids alone or with lower dose
steroids and azathioprine
Three randomized, controlled trials between
1971 and 1974 clearly displayed the benefits of
steroids
Generally felt that high dose steroids alone and
combo therapy are equal
Combo therapy allows lower dose steroids, and
lower frequency of side effects
However, there is limited data showing equal
efficacy of high dose steroids vs. low dose and
azathioprine
 TREATMENT MONITORING
A therapeutic response is seen in 80% of
patients, with prednisone and Imuran
Plan to do a liver biopsy, even if normal
liver enzymes every 2-3 years
 TREATMENT END POINTS
Remission is achieved (generally not achieved until 12
months)
Resolution of symptoms, improvement in lab values and
histology
65% achieve initial remission by 18 months
>80-95% achieve initial remission by 3 years
Deemed a treatment failure
Worsening clinical presentation, lab values
(aminotransferase levels increase by 70%) and
histology
5-10% of patients
Remain salvageable using mycophenolate and or
tacrolimus
Development of a liver drug toxicity
Approximately <1% of patients
Prednisone side effects ~15% of patients
 REMISSION
Sustained remission is achieved in 10-40%
of patients.
Sustained remission is defined as:
Resolution of symptoms
Decrease in ALT/AST to less than 0.5xULN =
healthy range
Normalization of bili/alk phos
Improvement in liver histology
Likelihood of relapse after cessation
of therapy is at least 80%
Great majority of patients will require
maintenance therapy
 TREATMENT FAILURE

Liver transplantation
Patients who deteriorate during or after
steroid therapy (development of
encephalopathy, ascites, etc.)
Five year survival > 80%
Usually there is a disappearance of
autoantibodies/hypergammaglobulinemia
within one year
WHAT IF?

What if patient had diabetes?

Not an absolute contraindication to use of steroids (even
if its brittle diabetes)
Low-dose prednisone and azathioprine
Close monitoring
What if patient pregnant?
Treatment deemed probably safe
AIH in pregnancy associated with higher risk of
prematurity, low birth weight and fetal loss
What if the patient is also infected with Hep C?
Treat HCV first with all oral DDA therapy and the
reassess to see if AIH