AUTOIMMUNE HEPATITIS

Gastroenterology Case Conference

Wednesday, March 18, 2009
Hendra Nurjadin
Autoimmune hepatitis
An unresolving inflammation of the liver of
unknown cause.
Characterized by the presence of :
interface hepatitis on histologic examination
Hypergammaglobulinemia
autoantibodies
Diagnosis requires the exclusion of
other chronic liver diseases:

Wilson disease
chronic viral hepatitis
1-anti-trypsin
deficiency
Hemochromatosis
drug-induced liver
disease
nonalcoholic
steatohepatitis
primary biliary cirrhosis
(PBC)
primary sclerosing
cholangitis (PSC)
autoimmune
cholangitis
EPIDEMIOLOGY
white northern Europeans:
incidence :1.9 cases per 100,000 persons per year
prevalence : 16.9 cases per 100,000 persons per year.
United States:
AIH affects 100,000 to 200,000 persons
2.6% of the transplantations in the European Liver Transplant
Registry and 5.9% in the National Institutes of Health Liver
Transplantation Database.
Alaskan natives :
43 per 100,000 population
white Norwegian:
16.9 per 100,000 population
AIH among patients with chronic liver disease in North
America: 11% - 23%.
populations are susceptible to AIH : African Americans,
Brazilians, Argentinians, Arabs, Japanese, and Indians.


PATHOGENESIS

The pathogenic mechanisms of AIH are unknown.
constellation of interactive factors : triggering agent,
genetic predisposition, and various determinants of
autoantigen display, immunocyte activation, and effector
cell expansion.
Triggering factors : infectious agents, drugs, and
toxins.
The CD4+ helper T cell is the principal effector cell
and its activation is the initial step in the pathogenic
pathway.
Liver cell destruction : cell-mediated cytotoxicity or
antibody-dependent cell-mediated cytotoxicity, or a
combination of both mechanisms



CLINICAL FEATURES


CLINICAL FEATURES

CLINICAL FEATURES

CLINICAL FEATURES
SCORING
CRITERIA
of AIH
SCORING CRITERIA of AIH

Pre-treatment score
Definite diagnosis >15
Probable diagnosis 10-15
Post-treatment score
Definite diagnosis >17
Probable diagnosis 12-17
The revised original scoring system performs
better in patients with few or atypical
features of AIH, and the simplified system is
better at excluding the diagnosis in diseases
with concurrent immune manifestations
Sensivity : 100% vs 95%
Specifity : 90% vs 73%
excluding the diagnosis in other diseases with
concurrent immune features : 83% vs 64%
Albert J. Czaja, May 2008

DIAGNOSTIC CRITERIA

The serologic tests essential for diagnosis are assays for
antinuclear antibodies (ANA), smooth muscle antibodies
(SMA), and antibodies to liver-kidney microsome type 1 (anti-
LKM1).
Peri-nuclear anti-neutrophil cytoplasmic antibodies (pANCAs)
are common in type 1 AIH
Antibodies to soluble liver antigen/liver pancreas (anti-
SLA/LP), actin (anti-actin), chromatin (anti-chromatin),
asialoglycoprotein receptor (ASGPR), and liver cytosol type 1
(anti-LC1) associated with severe disease, poor treatment
response, and relapse after drug withdrawal

CLINICAL CRITERIA

The definite diagnosis : exclusion of other similar
diseases
laboratory findings that indicate substantial
immunoreactivity
histologic features of interface hepatitis
A probable diagnosis : findings are compatible with
AIH but insufficient for a definite diagnosis

CLASSIFICATION

Three types of AIH : on the basis of serologic
markers, but only two types have distinctive
serologic profiles.
Variant forms : Patients who have atypical features
of AIH currently lack an official designation and
confident treatment strategy:
manifestations of AIH and another type of chronic liver
disease overlap syndrome
findings that are incompatible with AIH by current
diagnostic criteria outlier syndrome



Classification of
Autoimmune
Hepatitis Based on
Autoantibodies

Variant Forms of Autoimmune Hepatitis
Conventional Repertoire of
Autoantibodies
ANA can be found in primary biliary
cirrhosis, primary sclerosing cholangitis,
chronic viral, hepatitis, drug-related
hepatitis, nonalcoholic steatohepatitis and
alcohol-induced liver disease
ANA are the traditional markers of AIH :
present alone (13%) or with SMA (54%)
in 67% of patients with the disease
SMA are present in 87% of patients with
AIH, either as the sole marker of the
disease (33%) or in conjunction with ANA
(54%)
Anti-LKM1 typically occur in the absence
of SMA and ANA.

LABORATORY INDICES
Serum AST and gamma globulin levels the
severity of disease and immediate prognosis.
Sustained severe derangements poor
outcome unless therapy is started.
Less severe laboratory abnormalities better
prognosis
Spontaneous resolution is possible in 13% to
20% of patients regardless of disease activity.

HISTOPATHOLOGIC FINDINGS


The histologic findings : indices of disease
severity, pattern of liver cell injury
prognostic implication
Inactive cirrhosis develops in 41%.
Hepatocellular carcinoma also can occur in
patients with cirrhosis (small risk)

Precise histological evaluation of liver biopsy
specimen is indispensable for diagnosis and
treatment of acute-onset autoimmune hepatitis
J Gastroenterol 2008; 43:951958
Histological examination of the liver is necessary for
early diagnosis of acute-onset AIH. Moreover, we should
evaluate liver biopsy specimens precisely and should be
ready for a timely initiation of corticosteroid therapy to
improve the prognosis.
KEIICHI FUJIWARA1,2, YOSHIHIRO FUKUDA1,2, and OSAMU YOKOSUKA
PROGNOSTIC INDICES

the severity of liver inflammation at the
initial medical consultation :
the laboratory indices and the histologic
findings
HLA status and ethnicity influence disease
occurrence, clinical phenotype, and treatment
outcome



Prognosis of
Autoimmune
Hepatitis


Treatment Indications in
Autoimmune Hepatitis


Preferred Treatment Regimens
in Autoimmune Hepatitis
TREATMENT END POINTS
Glucocorticoid therapy until remission, treatment failure,
incomplete response, or drug toxicity occurs

Liver biopsy examination before drug withdrawal ensures an
optimal end point.
Improvement of the liver tissue to normal: relapse only 20% after
cessation of treatment.
Improvement to portal hepatitis alone 50% frequency of relapse.
Progression to cirrhosis or persistence of interface hepatitis 100%
frequency of relapse.
The presence of plasma cells within the portal tract persistent
immune reactivity and the propensity for relapse
End Points of Initial Treatment and
Courses of Action
Remission
the absence of symptoms, resolution
of inflammatory indices and histologic
improvement to normal or minimal
activity.

TREATMENT FAILURE
deterioration during therapy (9%)
It is characterized by worsening of the serum
AST or bilirubin levels by at least 67% of
previous values, progressive histologic activity,
or onset of ascites or encephalopathy.
Conventional glucocorticoid therapy should be
stopped, and a high-dose regimen should be
instituted.


INCOMPLETE RESPONSE
13% : clinical improvement but the findings
do not satisfy remission criteria
A low-dose prednisone regimen and the
administration of azathioprine (2 mg/kg
daily) as the sole drug are reasonable
approaches.
The goal of treatment is to reduce and
stabilize disease activity
DRUG TOXICITY
For patients with serious side effects from
therapy, treatment usually can be
continued with the single tolerated drug
(prednisone or azathioprine) in an
adjusted dose
Cyclosporine, 6-mercaptopurine, and
cyclophosphamide also have been used
successfully after drug toxicity in isolated
cases
LIVER TRANSPLANTATION
Liver transplantation is effective in the treatment of
decompensated AIH
Five-year survival rates for patients and grafts range
from 83% to 92%, and the actuarial 10-year survival
rate after transplantation is 75%.
Autoimmune hepatitis recurs in at least 17% of patients,
and AIH develops de novo in 3% to 5% of patients
undergoing transplantation for nonautoimmune liver
disease.
Acute rejection, glucocorticoid-resistant rejection, and
chronic rejection occur more commonly in patients
undergoing transplantation for AIH
RELAPSE
Relapse occurs in 50% within 6 months, and most patients
(70% to 86%) experience exacerbation within 3 years.
The major consequence of relapse and retreatment is the
development of drug-related complications (70% of those
who have multiple relapses and retreatments)
Patients who have had at least two relapses should be
given either low-dose prednisone or azathioprine as the
sole drug
87% can be managed long term on prednisone at less than 10 mg
per day (median dose, 7.5 mg per day).
Continuous azathioprine therapy (2 mg/kg per day) is an
alternative strategy that can be used in patients who are
not severely cytopenic.
83% remain in remission for up to 10 years
Recurrent AIH
typically is mild and develops in patients
who are inadequately immunosuppressed.
Dose adjustments usually are sufficient to
suppress the disease, but progression to
cirrhosis and graft failure have been
reported
THANK YOU

AND

GOOD DAY