Transcript Autoimmune Hepatitis

Autoimmune Hepatitis
Residents Conference
5/31/2005
Michael Le, MD
Overview
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Prevalence
Clinical manifestations
Pathogenesis
Subtypes
Diagnosis
Prognostic indices
Treatment
Autoimmune Hepatitis
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self-perpetuating hepatocellular inflammation
unknown cause
characterization:
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histologic features of interface hepatitis
hypergammaglobulinemia
serum autoantibodies
affects all ages, may be asymptomatic, frequently
has an acute onset, and can also present as
fulminant hepatitis.
Prevalence
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Mean annual incidence among white northern Europeans:
1.9 cases per 100,000 per year
US: 100,000-200,000 people
W>M 3.6:1, unexplained.
all ages, ethnic groups.
Frequency of AIH among pts with chronic liver disease in
North America is 11-23%
Accounts for 5.9% in the National Institutes of Health
Liver transplantation database.
Prevalence of AIH is greatest among northern European
white groups who have a high frequency of HLA-DR3 and
HLA-DR4
Clinical manifestations
Pathogenesis
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Unknown mechanism
Most popular hypotheses: interactive factors:
Triggering agent
 A genetic predisposition
 various determinants of autoantigen display
 immunocyte activation
 effector cell expansion.
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Pathogenesis
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Triggering agents
infectious agents, drugs, toxins.
 Multiple agents suggest that triggering epitope is a
short amino acid sequence that is common in many
antigens.
 Possible long lag time b/w exposure to the trigger
and onset of the disease
 Triggering factor may not be needed for
perpetuation of the disorder.
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Pathogenesis
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Loss of self-tolerance –
molecular mimicry of a foreign antigen
 self antigen
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Only the cytochrome monooxygenase P-450 IID6
(CYP2D6) has been recognized as an autoantigen.
multiple self-antigens or foreign antigens may
satisfy the minimal structural requirements and
serve as immunogenic peptides
Pathogenesis
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genetic predisposition
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Susceptibility HLA allelles encoding MHC class II:
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influences the presentation of these autoantigens to CD4+ helper T cell thereby
initiating an immune response.
the initiation of the immune response is dependent on the antigen binding groove
of the class II MHC molecule. The sequence of amino acids that make up this
antigen binding groove is encoded by a person’s HLA alleles. Thus, there are
specific alleles that make a person more susceptible to developing AIH by
influencing the immune response, and in turn the clinical manifestations and
behavior of AIH.
Autoimmune promoters:
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polymorphisms for TNF-α gene and cytotoxic T lymphocyte antigen 4 gene have
been associated with increased immune reactivity and disease severity of AIH type
I
Other: Vitamin D receptor (VDR) gene, point mutation of the tyrosine
phosphatase CD45 gene, polymorphisms of the Fas gene, MHC class 1 chainrelated A gene.
APC
MHC
Class II
CD4
Peptide
Antigen
Cytokines
TCR
CD4 T Cell
DRB1 gene
L
L
E Q
K
R
lysine
DRB1 gene
L
L
E Q
R
R
arginine
Pathogenesis
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Mechanism of Liver cell destruction via
cellular and humoral mechanisms
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Cell-mediated cytotoxicity
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Antibody-dependent cell-mediated
cytotoxicity
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TH1 response (IL-2, IFN-γ, TNF-α) 
clonal expansion of cytotoxic T
lymphocytes that infiltrate and destroy
hepatocytes.
Genetic polymorphism that affects TNF production may facilitate this pathway.
TH2 response (IL-4,5,6,8,10,13)  B cell
stimulation  Ab production
immunocyte complexes on hepatocyte
surface  targeted by NKT cells
Anti-inflammatory effects that counters
TH1 action
Combination of mechanisms
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Predominant mechanism depends on the
phenotypic differentiation of CD4+
helper T cell, which in turn reflects the
cytokine milieu, which in itself reflects
the polymorphisms of the cytokine genes
that favor excessive production of some
modulators, such as TNF-, or deficient
in others.
AIH subtypes
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AIH type 1
AIH type 2
AIH type 3
on the basis of immunoserologic markers.
The International Autoimmune Hepatitis Group
has not endorsed this subclassification.
Used mainly for descriptive value
AIH type 1
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Most common form worldwide
characterized by the presence or absence of SMA and/or
ANA in serum
Surrogate markers: Perinuclear antineutrophil cytoplasmic
antibodies which occur in PSC and chronic UC, are found
in 90% of patients who have type 1 AIH.
Bimodal age distribution (10-20; 45-70)
Female:male 3.6:1
Risk factors for type 1 AIH
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in whites of northern European descent [HLA-DR3 (DRB1*0301)]
and –DR4 (DRB1*0401)]
AIH type 1
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Associated with concurrent extrahepatic diseases
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Autoimmune thyroiditis (12%)
Graves disease (6%)
Chronic UC (6%) * (cholangiography to exclude PSC)
<1% RA, pernicious anemia, systemic sclerosis, Coomb’s test-positive HA,
ITP, symptomatic cryoglobulinemia, leukocytoclastic vasculitis, nephritis,
erythema nodosum, SLE, fibrosing alveolitis.
40% of AIH type 1 presents with an acute onset of symptoms/signs
indistinguishable from that of acute viral or toxic hepatitis and the
disease may appear fulminant in fashion.
target autoantigen is unknown, but ASGPR (asialoglycoprotein
receptor) found on hepatocyte surface is a candidate
Responds well to glucocorticoids
AIH type 2
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Characterized by presence of anti-LKM1 (liver/kidney microsome type 1) in serum
P-ANCA is not found
Mainly children (2-14 yo) but also seen in adults (in Europe, 20% of pts are adults; in US,
4% of pts are >18 yrs)
Only AIH with an identified target autoantigen: cytochrome monooxygenase P-450 IID6
(CYP2D6) found in the cytosol of hepatocytes.
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Acute or fulminant presentation is possible
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Recognized homologies b/w epitopes of CYP2D6 and genome of HCV.
<10% of Europeans with chronic Hep C have detectable anti-LKM1
Suggests molecular mimicry and antibody crossreactivity, multiple exposures to virus mimicking
self may be a way to break self-tolerance and induce AIH type 2.
Anti-LKM1 + pts with chronic Hep C in US pts is rare – differences in indigenous virus or host
susceptiblity?
Thus essential to screen all pts who have an acute decompensation for type-specific
autoantibodies.
Associated with HLQA-B14, -DR3, -C4A-QD
Susceptibility factor in German and Brazilians: DRB1*07
Like AIH type 1, also responds well to glucocorticoids
AIH type 2
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Distinct form of anti-LKM positive AIH
Occurs in association with autoimmune polyendocrinopathy disorder
(APECED) aka Polyglandular autoimmune syndrome type I (APS1)
rare autosomal recessive disorder
Caused by a signal gene mutation of the APS1 gene which encodes a
transcription factor, autoimmune regulator (AIRE) which is expressed
in epithelial and dendritic cells within the thymus where it regulates
clonal deletion of autoreactive T cells, thus can affect self tolerance
Features of this disease are ectodermal dystrophy, mucocutaneous
candidiasis, multiple endocrine gland failure (parathyroids, adrenals,
ovaries)
Marked by the presence of numerous organ and non-organ specific
autoantibodies and multiple concurrent autoimmune diseases.
most common among Finns, Sardinians, and Iranian Jews
Pts with APECED and AIH have an aggressive liver disease that does
not respond well to standard immunosuppressive regimens.
AIH type 3
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Least established form of the disease
Designation largely abandoned
Characterized by presence of antibodies to soluble liver
antigen and liver/pancreas (anti-SLA, anti- LP)
30-50 yo
Target autoantigens: thought to be Glutathione Stransferase, but a transfer ribonucleoprotein (tRNP) 50-kd
protein was described in 2000 as the more likely target.
Clinical and laboratory features that are indistinguishable
from AIH type 1
Also responds well to glucocorticoids
AIH subtypes
Variant forms
Diagnosis
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Determination of serum aminotransferase and –
globulin levels
Rule out ddx
Detection of ANA and /or SMA, or in their
absence, anti-LKM1
Liver tissue examination
Diagnosis
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Determination of serum aminotransferase and –globulin
levels
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Predominant serum aminotransferase abnormality
Hypergammaglobulinemia (definite dx: ≥1.5; probable dx: any
degree below)
exclusion of other chronic liver diseases that have similar
features
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hereditary causes: (Wilson disease, alpha1-antitrypsin deficiency,
genetic hemochromatosis
Infectious causes: chronic viral hepatitis A, B, C
drug-induced liver disease (ETOH, minocycline, nitrofurantoin,
INH, propylthiouracil, methyldopa)
NASH
immune cholangiopathies of PBC, PSC, autoimmune cholangitis
Diagnosis
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Detection of ANA and /or SMA, or in their absence, anti-LKM1
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conventional immunoserologic tests for AIH:
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antinuclear antibodies (ANA),
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smooth muscle antibodies (SMA),
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Directed against actin and nonactin components (tubulin, vimentin, desmin,
skeletin)
present (87%), sole marker (33%), with ANA (54%)
antibodies to liver/kidney microsome type 1 (anti-LKM1)
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present alone (13%), along with SMA (54%)
also be found in PBC, PSC, chronic viral hepatitis, drug-related hepatitis, NASH,
alcohol-induced liver disease
Typically occurs in absence of SMA and ANA
rare in the US (4% of adults with AIH in US)
perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs) are common in
type 1 AIH,
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useful in evaluation patients who lack conventional autoantibodies.
Used to reclassify patients with cryptogenic chronic hepatitis as AIH, but they have
not been formally assimilated into the diagnostic algorithm
Do not have diagnostic specificity nor do they have prognostic implications.
Diagnosis
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Detection of ANA and /or SMA, or in their absence, antiLKM1
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NEW antibodies:
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investigational in nature, but sufficient promise to support a probable
diagnosis, not generally available, assays are not standardized
actin (anti-actin)
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asialoglycoprotein receptor (anti-ASGPR)
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transmembrane glycoprotein on the hepatocyte surface which can capture,
internalize, display potential antigens
Seen in AIH type 1
soluble liver antigen/liver-pancreas (A),
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has less sensitivity, but greater specificity than SMA for AIH type 1
Seen in AIH type 3
used to reclassification of patients with cryptogenic chronic hepatitis as AIH
liver cytosol type 1 (anti-LC1).
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Have been proposed as an antigenic target.
Seen in AIH type 2
Prevalence is higher in pts < 20, Rare in pts >40
Diagnosis
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Liver tissue examination
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Liver bx is essential to establish diagnosis and assess disease severity to determine
need for treatment
histologic features of interface hepatitis (hallmark of the syndrome)
portal plasma cell infiltration typifies the disorder
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lack of portal plasma cell infiltration does not preclude dx
1999 update: lobular hepatitis is now part of histologic spectrum
aminotransferase and gamma-globulin levels do not predict histologic pattern of
injury or the presence or absence of cirrhosis.
Histologic changes, such as ductopenia or destructive cholangitis, may indicate a
variant syndrome of AIH and PSC, AIH an PBC, or autoimmune cholangitis.
Findings of steatosis or iron overload may suggest alternative diagnoses:
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NASH
Wilson disease
Chronic Hep C
Drug toxicity
genetic hemochromatosis
Interface hepatitis
Diagnosis
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Liver tissue examination
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Liver bx is essential to establish diagnosis and assess disease severity to determine
need for treatment
histologic features of interface hepatitis (hallmark of the syndrome)
portal plasma cell infiltration typifies the disorder
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lack of portal plasma cell infiltration does not preclude dx
1999 update: lobular hepatitis is now part of histologic spectrum
aminotransferase and gamma-globulin levels do not predict histologic pattern of
injury or the presence or absence of cirrhosis.
Histologic changes, such as ductopenia or destructive cholangitis, may indicate a
variant syndrome of AIH and PSC, AIH an PBC, or autoimmune cholangitis.
Findings of steatosis or iron overload may suggest alternative diagnoses:
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NASH
Wilson disease
Chronic Hep C
Drug toxicity
genetic hemochromatosis
Plasma cell infiltration
Diagnosis
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Liver tissue examination
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Liver bx is essential to establish diagnosis and assess disease severity to determine
need for treatment
histologic features of interface hepatitis (hallmark of the syndrome)
portal plasma cell infiltration typifies the disorder
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lack of portal plasma cell infiltration does not preclude dx
1999 update: lobular hepatitis is now part of histologic spectrum
aminotransferase and gamma-globulin levels do not predict histologic pattern of
injury or the presence or absence of cirrhosis.
Histologic changes, such as ductopenia or destructive cholangitis, may indicate a
variant syndrome of AIH and PSC, AIH an PBC, or autoimmune cholangitis.
Findings of steatosis or iron overload may suggest alternative diagnoses:
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NASH
Wilson disease
Chronic Hep C
Drug toxicity
genetic hemochromatosis
Lobular Hepatitis
Diagnosis
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Liver tissue examination
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Liver bx is essential to establish diagnosis and assess disease severity to determine
need for treatment
histologic features of interface hepatitis (hallmark of the syndrome)
portal plasma cell infiltration typifies the disorder





lack of portal plasma cell infiltration does not preclude dx
1999 update: lobular hepatitis is now part of histologic spectrum
aminotransferase and gamma-globulin levels do not predict histologic pattern of
injury or the presence or absence of cirrhosis.
Histologic changes, such as ductopenia or destructive cholangitis, may indicate a
variant syndrome of AIH and PSC, AIH an PBC, or autoimmune cholangitis.
Findings of steatosis or iron overload may suggest alternative diagnoses:
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NASH
Wilson disease
Chronic Hep C
Drug toxicity
genetic hemochromatosis
PBC
PSC
Diagnosis
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Liver tissue examination
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Liver bx is essential to establish diagnosis and assess disease severity to determine
need for treatment
histologic features of interface hepatitis (hallmark of the syndrome)
portal plasma cell infiltration typifies the disorder
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



lack of portal plasma cell infiltration does not preclude dx
1999 update: lobular hepatitis is now part of histologic spectrum
aminotransferase and gamma-globulin levels do not predict histologic pattern of
injury or the presence or absence of cirrhosis.
Histologic changes, such as ductopenia or destructive cholangitis, may indicate a
variant syndrome of AIH and PSC, AIH an PBC, or autoimmune cholangitis.
Findings of steatosis or iron overload may suggest alternative diagnoses:
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NASH
Wilson disease
Chronic Hep C
Drug toxicity
genetic hemochromatosis
Diagnostic Criteria
Scoring System
Prognosis
Prognosis
Prognosis
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40% develop with cirrhosis
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54% develop esophageal varices w/in 2 years
20% die from variceal hemorrhage if they don’t receive any treatment
hepatocellular carcinoma can occur in this pts but risk is small.
Presence of ascites or hepatic encephalopathy identifies pts with a poor
prognosis.
13-20% of patients can have spontaneous resolution regardless of
disease activity.
A critical determinant of survival in the untreated patient is early
tolerance of the disease.
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Of pts who survive the early, most active stage of the disease, inactive
cirrhosis develops in 41% of pts.
Untreated patients who have initial severe disease and survive the first 2
years of illness typically survive long term
When to treat
Treatment
Treatment
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Prednisone alone is appropriate for
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Combination regimen is appropriate:
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severe cytopenia,
undergoing a short treatment trial (< 6 months),
pregnant or contemplating pregnancy,
active malignancy
thiopurine methyltransferase deficiency.
for pts who will be treated continuously for at least six months
for pts at increased risk for drug-related complications (postmenopausal women, individuals
with emotional instability, osteoporosis, brittle diabetes, labile hypertension
if receiving prednisone, pts should periodically undergo eye exams for cataracts,
glaucoma
if receiving azathioprine, pts should be monitored for leucopenia and thrombocytopenia.
Recommend adjunctive therapies when individual risks are perceived:
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regular program of exercise, calcium and vitamin D supplementation, hormonal replacement
therapy may help preserve bone density.
For pts with osteopenia: consider Bisphosphonates:
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alendronate 10 mg/day,
etidronate 400 mg/day for 2 weeks q 3 months
Indication for liver transplantation
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Pts’ with ascites and hepatic encephalopathy identifies pt’s with poor
prognosis. They can still respond to glucocorticoid therapy and should be
treated before a decision regarding liver transplantation is made.
Indicated in decompensated pt with hepatic encephalopathy, ascites, and/or
variceal hemorrhage during therapy for treatment failure
When decompensated patient with multilobular necrosis have at least one
laboratory parameter that fails to normalize or hyperbilirubinemia that does
not improve during a 2 week treatment period, the immediate mortality rate is
high and evaluation for liver transplantation is warranted.
Effective in pts who deteriorate during or after corticosteroid tx.
After transplantation, the autoantibodies and hypergammaglobulinemia
disappear within 2 years
the 5 year survival rate is 96%. Actuarial 10 year survival 75%
Recurrent disease after transplantation is common but has been described
mainly in patients who have inadequate immunosuppression.
RARE cases (3-5%) pts can develop AIH de novo after undergoing
transplantation for non-autoimmune liver disease. Immunosuppression with
CyA is a common feature. TX with prednisone or azathioprine is effective.
Treatment endpoints
Drug-related side effects
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Regardless of regimen, facial rounding, dorsal hump formation,
obesity, acne or hirsutism occur in 80% of pts after 2 years.
18 months on higher dose prednisone (20 mg/day)  osteopenia with
vertebral compression, diabetes, cataracts, emotional lability,
hypertension
Protracted therapy, especially retreatment after relapse is associated
with increase risk of complications.
Azathioprine 50 mg/day: 10% of pts can be complicated by cholestatic
hepatotoxicity, veno-occlusive disease, pancreatitis, nausea, emesis,
rash, and cytopenia
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Avoided in pts contemplating pregnancy, or is pregnant b/c of theoretic
risk of teratogenicity.
Side effects will reverse if dose is reduced or termination of therapy
Treatment can usually be continued with single tolerated drug
(prednisone or azathioprine) in an adjusted dose.
Relapse
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Frequency of relapse:
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Pt’s who had 2 relapses require indefinite therapy with either low dose
prednisone (10 mg/day or less) or azathioprine (2 mg/kd/day).
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50% within 6 months, and most 70-86% experience exacerbation within 3
years.
20% - improvement to normal tissue after cessation of treatment:
50% -improvement to portal hepatitis
100% - Progression to cirrhosis or persistence of interface hepatitis
Lowest dose prednisone possible (usually 10 mg daily or less) to prevent
symptoms and maintain serum aminotransferase below 5-fold normal
Prednisone and azathioprine regimens have not been compared directly
and there is no objective basis for preferring one to the other.
In 2000, mycophenolate mofetil was reported pts resistant to or
intolerant of azathioprine, but future studies needed.
New Therapies
AIH Summary
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self-perpetuating hepatocellular inflammation of unknown cause
Genetic predispostion
Diverse clinical features
3 subtypes AIH and variants
Dx:
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interface hepatitis
 hypergammaglobulinemia
 serum autoantibodies
 Rule out other liver diseases
Consider in all pts with acute & chronic liver diseases and those with allograft
dysfunction after transplantation
Prednisone, Azathioprine
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Evolving treatment options
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Is it over
yet?
References
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Sleisenger & Fordtran’s Gastrointestinal and Liver
Disease, Pathophysiology, Diagnosis, Management. 7th
Edition. Feldman, Friedman, Sleisenger. Chapter 75.
Autoimmune Hepatitis.
www.uptodateonline.com. Keyword: Autoimmune
hepatitis.
“Current Concepts in Autoimmune Hepatitis”. Czaja,
Albert J. Annals of Hepatology 2005: 4(1): JanuaryMarch:6-24
“Treatment Challenges and Investigational
Opportunities in Autoimmune Hepatitis”. Czaja, Albert
J. Hepatology 2005:41:207-215.