Transcript AILD - AGA - CCRMC Wiki

Autoimmune Hepatitis
Thomas Hargrave M.D.
November 20, 2009
Autoimmune Hepatitis
Autoimmune Hepatitis
Autoimmune Hepatitis
Intermittently progressive
inflammatory liver disease
of presumed autoimmune
etiology
 High gamma globulins,
autoantibodies
 Predominately periportal plasma
cell hepatitis
 Usually responds favorably to
corticosteroids or
immnomodulators
Often Unrecognized Features
Autoimmune Hepatitis
Autoimmune Hepatitis
 First described by Waldenstrom in 1950 in a
young woman with idiopathic chronic hepatitis
 Now recognized as a chronic multisystem
disorder that occurs in males and females of
all ages.
 AIH can co-exist with other liver diseases
(hepatitis C) and can be triggered by drugs
(minocycline) and herbal agents
Often Unrecognized Features
Autoimmune Hepatitis
Autoimmune Hepatitis
 Annual incidence in North America of
1.9/100,000
 Prevalence 16.9/100,000
 Accounts for 6% of liver transplantations
 Affects all ages and ethnic groups
 70-80% of AIH are women but men may
predominate over the age of 70
Often Unrecognized Features
Autoimmune Hepatitis
Autoimmune Hepatitis
 Characterized by considerable heterogeniety
and fluctuating disease activity over time
 Liver injury is the result of cell-mediated
immunologic attack against genetically
predisposed hepatocytes
 HLA association with B8, B14,DR3,Dr4, Dw3
 There is little evidence that the autoantibodies
have a role in the pathogenesis of AIH
Clinical Features
Autoimmune Hepatitis
Clinical Features: Classic
 Middle-aged (or teenage) woman, non-drinker
without viral hepatitis
 Fatigue, arthralgias/myalgias, oligomenorrhea,
jaundice
 Increased ALT, AST, gamma globulins
 Positive ANA and SMA
 Interface hepatitis with lymphoplasmacytic
infiltrate
 Responds to corticosteroids
Clinical Features
Autoimmune Hepatitis
Clinical Features: Highly Variable
 Asymptomatic abnormal LFTs: up to 50%
 Acute hepatitis 18-30%
 Chronic fatigue, viral-like illness
 Fulminant hepatic failure (rare)
 Many patients found to have established
cirrhosis during initial acute presentation (20%)
 Long periods of sub-clinical disease may occur
both before and after presentation
Often Unrecognized Features
Autoimmune Hepatitis
Often Unrecognized Features
 May occur in men, children, or elderly
 Auto-antibodies may be absent or only transient
 Responses to immunosuppressive therapy may
be delayed or inadequate
 May have an acute presentation with no
laboratory, clinical or histological features
indicating chronicity
Autoimmune Hepatitis
Differential Diagnosis: Acute Hepatitis
 Viral Hepatitis
 Drug induced
 Herbal medications
 Wilson’s Disease:
F:M 4:1, KF Rings, Ceruloplasmin<20
 Cirrhosis
 Chronic active hepatitis,
 Fulminant hepatic failure.
Autoimmune Hepatitis
Often Unrecognized Features
Differential Diagnosis
 Drug-induced Autoimmune Hepatitis
 Minocycline
 Nitrofurantoin
 Orlistat
 Meloxicam





Inflixamab
INH
Statins (unmask AIH)
Allopurinol
Aldomet
 Herbal medications





Black cohosh
Chaparral leaf
Kava Kava
Valerian
St. John’s Wort
 Echinacea
 Noni Juice
Sub-Types of Autoimmune Hepatitis
Autoimmune Hepatitis
Sub-Types of Autoimmune Hepatitis
Type 1
Type 2
Age at Presentation
Any age
Predominantly
children
Female:Male
4:1
8:1
Ig G Levels
Elevated IgG
Variable Ig G
Ig A Levels
Normal
+/- Low IgA
Auto-antibodies
ANA, SMA
LKM-1
Cirrhosis at 3 yrs
~ 40%
~ 80%
Auto-Antibodies in AIH
Autoimmune Hepatitis
Auto-Antibodies in AIH
Antibody
Target Antigen
Prevalence
ANA
Multiple nuclear
proteins
60-80%
SMA
Actin
60-80%
pANCA
Lactoferrin, Other
unknown antigen
65-90%
LKM-1
CYP 2D6
≈ 4% US/20% EU
SLA/LP
UGA repressor
tRNA-associated
protein
10-30% (high
specificity)
Other Causes of AIH-Associated Auto-Antibodies
Autoimmune Hepatitis
Other Causes of AIH-Associated Auto-Antibodies
Other Disease
Associations
Drug
ANA
PBC, PSC, HCV,
NAFLD
nitrofurantoin,
minocycline and methyldopa
SMA
HCV, NAFLD,
Acute viral
hepatitis
nitrofurantoin,
methyldopa and germander
pANCA
PSC, PBC
propylthiouracil,
and minocycline
LKM
HCV
dihydralazine, halothane and
ticrynafen
SLA/LP
HCV
Antibody
Prevalence of ANA in Liver Disease
Autoimmune Hepatitis
Prevalence of ANA in Liver Disease
100
80
60
%
Positive
40
20
0
AIH
PBC
PSC NAFLD HCV
HBV
ALD
Utility of ANA Testing in Patients with Elevated Transaminases
Autoimmune Hepatitis
ANA Testing in Patients with Elevated
Transaminases Has Low Specifcity
Percent
ANA (+)
80
200
60
150
40
ANA (+) Patients
/ 100,000
100
20
50
16
0
0
AIH
NAFLD
HCV
*Sem. Liv. Dis 2002, 22:339 Amer. J. Gastro 2004, 99:1316 Hepatology 1995, 21:613
**J. Gastro. Hepatol. 2003 18:1118 Hepatology 2004, 40:1387 NEJM 1999, 341:556
Recognition and Diagnosis of AIH
Autoimmune Hepatitis
Extrahepatic Manifestations
 Concurrent immunologic disease present in 38%
of patients with AIH
 Celiac disease 10%
 Thyroiditis/ Graves Disease
 Ulcerative Colitis
 Uveitis
 Rheumatoid arthritis
 Up to 18% overlap syndromes: AIH/PBC, AIH/PSC
Recognition and Diagnosis of AIH
Autoimmune Hepatitis
Diagnosis of AIH
 Should be considered in patient with elevated
AST/ALT or cirrhosis of uncertain etiology
 The diagnosis of AIH must be based on a
constellation of clinical and lab findings
 ANA, SMA and other autoantibody tests are
poor “screening tests”
 A diagnosis of AIH is often a “work in progress”
Autoimmune Hepatitis
Laboratory Features
 In general, transaminase elevations (5-10x) are more
impressive than alkaline phosphatase or bilirubin
elevations: Alt averages 200-300 U/L
 Occasional cholestatic presentation with high
conjugated bilirubin and alkaline phosphatase
 IgG polyclonal hypergammaglobulinemia almost
universal: AIH highly improbable with normal globulins
 Gamma globulin typically 3-4 g/dl
 IgA deficiency common in children with both type I and
type II AIH
IgG Polyclonal
Hypergammaglobulinemia
Criteria for Definite Autoimmune Hepatitis
Autoimmune Hepatitis
Criteria for Definite Autoimmune
Hepatitis
 Elevated AST, ALT, IgG
 ANA, SMA or anti-LKM-1 ≥ 1:80 (≥ 1:20 in children)
 Liver biopsy showing interface hepatitis with no biliary
lesions, granulomas, or prominent steatosis
 Absence of:
 Genetic liver disease
 HCV RNA
 HBV DNA, IgM anti-HAV
 Alcohol, drugs, toxins
International AIH Scoring System
 Female sex
 ALP/ALT Ratio
 <1.5:
 1.5-3.0:
 >3.0:
 Globulinn
 >2x:
 1.5-2.0x:
 1.0-1.5X:
 ANA/ASMA/LKM
 >1:80
 1:80:
 1:40
 <1:40
 AMA +
+2
+2
0
-2
+3
+2
+1
+3
+2
+1
0
-4




Negative HBV/HCV
ETOH < 25gm/d
Other autoimmune
Response to steroids
 Complete
 Relapse
 Liver Biopsy
 Interface hepatitis
 Lymphoplasmacytic
 Neither
+1
+2
+2
+2
+3
+3
+1
-5
Pre-treatment
Score > 15 : Definite AIH (>17 post-Rx)
Score 10-15: Prob. AIH (12-17 post-Rx)
Recognition and Diagnosis of AIH
Autoimmune Hepatitis
Diagnosis of AIH
 Liver biopsy essential in confirming the
clinical diagnosis of AIH and stage degree
of liver injury
 Interface hepatitis is the hallmark of the disease
 Plasma cell infiltration typical
 Neither finding is disease specific
 Absence of plasma cells does not exclude the
disease
Not All Cases With ANA Will Have Autoimmune Hepatitis
Not All Cases With ANA Will Have Autoimmune Hepatitis
ANA positive
steatohepatitis
ANA positive,
Near normal biopsy
Dig Dis Sci 2003; 48:2173
Interface Hepatitis of AIH
 Portal tract
expanded with
mononuclear
inflitrate
 Limiting plate
disrupted
 Inflammation
extends into acinus
Portal Tract Inflammation Histology
Plasma
cells
Plasma cell
cluster;
occasional
eosinophils
Natural History of Untreated Autoimmune Hepatitis
Autoimmune Hepatitis
Natural History of Untreated Autoimmune
Hepatitis
100
80
%
Survival
60
40
20
0
0
1
2
3
Years of follow-up
Kirk AP, Jain S, Pocock S, Thomas HC & Sherlock S, Gut, 1980, 21:78
4
5
Autoimmune Hepatitis
10-Year Survival for Treated AIH 90%
Autoimmune Hepatitis
Treatment
 Appropriate management can:
 Improve quality of life
 Prolong survival/ Delay need for liver
transplant
 Treated patients have a life-expectancy similar
to age and gender matched controls followed
up to 20 years
 After > 3 decades, prednisone and
azathioprine remain the mainstays of
treatment
AASLD Practice Guidelines, Hepatology 2002, 36:479
Indications for Treatment Based on the results of
Autoimmune Hepatitis
Indications for Treatment
Absolute
Relative
None
AST  10x normal
Symptoms
No symptoms
AST  5x normal
and -globulin
 2x normal
AST < 5x normal
-globulin
< 2x normal
Inactive
cirrhosis
Bridging necrosis
Interface
hepatitis
Portal hepatitis
AASLD Practice Guidelines, Hepatology 2002, 36:479
Therapy in Adults
Autoimmune Hepatitis
Therapy in Adults
Combination
Therapy
Monotherapy
Interval
Prednisone
Prednisone
Azathrioprine
mg/d
mg/d
mg/d
Week 1
60
30
50
Week 2
40
20
50
Week 3
30
15
50
Week 4
30
15
50
Daily until
endpoint
20
10
50
AASLD Practice Guidelines, Hepatology 2002, 36:479
Reasons for Selecting Treatment Regimens
Autoimmune Hepatitis
Reasons for Selecting Treatment Regimens
Prednisone Monotherapy
Combination (Pred+Aza)
 Severe cytopenia
 Postmenopausal state
 TPMT deficiency
 Osteoporosis
 Prior Aza intolerance
 Brittle diabetes
 Pregnancy
 Obesity
 Malignancy
 Acne
 Emotional lability
 Hypertension
AASLD Practice Guidelines, Hepatology 2002, 36:479
Autoimmune Hepatitis
Reasons for Selecting Treatment Regimens
Toxicity of Azathioprine/6-MP
 The toxicity of AZA/6-MP is related to their
metabolites
 Two important enzymes
 Thiopurine methyltranferase (TPMT)
 Hypoxanthine phosphoribosyl tranferase (HPRT)
 The toxicity of AZA/6-MP is predominantly related to
the activity of TPMT
 11% of the population is heterozygous and 0.3%
homozygous for TPMT deficiency
 Testing for TPMT before initiating AZA/6MP
becoming the standard of care
AASLD Practice Guidelines, Hepatology 2002, 36:479
HPRT
TPMT
Autoimmune Hepatitis
Response To Treatment
Definition of Remission
 90% of adults have improvement in bilirubin,
transaminases, and globulin levels within 2
weeks
 Histologic improvement lags behind laboratory
improvement by 3-6 months
 Remission is rarely achieved in less than 12
months
 65% remission at 18 months
 80% remission at 3 years
 13% partial response
 9% treatment failure
Definition of Remission
Autoimmune Hepatitis
Definition of Remission
All of the following:
 Disappearance of symptoms
 Normal serum bilirubin, -globulin
 AST, AST < 2x normal
 Normal hepatic histology or
minimal inflammation, no interface
hepatitis
Maintenance Therapy
Autoimmune Hepatitis
Maintenance Therapy
 Lowest effective dose for Prednisone ≤ 10 mg/d
or
 Azathioprine, 1.5-2.0 mg/kg/d
or
 Low dose Prednisone ≤10mg/d plus Azathioprine 50 mg/d
 Add Vitamin D (50,000 U/wk) and Ca (1-1.5 g/d) to
Prednisone
 Monitor for hypertension, cataracts, glaucoma,
bone disease in Prednisone recipients
 Monitor WBC, platelets in Azathioprine recipients
Autoimmune Hepatitis
Maintenance Therapy
 Prednisone taper 2.5 mg/mo. until lowest
dose reached which maintains clinical
remission
 87% can be maintained on </= 10 mg/day
 Azathioprine 2.0 mg/kg monotherapy also
87% effective in maintaining remissions for
up to 67 months
Autoimmune Hepatitis
Should Therapy Be Discontinued?
 Once remission is achieved steroids should first
be tapered and eventually discontinued, followed
by azathioprine 50 mg/12 weeks
 Between 10-40% can be withdrawn from
treatment for up to 5 years
 Liver biopsy assessment is preferred, but not
essential, prior withdrawing patients from
therapy
 Relapse occurs in 20-90% of AIH depending on
the histologic findings at time of withdrawal
End of Therapy Liver Histology Predicts Relapse
Autoimmune Hepatitis
End of Therapy Liver Histology Predicts Relapse
Normal Histology
Interface Hepatitis
Inactive Cirrhosis
Portal Plasma Cells
0
20
40
60
80
100
Risk of Relapse (%)
Czaja, AJ, Davis, GL, Ludwig, J, Taswell, HF. Hepatology 1984, 4:622
Czaja, AJ, Carpenter, HA. Liver International 2003, 23:116
Options When Conventional Treatments Fail
Autoimmune Hepatitis
Options When Conventional Treatments Fail
Treatment failures:
 Prednisone 60 mg/d or Prednisone 30 mg/d +
Azathioprine 150 mg/d
Drug intolerance or treatment failure:
 Mycophenolate mofetil (1 g BID)
 Tacrolimus (4 mg BID, trough level = 6-10 ng/ml)
 Cyclosporin (5-6 mg/kg/d, trough level = 200-250 ng/ml)
Heneghan MA, McFarlane, IG. Hepatology 2002, 35:7
Cjaga, AJ. Seminars in Liv. Dis., 2002, 22:365
Pregnancy
Autoimmune Hepatitis
Pregnancy and AIH
 If AIH in remission, pregnancy well tolerated unless
complications of portal hypertension are present
 Increased frequency of prematurity and fetal loss
 Pregnancy or planned pregnancy are not a
contraindication to immunosuppression
 Teratogenicity observed with azathioprine treatment in
mice but little evidence for teratogenicity in humans
 Many reports of AIH flares post-partum, but AIH also
may exacerbate or present during pregnancy
Pitfalls in Therapy of AIH
Autoimmune Hepatitis
Pitfalls in Therapy of AIH
 Inadequate initial therapy (histological remission lags
behind biochemical remission)
 Failure to consider steroid-sparing (or steroid free)
regimens
 Initiation of therapy without appropriate
indication (mild hepatitis, inactive cirrhosis, wrong
disease)
 Persistent (“lifelong”) therapy in those in first
complete remission with benign follow-up
biopsies
Liver Transplantation
Autoimmune Hepatitis
Liver Transplantation
 Overall 5-year survival rates 80-90%
 Increased frequency of acute allograft
rejection
 AIH recurrence in 30-40%
 Surveillance liver biopsies may be warranted
 Manage with corticosteroids
Liver Transplantation
Autoimmune Hepatitis
AIH Treatment: Summary
 Treatment Indications:
 ALT> 10 fold
 ALT>5 fold with hyper globulinemia
 ALT <5x with symptoms
 Bridging necrosis or multiacinar necrosis
 Interface hepatitis without necrosis does not
compel treatment
Liver Transplantation
Autoimmune Hepatitis
AIH Treatment: Summary
 Start therapy with prednisone alone, adding
azathioprine/6MP if remission not achieved
within 3 months
 Test for TPMT before starting azathioprine/6-MP
 Maintain fixed daily dose of medication until
remission
 Continue treatment until remission, treatment
failure or drug toxicity
Liver Transplantation
Autoimmune Hepatitis
AIH Treatment: Summary
 Vaccination for for HBV and HAV
recommended
 Drug withdrawal should be attempted once
remission obtained, preferably based on liver
biopsy findings
 10-40% can eventually be maintained off
medication but multiple relapses may occur
before sustained remission achieved
What are Overlap Syndromes?
Overlap Syndromes
What are Overlap Syndromes?
 Two simultaneous autoimmune liver
diseases AIH/PBC, AIH/PSC
 Two sequential autoimmune liver
diseases
 One autoimmune liver disease with
features of another
Diagnostic Criteria
Overlap Syndromes
Diagnostic Criteria
AIH
malaise,
jaundice
PBC
fatigue,
pruritus
Asymptomatic
occasionally
often
Gender
female>male
Symptoms
PSC
fatigue
pruritus
often
female>male female>male
Biochemistry
ALT
ALP
ALP
and/or GGT
Immunoglobulins
IgG
IgM
IgM/IgG
AMA
none specific
(low Ig A type2)
Autoantibodies SMA/anti LKM1
ERC/MRC
overlap PSC
(young)
normal
Diagnostic
hallmark
What are Overlap Syndromes?
Overlap Syndromes
How to Treat Overlap Syndromes