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Autoimmune Hepatitis
Robert H. Squires, Jr., MD
Professor of Pediatrics
Children’s Hospital of Pittsburgh
Northwest Pediatric Liver Disease Symposium
April 11,12, 2008
Seattle, Washington
Common Liver Tests
• Hepatocellular Damage
– AST, ALT
• Can be elevated in patients with myopathy
• Cholestasis
– Bilirubin, GGTP, serum bile acids
– Alkaline phosphatase (not helpful in children)
• Note: benign elevation of alkaline phosphatase
• Liver function tests
– PT, INR, albumin, glucose, factor VII, ammonia
Interpretation of Liver Tests
• Must be in placed in clinical context
– Signs/symptoms of chronic liver disease
– Hepatic failure
– Incidental finding
• Risk factors
– Viral hepatitis
– Alcohol
– Obesity
– Medications
Costs of Selected Tests
(US dollars, 2001)
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AST, ALT, alkaline phosphatase, bilirubin
Prothrombin time
GGTP
Hep A-IgM
HBsAg
HBV-DNA
Hep C Ab
HCV-RNA (Quant)
HCV-genotype
ANA
Smooth Muscle Ab
Anti-LKM
Alpha-1 antitrypsin
Ceruloplasmin
Abdominal sono
Liver biopsy
60-104
29-44
28-65
79-111
55-58
250-300
92-104
327-340
578-590
58-113
73-117
136-205
83-99
65-78
600
1,500
Gastroenterology 2002;123:1367-84
Proposed “Healthy Ranges” of ALT
Prati D et al Ann Intern Med 2002:137:1-9
Variation in serum Alkaline
Phosphatase by age
Reichling JJ et al Diges Dis Sci 1988:33:1601-14
Prevalence of elevated ALT among US
adolescents: NHANES 1999-2004
Fraser A, et al Gastroenterology 2007;133:1814
Isolated Unconjugated
Hyperbilirubinemia
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Gilbert’s syndrome
Neonatal jaundice
Hemolysis, blood transfusion
Resorption of a large hematoma
Crigler-Najjar syndrome
“Shunt” hyperbilirubinemia
Evaluation of Abnormal Liver Tests
• Mild elevation (< 2x ULN)
– Variation of normal
– Follow clinically, if no sign of chronic liver disease
– Look for simple things: medications, obesity, myopathy,
viral exposure, history of autoimmune disease, celiac
disease
– Consider further evaluation if aminotransferase levels
increase or persist beyond 4-6 months, despite lifestyle changes
• Would check aminotransferase levels between 3-6
weeks after initial elevation in the asymptomatic
patient, or sooner as clinical circumstances change.
Evaluation of Abnormal Liver Tests
• Moderate elevation (< 5x ULN)
– Infection
• Hep B, C, EBV, CMV
– Fatty liver/Steatohepatitis
– Medications/toxins
• Meds: Acetaminophen, NSAID’s, augmentin, anti-fungal,
analeptics
• Herbs: Germander, Jin Bu Huan, Senna, Vitamin A
• Illicit drugs: Anabolic steroids, cocaine, ecstasy,
phencyclidine
• Toxins: Alcohol, mushroom
– Autoimmune hepatitis
– Alpha-1 antitrypsin deficiency
– Wilson disease
– Celiac disease
– Non-hepatic
• Hemolysis, myopathy, thyroid disease, strenuous exercise
Evaluation of Abnormal Liver Tests
• Severe elevation (>15 x ULN)
– Infection
• Viral A-E, Herpes
– Medications/Toxins
– Vascular injury to the liver
• Ischemic hepatitis
• Acute Budd-Chiari syndrome
• Hepatic artery ligation
– Autoimmune hepatitis
– Wilson disease
– Acute bile duct obstruction
AST/ALT elevation in skeletal
muscle diseases
Nathwani RA et al Hepatology 2005:41:380-82
Unusual causes of elevated AST/ALT
• AST macroenzyme
– Fortunato G et.al. J Pediatrics 1998;133:286
• Subclinical Addison’s Disease
– Boulton R, et al Gastroenterology 1995;109:1324
• Rotavirus
– Grimwood K, et al J Pediatrics 1988;112:597
Autoimmune Hepatitis in Children
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2-5% of chronic liver disease in children
Phenotypic variability
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Acute hepatitis (most common) 25-56%
Indolent presentation over some months
Acute liver failure
Cryptogenic cirrhosis
Associated immune-mediated disorders
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Thyroiditis
Ulcerative colitis
Celiac disease
Vitiligo
-----
Hypereosinophilic syndrome
Hemolytic anemia
Diabetes mellitus
Myasthenia gravis
Diagnosis of Autoimmune Hepatitis
• Elevated aminotransferase levels
• Elevated serum globulin
• Autoantibodies
– ANA, SMA, anti-LKM1, SLA
• Absence of viral markers for hepatitis
• Histologic evidence of interface hepatitis
• Absence of other conditions
– Infection, toxic injury, metabolic defect
Clinical and Immunological
Features
Clinical Features
Type 1
Type 2
Autoantibodies
SMA/ANA
LKM-1
Age (yr)
10-20; 45-75
2-14
Women (%)
78
89
Elevated Gamma Globulin
+++
+
HLA Association
B8, DR3, DR4 B14, DR3,
C4AQO
Other immune disease(%)
41
34
Steroid response
+++
++
Progress to cirrhosis (%)
45
82
Type 3
SLA
10-50
90
++
?
58
+++
75
Interface Hepatitis
Multinucleated cells
Plasma cells
Cholestasis
Autoimmune Hepatitis in Children
Gregorio GV, et.al. Hepatology 1997;25:541
• 73 patients from 1973-1993 with autoimmune liver disease
• 21 sclerosing cholangitis were excluded
• 52 with autoimmune hepatitis were evaluated
SEROLOGICAL MARKERS AT THE TIME OF PRESENTATION
Marker
Titer
#
ANA
1:80-320
4
SMA
1:40-2560
10
ANA + SMA
Comments
14
Anti-LSP
1:400-1300
4
LKM-1
1:40-10400
18
LKM + ANA
1
No marker
1
Weak ANA=2; ANA + after 1,3 mo
3 y/o spherocytosis; +LKM/SMA
Autoimmune Hepatitis in Children
ANA/SMA
(N = 32)
LKM-1
N = (20)
p-value
Age (yr)
10.5 (2.3-14.9)
7.4 (0.8-14.2)
0.011
Female
24 (75%)
15 (75%)
1.00
Length of illness*
4 (.2-24.6)
1.7 (.03-15.4)
0.06
Fulminant failure
1 (3%)
5 (25%)
0.05
Autoimmune
disorders (AD)
7 (22%)
4 (20%)
0.85
First degree
relative with AD
13 (43%)
8 (40%)
0.81
* Months
Gregorio GV, et.al. Hepatology 1997;25:541
AIH in Children: Laboratory
ANA/SMA
LKM-1
N = 32
N = 20
62 (6/462)
188 (13-773)
0.007
AST IU/L (< 50)
632 (81-2500)
1146 (93-2440)
0.047
GGT IU/L (< 50)
126 (11-871)
91 (36-299)
0.055
SAP IU/L (< 350)
376 (131-1578)
377 (102-1677)
0.087
1.6 (1-2.5)
1.6 (1-8.6)
0.39
IgG g/L (5-15)
28 (13.4-73.3)
21 (10.2-40)
0.06
Alb g/L (35-50)
32 (20-43)
38 (25-54)
0.02
ANA titer (N=20)
120 (10-5120)
NA
SMA titer (N=26)
160 (10-2560)
NA
LKM1 titer (N=19)
NA
640 (40-10400)
T.Bili µmol/L (< 20)
INR (0.9-1.2)
p-value
Gregorio GV, et.al. Hepatology 1997;25:541
52 patients (20 LKM)
6 fulminant failure (5 LKM)
47 medical Rx
1 Rx steroids
4 OTLTx
1 died
3 elevated AST
2 died
9 OTLTx
5 OTLTx
1 @ 15mo
3 died
44 remission (13 LKM)—7mo (1 wk-7yr)
6 pred
35 pred + Aza
3 other
13 (4 LKM) ended Rx
6 (0 LKM) success
Lasting 9-13 yr
7 (4 LKM) relapse
2 mo (1-15 )
Gregorio, 1997
Observations
• Excluding ALF, Type 1 and Type 2 have similar
presentation and initial response to therapy
• Most require treatment “life-long”, particularly
LKM
• “Standard” autoantibodies may be absent
initially
• 56% of patients present with acute hepatitis
• Normal IgG in 20%
• Cirrhosis at presentation is more common in
ANA/SMA +ve patients
Management of AIH in Children
• Standard immunosuppression
– Prednisone
– Azathioprine
• Calcineurin Inhibitors
– Cyclosporine
– FK 506
• Antimetabolites
– Mycophenolate mofetil
– Cyclophosphamide
– Methotrexate
• Other
– Ursodeoxycholic acid
– D-Penicillamine
• Liver transplantation
Overlap Syndromes
• AIH and Primary Biliary Cirrhosis
– AMA +ve; elevated AST/ALT/GGT/SAP
– Biliary damage, piecemeal necrosis
– Steroids and UDCA
• AIH and Primary Sclerosing Cholangitis
– pANCA +ve; elevated AST/ALT/GGT/SAP
– Abnormal cholangiogram; associated with IBD
– Cholangitis, piecemeal necrosis
– Steroids
• AIH and Hepatitis C
– ANA and/or SMA and/or anti-LKM1 +ve; Hep C Ab +ve
– Portal lymphocytic infiltrate, steatosis, bile duct injury
– Treatment is problematic
Variant Syndromes
• Autoimmune cholangitis
– ANA and/or SMA +ve; AMA absent
– Cholestasis; normal cholangiogram
– Biliary damage
– Prednisone and/or UDCA response is poor
• Cryptogenic cirrhosis
– Autoantibody negative
– Histologic features of AIH
– Good response to Prednisone
Autoimmune Hepatitis/Sclerosing
Cholangitis in Childhood: 16 yr study
Gregorio GV, et al Hepatology 2001;33:544
• 76 patients with liver disease and circulating antibodies
• 21 too ill to undergo cholangiography
• 55 underwent cholangiography (ERCP = 51), 54 had sigmoidoscopy / bx
• Recruited 1984-1997
• Followed through 1999
•55 patients were antibody positive
• Sclerosing cholangitis (AIH-SC)
• Normal cholangiogram (AIH)
27
28
• 22 patient with sclerosing cholangitis from other causes during the study (not included)
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Primary immunodeficiency
Langerhan cell histiocytosis
Neonatal sclerosing cholangitis
Primary sclerosing cholangitis
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2
5
9
OLS AIH-SC in Children:
Demographics
Age (yr)
OCS AIH-SC
AIH
(N = 27)
(N = 28)
11.8 (2.3-16) 10.5 (2.2-14)
p-value
.16
Female
15 (55%)
22 (79%)
.12
Jaundice
15 (56%)
19 (68%)
NS
2 (7%)
7 (25%)
.08
IBD
12 (44%)
5 (18%)
.03
Immune
disorders
13 (48%)
11 (39%)
NS
Pruritis
Gregorio GV ,et.al Hepatology 2001:33:544
OLS AIH-SC in Children: Laboratory
OLS AIH-SC
AIH
(N = 27)
(N = 28)
20 (4-178)*
35 (4-306)
.04
AST (IU/L)
102 (18-1215)
333 (24-4830)
.002
GGT (IU/L)
129 (13-948)
76 (29-333)
NS
SAP (IU/L)
303 (1.4-1710)
356 (131-878)
NS
1.1 (.9-1.6)
1.2 (.96-2.5)
.009
IgG (g/L)
19.4 (7.8-70.8)
24 (7.8-73.3)
NS
Alb (g/L)
39 (27-54)
35 (25-47)
.051
ANA +ve
20
18
SMA +ve
20
13
LKM1 +ve
1
8
74%
36%
T.Bili (µmol/L)
INR
pANCA +ve
* = median (range)
p-value
.014
Gregorio GV ,et.al Hepatology 2001:33:544
OLS AIH-SC in Children:
Time to Normalization* of Lab
AIH-SC
AIH
p-value
AST
2.1 (.2-107)
6 (.8-25)
NS
GGT
7 (1-96)
12 (1-40)
NS
SAP
T. Bili
2 (1-40)
1.5 (.5-12)
5 (1-48)
1.25 (.25-16)
.015
NS
Alb
INR
0.5 (.5-1)
1 (1-6)
2 (.25-8)
6 (.5-15)
.016
.021
* In months
Gregorio GV ,et.al Hepatology 2001:33:544
OLS AIH-SC and AIH in Children:
Conclusions
• Sclerosing cholangitis is present in 50% of children with
“typical” AIH
• Normal SAP can be present in children, onion-skin
fibrosis is rare
• Biochemical markers do not predict bile duct disease
• Concordance between histology and radiographic
findings is poor
• Response to immunosuppression is good in both
conditions
• AIH and ASC appear to constitute a spectrum of the
same disease
Primary Sclerosing Cholangitis in
Children (N = 9)
• Autoantibody negative; abnl bile ducts
• Male predominance (6/9)
• Associated immune disorders (4/9)
– Ulcerative colitis (3/4)
• Presenting symptoms similar to AIH
– Diarrhea (6/9) and hematochezia (3/6)
• Jaundice is infrequent at presentation (8/9)
Pediatric Variants
• Autoimmune polyendocrinopathy-candidiasisectodermal dysplasia (APECED)
• Celiac disease and chronic hepatitis
• Hyper-eosinophilic syndrome and CAH
• Neonatal liver disease and placental transfer of
AMA
• De novo autoimmune hepatitis after liver
transplant
• Autoimmune lymphoproliferative syndrome
(ALPS) and AIH
Autoimmune Polyendocrinopathycandidiasis-ectodermal dysplasia (APECED)
• Mutation of autoimmune regulator (AIRE) gene located
on chromosome 22q22.3
– Transcription factor expressed in the thymus
• Associated autoimmune conditions
– Hypoparathyroidism
– Addison’s disease
– Autoimmune enteropathy
-- Hepatitis (10-20%)
-- Diabetes
-- Graves disease
• Clinical features
– Variable; Onset in the first decade of life, but can occur anytime
– Anti-CYP1A2 specific but insensitive marker
– Responds to immunosuppressive medications
Eisenbarth GS NEJM 2004:350:2068-79
Autoimmune Polyglandular
Syndrome type 1 (APS 1)
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Also known as:
– Autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy syndrome (APECED)
– Autoimmune polyendocrine syndrome type I
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Characterized by the presence of 2 of 3 major clinical
manifestations:
– Chronic mucocutanous candidiasis
– Hypoparathyroidism
– Addison disease
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APS type II includes
– Addison disease
– Autoimmune thyroid disease
– And/or type 1 diabetes mellitus
Clinical Features
• Candidiasis is usually the first clinical
manifestation (initial manifestation in 60%)
• Typically followed by hypoparathyroidism (79%)
• Addison disease (72%)
• All components present together in about half of
patients
• 3 main diseases develop in first 20yrs with
accompanying diseases appearing until at least
5th decade
Clinical Features
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Type I diabetes mellitus
Autoimmune thyroid disease
Primary hypogonadism
Chronic atrophic gastritis
Autoimmune Hepatitis
– 10-20% lifetime risk
• Pernicious anemia
• Ectodermal Dystrophy
• Keratocojunctivitis
• Autoimmune skin diseases
– Vitiligo
– Alopecia
• Pituitary Defects
Autoimmune Regulator Gene
(AIRE)
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AIRE teaches “self”
– AIRE regulates transcription of peripheral tissue-restricted antigens in thymic
medullary epithelial cells.
– Knock out mice have defined autoimmune diseases
– In vitro studies show increased T cell thymic survival in absence of AIRE.
Celiac Disease and Chronic Hepatitis
• “Gluten Hepatitis” up to 60% of children
– Transient, no associated symptoms
– Resolves within 2-8 weeks of gluten-free diet
• Nonspecific reactive hepatitis
– Celiac disease may be silent
• Autoimmune hepatitis
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Rare
Associated with elevated IgG, compatible histology
Type 1 markers, or marker “negative”
Responds to immunosuppressive medications
Rubio-Tapia A and Murray JA Hepatology 2007:46:1650-58
Celiac disease and cryptogenic
ALT elevation
Volta U et al Lancet 1998;352:26-29
Hyper-eosinophilic Syndrome and
Chronic Hepatitis
• Clinical features
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Asymptomatic or mild systemic symptoms
Mild lymphadenopathy
Eosinophilia (20-77%)
Elevated IgG (50%), ALT 150-1700, total bili <5.0
Type 1 markers; compatible histology
• Treatment
– Histology, symptoms, and biochemical markers
improved with prednisone and azathioprine
– Relapse may be heralded by rise in eosinophil count
Digest Dis Sci 1988;33:233
Hepatology 1991;13:1090
Molecular Mimicry and AIH Type 2
• CYP2D6 is the microsomal target of LKM-1 antibody
• Peptide sequence between 193 and 212 was the target in 12/13 patients
• Within one hexameric aminoacid sequence of the CYP2D6 protein:
• 5/6 aminoacids were shared with HCV
• 6/6 aminoacids were shared with CMV
• Conclude: Multiple exposures to viruses mimicking self may represent
an important pathway to the development of autoimmunity.
Kerkar N. J Immunology 2003; 170:1481
Final Take on AIH in Children
• An animal model is desperately needed.
• If it is not in the differential, you will not make the
diagnosis.
• Prednisone and Azathioprine work pretty well,
but are there other treatment strategies we
should consider?
• It is time to initiate a multi-center approach to the
diagnosis, management, and pathophysiological
understanding of AIH in children.