Autoimmune pancreatitis
Petr Dítě
Dept. of Hepatogastroenterology
Univ. Hospital Brno – Czech Republic
Incidence of Chronic Pancreatitis
Switzerland
Poland
Germany
Czech Rep.
Hungary
Denmark
Sweden
Finland
United States
1.2/100 000/year
4.0/100 000/year
7.4/100 000/year
7.9/100 000/year
8.0/100 000/year
10.0/100 000/year
10.0/100 000/year
23.0/100 000/year
5.7-7.6/100 000/year
Chronic pancreatitis is a
progressive inflammatory disease of
the pancreas with irreversible
damage of pancreatic tissue
exocrine and endocrine
insufficiency
TIGARO Classification
T
I
G
A
R
O
-oxic-metabolic
-diopathic
-enetic
-utoimmune
-ecurrent acute pancreatitis
-bstructive
Etemed, Whitcomb, 2001
AUTOIMMUNE PANCREATITIS chronic pancreatitis with distinct
clinical, serological, histological and
imaging features and it is involved in
hyper- IgG4 group of diseases.
Autoimmune pancreatitis
1961 H. Sarles
Chronic inflammatory sclerosis
of the pancreas
(Patients with jaundice, painful crises, hyperglobulinemia,
no dilatation of pancreatic duct, lymphatic infiltration)
1975 R. Waldram et al
Chronic pancreatitis, sclerosing
cholangitis and sicca sy
in two siblings
1978 S. Nakano et al
Vanishing tumor of the abdomen
in patient with Sjögren´s sy
1995 K. Yoshida
Concept of autoimmune pancreatitis
2001 B. Etemed, D. Whitcomb
TIGARO classification
Epidemiology of autoimmune
pancreatitis
Japan
21/451
4,6%
Yoshida et al.
Dig.Dis.Sci. 1995
Korea
17/315
5,4%
Kim et al.
Am.J.Gastroenterol. 2004
Italy
23/383
6,0%
Parson et al.
Pancreas 2003
Czech Rep.
9/185
4,8%
Dite et al Best Practice
and Res.
Sex ang age onset of autoimmune pancreatitis
Nishimori I. et al., Gastroent., 2007
Antibodies in patients with AIP
%
Okazaki et al.
J. Gastroent. 2001
HISORt CRITERIAS OF AIP
Category
A. Histology
B. Imaging
Criteria
1. Diagnostic (any one):
a) Pancreatic histology showing periductal lymphoplasmacytic
infiltrate with obliterative hlebitis (LPSP)
b) Lymphoplasmacytic infiltrate with abundant (>10 cells/hpf) IgG4
positive cells in the pancreas
2. Supportive (any one)
a) Lymphoplasmacytic infiltrate with abundant (>10 cells/hpf) IgG4
positive cells in involved extra-pancreatic organ
b) Lymphoplasmacytic infiltrate with fibrosis in the pancreas
Typical imaging features:
1. CT/MR: diffusely enlarged gland with delayed (rim) endhancement
2. ERCP: Diffusely irregular, attenuated main pancreatic duct
Atypical Imaging Features: Pancreatitis, focal pancreatic mass, focal
pancreatic duct stricture, pancreatic atrophy, pancreatic calcification
C. Serology
D. Other Organ
involvement
Elevated serum IgG4 level (normal 8-140 mg/dl)
E. Response to
steroid therapy
Resolution/marked improvement of pancreatic/extrapancreatic
manifestation with steroid therapy
Hilar/intrahepatic biliary strictures, persistent distal biliary stricture,
Parotid/lacrimal gland involvement, Mediastinal lymphadenopathy,
Retroperitoneal fibrosis
CLINICAL DIAGNOSTIC CRITERIA
FOR AIP 2006
1. Diffuse or segmental narrowing of the MPD with irregular
wall and diffuse or localized enlargement of the pancreas by
imaging studies, such as abdominal US, CT, and magnetic
resonance
2. High serum γ-globulin, IgG, or IgG4, or the presence of
autoantibodies such as antinuclear antibodies and
rheumatoid factor
3. Marked interlobular fibrosis and prominent infiltration of
lymphocytes and plasma cells in the periductal area,
occasionally with lymphoid follicles in the pancreas
Diagnosis of AIP is established when criterion 1 and criterion 2
and/or 3 are fulfilled. However, it is necessary to exclude
malignant diseases.
AUTOIMMUNE PANCREATITIS - SUBTYPES
TYP 1 – LYMPHOPLASMATIC SCLEROSING PANCREATITIS –
LPSP
- PERIDUCTAL LYMPHOPLASMATIC INFILTRATE
- HIGH AMMOUNT IgG4
- POSITIVE PLASMA CELLS
- SWIRLING FIBROSIS
- OBLITERATIVE VENULITIS
TYP 2 – IDIOPATHIC DUCT-CENTRIC PANCREATITIS – IDCP
(“non-alcoholic duct destructive pancreatitis“)
- DUCTAL EPITHELIAL GRANULOCYTIC INFILTRATION
DUCTAL DAMAGE
OBLITERATION
COMPARISON OF TYPE 1 AND TYPE 2 AIP
Type 1 AIP
Type 2 AIP
Mean age
Sixth decade
Fourth decade
Gender distribution
Predominantly male
Equal
Histological pattern
Lymphoplasmacytic
sclerosing pancreatitis
Duct-destructive
pancreatitis
Histological hallmarks
Periductal
lymphoplasmacytic infiltrate
Swirling fibrosis
Obliterative venulitis
Lymphoplasmacyic infiltrate
Granulocyte epithelial lesion
with partial/complete duct
obstruction
IgG4 cells on
immunostaining
Moderate-severe (98%)
Moderate (40%) in one
study
Serum IgG4 levels
Elevated
Normal
Other organ involvement
Chronic sclerosing sialadenitis,
IgG4-associated cholangitis,
retroperitoneal fibrosis, IgG4associated tubulointerstitial
nephritis
Inflammatory bowel
disease
AIP,autoimmune pancreatitis, IgG4, immunoglobulin G4
CLINICAL PRESENTATIONS OF TYPE 1 AUTOIMMUNE
PACREATITIS
Clinical presentations of type I AIP
Pancreatic
Acute
Obstructive
jaundice
Predominantly
extra-pancreatic
Post-acute/late
Persistent
mass
Steatorrhea
Biliary stricture,
sclerosing cholangitis
Interstitial nephritis,
renal failure
Pancreatitis
Calcification,
atrophy
Steatorrhea
Retroperitoneal fibrosis
with complications
(e.g., ureteral obstruction)
Park, D.H. 2009
AUTOIMMUNE PANCREATITIS
23,0% FOCAL FORM
(LIKE MALIGNANT LESION)
DIFFUSE FORM 77,0%
(LIKE ACUTE PANCREATITIS)
Scattergram of IgG4 values for patients with autoimmune pancreatitis and
related diseases. PBC primary biliary cirrhosis, PSC primary sclerosing
cholangitis
Kawa et al., Gastroent., 2007
Usefulness of IgG4 in differentiating between pancreatic cancer
and autoimmune pancreatitis
Kawa et al., Gastroent., 2007
Abundant IgG4 – bearing plasma cell infiltration
in patients with autoimmune pancreatitis and
gastric ulcer
• 23 pts with AIP and 230 control patients examined
by EGD
• In 8 pts with autoimmune pancreatitis gastric ulcer
was found (34.8%). In control group during EGD
was gastric ulcer found in 31 pts (13.3%) = p.0007
• Conclusion: AIP is closely associated with gastric
ulcer with abundant IgG4-bearing plasma cell
infiltration
Shinji, A. et al.
Gastrointest. Endosc. 2004
SET OF PATIENTS WITH AUTOIMMUNE PANCREATITIS
(N = 10)
Gender
Age
Others autoimmune disease
Male
36
sclerosing cholangitis
Male
43
Sjögren sy
Male
53
Sjögren sy, sick – sinus sy
Female
54
Sjögren sy, autoim. hepatitis
Male
56
autoimmune hepatitis
Male
32
autoimmune hepatitis
Female
55
primary biliary cirrhosis
Male
51
IBD
Male
46
xxx
Female
33
xxx
Female
58
IgG4 pos. mastitis, sialoadenitis
Female
52
Sicca syndrom
Male
49
IgG4 pos. sclerosing cholangitis
One patient died during hospitalization – pancreatic cancer
Dítě,P. al 2010
Review of AIP cases with systemic extrapancreatic lesions
Western countries
(n=172)
Japan
(n=132)
13
24
P<0.01
UC
14
5
NS
CD
4
0
NS
Total
18
5
P<0.05
Retroperitoneal
fibrosis
9
8
NS
Thyroid disease
4
1
NS
Autoimmune
hepatitis
0
2
NS
Malignant lymphoma
2
0
NS
Sjögren´s syndrome
IBD
IBD imflammatory bowel disease,UC ulcerative colitis, CD Crohn´s disease, ITP idiopathic
trombocytopenic purpura, RA rheumatoid arthritis, SLE systematic lupus erythematosus
Ohara et al, Pancreas 2005
AUTOIMMUNE PANCREATITIS IN PATIENTS WITH
“IDIOPATHIC CHRONIC PANCREATITIS“
66 PATIENTS WITH IDIOPATHIC CHRONIC
PANCREATITIS /ICP/
AUTOIMMUNE DISEASE WAS PRESENT IN 10
PATIENTS (UC 5 pts, PSC 2 pst, Sjögren sy 1 pts,
Hashimoto´s thyroiditis 1 pts, Graves disease 1 pts)
POSITIVITY OF BIOCHEMICAL AND CLINICAL
PARAMETRES – IN 40%
CONCLUSION: CLINICAL OR BIOCHEMICAL
AUTOIMMUNE STIGMATA ARE PRESENT IN 40%
pts WITH ICP, AUTOIMMUNE MECHANISMS MAY
BE FREQUENT IN ICP.
Uzan,K.N. et al. Clin Gastroent. Hepatol. 2005
CHRONIC PANCREATITIS IN CHILDREN –
AUTOIMMUNE ETIOLOGY?
In the set of 31 children (age 3-18 years)
• markers of AIP were found in
• Genetic markers
17 pts (41,5%)
10 pts (32,5%)
Oracz G. et al, Clin Gastroent Hepat 2006
Steroid therapy in patients with AIP
• Initial doses
30 – 40 mg per
day for 2 – 4 weeks
• The steroid therapy could be stopped after the period of
6 – 12 months.
• Monitoring of laboratory and clinical symptoms
are essential.
• When AIP still appears after steroid therapy --- re-evaluation
should be carried out taking pancreatic CARCINOMA into
consideration!
J.Jpn.Pacreas Soc., 2002
THERAPEUTIC OPTIONS IN PATIENTS
WITH AIP
A) MAYO CLINIC – 11 WEEKS STEROIDS WITH
TAPPERING DOSE 5 mg / WEEK
B) KIM – 1 mg/kg FOR 4 WEEKS AND TAPPERING
THE DOSE 5 mg/WEEK
C) FRULLONI – 0,5 mg/kg FOR 4 WEEKS AND
TAPPERING THE DOSE 5 mg/WEEK
UNEFFECTIVE THERAPY – PANCREATIC CANCER
Long-term follow up study treating patients with
AIP
23 patients with AIP
Choledocho
duodenostomy
(N=4)
Pancreatoduode
nectomy (N=6)
Supportive therapy
(N=3)
Steroids (N=10)
Steroid therapy
60 mg/day
40 mg/day
30 mg/day
5 mg/day
1 pts
1 pts
7 pts
1 pts
Duration from 21 – 37 months
Dose was tappered by 2.5 – 5.0 mg every two weeks
Maintenance therapy: 5mg daily
Follow up period – 4 years 6 monts
Kamisawa et al.
Pancreatology 2005
Long term therapy patients with AIP - prognosis
Group
Prognosis (month)
Died
Pancreatoduodenectomy (N=6)
- pulmonary cancer (12)
- hepatic failure (48)
- pneumonia (12)
Alive
- 12 and 82 months
Unclear - 36 months
Died
Alive
- pulmonary cancer (12)
- renal failure (72)
- 240 months
Died
Alive
- esophageal cancer (12)
- 12, 12, 24, 36, 48, 48, 60, 72, 120
Palliative therapy(N=3)
Steroids (N=10)
Kamisawa et al.
Pancreatology 2005
AIP – ENDOCRINE AND EXOCRINE
FUNCTION AFTER STEROID THERAPY
21 CASES AIP WITH STEROID THERAPY
10 CASES WITH EXOCRINE INSUFICIENCY
- NORMALIZATION
8
- NO CHANGE
2
11 CASES WITH DIABETES MELLITUS
- IMPROVEMENT
5
- AGGRAVATION
3
- NO CHANGE
3
Ito et al. 2007
Recurrence of autoimmune
pancreatitis
Takayama et al (Amer.J.Gastroent. 2004)
Wakabyashi et al.(Pancreas 2005)
Zamboni et al. Wirchow Arch. 2004)
Kim et al. (A.J. Gastroent. 2004)
Ramisawa et al. (J.Gastroenterol. 2007)
42(11)
36( 6)
22( 5)
17( 1)
32( 2)
26%
17%
23%
6%
6%
THE THERAPY OF AIP
RECCURENCE
STEROID
+
AZATHIOPRINE
1mg/kg
2mg/kg
FOR 11 WEEKS
Mycophenolate or Rituximab are not effective
S.CHari Abstr. DDW 2009
AUTOIMMUNE PANCREATITIS VS PANCREATIC
CANCER - RADIOLOGIC IMAGING
Autoimmune
pancreatitis
Pancreatic cancer
Complete cutoff of main
pancreatic duct
Uncommon
Common
Ductal stricture
Multiple
Localized (Single)
Upstream duct dilatation
Mild
Marked
Duct in the mass
Present
Absent
Diffuse swelling of the pancreas
Almost always
Rare
Double duct sign
Common
Common
Kim et al., 2004
Usefulness of IgG4 in differentiating between pancreatic cancer
and autoimmune pancreatitis
Kawa et al., Gastroent., 2007
COMPARISON OF SUBJECTS WITH AIP AND PANCREATIC
CANCER
AIP (N=45)
Pacreatic Cancer
(N=135)
P Value
Gender, % male
37/45 (82%)
79/135 (59%)
0,004
Mean age ± SEM
59,6 ± 2,5
67,3 ± 1,1
0,001
% ≥ age 50 yr
34/45 (76%)
125/135 (93%)
0,002
CA 19-9 > 100
3/33 (9%)
91/126 (71%)
<0,001
Mean value of S. IgG4
(range)
550 ± 98,6 (3-2,890)
69,5 ± 9,4 (3-1,140)
<0,001
% with serum IgG4 >
140mg/dL
34/45 (76%)
13/135 (10%)
<0,001
% with serum IgG4 >
280 mg/dL
24/45 (53%)
2/135 (1%)
<0,001
Multivariate Analyses of
Factors predicting AIP
Odds Ratio
Confidence Interval
P Value
IgG4 > 140 mg/dL
37,4
10,6-173,5
<0,001
CA19-9 < 37
11,7
3,70-46,2
<0,001
Ghazele A. et al. 2007
CONCLUSION AND PRACTICE POINTS
1)
2)
3)
4)
5)
6)
7)
8)
AIP IS NOT FREQUENT DISEASE IN EUROPE, MORE
FREQUENT IN ASIA.
CLINICAL SYMPTOMS ARE USUALLY MILD (MOSTLY
ABDOMINAL “DISCOMFORT“ WITHOUT PAIN ATTACKS)
IN CT, EUS OR US-DIFFUSE ENLARGEMENT OF PANCREAS
(sausage pancreas), IN NMR-CP OR ERCP IRREGULAR
NARROWING OF THE MAIN PANCREATIC DUCT ARE
TYPICAL
PRESENCE NON-SPECIFIC ANTIBODIES IN BLOOD SERUM
AND INCREASED LEVEL OF IgG AND IgG4 IN SERUM AND
TISSUE
ASSOCIATION WITH OTHER AUTOIMMUNE DISEASE-TYP1
AIP
PANCREATIC CALCIFICATIONS AND/OR CYSTOIDS ARE
NOT FREQUENT
THERAPY WITH STEROIDS IS EFFECTIVE
IN DIF. DG DIAGNOSIS AIP VS PANCREATIC CANCER – EUS
GUIDED BIOPSY IS FUNDAMENTAL PROCEDURE