Autoimmune pancreatitisAutoimmune pancreatitis
Petr DítěPetr Dítě
Dept.Dept. of of Hepatogastroenterology HepatogastroenterologyUniv. Hospital Brno – Czech RepublicUniv. Hospital Brno – Czech Republic
Incidence of Chronic PancreatitisSwitzerland 1.2/100 000/yearPoland 4.0/100 000/yearGermany 7.4/100 000/yearCzech Rep. 7.9/100 000/yearHungary 8.0/100 000/yearDenmark 10.0/100 000/yearSweden 10.0/100 000/yearFinland 23.0/100 000/yearUnited States 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
-oxic-metabolic -diopathic -enetic-utoimmune-ecurrent acute pancreatitis-bstructive
Etemed, Whitcomb, 2001
TIGARO Classification
TI GARO
AUTOIMMUNE PANCREATITIS - chronic pancreatitis with distinct clinical, serological, histological and imaging features and it is involved in hyper- IgG4 group of diseases.
Autoimmune pancreatitisAutoimmune pancreatitis19611961 H. SarlesH. Sarles Chronic inflammatory sclerosis Chronic inflammatory sclerosis of of
the pancreasthe pancreas(Patients with jaundice, painful crises, hyperglobulinemia, no (Patients with jaundice, painful crises, hyperglobulinemia, no
dilatation of pancreatic duct, lymphatic infiltration)dilatation of pancreatic duct, lymphatic infiltration)
19751975 R. Waldram et al R. Waldram et al Chronic pancreatitis, sclerosing Chronic pancreatitis, sclerosing cholangitis and cholangitis and sicca sy sicca sy in two siblingsin two siblings
19781978 S. Nakano et alS. Nakano et al Vanishing tumor of the abdomen Vanishing tumor of the abdomen in in patient with Sjögren´s sypatient with Sjögren´s sy
19951995 K. YoshidaK. Yoshida Concept of autoimmune pancreatitisConcept of autoimmune pancreatitis
20012001 B. Etemed, D. Whitcomb B. Etemed, D. Whitcomb TIGARO classificationTIGARO classification
Epidemiology of autoimmune Epidemiology of autoimmune pancreatitispancreatitis
JapanJapan 21/45121/4514,6% 4,6% Yoshida et al. Yoshida et al. Dig.Dis.Sci. 1995Dig.Dis.Sci. 1995
KoreaKorea 17/31517/3155,4% 5,4% Kim et al. Kim et al. Am.J.Gastroenterol. 2004Am.J.Gastroenterol. 2004
ItalyItaly 23/38323/3836,0%6,0% Parson et al. Parson et al. Pancreas 2003Pancreas 2003
Czech Rep. Czech Rep. 9/1859/185 4,8%4,8% Dite et al Best Practice Dite et al Best Practice and Res. and Res. Clin. Gastroent., 2008Clin. Gastroent., 2008
Sex ang age onset of autoimmune pancreatitis
Nishimori I. et al., Gastroent., 2007
Antibodies in patients with AIPAntibodies in patients with AIP
%
Okazaki et al.J. Gastroent. 2001
HISORt CRITERIAS OF AIPCategory CriteriaA. Histology 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 pancreas2. 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
B. Imaging Typical imaging features:1. CT/MR: diffusely enlarged gland with delayed (rim) endhancement2. ERCP: Diffusely irregular, attenuated main pancreatic duct Atypical Imaging Features: Pancreatitis, focal pancreatic mass, focal pancreatic duct stricture, pancreatic atrophy, pancreatic calcification
C. Serology Elevated serum IgG4 level (normal 8-140 mg/dl)D. Other Organ involvement
Hilar/intrahepatic biliary strictures, persistent distal biliary stricture, Parotid/lacrimal gland involvement, Mediastinal lymphadenopathy, Retroperitoneal fibrosis
E. Response to steroid therapy
Resolution/marked improvement of pancreatic/extrapancreatic manifestation with steroid therapy
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 resonance2. High serum γ-globulin, IgG, or IgG4, or the presence of autoantibodies such as antinuclear antibodies and rheumatoid factor3. 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 - SUBTYPESTYP 1 – LYMPHOPLASMATIC SCLEROSING PANCREATITIS – LPSP - PERIDUCTAL LYMPHOPLASMATIC INFILTRATE - HIGH AMMOUNT IgG4 - POSITIVE PLASMA CELLS - SWIRLING FIBROSIS - OBLITERATIVE VENULITISTYP 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 AIPType 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 infiltrateSwirling fibrosisObliterative venulitis
Lymphoplasmacyic infiltrateGranulocyte 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, IgG4-associated 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 Predominantly extra-pancreatic
Biliary stricture, sclerosing cholangitis
Interstitial nephritis,
renal failure
Retroperitoneal fibrosiswith complications
(e.g., ureteral obstruction)
Acute Post-acute/late
Obstructive jaundice
Pancreatitis
Steatorrhea
Persistent mass
Steatorrhea
Calcification,atrophy
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 Abundant IgG4 – bearing plasma cell infiltration in patients with autoimmune pancreatitis and in patients with autoimmune pancreatitis and
gastric ulcergastric ulcer
• 23 pts with AIP and 230 control patients examined 23 pts with AIP and 230 control patients examined by EGDby EGD
• In 8 pts with autoimmune pancreatitis gastric ulcer In 8 pts with autoimmune pancreatitis gastric ulcer was found (34.8%). In control group during EGD was found (34.8%). In control group during EGD was gastric ulcer found in 31 pts (13.3%) = p.0007was gastric ulcer found in 31 pts (13.3%) = p.0007
• Conclusion: AIP is closely associated with gastric Conclusion: AIP is closely associated with gastric ulcer with abundant IgG4-bearing plasma cell ulcer with abundant IgG4-bearing plasma cell infiltrationinfiltration
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 syFemale 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
Dítě,P. al 2010One patient died during hospitalization – pancreatic cancer
Review of AIP cases with systemic extrapancreatic lesionsReview of AIP cases with systemic extrapancreatic lesions
Western countries(n=172)
Japan (n=132)
Sjögren´s syndrome 13 24 P<0.01
IBD
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
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 2005Ohara 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 17 pts
(41,5%)• Genetic markers 10 pts
(32,5%)
Oracz G. et al, Clin Gastroent Hepat 2006
Steroid therapy in patients with AIPSteroid therapy in patients with AIP
• Initial dosesInitial doses 30 – 40 mg per 30 – 40 mg per day for 2 – 4 day for 2 – 4 weeksweeks• The steroid therapy could be stopped after the period The steroid therapy could be stopped after the period ofof
6 – 12 months.6 – 12 months.• Monitoring Monitoring of of laboratory and clinical symptoms laboratory and clinical symptoms
are essential. are essential.• When AIP still appears after steroid therapy --- re-evaluation When AIP still appears after steroid therapy --- re-evaluation
should be carried out taking pancreatic CARCINOMA into should be carried out taking pancreatic CARCINOMA into consideration!consideration!
J.Jpn.Pacreas Soc., 2002J.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 Long-term follow up study treating patients with AIPAIP
23 patients with AIP
Pancreatoduode nectomy (N=6)
Choledocho duodenostomy
(N=4)
Supportive therapy (N=3) Steroids (N=10)
Steroid therapy
60 mg/day 1 pts40 mg/day 1 pts Duration from 21 – 37 months30 mg/day 7 pts5 mg/day 1 pts
Dose was tappered by 2.5 – 5.0 mg every two weeksMaintenance therapy: 5mg dailyFollow up period – 4 years 6 monts
Kamisawa et al.Pancreatology 2005
Long term therapy patients with AIP - prognosisLong term therapy patients with AIP - prognosis
Group Prognosis (month)
Pancreatoduodenectomy (N=6)
Died - pulmonary cancer (12) - hepatic failure (48) - pneumonia (12)Alive - 12 and 82 monthsUnclear - 36 months
Palliative therapy(N=3)Died - pulmonary cancer (12) - renal failure (72)Alive - 240 months
Steroids (N=10) Died - esophageal cancer (12)Alive - 12, 12, 24, 36, 48, 48, 60, 72, 120
Kamisawa et al.Pancreatology 2005
AIP – ENDOCRINE AND EXOCRINE FUNCTION AFTER STEROID THERAPY
21 CASES AIP WITH STEROID THERAPY10 CASES WITH EXOCRINE INSUFICIENCY- NORMALIZATION 8- NO CHANGE 211 CASES WITH DIABETES MELLITUS- IMPROVEMENT 5- AGGRAVATION 3- NO CHANGE 3
Ito et al. 2007
Recurrence of autoimmune Recurrence of autoimmune pancreatitispancreatitis
Takayama et al (Amer.J.Gastroent. 2004)Takayama et al (Amer.J.Gastroent. 2004) 42(11)42(11)26%26%
Wakabyashi et al.(Pancreas 2005)Wakabyashi et al.(Pancreas 2005) 36( 6)36( 6)17%17%
Zamboni et al. Wirchow Arch. 2004)Zamboni et al. Wirchow Arch. 2004) 22( 5)22( 5) 23%23%Kim et al. (A.J. Gastroent. 2004)Kim et al. (A.J. Gastroent. 2004) 17( 1)17( 1)
6%6%Ramisawa et al. (J.Gastroenterol. 2007)Ramisawa et al. (J.Gastroenterol. 2007) 32( 2)32( 2)
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%) <0,001Mean 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 <0,001CA19-9 < 37 11,7 3,70-46,2 <0,001
Ghazele A. et al. 2007
CONCLUSION AND PRACTICE POINTS
1) AIP IS NOT FREQUENT DISEASE IN EUROPE, MORE FREQUENT IN ASIA.
2) CLINICAL SYMPTOMS ARE USUALLY MILD (MOSTLY ABDOMINAL “DISCOMFORT“ WITHOUT PAIN ATTACKS)
3) 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
4) PRESENCE NON-SPECIFIC ANTIBODIES IN BLOOD SERUM AND INCREASED LEVEL OF IgG AND IgG4 IN SERUM AND TISSUE
5) ASSOCIATION WITH OTHER AUTOIMMUNE DISEASE-TYP1 AIP
6) PANCREATIC CALCIFICATIONS AND/OR CYSTOIDS ARE NOT FREQUENT
7) THERAPY WITH STEROIDS IS EFFECTIVE8) IN DIF. DG DIAGNOSIS AIP VS PANCREATIC CANCER – EUS
GUIDED BIOPSY IS FUNDAMENTAL PROCEDURE