A. Autoimmune Pancreatitis
By David Whitcomb MD PhD . For general information, see original sources for details and clinical guidance. This is an outline for discussion with physicians, and many of the details are not given in this outline.
Autoimmune pancreatitis (AIP) is a distinct sub-type of chronic pancreatitis that often presents as obstructive jaundice/pancreatic mass with or without localizing pain, and regresses or resolves with steroid treatment. Autoimmune pancreatitis is often part of a systemic fibroinflammatory disease syndrome called IgG4-associated systemic disease (ISD). A second type of AIP is now recognized that is IgG4 negative, termed Type 2 AIP (see below)
Table 1. Characteristics of IgG4-associated systemic disease.
- increase in serum IgG4
- lymphoplasmacytic infiltrate rich in IgG4-positive cells
- intense fibrosis
- multiple organ involvement
- bile duct
- salivary glands
- lymph nodes
In autoimmune pancreatitis, the pancreatic gland may show focal or diffuse swelling (often with a peripancreatic “halo” on CT scan), and pancreatography may demonstrate diffuse or segmental narrowing of the pancreatic duct. Pancreatic core biopsies reveal lymphoplasmacytic sclerosis, which tends to be concentrated around ducts and veins (type 1 AIP) or granulocyte epithelial lesions (type 2 AIP) (1). In a 10 year review of cases from the University of Pittsburgh (2), we found the following clinical features (all comers):
Table 2. Clinical features of autoimmune pancreatitis in Pittsburgh.
Median age at presentation 62.5 years (range: 23-86),
Sex: 65% men
Race: 88% Caucasians.
- Mild abdominal pain 65%
- Jaundice 62%
- Weight loss 42%
- Mass or enlargement 85%
- Serum IgG4 >140 mg/dl 44% (at presentation)
- Not meeting strict criteria 15%
These patients may have severe exocrine pancreatic insufficiency, which may be associated with focal or diffuse compression of the main pancreatic duct in early stages.
2. Diagnostic criteria:
Multiple diagnostic criteria have been proposed for autoimmune pancreatitis (3-6), with newer studies continue to challenge initial observations. One of the striking features of AIP, although not always present, is the “sausage” shape of the pancreas during active disease (Figure 1) which resolves with treatment (Figure 2).
<– Figure 1. A CT scan of a patient with autoimmune pancreatitis at the time of diagnosis. These patients will typically have elevated IgG4 levels, vague abdominal pain, diarrhea, weight loss and may be jaundiced because of bile duct obstruction.
Figure 2–>. The same patient after 3 weeks of steroid treatment. Note that the swelling of the pancreas is markedly reduced. Not visible on the CT – the patient fells 100% better!
The criteria most commonly used in the United States is the revised HISORt criteria developed at the Mayo Clinic. The criteria are given in Table 3, the combination of features needed to make a diagnosis is given in Table 4. Note that there is an international consensus guideline that is being debated through the International Association of Pancreatologists.
Table 3. HISORt Diagnostic Criteria for Autoimmune pancreatitis (3, 6). (1=AIP, 2=suggestive of AIP; 3=suggestive of pancreatic cancer)
(H) Histology (H1=typical histology, H2=fibrosis, H3=pancreatic cancer)
(I) Pancreatic imaging (I1=suggestive of AIP, I3=suggestive of CA)
(S) Serology (S1=IgG4 >2-fold ULN, S3=CA19-9 > 150 IU/ML)
(O) Other organ involvement (O1=histology, O2=CT, O3=CT c/w liver mets)
- Biliary strictures (similar to PSC)
- Salivary gland involvement
- mediastinal lymphadenopathy,
- retroperitoneal fibrosis
(Rt) Response to Steroid Treatment Rt1=resolution, Rt3=minimal resolution
Table 4. Diagnosis of AIP (6)
A. Diagnostic histology: (H1)
1) On resection specimen Or
2) On pancreatic core biopsy (indicated when a patient with pancreatic mass and/or obstructive jaundice due to distal bile duct obstruction has a negative work-up for cancer and lacks the necessary collateral evidence of AIP on serology or other organ involvement
B. Typical imaging (I1) PLUS any one of the following:
- Elevated IgG4 (S1/S2)
- Other organ involvement (O1/O2)
- Compatible histology (H2)
C. Response to steroids (Rt1): Resolution/marked improvement in pancreatic/extrapancreatic manifestations in patients meeting criteria for steroid use:
(1) Patients in groups A and B
(2) Patients without typical imaging findings (I2/3) with negative work-up for cancer and who have 1 highly suggestive feature of AIP (serum IgG4 >2 times upper limit of normal [S1] or definitive other organ involvement [O1] or 2 supportive features of AIP [<2-fold elevation of serum IgG4 (S2), clinical/radiologic evidence of other organ involvement [O2], compatible histology [H2])
(3) A steroid trial in the absence of adequate or no collateral evidence of AIP must be used with caution
A pancreatic core biopsy, steroid trial, or surgery is required for diagnosis in approximately 30% of patients with AIP (6)
There has been interest in the antibodies associated with AIP. In addition to elevated IgG4, an antibody to plasminogen-binding protein (PBP) of Helicobacter pylori that cross-reacts with ubiquitin-protein ligase E3 component n-recognin 2 (UBR2) from the pancreas was identified, but it is also elevated in some cases of pancreatic cancer (7). Others have identified autoantibodies to trypsinogen and other acinar or duct cell proteins (8).
Type 2 AIP.
The heterogeneity of AIP has led some to argue for two subtypes (9-11). Type1 is described above (elevated serum IgG4 levels`, IgG4-postitive cell infiltration`, involvement of multiple organs`, significant fibrosis). Type 2 AIP patients are on average a decade or more younger than type 1 patients and do not show the gender bias seen in type 1 AIP (11). Type 2 is rare in Asia, but seen in up to ~40% of cases in some series from the USA and Europe (9, 11). Type 2 AIP does not appear to be related to ISD, with inflammatory bowel disease being the only association described in ~ 10-40% of patients (9, 11). Histology reveals granulocyte epithelial lesions (GEL) or duct centric pancreatitis rather than the IgG4-postivie cells (1). Like Type 1 AIP, Type 2 responds to steroids, but is less likely to recur (9).
Unlike typical CP there is often significant improvement of pancreatic insufficiency with steroid treatment (12, 13), but this is not a uniform finding and some patients continue to have moderate to severe exocrine pancreatic insufficiency. Recurrences in our series were common and necessitated the concomitant use of azathioprine to maintain remission (2). Recurrences were seen more frequently in patients who had extrapancreatic biliary strictures (2).
Typical corticosteroid dose (6, 14): Prednisone, 40 mg orally x 4 weeks, then taper by 5 mg every week.
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2. Raina A, Yadav D, Krasinskas AM, McGrath KM, Khalid A, Sanders M, et al. Evaluation and Management of Autoimmune Pancreatitis: Experience at a Large US Center. Am J Gastroenterol. 2009 Jun 16;104(9):2295-306.
3. Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006 Aug;4(8):1010-6; quiz 934.
4. Kim KP, Kim MH, Kim JC, Lee SS, Seo DW, Lee SK. Diagnostic criteria for autoimmune chronic pancreatitis revisited. World J Gastroenterol. 2006 Apr 28;12(16):2487-96.
5. Otsuki M, Chung JB, Okazaki K, Kim MH, Kamisawa T, Kawa S, et al. Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea Symposium on Autoimmune Pancreatitis. J Gastroenterol. 2008;43(6):403-8.
6. Chari ST, Takahashi N, Levy MJ, Smyrk TC, Clain JE, Pearson RK, et al. A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer. Clin Gastroenterol Hepatol. 2009 Oct;7(10):1097-103.
7. Frulloni L, Lunardi C, Simone R, Dolcino M, Scattolini C, Falconi M, et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med. 2009 Nov 26;361(22):2135-42.
8. Lohr JM, Faissner R, Koczan D, Bewerunge P, Bassi C, Brors B, et al. Autoantibodies Against the Exocrine Pancreas in Autoimmune Pancreatitis: Gene and Protein Expression Profiling and Immunoassays Identify Pancreatic Enzymes as a Major Target of the Inflammatory Process. Am J Gastroenterol. 2010 Apr 20.
9. Sah RP, Chari ST, Pannala R, Sugumar A, Clain JE, Levy MJ, et al. Differences in Clinical Profile and Relapse Rate of Type 1 Versus Type 2 Autoimmune Pancreatitis. Gastroenterology. 2010 Mar 27.
10. Frulloni L, Scattolini C, Falconi M, Zamboni G, Capelli P, Manfredi R, et al. Autoimmune pancreatitis: differences between the focal and diffuse forms in 87 patients. Am J Gastroenterol. 2009 Sep;104(9):2288-94.
11. Sugumar A, Kloppel G, Chari ST. Autoimmune pancreatitis: pathologic subtypes and their implications for its diagnosis. Am J Gastroenterol. 2009 Sep;104(9):2308-10; quiz 11.
12. Chari ST. Current concepts in the treatment of autoimmune pancreatitis. Jop. 2007;8(1):1-3.
13. Frulloni L, Scattolini C, Katsotourchi AM, Amodio A, Gabbrielli A, Zamboni G, et al. Exocrine and Endocrine Pancreatic Function in 21 Patients Suffering from Autoimmune Pancreatitis before and after Steroid Treatment. Pancreatology. 2010 May 12;10(2-3):129-33.
14. Hirano K, Tada M, Isayama H, al e. Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment. Gut. 2007;56:1719–24.