Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis characterized by diffuse enlargement of the pancreas, narrowing of the pancreatic duct, and lymphoplasmacytic infiltration and fibrosis. AIP presents similarly to pancreatic cancer, so definite diagnosis is imperative to avoid unnecessary major surgery.
Type I AIP is the pancreatic manifestation of systemic IgG4-related isease. Histologically, it is a lymphoplasmacytic sclerosing pancreatitis (LPSP). Refer to ARUP Consult’s IgG4-related disease topic for more information.
Type 2 AIP, or idiopathic duct-centric pancreatitis, is IgG4 negative and is characterized by granulocytic lesions. Type 2 is more rare and less well understood.
Both types respond to steroid therapy, although type 1 AIP will often (20-60% of the time) relapse (Hart, 2015).
Diagnosis
Indications for Testing
- Painless obstructive jaundice
- Chronic or recurrent abdominal pain
- Pancreatic mass
- Decrease in pancreatic function resulting in hyperglycemia or steatorrhea
- Acute pancreatitis
Criteria for Diagnosis
Criterion | Type 1 AIP | Type 2 AIP | ||
---|---|---|---|---|
Level 1 Criteria | Level 2 Criteria | Level 1 Criteria | Level 2 Criteria | |
Parenchymal imaging |
Typical – diffuse enlargement with delayed enhancement |
Indeterminate – focal enlargement with delayed enhancement |
Typical – diffuse enlargement with delayed enhancement |
Indeterminate – focal enlargement with delayed enhancement |
Ductal imaging (ERP) |
Long or multiple strictures (>1/3 duct length) without upstream dilatation |
Focal narrowing without upstream dilatation (<5 mm) |
Long (>1/3 duct length) or multiple strictures without upstream dilatation |
Focal narrowing without upstream dilatation (<5 mm) |
Serology |
IgG4 >2x upper limit |
IgG4 1-2x upper limit |
n/a |
n/a |
Other organ involvement |
Extrapancreatic organ histology – any 3 of the following
Typical radiology – any 1 of the following
|
Extrapancreatic organ histology including bile duct biopsies – both of
Physical or radiological evidence of ≥1 of the following
|
Clinically diagnosed IBD |
n/a |
Histology of pancreas |
LPSP and 3 of the following
|
LPSP and 2 of the following
|
IDCP and both of the following
|
Both of the following
|
Response to steroid (Rt) |
Rapid (<2 wk) radiological demonstration of marked improvement in pancreatic/extrapancreatic manifestations |
Rapid (<2 wk) radiological demonstration of marked improvement in manifestations |
||
O’Reilly, 2014 AIP, autoimmune pancreatitis; IBD, inflammatory bowel disease; IDCP, idiopathic duct-centric pancreatitis; H, histology; HPF, high powered field; LPSP, lymphoplasmacytic sclerosing pancreatitis; OOI, other organ involvement; Rt, response to steroid therapy; S, serology |
Type 1 AIP | Type 2 AIP | |||||
---|---|---|---|---|---|---|
Cardinal feature | Imaging evidence | Collateral evidence | Imaging evidence | Collateral evidence | ||
Definitive diagnosis |
Histology |
Typical/indeterminate |
Confirmed LPSP |
Typical/ indeterminate |
Histologically confirmed or clinical IBD and level 2H and Rt |
|
Imaging |
Typical |
Any level ½ |
Typical/ indeterminate |
Histologically confirmed or clinical IBD and level 2H and Rt |
||
Indeterminate |
≥2 level 1 |
Typical/ indeterminate |
Histologically confirmed or clinical IBD and level 2H and Rt |
|||
Steroid response |
Indeterminate |
Level 1 S/OOI and Rt OR Level 1 D and level 2 S/OOI/H and Rt |
Typical/ indeterminate |
Histologically confirmed or clinical IBD and level 2H and Rt |
||
Probable diagnosis |
n/a |
Indeterminate |
Level 2S/OOI/H and Rt |
Typical/ indeterminate |
Level 2H/clinical IBD and Rt |
|
O’Reilly, 2014 AIP, autoimmune pancreatitis; IBD, inflammatory bowel disease; IDCP, idiopathic duct-centric pancreatitis; H, histology; HPF, high powered field; LPSP, lymphoplasmacytic sclerosing pancreatitis; OOI, other organ involvement; Rt, response to steroid therapy; S, serology |
- Several diagnostic criteria have been developed, relying primarily on imaging and histology, and incorporating additional information about other organs involved and response to steroids
- Serum IgG4 elevations – helpful in diagnosis of type 1 AIP (~66% will have elevations)
- Not helpful for type 2 AIP (only ~25% have elevated serum IgG4)
- Although significant differences exist among these criteria, overlaps occur in certain aspects
- Serum IgG4 elevations – helpful in diagnosis of type 1 AIP (~66% will have elevations)
- The most comprehensive diagnostic criteria for AIP is from the new international consensus – requires imaging plus laboratory and/or histopathologic findings
- HISORt (histology, imaging, serology, other organ involvement, and response to therapy) diagnostic criteria for autoimmune pancreatitis (Chari, 2006)
HISORt Diagnostic Criteria for Autoimmune Pancreatitis Group Criteria A. Histology
Diagnostic (any 1)
- Pancreatic histology showing LPSP
- Lymphoplasmacytic infiltrate with abundant (>10 cells/HPF) IgG4-positive cells in pancreas
Supportive (any 1)
- Lymphoplasmacytic infiltrate with abundant (>10 cells/HPF) IgG4-positive cells in involved
extrapancreatic organ - Lymphoplasmacytic infiltrate with fibrosis in pancreas
B. Imaging
Typical imaging features
- CT/MRI – diffusely enlarged gland with delayed (rim) enhancement
- ERCP – diffusely irregular and 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
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
F. Diagnosis
- Group A, diagnostic histology alone
- Group B, typical imaging features and elevated serum IgG4
- Group C, unexplained pancreatic disease with serology or other organ involvement and response to steroid
Source: Chari, 2006
CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; HPF, high power field; LPSP, lymphoplasmacytic sclerosing pancreatitis; MRI, magnetic resonance imaging
-
Diagnostic criteria for autoimmune pancreatitis by the Japan Pancreas Society (Okazaki, 2009)
- Findings on imaging radiography (1 required)
- Cross-sectional imaging
- Diffusely enlarged pancreas
- Enhanced peripheral rim of hypoattenuation “halo”
- Low-attenuation mass in head of pancreas
- Endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP)
- Segmental pancreatic ductal narrowing
- Focal pancreatic ductal narrowing
- Diffuse pancreatic ductal narrowing
- Cross-sectional imaging
- Serologic and histologic findings (1 required)
- Serologic analysis
- Elevated serum IgG4 level
- Elevated serum IgG or gammaglobulin level
- Presence of antilactoferrin antibody (ALA), anticarbonic anhydrase II antibody (ACA II), antismooth muscle antibody (ASMA), or antinuclear antibody (ANA)
- Pancreatic-biliary histologic analysis
- Periductal lymphoplasmacytic infiltration or fibrosis
- Obliterative phlebitis
- IgG4-positive plasma cells in tissue (the presence of tissue IgG4-positive cells is not necessarily abnormal, but an increased number of infiltrating IgG4-positive plasma cells is abnormal)
- Nongastrointestinal histologic analysis
- Tubulointerstitial nephritis with immune deposits within tubular basement membranes
- Pulmonary interstitial lymphoplasmacytic infiltration with IgG4-positive plasma cells (the presence of tissue IgG4-positive cells is not necessarily abnormal, but an increased number of infiltrating IgG4-positive plasma cells is abnormal)
- Chronic sialadenitis with IgG4-positive plasma cells (the presence of tissue IgG4-positive cells is not necessarily abnormal, but an increased number of infiltrating IgG4-positive plasma cells is abnormal)
- Serologic analysis
- Findings on imaging radiography (1 required)
- Kim diagnostic criteria for autoimmune pancreatitis (Kim, 2006)
- For diagnosis, criterion I must be present, together with any of criteria II to IV
- Criterion I. Pancreatic imaging (essential)
- Diffuse enlargement of pancreas and
- Diffuse/segmental irregular narrowing of main pancreatic duct
- Criterion II. Laboratory finding
- Elevated levels of IgG or IgG4 or
- Detected autoantibodies
- Criterion III. Histopathology
- Fibrosis and lymphoplasmacytic infiltration
- Criterion IV. Response to steroid
- HISORt (histology, imaging, serology, other organ involvement, and response to therapy) diagnostic criteria for autoimmune pancreatitis (Chari, 2006)
- Initial testing
- Liver enzymes
- May show an obstructive pattern
- Lipase
- May be elevated
- Nonspecific marker for pancreatic damage
- CBC
- Useful in evaluation for malignancy
- Does not provide information for diagnosis of AIP
- Serum IgG4
- ≥2-fold elevation of IgG4 highly suggestive of AIP
- IgG4 elevated in ~66% of patients (Hart, 2015)
- CA19-9 – elevated in 50% of patients with AIP
- Also elevated in malignancy, but not specific for malignancy
- Liver enzymes
- Characterized by lymphocyte and plasma cell infiltration
- Important in differentiating AIP from acute and chronic pancreatitis, lymphoma, and pancreatic cancer
- Endoscopic ultrasound – diffusely irregular and attenuated main pancreatic duct
- Computed tomography (CT)/magnetic resonance imaging (MRI) – typically shows diffuse enlargement of the pancreas (sausage shape)
- Endoscopic retrograde cholangiopancreatography (ECRP)/magnetic resonance cholangiopancreatography (MRCP) – may be necessary for equivocal cases
- Pancreatic cancer
- Cholangiocarcinoma
- Idiopathic pancreatitis
- Primary sclerosing cholangitis
- Primary biliary cholangitis
- Prevalence – 0.82/100,000 in Japan (no U.S. or European data available) (Martins, 2017)
- Age (Martins, 2017)
- Type 1 AIP – mean age 61.4
- Type 2 AIP – mean age 39.9
- Sex (Martins, 2017)
- M>F, 3:1
- Type 1 AIP
- Pancreatic manifestation of immunoglobulin IgG4-related disease, a multiorgan disease
- LPSP
- Type 2 AIP
- Pancreas specific disorder not associated with elevated IgG4
- Idiopathic duct-centric pancreatitis (IDCP)
- May be associated with inflammatory bowel disease, especially ulcerative colitis
- Type 1 AIP
- Histologic hallmark is collar-like preductal infiltrates composed of lymphocytes and plasma cells termed LPSP
- Other organs involved – gallbladder, bile ducts, kidney, lung, and salivary glands most common
- IgG4-positive plasma cells have been identified in some patients
- Histologic hallmark is collar-like preductal infiltrates composed of lymphocytes and plasma cells termed LPSP
- Type 2 AIP
- May be focal or diffuse (duct centric)
- Focal often resembles pancreatic mass (cancer)
- Histologic hallmark is idiopathic, duct-centric pancreatitis
- May be focal or diffuse (duct centric)
- Constitutional symptoms – weight loss, fatigue
- Marked anorexia, cachexia suggest carcinoma
- Pancreatic symptoms
- Obstructive jaundice – often painless
- Abdominal pain – not severe
- Marked pain suggests carcinoma
- Hyperglycemia
- Steatorrhea
- Type 2 AIP may have coexisting inflammatory bowel disease
- Type 1 AIP frequently has multiorgan involvement
ARUP Laboratory Tests
Evaluate for presence of pancreatitis
Quantitative Enzymatic Assay
Aid in diagnosis of immunodeficiencies
Quantitative Immunoturbidimetry
Quantitative Electrochemiluminescent Immunoassay
Aid in the diagnosis of autoimmune pancreatitis
Stained and returned to client pathologist for interpretation; consultation available if needed
Immunohistochemistry
Evaluate for presence of pancreatitis
Quantitative Enzymatic Assay
Initial screening for hepatobiliary inflammation
Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Panel includes albumin; alkaline phosphatase (ALP); aspartate aminotransferase (AST); alanine aminotransferase (ALT); bilirubin, direct; protein, total; and bilirubin, total
Aid in initial diagnosis of connective tissue disease
Positive nuclear patterns reported include homogeneous, speckled, centromere, nucleolar, or nuclear dots; positive cytoplasmic patterns reported include reticular/AMA, discrete/GW body-like, polar/golgi-like, rods and rings, or cytoplasmic speckled patterns
Reported to have lower sensitivities than ANA indirect fluorescent antibody (IFA) for systemic autoimmune rheumatic diseases
Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Aid in initial diagnosis of connective tissue disease
Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
May be useful in confirming a diagnosis of primary biliary cholangitis (PBC)
Differentiates autoimmune pancreatitis (AIP) from PBC
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
References
21547125
Frulloni L, Amodio A, Katsotourchi AM, et al. A practical approach to the diagnosis of autoimmune pancreatitis. World J Gastroenterol. 2011;17(16):2076-2079.
25770706
Hart PA, Zen Y, Chari ST. Recent advances in autoimmune pancreatitis. Gastroenterology. 2015;149(1):39-51.
23749606
Kamisawa T, Chari ST, Lerch MM, et al. Recent advances in autoimmune pancreatitis: type 1 and type 2. Gut. 2013;62(9):1373-1380.
16688792
Kim KP, Kim MH, Kim JC, et al. Diagnostic criteria for autoimmune chronic pancreatitis revisited. World J Gastroenterol. 2006;12(16):2487-2496.
29255773
Martins C, Lago P, Sousa P, et al. Type 2 autoimmune pancreatitis: a challenge in the differential diagnosis of a pancreatic mass. GE Port J Gastroenterol. 2017;24(6):296-300.
25469024
Matsubayashi H, Kakushima N, Takizawa K, et al. Diagnosis of autoimmune pancreatitis. World J Gastroenterol. 2014;20(44):16559-16569.
24891978
O'Reilly DA, Malde DJ, Duncan T, et al. Review of the diagnosis, classification and management of autoimmune pancreatitis. World J Gastrointest Pathophysiol. 2014;5(2):71-81.
22350841
Sah RP, Chari ST. Autoimmune pancreatitis: an update on classification, diagnosis, natural history and management. Curr Gastroenterol Rep. 2012;14(2):95-105.
21412117
Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40(3):352-358.
26141331
Stone JH, Brito-Zerón P, Bosch X, et al. Diagnostic approach to the complexity of IgG4-related disease. Mayo Clin Proc. 2015;90(7):927-939.
22316447
Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539-551.
21884246
Sugumar A, Chari ST. Autoimmune pancreatitis. J Gastroenterol Hepatol. 2011;26(9):1368-1373.
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