Autoimmune Pancreatitis

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 disease. 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

International Consensus Diagnostic Criteria Levels 1 & 2 for Autoimmune Pancreatitis (AIP) Types 1 & 2
Criterion	Type 1 AIP		Type 2 AIP
Criterion	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 Lymphoplasmacytic infiltration with fibrosis and without granulocytic infiltration Storiform fibrosis Obliterative phlebitis >10 cells/HPF IgG4-positive cells Typical radiology – any 1 of the following Segmental/multiple proximal or distal biliary stricture Retroperitoneal fibrosis	Extrapancreatic organ histology including bile duct biopsies – both of Marked lymphoplasmacytic infiltration without granulocytic infiltration 10 cells/HPF IgG4-positive cells Physical or radiological evidence of ≥1 of the following Enlarged salivary/lachrymal glands Renal involvement	Clinically diagnosed IBD	n/a
Histology of pancreas	LPSP and 3 of the following Periductal lymphoplasmacytic infiltrate without granulocytic infiltration Obliterative phlebitis Storiform fibrosis >10 cells/HPF IgG4-positive cells	LPSP and 2 of the following Periductal lymphoplasmacytic infiltrate without granulocytic infiltration Obliterative phlebitis Storiform fibrosis >10 cells/HPF IgG4-positive cells	IDCP and both of the following Granulocytic infiltration of duct wall with or without acinar inflammation 0-10 cells/HPF IgG4-positive cells	Both of the following Granulocytic and lymphoplasmacytic acinar infiltrate 0-10 cells/HPF IgG4-positive cells
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

Diagnosis of Types 1 and 2 AIP
	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
	Imaging	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

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
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
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)

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

Laboratory Testing

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

Histology

Characterized by lymphocyte and plasma cell infiltration
- Important in differentiating AIP from acute and chronic pancreatitis, lymphoma, and pancreatic cancer

Imaging Studies

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

Differential Diagnosis

Pancreatic cancer
Cholangiocarcinoma
Idiopathic pancreatitis
Primary sclerosing cholangitis
Primary biliary cholangitis

Background

Epidemiology

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

Classification

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

Pathophysiology

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
Type 2 AIP
- May be focal or diffuse (duct centric)
  - Focal often resembles pancreatic mass (cancer)
- Histologic hallmark is idiopathic, duct-centric pancreatitis

Clinical Presentation

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 Lab Tests

Primary Tests

Evaluate for presence of pancreatitis

0020014

Lipase, Serum or Plasma 0020014

Method

Quantitative Enzymatic

Aid in diagnosis of immunodeficiencies

0050576

Immunoglobulin G Subclass 4 0050576

Method

Quantitative Nephelometry

0080461

Cancer Antigen-GI (CA 19-9) 0080461

Method

Quantitative Electrochemiluminescent Immunoassay

Aid in the diagnosis of autoimmune pancreatitis

Stained and returned to client pathologist for interpretation; consultation available if needed

2005844

Immunoglobulin G4 by Immunohistochemistry 2005844

Method

Immunohistochemistry

Related Tests

Evaluate for presence of pancreatitis

0020013

Amylase, Serum or Plasma 0020013

Method

Quantitative Enzymatic

Initial screening for hepatobiliary inflammation

0020416

Hepatic Function Panel 0020416

Method

Quantitative Enzymatic/Quantitative Spectrophotometry

Panel includes albumin; alkaline phosphatase (ALP); aspartate aminotransferase (AST); alanine aminotransferase (ALT); bilirubin, direct; protein, total; and bilirubin, total

Evaluate for presence of infection

0040002

CBC with Platelet Count 0040002

Method

Automated Cell Count

Aid in initial diagnosis of connective tissue disease

Antinuclear antibodies (ANA) enzyme-linked immunosorbent assay (ELISA) screen is designed to detect antibodies against double-stranded DNA (dsDNA), histones, SS-A (Ro), SS-B (La), Smith, Smith/RNP, Scl-70, Jo-1, centromere proteins, and other antigens extracted from the HEp-2 cell nucleus

Reported to have lower sensitivities than ANA indirect fluorescent antibody (IFA) for systemic autoimmune rheumatic diseases

0050080

Antinuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, HEp-2 Substrate, IgG by IFA 0050080

Method

Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Aid in initial diagnosis of connective tissue disease

0050317

Antinuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA HEp-2 Substrate, IgG by IFA and ENA Confirmation 0050317

Method

Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

May be useful in confirming a diagnosis of primary biliary cholangitis (PBC)

Differentiates autoimmune pancreatitis (AIP) from PBC