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 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

International Consensus Diagnostic Criteria Levels 1 & 2 for Autoimmune Pancreatitis (AIP) Types 1 & 2
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

  • 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

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

      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
      • 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

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 Laboratory Tests

Primary Tests

Evaluate for presence of pancreatitis

Aid in diagnosis of immunodeficiencies

Aid in the diagnosis of autoimmune pancreatitis

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

Related Tests

Evaluate for presence of pancreatitis

Initial screening for hepatobiliary inflammation

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

Evaluate for presence of infection

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

Aid in initial diagnosis of connective tissue disease

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

Differentiates autoimmune pancreatitis (AIP) from PBC

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Executive Vice President, ARUP Laboratories
Division Chief of Clinical Pathology, University of Utah and ARUP Laboratories
Professor of Clinical Pathology, University of Utah
Medical Director, Protein Immunology and Immunologic Flow Laboratories, ARUP Laboratories
Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer: Medical Director, Automated Core Laboratory, ARUP Laboratories

References

Additional Resources
Last Update: October 2020 Content Review: December 2017

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