Pancreatitis, Autoimmune

Diagnosis

Indications for Testing

• Abdominal pain, jaundice; presence of recurrent or chronic pancreatitis

Criteria for Diagnosis

• Currently, no consensus diagnostic criteria for AIP has been established; however, several groups have outlined useful diagnostic criteria  
  • Diagnostic criteria for autoimmune pancreatitis by the Japan Pancreas Society (JPS)

    JPS Diagnostic Criteria for Autoimmune Pancreatitis
    Findings on imaging radiography (one 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 (one required) Serologic analysis Elevated serum IgG4 level Elevated serum IgG or gammaglobulin level Presence of antilactoferrin antibody (ALA), anti-carbonic anhydrase II antibody (ACA II), anti-smooth muscle antibody (ASMA), or antinuclear antibody (ANA) Pancreatic-biliary histologic analysis Periductal lymphoplasmacytic infiltration or fibrosis Obliterative phlebitis IgG4-positive plasma cells in tissue* Nongastrointestinal histologic analysis Tubulointerstitial nephritis with immune deposits within tubular basement membranes Pulmonary interstitial lymphoplasmacytic infiltration with IgG4-positive plasma cells* 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 (Korea)

    Kim Diagnostic Criteria for Autoimmune Pancreatitis

    Diagnostic Criteria

    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

    For diagnosis, criterion I must be present, together with any of criteria II to IV

    HISORt diagnostic criteria for autoimmune pancreatitis (USA)

    HISORt Diagnostic Criteria for Autoimmune Pancreatitis
    Group	Criteria
    A. Histology	Diagnostic (any one) Pancreatic histology showing lymphoplasmacytic sclerosing pancreatitis (LPSP) Lymphoplasmacytic infiltrate with abundant (>10 cells/HPF) IgG4-positive cells in pancreas Supportive (any one) 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
    CT: computed tomography; MRI: magnetic resonance imaging; ERCP: endoscopic retrograde cholangiopancreatography; HPF: high power field

    Diagnostic criteria for autoimmune pancreatitis by the Italian Group

    Diagnostic Criteria for Autoimmune Pancreatitis by Italian Group

    Histology and cytology Dense lymphocyte infiltration and destruction of the exocrine glands, “destructive pancreatitis” on histology or rich inflammatory cells on cytology The association with other postulated autoimmune disease Response to the steroid therapy

• Although significant differences exist among these criteria, overlaps occur in certain aspects
  • The most comprehensive diagnostic criteria for AIP is from the JPS and requires imaging plus laboratory and/or histopathologic findings

Laboratory Testing

• Initial testing – IgG4, CA19-9, liver enzymes, CBC, amylase and lipase
  • Marked elevation of any of these tests is rare except for IgG4
    • Twofold elevation of IgG4 highly suggestive of AIP
    • IgG4 elevated in <50% of U.S./European patients
  • CA19-9 – elevated in 50% of patients with AIP and does not necessarily indicate malignancy
• Nonspecific autoantibody testing
  • Nonspecific testing may have already been performed
  • ANA – positive in >50%
  • RF, anti SS-A, anti SS-B, AMA – positive in 20%
  • ALA, ACA, ASMA
    • Sensitivity of these markers is unknown

Histology

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

Imaging Studies

• Ultrasound/CT/MRI – typically shows diffuse enlargement of the pancreas (sausage shape)
• ECRP/MRCP

Differential Diagnosis

• Pancreatic or biliary cancer (main differential) 
• Acute pancreatitis
• Primary sclerosing cholangitis
• Primary biliary cirrhosis
• Inflammatory bowel diseases – ulcerative colitis, Crohn disease
• Autoimmune hepatitis
• Castleman disease
• Sjögren syndrome

Clinical Background

Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterized by diffuse enlargement of the pancreas, narrowing of the pancreatic duct, lymphoplasmacytic infiltration and fibrosis, and increased serum IgG4. A response to steroid treatment is also characteristic.

Epidemiology

• Incidence – rare, <1/100,000 (including Japan)
• Age
  • Type 1 – usually 60s
  • Type 2 – usually 50s
• Sex
  • Type 1 – M>F; 2-3:1
  • Type 2 – M:F, equal

Classification

• Type 1 – elevated IgG4-associated systemic disease (bile duct, salivary gland, lymph nodes, kidneys, retroperitoneum)
• Type 2 – not associated with elevated IgG4; systemic organ disease includes only inflammatory bowel disease to this point

Pathophysiology

• Type 1
  • Histologic hallmark is collar-like preductal infiltrates composed of lymphocytes and plasma cells termed lymphoplasmacytic sclerosing pancreatitis (LPSP)
    • Other organs may be involved, including the gallbladder, bile ducts, kidney, lung and salivary glands
    • IgG4-positive plasma cells have been identified in some patients
• Type 2
  • May be focal or diffuse
    • Focal often resembles pancreatic mass (cancer)
  • Histologic hallmark is idiopathic, duct-centric pancreatitis

Clinical Presentation

• AIP may coexist in about 40-60% of patients with another autoimmune disease, such as chronic sclerosing sialoadenitis, primary sclerosing cholangitis or primary biliary cirrhosis
  • Constitutional symptom – weight loss
• Pancreatic symptoms
  • Obstructive jaundice
  • Abdominal pain
  • Diabetes
  • Weight loss
• Extrapancreatic symptoms
  • Pulmonary – discrete nodules, diffuse infiltrate, hilar adenopathy
  • Renal – lesions, mild renal insufficiency

Treatment

• Steroids
  • 2- 3-week course
  • Positive response to steroids confirms diagnosis

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA 0050080 Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody	Screen for connective tissue disease as cause of disease All ELISA results reported as Detected are further tested by IFA ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells ANA ELISA assays have been reported to have lower sensitivities for antibodies associated with nucleolar and specked ANA-IFA patterns
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflexes to ANA, IgG by IFA and to dsDNA, RNP, Smith, SSA, and SSB Antibodies, IgG 0050317 Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay	If ELISA screen is positive, then IFA using HEp-2 substrate will be added; if confirmed by IFA, titer and pattern will be reported and testing for dsDNA antibody and ENA antibodies will be added
Rheumatoid Factors, IgA, IgG, and IgM by ELISA 0051298 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Enzyme-Linked Immunosorbent Assay.	Screen for rheumatoid arthritis as cause of disease
Mitochondrial M2 Antibody, IgG (ELISA) 0050065 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Differentiate AIP from PBC
F-Actin (Smooth Muscle) Antibody, IgG 0055248 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	F-actin antibodies have greater sensitivity and specificity for autoimmune disease than anti-smooth muscle antibodies