1. RECAP: Autoimmune Pancreatitis
Type 2: Idiopathic duct-centric pancreatitis
GELs: granulocite, ephitelial lesions

2. IgG-4 Related Diseases
Various organ manifestations of a fibro-inflammatory condition characterized by tumefactive lesions recognised as a systemic condition in 2003
Linked by the same histopathological characteristics and elevated serum IgG4 concentrations.
Multiple immune-mediated mechanism contribute to the fibro-inflammatory process, being autoimmunity and infectious agents potential triggers of a Th-2 and T-reg response.

3. Pathophysiology
Stone J, Zen Y. IgG4-Related Disease N Engl J Med 2012;366:

4. IgG-4 Related Diseases

5. IgG-4 Related Pancreato-biliary Diseases
Majority of patients are men (60-73%), > 60 years
Prevalence 0,2-0,8/
Lack of familiarity!
Up to 40% of patients have allergic diseases (atopy, eczema, asthma, chronic sinusitis)
30% normal serum IgG-4 concentrations
IgG-4 related sclerosing cholangitis associated with AIP in 47–92% of pt

6. IgG-4 Pancreatitis Clinical presentation Acute vs Chronic symptoms
Painless obstructive jaundice 33–60%
Steatorrhea - exocrine functional abnormalities in up to 80%
Abdominal pain 32%
Back pain and weight loss 15%
Serologic marker:
 titers of g-globulin (>2000 mg/dL)
 IgG (>1800 mg/dL)
 IgG4 (>140 mg/dL)
Serum IgG4 >140 mg/dL
86% SN, 96% SP

7. IgG-4 Pancreatitis Imaging features
Enlarged pancreas “sausage-like appareance” %
Focal masses 30%
Soft tissue hypoenhancing rim
Narrowing of main pancreatic duct
“Duct-penetrating” sign at secretin-MRCP

8. IgG4 Pancreatitis: DD

9. IgG-4 Pancreatitis Role of EUS-FNA
Histological proof of the disease: GOLD STANDARD
Exclusion of carcinoma
Discrimination of type 1 from type 2 AIP
Diffuse lymphoplasmacytic
infiltration and storiform fibrosis
IgG4-positive
plasma cells
> 10/hpf

10. IgG-4 Pancreatitis Hystology is the GOLD STANDARD:
Diffuse lymphoplasmacytic infiltration with mild- moderate eosinophilia
Obliterative flebitis and storiform fibrosis
IgG4 immunostaining:
> 50 IgG4 plasma cells/HPF for surgical specimens
> 10 IgG4 plasma cells/HPF for biopsy samples
Ratio IgG4-positive/IgG-positive plasma cells > 40%

11. Storiform Fibrosis

12. IgG-4 Pancreatitis: diagnosis
The MAYO Clinic HISORt criteria

13. IgG-4 Cholangitis Clinical presentation
70% obstructive jaundice with pruritus and abdominal pain
Asymptomatic jaundice less common than AIP
7-10% cirrhosis manifestation (hepatic failure, ascites, hepatic encephalopathy or variceal bleeding)
Serologic marker:
 titers of g-globulin (>2000 mg/dL)
 IgG (>1800 mg/dL)
 IgG4 (>140 mg/dL)
 reumatoid factor, antinucleus antibody

14. IgG-4 Cholangitis Imaging features
Isolated intrapancreatic CBD strictures
Localized hilar hepatic lesion (strictures or masses)
Intense and diffuse extension of bile duct wall homogeneous thickening (often circular)
IDUS: inflamed submucosa and preserved epithelium, circular symmetric wall thickening

15. IgG-4 Cholangitis DD
IDUS: eccentric wall thickening with an irregular luminal surface, disruption of the bile duct wall layered structure, and a hypoechoic mass with irregular margins

16. IgG-4 Cholangitis DD
IDUS: all bile duct layers inflamed, bile duct epithelium severely damaged, disappearance of the three layers
Imaging: diverticulum-like out-pouching, and beaded - tree appearance

17. Therapy INDUCTION 0,6-1 mg/kg oral prednisolone
TAPERING 5 mg/wk reduction
MAINTENANCE: 2,5-5 mg/die oral prednisolone or AZA
Pancreatic enzyme supplementation (pancrelipasis) for exocrine insufficiency if: steatorrhoea, weight loss, metabolic bone disease, vitamin deficiency
Oral hypoglicemic agents or insulin for diabetes mellitus
Biliary stenting in obstructive jaundice (case-by-case)

18. Outcomes Spontaneous resolution in up to 30%
Response to steroid therapy in 90% to 95% with improvement of imaging findings and serology within 2 weeks + symptoms regression
New onset diabetes mellitus usually improves with corticosteroid therapy
Chronic pancreatitis in about 10%
Very rarely progression to cirrhosis in IgG-4 cholangitis

19. Outcomes
Response to steroid therapy in 90% to 95% of both parenchymal and ductal changes
Before (A) steroid therapy and after (B)

20. TAKE HOME MESSAGES Suspect! May have acute or chronic manifestation
Typical imaging findings (CT/MRI)
Mandatory is exclusion of carcinoma
Characteristic histopathological appearance: histology is the GOLD STANDARD
Not always elevated IgG and IgG-4 levels
Systemic disease: look for biliary and retroperitoneal involvement

21. Bibliografia
Stone J, Zen Y. IgG4-Related Disease N Engl J Med 2012; 366:
Kamisawa T, Zen Y. Advances in IgG4-related pancreatobiliary diseases. Lancet Gastroenterol Hepatol 2018; 3: 575–85.
Sandrasegaran K, Menias C. Imaging in Autoimmune Pancreatitis and Immunoglobulin G4–Related Disease of the Abdomen. Gastroenterol Clin N Am Article in press.