1. 췌장 종괴 경희대학교 부속병원 소화기 내과 동 석 호

2. 유 O 세 (F/60) 입원일 : 2008.11.21 Case Chief Complaint uncontrolled DM, weight loss 6kg Present Illness 60 세 여자, 1 년 7 개월전 우연히 시행한 혈당 검사 결과 당뇨 진단받아 혈당강하제 복용하여 잘 조절되던 중에 1 년전 당뇨 약을 임의로 중단하고 건강보조식품에 의존하던 환자로 2 개 월전 측정한 혈당 검사 결과 glucose 390mg/dL, HbA1c 13.7% 로 혈당 조절위해 내분비 내과 입원함.

3. CBC/DC 8150 – 14.0 g/dL – 40.4% - 275k (seg. 67.9%) Chemistry TB / DB : 0.20 / 0.06 mg/dL CRP < 0.5 mg/dL AST /ALT : 14 / 18 IU/L Protein / Alb : 6.3 / 3.4 mg/dL ALP : 91 IU/L GGT : 20 IU/L BUN / Cr : 10 / 0.5 mg/dL Na / K / Cl : 141 / 3.3 / 102 mmol/L Ca / P / Mg : 8.3 / 3.0 / 1.9 mg/dL Uric acid : 2.1 mg/dL T-cholesterol : 148 mg/dL Glucose : 290 mg/dL Amylase : 103 IU/L Lipase : 41 IU/L Initial Lab Findings CA19-9 : 2.0 IU/mL

4. Uncontrolled type 2 DM S> polydipsia, polyuria, fatigue, weight loss O> blood glucose : 390 mg/dL, HbA1c : 13.7% A> Uncontrolled DM P> insulin therapy consider abdominal imaging study Problem List

5. 초음파 2008.11.22 Diffuse swelling, mass formation of pancreas head and body

6. diffuse enlargement of pancreas head CT 2008.11.22 diffuse enlargement of pancreas body pancreatic duct dilatation in tail portion diffuse enlargement of pancreas head and body

7. MRCP 2008.11.26 double duct sign Upstream P-duct dilatation main P-duct stricture

8. Abdominal imaging pancreatic mass with upstream p-duct dilatation

9. Mass with dilated duct ; adenocarcinoma, chronic pancreatitis Diffuse enlargement of head and body ; lymphoma, metastasis focal pancreatitis, tuberculosis, autoimmune pancreatitis,

10. 1.PET 2.ERCP 3.EUS-guided FNA or trucut biopsy 4.Exploratory surgery Clinical Question 1. What is diagnostic strategy for confirming this pancreas mass?

11. EUS-guided FNA 2008.11.27

12. Procedure name : EUS-guided FNA Specimen adequacy : Satisfactory Diagnosis : Pancreas, No malignant cells Cytology Report

13. Mass-related symptom and sign : no abdominal pain, no jaundice Abnormal lab finding : Only elevated serum glucose Imaging study (CT and MRI) : suggestive of AIP (autoimmune pancreatitis) Pancreas mass

14. Asian diagnostic criteria for AIP (2008)

15. EUS-guided FNA : exclude pancreas cancer ERCP : diffuse/segmental/focal main pancreatic duct narrowing Serum IgG, IgG4, autoantibody Diagnostic plan for AIP

16. PET 2008.11.28 SUV 3.32

17. ERCP 2008.12.1

18. Diffuse narrowing of the main pancreatic duct with irregular wall (more than 2/3 length of the entire pancreas) with distal CBD stenosis ERCP finding

19. Duodenal papilla

20. x200

21. Plasma cell x400

22. x200, IgG4(+)

23. Specimen : Major duodenal papilla Diagnosis, endoscopic biopsy : Chronic inflammation Immunohistochemical finding : IgG4 (+) Pathology Report

24. Serum IgG and IgG4 level 검사 명칭 (serum) 결과치 (mg/dL) 참고치 (mg/dL) IgG1730 ↑694~1618 IgA15868~378 IgM31.4 ↓60~263 IgE494 ↑~100 검사 명칭 (serum) 결과치 (mg/dL) 참고치 (mg/dL) IgG1585.0423~1060 IgG2702.0 ↑64~495 IgG359.623~196 IgG4294.0 ↑11~157

25. Autoantibody (normal range) ANA : non-reactive RA factor : 9.75 IU/mL (~20 IU/mL) anti-Sm : negative anti-SSA/SSB : negative anti-dsDNA : negative anti-Ro-52 : negative anti-Scl-70 : negative anti-Pm-Scl : negative anti-CentB : negative anti-AMA-M2 : negative C-ANCA : negative P-ANCA : negative Serum Autoantibody

26. Asian diagnostic criteria for AIP (2008) ?

27. Clinical Question 2. Is it possible that major duodenal papillary biopsy is substituted for the pancreatic biopsy?

28. Extreme specificity : 100% Moderate sensitivity : 53% Useful diagnostic tool of AIP, especially when AIP is suspected clinically but serum IgG4 levels are normal or pancreatic tissue is not available Usefullness of IgG4 immunostaining of duodenal papillary biopsy specimen Moon SH et al. Gastrointest Endosc 2010

29. Abdomen sono-guided needle biopsy 2008.12.2

30. x200

31. x400

32. x400, IgG4(+)

33. Microscopic finding : Section from pancreas shows dense fibrosis and lymphoplasma cells infiltration with Russell bodies, especially around vascular channels Diagnosis, sono-guided needle biopsy : Chronic inflammation and fibrosis Immunohistochemical finding : IgG4 (+) Pathology Report

34. Asian diagnostic criteria for AIP (2008)

35. Definite autoimmune pancreatitis Asian diagnostic criteria : l + ll + lll Clinical Diagnosis

36. Clinical Question 3. Is this patient indicated for steroid therapy?

37. Obstructive jaundice (m/c etiology) Persistent abdominal or back pain Associated symptomatic extrapancreatic lesions Retroperitoneal fibrosis Interstitial pneumonia Tubulointerstitial nephritis Hepatic or pulmonary pseudotumor Diabetes associated with AIP Diagnostic trial of suspected AIP (short-term) Steroid Treatement Indication

38. Often (43~68%) observed in AIP patients Suggested pathogenesis Corticosteroid-responsive diabetes mellitus associated with AIP Diabetes of AIP patients

39. Suggested Pathogenesis Inflammatory cell infiltration surrounding ductal cells and extensive fibrosis CD8+ T-cells may play an important role in the destruction of islet β-cells Islet cells fall into ischemia because of the reduction in blood flow Volume of β-cells was reducted in patients with AIP Tanaka et al. Diabetes Care 2001, Ito et al. Pancreas 2007

40. Intact islet cell surrounded by fibrosis

41. Damaged islet cell accompanied with lymphoplasmatic cell infiltration and fibrotic change

42. Suggested Pathogenesis Inflammatory cell infiltration surrounding ductal cells and extensive fibrosis CD8+ T-cells may play an important role in the destruction of islet β-cells Islet cells fall into ischemia because of the reduction in blood flow Volume of β-cells was reducted in patients with AIP Steroid Treatment

43. Nishimori et al. Pancreas 2006

44. Glucose 5 회 연속 94153247284318 Insulin 2 회 연속 3.213.1 C-peptide 0,30M 1.2 2.2 Glucose 5 회 연속 260327396460514 Insulin 2 회 연속 4.54.1 C-peptide 0,30M 0.50.6 2008.11 2009.07

45. Autoimmune pancreatitis C/W Autoimmune pancreatitis Start steroid treatment (dose : oral prednisolone 40mg qd) F/U CT and IgG4 titer

46. 2008.11.24 2008.12.22 After PDL 40mg qd for 3 weeks After steroid treatment for 7 months 2009.7.6

47. Steroid treatment course 2008.12.32008.12.232009.1.62009.5.62009.7.9 40mg 30mg 20mg 10mg 5mg 2.5mg 최초 진단 첫번째 F/U 두번째 F/U 3주3주 2주2주 4 개월 2 개월 총 7 개월

48. BUT…

49. AIP recurrence after 7 months 2010.1.29

50. AIP recurrence after 7 months 2010.2.11

51. Recurrent autoimmune pancreatitis Steroid retreatment (dose : oral prednisolone 30mg qd) Steroid dependency later ?

52. After steroid retreatment for 2 months 2010.1.29 2010.4.2

53. Steroid retreatment course 2008.12.32008.12.232009.1.62009.5.62009.7.9 40mg 30mg 20mg 10mg 5mg 2.5mg 최초 진단 첫번째 F/U 3주3주 2주2주 4 개월 2 개월 2010.2.52010.2.122010.2.252010.3.122010.4.6 2010.5.4 두번째 F/U 7 개월간 관해 상태 1주1주 2주2주 2주2주 >3 주 1 개월 : PDL 2.5mg qd + azathioprine 50mg qd 재 발재 발 재치료 후 F/U 294.0 IgG4 (mg/dL) 1000 500 250 75.8 125.4 959.0 125 750