1. CLASSIFICATION OF CHRONIC PANCREATITIS EAGE, Podstgraduate Course, Prague, April 2010. Tomica Milosavljević Tomica Milosavljević School of Medicine, Clinical Center University of Belgrade of Serbia,Belgrade

2. The phrase “chronic pancreatitis” in the clinical context: in the clinical context: –syndrome of destructive,inflammatory conditions –many sequelae of long-standing pancreatic injury (irregular fibrosis, acinar cell loss, islet cell loss, and inflammatory cell infiltrates) (irregular fibrosis, acinar cell loss, islet cell loss, and inflammatory cell infiltrates)

3. Chronic pancreatitis, morphologically Irregular sclerosis Irregular sclerosis Destruction, permanent loss of the exocrine parenchyma Destruction, permanent loss of the exocrine parenchyma May be either, focal, segmental or diffuse May be either, focal, segmental or diffuse Varying degrees of dilatation of the duct system Varying degrees of dilatation of the duct system

4. Problems in definition Chronic pancreatitis implies longstanding disease, both in pathogenesis and effect. Chronic pancreatitis implies longstanding disease, both in pathogenesis and effect. Defining features : Defining features : –must consider the etiology –characteristic clinical evidence –sequelae of organ pathology –including complications

5. Clasiffication 1 The clinical course is still unpredictable The clinical course is still unpredictable The lack of the availability of a clinical classification The lack of the availability of a clinical classification

6. Clasiffication 2 The King’s College Cambridge 1983 The King’s College Cambridge 1983 –clinically utilizable system –based on ERCP The Marseilles 1963,1984 The Marseilles 1963,1984 –various subtypes and clinical entities Rome 1985: pathogenesis and evolution Rome 1985: pathogenesis and evolution Zurich 1996 Zurich 1996 –alcohol related –not provided prognostic information Zurich international clasiffication (1997-98) Zurich international clasiffication (1997-98)

7. Clasiffication 3 TIGAR-O (2001.) TIGAR-O (2001.) ABC criteria (Ramesh 2002) ABC criteria (Ramesh 2002) Manchester 2006 (ABC) Manchester 2006 (ABC) M-ANNHEIM 2007 (Schneider) M-ANNHEIM 2007 (Schneider)

8. Etiologic risk factors – TIGAR-O system Toxic-metabolic – –Alcochol – –Tobacco – –Hypercalcemia – –Hyperlipidemia – –Chronic renal failure – –Medications (Phenacetin abuse) – –Toxins( organotonin compounds) Idiopathic –Early onset –Late onset –Tropical Tropical calc.pancr. Fibrocalculous diab. Other

9. Etiologic risk factors – TIGAR-O system Genetic – –Autosomal dominant Cationic trypsinogen (Codon 29, 122 mut.) – –Autosomal recessive/modifier genes CFTR mutations SPINK1 mutations Cationic trypsinogen ( codon 16,22,23 mut.) Alfa 1 antitrypsin defficiency (possible ) Autoimmune –Isolated autoimmune –Syndromic autoimmune Sjogren IBD associated Prim.bill.cirrhosis assoc.

10. Etiologic risk factors – TIGAR-O system Recurrent and severe acute – –Postnecrotic acute – –Recurrent acute – –Vascular dis./ishemic – –Postirradiation Obstructive –Pancreas divisum –Sphincter Oddi disorders (controversial) –Duct obstruction (tumor) –Preampullar duodenal wall cyst –Posttraumatic pancreatic duct scars

11. Why new clinical clasiffication? Clinical experience Clinical experience Progress in diagnostic methods Progress in diagnostic methods New molecular technologies for the assessment New molecular technologies for the assessment Key clinical aspects is crucial Key clinical aspects is crucial M W Büchler, M E Martignoni, H Friess, P Malfertheiner BMC Gastroenterol. 2009; 9: 93. M W Büchler, M E Martignoni, H Friess, P Malfertheiner BMC Gastroenterol. 2009; 9: 93.

12. Ideal Classification for chronic pancreatitis : User friendly, User friendly, transparent, transparent, relevant, relevant, prognosis- as well as treatment- related prognosis- as well as treatment- related and offers a frame for future disease evaluation. and offers a frame for future disease evaluation. M W Büchler, M E Martignoni, H Friess, P Malfertheiner BMC Gastroenterol. 2009; 9: 93. 2009

13. Facts and state-of-the-art knowledge in chronic pancreatitis (I) 1) Different etiologies 1) Different etiologies 2) There are no serologic or blood markers 2) There are no serologic or blood markers 3) Pathognomonic lesions are detectable by imaging 3) Pathognomonic lesions are detectable by imaging 4) Loss of exocrine and endocrine function develops 4) Loss of exocrine and endocrine function develops

14. Facts and state-of-the-art knowledge in chronic pancreatitis (II) 5) The end stage steatorrhea and insulin- dependent diabetes mellitus. 5) The end stage steatorrhea and insulin- dependent diabetes mellitus. 6) Complications are known such as common bile duct, duodenal, main pancreatic duct and vascular obstruction/stenosis. 6) Complications are known such as common bile duct, duodenal, main pancreatic duct and vascular obstruction/stenosis. 7) Risk factor for pancreatic cancer. 7) Risk factor for pancreatic cancer. 8) Overall life expectancy is reduced. 8) Overall life expectancy is reduced.

15. Unresolved issues in chronic pancreatitis (I) 1) The relationship between acute and chronic pancreatitis is not completely defined. 1) The relationship between acute and chronic pancreatitis is not completely defined. 2) Disease progression, arrest and regression of functional and morphologic findings occur is debated. 2) Disease progression, arrest and regression of functional and morphologic findings occur is debated. 3) Diagnosis of early chronic pancreatitis by imaging is not established. 3) Diagnosis of early chronic pancreatitis by imaging is not established. 4) The role and validity of exocrine pancreatic function tests in the diagnosis is not established. 4) The role and validity of exocrine pancreatic function tests in the diagnosis is not established.

16. Unresolved issues in chronic pancreatitis (II) 5) The pathogenesis of pain is at least multifactorial and not defined. 5) The pathogenesis of pain is at least multifactorial and not defined. 6) The burn-out hypothesis is still debated and not defined with regard to time evolution in different etiologies. 6) The burn-out hypothesis is still debated and not defined with regard to time evolution in different etiologies. 7) There is disagreement over whether to use enzyme treatment to influence pain. 7) There is disagreement over whether to use enzyme treatment to influence pain. 8) The role of endoscopic intervention is not defined under evidence-based criteria. 8) The role of endoscopic intervention is not defined under evidence-based criteria. 9) The role of surgery is not defined under evidence-based criteria 9) The role of surgery is not defined under evidence-based criteria

17. Clinical Criteria pain pain attacks of acute pancreatitis attacks of acute pancreatitis complications of CP complications of CP steatorrhea steatorrhea diabetes mellitus diabetes mellitus

18. Definition of complications (1) bile duct obstruction/stenosis with cholestasis or jaundice/ bile duct obstruction/stenosis with cholestasis or jaundice/ duodenal obstruction/stenosis with clinical signs/ duodenal obstruction/stenosis with clinical signs/ vascular obstruction/stenosis with clinical or morphological signs of portal/splenic vein hypertension vascular obstruction/stenosis with clinical or morphological signs of portal/splenic vein hypertension

19. Definition of complications (2) pancreatic pseudocysts with clinical signs (compression of adjacent organs, infection, bleeding, etc.) pancreatic pseudocysts with clinical signs (compression of adjacent organs, infection, bleeding, etc.) pancreatic fistula (internal or external) pancreatic fistula (internal or external) pancreatogenic ascites pancreatogenic ascites other rare complications related to organs in vicinity (i.e., colonic stenosis, splenic pseudocyst, etc.) other rare complications related to organs in vicinity (i.e., colonic stenosis, splenic pseudocyst, etc.)

20. Imaging criteria for chronic pancreatitis Ductal changes: Irregularity of the main pancreatic duct or side branches ± intraductal filling defects, calculi, duct obstruction (stricture), duct dilatation (>3 mm) Ductal changes: Irregularity of the main pancreatic duct or side branches ± intraductal filling defects, calculi, duct obstruction (stricture), duct dilatation (>3 mm) Parenchymal changes: General or focal enlargement of the gland, cysts, calcifications, heterogenous reflectivity. Parenchymal changes: General or focal enlargement of the gland, cysts, calcifications, heterogenous reflectivity.

21. Etiology of chronic pancreatitis alcohol alcohol idiopathic (unknown origin) idiopathic (unknown origin) hereditary autoimmune or in combination with specific diseases (Crohn's, PBC) hereditary autoimmune or in combination with specific diseases (Crohn's, PBC) tropical tropical cystic fibrosis cystic fibrosis obstructive (pancreatic duct) obstructive (pancreatic duct) drugs drugs

22. Specific definition of chronic pancreatitis stage A (1) Stage A: Stage A: –the early stage, complications have not yet appeared, the clinical exocrine and endocrine function is preserved; –subclinical signs (impaired glucose tolerance, reduced exocrine function but without steatorrhea) might already be apparent.

23. Specific definition of chronic pancreatitis stage A (2) Stage A is accepted under the following conditions: Stage A is accepted under the following conditions: –Pain of any type and degree and/or attacks of acute pancreatitis, –no complications, –no steatorrhea, – no insulin-dependent diabetes mellitus.

24. Specific definition of chronic pancreatitis stage B (1) Stage B: Stage B: – the intermediate stage where chronic pancreatitis has led to complications, – but clinical exocrine and endocrine function is still preserved.

25. Specific definition of chronic pancreatitis stage B (2) The type of complication is specified (e.g., stage B, bile duct) The type of complication is specified (e.g., stage B, bile duct) Stage B is accepted under the following conditions: Stage B is accepted under the following conditions: –Patients with complications, –but without steatorrhea or diabetes mellitus

26. Specific definition of chronic pancreatitis stage C (1) Stage C Stage C –is the end stage of chronic pancreatitis, fibrosis has led to clinical exocrine and/or endocrine pancreatic function loss (steatorrhea and/or diabetes mellitus); complications of chronic pancreatitis might or might not be present –the type of exocrine and/or endocrine pancreatic function loss is specified (e.g., stage C, steatorrhea)

27. Specific definition of chronic pancreatitis stage C (2) Stage C can be sub classified into three categories: Stage C can be sub classified into three categories: –C1: Patients with endocrine function impairment –C2: Patients with exocrine function impairment –C3: Patients with exocrine/endocrine function impairment and/or complications Stage C is accepted under the following conditions: Stage C is accepted under the following conditions: –Patients with clinical manifestation of end-stage functional impairment with or without complications.

28. Controversies in chronic pancreatitis clasifficaton Endoscopical interventions, yes/no ? Endoscopical interventions, yes/no ? Surgical dilemma-resection/drenaige ? Surgical dilemma-resection/drenaige ? Follow-up the patients and reconsider clasiffication Follow-up the patients and reconsider clasiffication

29. Thank you very much for your attention Prof. Dr Tomica Milosavljević MD PhD School of Medicine, Clinical Center University of Belgrade of Serbia,Belgrade