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Acute Pancreatitis Pathogenesis and clininical implications Peter Malfertheiner Department of Gastroenterology, Hepatology and Infectious Diseases Otto-von-Guericke-University Magdeburg Acute Pancreatitis Two clinical categories - localized to the pancreas Mild Severe - rapid improvement - restitutio ad integrum - local - cardiovascular - respiratory - renal - septic - metabolic - Defective healing complications Acute Pancreatitis Mild form (edematous pancreatitis) 85% Severe form Buechler MW, Uhl W, Malfertheiner P, Sarr MG. Diseases of the pancreas. Karger 2004. (necrotizing pancreatitis) 15% Sterile necrosis Infected necrosis 60% 40% Lethality Lethality Lethality < 1% 5% 10-20% Acute Pancreatitis Pathophysiology • etiology • mechanisms of cell damage • translation of basic knowledge for prognostic assessment and drug development Acute Pancreatitis Etiology • Autoimmune • Drug-induced • Iatrogenic Idiopathic • IBD-related • Infectious Alcoholic Other • Inherited • Metabolic • Neoplastic Biliary • Structural • Toxic • Traumatic • Vascular Infectious disease and pathogens associated with acute pancreatitis Viral Bacterial Mumps Yersinia enterolcolica and Y.pseudotuberulosis Salmonella typhimurium and S. enteriditis Viral hepatitis Coxsackie virus B Echovirus Cytomegalovirus (CMV) Varicella-zoster virus (VZV) Epstein-Barr virus (EBV) Human immunodeficiency virus (HIV) Herpes simples virus (HSV) Rabies Rubella virus Rotarius enteritis Campylobacter jejuni Typhoid fever Tuberculosis Mycobacterium aviumintracellulare Leptosprosis Legionnaires´disease Connatal lues Infectious disease and pathogens associated with acute pancreatitis Parasitis Fungal Ascaris lumbricoides Clonorchis senensis Fasciola hepatica Taenia saginata Giardia lamblia Echinococcus Pneumocystis carinii Toxoplasma gondii Candida Exophiala dermatitidis Cryptococcus neoformans Cryptosporidium Aspergillus Classification of drugs published as causing acute pancreatitis Class I Alpha-methylopa 5-Aminosalicylate (ASA) Azathioprine Cimetidine Cytosine arabinoside Dexamethasone Ethinylestradiol/lynestrenol Furosemide Isoniazid 6-Mercaptopuride Metronidazole Norethindrone/mestranol Procainamide Pentamidine Stibogluconate Sulindac Sulfamenthazole Sulfamethoxazole Sulfasalazine Sulindac Tetracycline Trimethoprim/sulfamethoxazole Valproic acid Latencies of drugs implicated in causing AP Pathogenesis Etiologic factors Toxic factors (e.g. alcohol) 0bstructive factors (e.g. Gallstones) Intra-acinar triggering Intra-acinar triggering Intracellular enzyme activation Increases intraductal pressure with disruption of the duct barrier Interstitial enzyme activation Inflammation Enzyme activation Büchler,Uhl,Malfertheiner,Pancreatic diseases 2004l Disruption of compartmentalization with colocalization ‚Autodigestion‘ Schematic representation of working hypothesis for the onset of acute pancreatitis Model Animal Severity Diet-induced Secretagogueinduced Mouse Severe Rat Mild Duct obstruction- Duct obstructioninduced induced Rat/rabbit Mild Opossum Severe Blockage of digestive enzyme secretion Redistribution of lysosomal hydrolases and colocalization with digestive enzyme zymogens Intra-acinar cell activation of digestive enzymes Acinar cell injury Pancreatitis Acute Pancreatitis 3 phenotypic responses in early phase • changes in secretion • intracellular activation of proteases • induction of inflammatory responses Pathophysiology (Acinar Cells) Lumen Triggering factor Defense mechanisms against intracellular enzyme activation Physiologic enzyme synthesis and secretion 1= zymogen granules 2= hydrolsis Intracellular injury resulting from enzyme activation (crinophagy) Physiologic regulated apical exocytosis and pathologic basolateral exocytosis in pancreatitis SNARE proteins mediate exocytosis Gaisano and Gorelick, Gastroenterology 2009;136:2040-2044 Zymogen activation during acute pancreatitis Proposed compartments Possible role of Inflammatory cells and zymogen activation -Lysosomes/endosomes -Autophagic vacuoles -Secretory granules release factor(s) that stimulate zymogen activation in the acinar cell activate or degrade zymogens secreted basolaterally Gaisano and Gorelick., Gastroenterology 2009;136:2040-2044 Acute Pancreatitis Pathophysiology EARLY EVENTS • Trypsinogen autoactivation • Cleavage of trypsinogen to trypsin by cathepsin B • Intracellular pancreatic trypsin inhibitor decreased • loss of compartimentalisation of zymogens and lysosomal enzymes • Trypsinogen activation by calcium Acinar lumen Cathepsin B activation Disruption in CA2+ signaling/ Trypsinogen autoactivation/ Inappropriate trypsinogen activation Zymogen activation Organelle rupture Cellular injury Cell death Acute Pancreatitis Cell death • necrosis • apoptosis • autophagy Cell death pathways Cell Stress Initiator caspases Lyosomes ER Mitochondria Calcium PARP Effector caspases Cathepsin B Cytochrome c ATP Trypsin Effector caspases PI3-kinase IAPs NF-B Apoptosis Necrosis Effector caspases Acute Pancreatitis Pathophysiology The form of acinar cell death itself an important determinant of the severity of acute pancreatitis Bhatia M,Am J Physiol 2004 Induction of apoptosis reduces severity of experimental pancreatitis Caspase-dependent and caspaseindependent routes to cell death Maiuri et al, Molecular Cell Biology 2007;8:741-752 Autophagic process María I. Vaccaro, Pancreatology 2008;8:425-429 Autophagy, autodigestion and cell death are early cellular events in acute pancreatitis Acute pancreatitis Early cellular events Autophagy Autodigestion Cell death Necrosis Programmed cell death Cell survival María I. Vaccaro, Pancreatology 2008;8:425-429 Acute necrotizing pancreatitis Usually occurs within 96h Ranson Apache 2 CRP>150 Pancreatic Necrosis h after onset of pain <24 46 70 24-<48 97 48-<72 72-<96 100 0 20 40 60 80 100% Development of pancreatic necrosis. After 96 h, all patients with necrotizing pancreatitis exhibit signs of necrosis (CRP, CT). Pathophysiology of severe acute pancreatitis The two-phase-model Initial phase week 1 late phase 2 SIRS Inflammation cascade 3 4 Sepsis Infection of necrosis Systemic Complications Routes of Infection 1 = Hematatogenous; 2 = reflux of enteric content from the duodenum; 3 = reflux of bacteriobilia; 4 = lymphogenous (translocation); Acute Pancreatitis: Pathophysiology Alcohol other agents gallstones Pancreatic cell-damage PMN-and Macrophages-Activation release activated enzymes endothelial damage PAF PMN-Elastase, PLA2, O-Radicals TNFa; IL1, 6, 8 Tissue damage Activation of proteolytic cascade MOF CRP circulatory effects Acute Pancreatitis Pathophysiology • etiology • mechanisms of cell damage • translation from basic mechanisms to prognostic assessment and drug development Acute Pancreatitis Biochemical markers • CRP • Serum Amyloid A • Procalcitonin • Interleukin1;6 • Trypsinogen activation peptide (TAP) • PMN elastase • Hematocrit Acute Pancreatitis Pathophysiology- Conclusion • Unravelling the basic mechanisms in the early phase and during disease progression will help to develop approaches to block the damaging responses • Towards autophagy and apoptosis to prevent the more deleterious necrotic cell death (with recruitment of inflammatory cells) (?) Acute Pancreatitis: Pathophysiology Alcohol other agents gallstones Pancreatic cell-damage PMN-and Macrophages-Activation release activated enzymes endothelial damage PAF PMN-Elastase, PLA2, O-Radicals TNFa; IL1, 6, 8 Tissue damage Activation of proteolytic cascade MOF CRP circulatory effects
