Peter MalfertheinerDepartment of Gastroenterology,

Hepatology and Infectious Diseases

Otto-von-Guericke-University Magdeburg

Acute Pancreatitis

Pathogenesis and clininical implications

Acute PancreatitisAcute Pancreatitis

Two clinical categoriesTwo clinical categories

Mild Mild

SevereSevere

- - localized to the pancreaslocalized to the pancreas- rapid improvement- rapid improvement- restitutio ad integrum- restitutio ad integrum

- - locallocal- cardiovascular- cardiovascular- respiratory- respiratory- renal- renal- septic- septic- metabolic- metabolic

- Defective healing- Defective healing

complicationscomplications

Mild form

(edematous pancreatitis) 85% Severe form

(necrotizing pancreatitis) 15%

Sterile necrosis

60%

Infected necrosis

40%

Lethality

< 1%

Lethality

5%

Lethality

10-20%

Buechler MW, Uhl W, Malfertheiner P, Sarr MG. Diseases of the pancreas. Karger 2004.

Acute Pancreatitis Acute Pancreatitis

• etiologyetiology

• mechanisms of cell damagemechanisms of cell damage

• translation of basic knowledge for prognostic translation of basic knowledge for prognostic

assessment and drug developmentassessment and drug development

Acute Pancreatitis Acute Pancreatitis

PathophysiologyPathophysiology

Acute PancreatitisEtiology

Alcoholic

Biliary

Idiopathic

Other

• Autoimmune

• Drug-induced

• Iatrogenic

• IBD-related

• Infectious

• Inherited

• Metabolic

• Neoplastic

• Structural

• Toxic

• Traumatic

• Vascular

Infectious disease and pathogens associated with acute pancreatitis

Viral

Mumps 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

Bacterial

Yersinia enterolcolica and Y.pseudotuberulosis Salmonella typhimurium and S. enteriditis

Campylobacter jejuni Typhoid fever Tuberculosis Mycobacterium avium-intracellulare Leptosprosis Legionnaires´disease Connatal lues

Infectious disease and pathogens associated with acute pancreatitis

Parasitis

Ascaris lumbricoides Clonorchis senensis Fasciola hepatica Taenia saginata Giardia lamblia Echinococcus Pneumocystis carinii Toxoplasma gondii

Fungal

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

PathogenesisEtiologic factors

Toxic factors (e.g. alcohol)

0bstructive factors (e.g. Gallstones)

Intra-acinar triggering

Intracellular enzyme activation

Intra-acinar triggering

Increases intraductal pressure with disruption of the duct barrier

Interstitial enzyme activation

Inflammation Enzyme activation

Disruption of compartmentalization with colocalization ‚Autodigestion‘Büchler,Uhl,Malfertheiner,Pancreatic diseases 2004l

Schematic representation of working hypothesis for the onset of acute pancreatitis

Diet-induced

Mouse Severe

Secretagogue-induced

Rat Mild

Duct obstruction-induced

Rat/rabbit Mild

Duct obstruction-induced

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

Model

Animal Severity

Acute Pancreatitis

• changes in secretion

• intracellular activation of proteases

• induction of inflammatory responses

3 phenotypic responses in early phase

Pathophysiology (Acinar Cells)

Triggering factor

Physiologic enzyme synthesis and secretion

1= zymogen granules 2= hydrolsis

Lumen

Defense mechanisms against intracellular enzyme activation

Intracellular injury resulting from enzyme activation (crinophagy)

Physiologic regulated apical exocytosis and pathologic basolateral exocytosis in pancreatitis

Gaisano and Gorelick, Gastroenterology 2009;136:2040-2044

SNARE proteinsmediate exocytosis

Zymogen activation during acute pancreatitis

Gaisano and Gorelick., Gastroenterology 2009;136:2040-2044

Proposed compartments

-Lysosomes/endosomes

-Autophagic vacuoles

-Secretory granules

activate or degrade zymogens secreted basolaterally

release factor(s) that stimulate zymogen activation

in the acinar cell

Possible role of Inflammatory cells and zymogen activation

Acute Pancreatitis Pathophysiology

• 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

EARLY EVENTS

Acinar lumen

Cathepsin B activation

Disruption in CA2+ signaling/

Trypsinogen autoactivation/

Inappropriate trypsinogen activation

Zymogen activation

Organelle rupture

Cellular injury

Cell death

Acute Pancreatitis

• necrosis

• apoptosis

• autophagy

Cell death

Cell death pathways

Initiatorcaspases

Mitochondria

Cell StressCell Stress

Calcium

ERLyosomes

Cathepsin B

Trypsin Effector caspases

NecrosisApoptosis

Effector caspases

PARP

Effector caspases

ATP

Cytochrome c

PI3-kinase NF-B IAPs

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 caspase-independent 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

María I. Vaccaro, Pancreatology 2008;8:425-429

Acute pancreatitis

Early cellular events

Autophagy Autodigestion

Cell death Necrosis

Programmed cell death

Cell survival

Acute necrotizing pancreatitis Acute necrotizing pancreatitis

Usually occurs within 96hRansonApache 2CRP>150

Pancreatic Necrosis

0 20 40 60 80 100%

24-<48

48-<72

72-<96

70

97

100

46<24

h after onset of pain

Development of pancreatic necrosis. After 96 h, all patients with necrotizing pancreatitis exhibit signs of necrosis (CRP, CT).

week 1week 1 22 33 44

late phaselate phaseInitial phaseInitial phase

SepsisSepsisInfection of necrosisInfection of necrosis

Pathophysiology of severe acute Pathophysiology of severe acute pancreatitispancreatitis

The two-phase-modelThe two-phase-model

SIRSSIRSInflammation cascadeInflammation cascade

Systemic Complications

Routes of Infection

1 = Hematatogenous; 2 = reflux of enteric content from the duodenum;

3 = reflux of bacteriobilia; 4 = lymphogenous (translocation);

5 = direct transperitoneal spread

Pancreatic cell-damage

Alcohol other agents gallstones

PMN-andMacrophages-Activation

PMN-Elastase,PLA2, O-Radicals

Activation of proteolyticcascade

releaseactivated enzymes

PAFTNF; IL1, 6, 8

Tissue damage

MOF

endothelialdamage

circulatoryeffects

Acute Pancreatitis: Pathophysiology

CRP

• etiologyetiology

• mechanisms of cell damagemechanisms of cell damage

• translation from basic mechanisms to translation from basic mechanisms to

prognostic assessment and drug developmentprognostic assessment and drug development

Acute Pancreatitis Acute Pancreatitis

PathophysiologyPathophysiology

Acute Pancreatitis

• CRP

• Serum Amyloid A

• Procalcitonin

• Interleukin1;6

• Trypsinogen activation peptide (TAP)

• PMN elastase

• Hematocrit

Biochemical markers

• Unravelling the basic mechanisms in the early Unravelling the basic mechanisms in the early

phase and during disease progression will help to phase and during disease progression will help to

develop approaches to block the damaging develop approaches to block the damaging

responsesresponses

• Towards autophagy and apoptosis to prevent the Towards autophagy and apoptosis to prevent the

more deleterious necrotic cell death (with more deleterious necrotic cell death (with

recruitment of inflammatory cells) (?)recruitment of inflammatory cells) (?)

Acute Pancreatitis Acute Pancreatitis Pathophysiology- ConclusionPathophysiology- Conclusion

Pancreatic cell-damagePancreatic cell-damage

AlcoholAlcohol other agentsother agents gallstonesgallstones

PMN-andPMN-andMacrophages-ActivationMacrophages-Activation

PMN-Elastase,PMN-Elastase,PLAPLA22, O-Radicals, O-Radicals

Activation of proteolyticActivation of proteolyticcascade cascade

releasereleaseactivated enzymesactivated enzymes

PAFPAFTNFTNF; IL1, 6, 8; IL1, 6, 8

Tissue damageTissue damage

MOFMOF

endothelialendothelialdamagedamage

circulatorycirculatoryeffectseffects

Acute Pancreatitis: PathophysiologyAcute Pancreatitis: Pathophysiology

CRP