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Pathophysiology of pancreatitis and gallstone formation
Stavros [email protected]
PANCREAS PHYSIOLOGY
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Major functional units
ACINUSDigestive enzyme secretion
DUCTULEWater, bicarbonate secretion
Regulation of Bicarbonate SecretionDuodenal pH <4.5(intestinal phase)
Vagal Afferents
Dorsal VagalComplex
Vagal efferents
pH sensitiveSecretin-releasing factor
Secretin release by duodenal S cells
ACH
DAG/IP3
Secretin
cAMP
Food cues(cephalic phase)
Distention(gastric phase)
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DUCTAL CELL PHYSIOLOGYDuct cell model
HCO3
H2O + CO2C.A.
Na3Na
2K
K
Na-HCO3Cotransporter
Na-KATPase
Cl-HCO3Antiport
Cl
ClHCO3
CFTR(cAMP)
BASOLATERAL LUMINAL
Na, K, H2O
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Regulation of Enzyme SecretionCCK from I cells(intestinal phase)
Vagal Afferents
Dorsal VagalComplex
Vagal efferents
ACH,GRP,CCK
DAG/IP3
Food cues(cephalic phase)
Distention(gastric phase)
FAAA
Proteins(intestinal phase)
VIP
cAMPisletPP
CCK-RFMonitor peptide
CCK A
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PATHOGENESIS OF PANCREATITIS
Classification of pancreatitisFunctional and
morphologic changes
Time
CHRONICe.g. ETOH, hereditaryOutcome:PainEndocrine insufficiencyExocrine insufficiency
ACUTE RECURRENTe.g. sludge, SODOutcome:Recovery or death
ACUTEe.g. stone, drug, toxinOutcome:Recovery or death
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Acute PancreatitisAcute Pancreatitis
OtherOther
• Autoimmune• Drug-induced• Iatrogenic• IBD-related• Infectious• Inherited• Metabolic• Neoplastic• Structural• Toxic• Traumatic• Vascular
• Autoimmune• Drug-induced• Iatrogenic• IBD-related• Infectious• Inherited• Metabolic• Neoplastic• Structural• Toxic• Traumatic• Vascular
AlcoholicAlcoholic
BiliaryBiliary
IdiopathicIdiopathic
Etiologies
Pathogenesis of pancreatitis
Ca++
cathepsin B
↑Duct PressureToxin
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Model for Inflammatory and Acinar Cell Death Responses in Pancreatitis
Cytokine productionCytokine
production
Regulation ofcell death
Regulation ofcell death
Insult
MacrophageMacrophageNeutrophilNeutrophil
Chemoattractionand activation
Chemoattractionand activation
PancreaticAcinar CellPancreaticAcinar Cell
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ProinflammatoryProinflammatory
Cytokine ProductionCytokine Production
MicrocirculationMicrocirculation
PAFEndothelin
INOS ICAM-1
PAFEndothelin
INOS ICAM-1
TNFαIL-1βIL-61
TNFαIL-1βIL-61
ICAM-1IL-1βTNFαPAF
ICAM-1IL-1βTNFαPAF
LungsLungs
LiverLiver
mediates liver, lung and vascular dysfunction
Cystic fibrosis
Hereditary pancreatitis
Hypertriglyceridemia
Autoimmune
Fibrocalcific (Tropical)
Cystic fibrosis
Hereditary pancreatitis
Hypertriglyceridemia
Autoimmune
Fibrocalcific (Tropical)
Alcoholic
Idiopathic
OtherOther
Etiology of chronic pancreatitis
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CalcificationCalcification
Cytotoxiclymphocytes
Cytotoxiclymphocytes
FibrosisFibrosis Decreased blood flowDecreased blood flow
Altered protein synthesis
Altered protein synthesis
Chronic PancreatitisChronic Pancreatitis
Direct effectsDirect effects
Chronic effects of ethanol
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PANCREATITIS CLINICAL CONSIDERATONS
Conditions Associated with Hyperamylasemiaand Hyperlipasemia
ParotitisParotitis
DIAGNOSIS
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CT without IV contrast
Mild acute pancreatitis Severe acute pancreatitisCT with IV contrast
Interstitial pancreatitis Necrotizing pancreatitis
DIAGNOSIS:
PROGNOSIS OF ACUTE PANCREATITISRanson’s severity score & mortality
Admission• Age > 55 years• WBC > 16,000 mm3
• Glucose > 200 mg/dl• LDH > 350 IU/L• AST > 120 IU/L
Admission• Age > 55 years• WBC > 16,000 mm3
• Glucose > 200 mg/dl• LDH > 350 IU/L• AST > 120 IU/L
After 48 hrs• Hct decrease >10%• BUN increase > 5 mg/dl• Ca2+ < 8 mg/dl• PaO2 < 60 mm Hg• Base deficit > 4 mEq/L• Negative fluid balance > 6L
After 48 hrs• Hct decrease >10%• BUN increase > 5 mg/dl• Ca2+ < 8 mg/dl• PaO2 < 60 mm Hg• Base deficit > 4 mEq/L• Negative fluid balance > 6L
002020404060608080
100100
0 to 20 to 2 3 to 53 to 5 6 to 86 to 8 9 to 119 to 11
%Mortality
%Mortality
ScoreScore
Most patients with severe pancreatitis
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Acute Pancreatitis Complications
Grey-Turner sign
ARDS
ObstructingPseudocyst
PANCREATIC FLUID COLLECTION NOMENCLATURE
A.P./C.P./ trauma, peripanc. collection of pus, no debris
Pancreatic abscess
C.P., walled juice/”retention”Chronic pseudocyst
A.P.,>4 wks, walled juiceAcute pseudocyst
A.P.,>2-4 wks, partially walled necrotic debris & panc. juice
Organized necrosis
A.P., 1-2 wks>30 % necr., no wallPancr. Necrosis (early)
A.P./ trauma, <48 hrs, no wallAcute collection
Adapted from Bradley et al Atlanta Symposium, Arch Surg 1993 & Baron et al GIE 2002
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Infected Pancreatic NecrosisDiagnosis
Treatment
(EUS)(EUS)
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Calcific Chronic Pancreatitis
Abdominal X-ray Abdominal Ultrasound
ERCPCT scan
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Less pain
CCK-RF cellCCK-RF cell
Exogenous Proteases degrading
CCK-RF
Exogenous Proteases degrading
CCK-RF
FoodFood
CCKCCK
Exogenous Protease
Exogenous Protease
Exogenous proteases may decrease CCK release and pain in chronic pancreatitis
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GALLSTONES
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Factors Favoring Cholesterol Gallstones
• Hepatic Production of Lithogenic BileA. Decreased Secretion of Bile Acids1. Fasting (pooling of bile salts in gallbladder)2. Decreased bile salt synthesis despite diminished pool3. Cyp7a mutations (rare) 4. Decreased bile acid return to liver (ileal resection)
STASIS NUCLEATION
SUPERSATURATION
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• Gallbladder Factors1. Stasis (TPN, progestins, crash diet)2. Nucleation (increased mucoproteins)3. Infection (deconjugation of bilirubin)2. Effect of removing the gallbladder
Factors Favoring Cholesterol Gallstones• Hepatic Production of Lithogenic Bile
B. Excess cholesterol secretion1. Obesity2. Estrogens3. Ethnicity (Pimas)