pathophysiology of pancreatitis and gallstone formation · mild acute pancreatitis severe acute...

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Pathophysiology of pancreatitis and gallstone formation

Stavros Stavropoulossns10@columbia.edu

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)