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1
Pathophysiology of Gallstone Formation and Pancreatitis
Robert F. Schwabe
S.N.S
Pancreatic secretions and bile are required for digestion• Bile: Emulsification of fat
• Pancreatic secretions: -Digestion of proteins, carbohydrates and fat-Neutralization of the acidic chyme
S.N.S
2
Bile
- Secreted by hepatocytes
- Transported through the biliary systemTransported through the biliary system
- Stored and concentrated in the gallbladder
- Released into duodenum after ingestion of food (mediated by CCK)
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of food (mediated by CCK)
Bile composition
Miscellaneous (Pigment, Protein)Cholesterol
Bile Salts
Phospholipids(Lecithin)
H 04%0.7%
84.3%
H20
12%
1%4%
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3
Bile salts are conjugated with glycine or taurine to increase their solubility at lower pH
Primary bile salts
Dehydroxylation Dehydroxylation
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Secondary bile salts
Important functions of bile
1. Emulsification of fats in the intestine
2. Cholesterol excretiona. Bile salts are generated from cholesterol and their
synthesis thus decreases the cholesterol pool
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synthesis thus decreases the cholesterol poolb. Cholesterol is excreted into bile
4
Formation and secretion of bile acids
Cholesterol
1. Synthesis (0.3-0.6g) 2. Enterohepatic circulation (5-10x daily)
ABCG11 ABCG11 ABC transportersCholesterol
Bile acids
Cyp7a
Pool =2-3g
Various proteins located at the basolateral membrane that mediate transport of bile acids, cholesterol and phospholipids into bile
S.N.S
Bile acidsABCG11
Fecal loss 0.3-0.6g (equals hepatic synthesis)
Why do we have a mechanism for enterohepatic circulation of bile acids?
Reabsorption and redelivery of bile acids allows to very p y yquickly replenish the pool of bile acids in the liver/gallbladder
The digestive tract is prepared for the next meal
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The digestive tract is prepared for the next meal within a relatively short time.
5
FXR is a sensor of bile acids and prevents bile acid toxicity
CholesterolCyp7a
Hepatocyte
The Nuclear receptors FXR plays an important role in bile salt metabolism
FXR stimulation:
Bile salts are hepatoxic at high concentrations
FXR
yp
Bile acids
1. Decreased bile salt synthesis
2. Increased bile salt secretion
Lowers intracellular bil id l
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ABCG11
Synthetic FXRAgonists(Moschetta et al, Nat Med 2004)
increasing bile acidsecretion into bile mayprevent gallstone formation
bile acid pool
Secretion of cholesterol
SR-BIHDL LDL
SynthesisLDL-R
Cholesterol
y
Export intoPeriphery (VLDL)
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ABCG5/8
Bileacids
p y ( )
6
The nuclear receptor LXR is a cholesterol sensor and lowers intracellular cholesterol levels
CholesterolCholesterol
Cholesterol
ABCG5/8
BileacidsBile
acids
LXRCyp7a LXR stimulation:
1. Increased bile salt synthesis decreases cholesterol
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ABCG5/8
2. Increased cholesterol secretion
Cholesterol requires bile salts for solubilization
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7
Excess cholesterol precipitates to form cholesterol crystals and stones
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Composition of Gallbladder Bile
Composition of Gallbladder bile
Healthy controlsPatients with Gallstones
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8
Where do gallstone develop?
Very large stonesBile ducts:-Constant flow-Bile is not concentrated
Unlikely to pass into the duct but more likely to cause local problemsSmaller stonesCan pass into the duct andcause biliary colic/cholestasis/pancreatitis
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Gallbladder:-Stasis of bile-Bile is concentrated
Sludge (viscous aggregate of crystals and mucus)Can pass into the duct but is much less likely to cause problems as it can easier pass the papilla
pancreatitis
Factors influencing the prevalence of gallstonesAgeunder 30y 1-6%50-60y 9-30%
PREGNANCY2. Trim 3. Trim 4-6w pp5.1% 7.9% 10.2%
Female gender/ sex hormonesMen under 30 1-3%Women under 30 2-6%Men 50-60y 9-22%Women 50-60y 16-30%
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Environmental and genetic factorsFemale Pima Indians >25y 73%Low prevalence in Asia and Africa
y %
9
Cholesterol stones:
- Great majority of all stones in the US (>80%)- either pure cholesterol stones or mixed stones (more than 50% cholesterol content)
1 cm
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Main contributing factors:
-Decreased bile acids-Increased biliary cholesterol-Gallbladder factors allowing for stasis/nucleation
Supersaturation
Pigment stones:- much less common in US than Cholesterol stones- contain pigment = bilirubin
usually due to increased hemolyis- or due to decreased bilirubin conjugation1 cm
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Main causes
Chronic Hemolysis excess bilirubinDecreased bilirubin conjugation decreased bilirubin solubility(cirrhosis, bacterial infections)
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x-Ray Appearance of GallstonesRadio-opaque Radioluscent
S.N.SS.N.S
27% = Cholesterol Stones73% = Pigment Stones
83% = Cholesterol Stones17% = Pigment Stones
Factors Favoring Cholesterol Gallstones
SUPERSATURATION
• Hepatic Production of Lithogenic BileA. Excess cholesterol secretion
STASIS NUCLEATION
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1. Obesity2. Estrogens3. Crash diet4. Genetic factors/Ethnicity (Pimas) - Point Mutation in ABCA8 accounts probably for 10% of gallstones (Nat. Genetics 2007)
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• Hepatic Production of Lithogenic BileB. Decreased Secretion of Bile Acids
Factors Favoring Cholesterol Gallstones
1. Decreased bile salt synthesis despite diminished pool, e.g. Cyp7a mutations (rare) 2. Decreased bile acid return to liver (ileal resection)
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• Gallbladder Factors1. Stasis (TPN, fasting, progestins)2. Nucleation (increased mucoproteins)
• 80% of all gallbladder stones will nevercause symptoms
Natural History of GallstonesUltrasound
• 1-4% of gallbladder stones/year cause symptoms (e.g. colic, pancreatitis, cholecystitis)
Ultrasound ERCPDilated Duct
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Intraductal stone(not always visible)
12
Gallstones
Asymptomatic Symptomatic
Schematic diagram for the management of gallstone disease
Follow-up
LaparoscopicCholecystectomy+/-ERCP
ComplicatedUncomplicated
LaparoscopicCholecystectomy+/-ERCP
Endoscopic retrograde cholangio-pancreatography (ERCP)
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Only if contraindications for surgery:•Observation•Ursodiol•Possibly emergency surgery
UrsodiolGood success with small Cholesterol stonesVery high recurrence rate
-Visualize biliary tree andpancreatic ducts
-Extract stones
SUMMARY GALLSTONES
1. Over 80% of gallstones are CHOLESTEROL stones caused by a d b l b t h l t l d bil id i bildysbalance between cholesterol and bile acids in bile
2. FASTING (Gallbladder stasis), OBESITY (increased cholesterol secretion) and ESTROGEN (increased cholesterol secretion) promote gallstone formation
3 SMALLER GALLSTONE pass easier into the duct
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3. SMALLER GALLSTONE pass easier into the duct
4. 80% of gallstones remain unsymptomatic
5. Therapy of choice for symtopatic gallstone disease is laparoscopic cholecystectomy
13
PANCREAS PHYSIOLOGY
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Pancreas macro- and microanatomy
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14
Major functional units
ACINUSACINUSDigestive enzyme secretion
(Trypsin, Elastase, Amylase, Lipase )
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DUCTULEWater, bicarbonate secretion
HC03 concentration and pH increase with increased pancreatic secretion
Meal-stimulated secretion
The increase in HC03 serves to buffer the acidic pH of food after it passes into the duodenum.
160140120100
8060n
(mE
q/L
) 8.0
pH
Meal stimulated secretion
S.N.S
604020
0
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4Secretory rate (ml/min)
Io
7.0
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Bicarbonate secretion is regulated through hormonal and neural mechanisms
Dorsal Vagal Complex
Cephalic phase Food cues
Gastric phase
DistentionVagal Afferents
Ach
Vagal Efferents
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Intestinal phase
duodenalpH<4.5
pH sensitiveSecretin-releasing factor
SecretinS-cells
Secretin
H20, NaHC03 CFTR
Regulation of Enzyme Secretion is mediated by Neural Mechanisms
Dorsal Vagal Complex
Cephalic phase Food cues
V l Eff
CCK-sensingVagal Afferents
Gastric phase
Distention
Vagal Efferents
Ach, VIP, GRP
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Intestinal phaseCCK-RF
CCK(I-cells)
Proteins, AA, FA
DigestiveEnzymes
16
Enterokinase
Activation of pancreatic enzymes in the intestine
SPINK
TrypsinogenChymotrypsinogen
Trypsin
TrypsinChymotrypsin
TrypsinogenTrypsinogen Trypsin
SPINK
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ChymotrypsinogenProelastase
ProcarboxypeptidaseProphospholipase
Procolipase
ChymotrypsinElastaseCarboxypeptidasePhospholipaseColipase
2 Mechanisms to prevent autodigestion:-Trypsinogen activation occurs outside of the pancreas -Pancreatic inhibitor prevents trypsinogen activation
PATHOGENESIS OF PANCREATITIS
Activation of pancreatic enzymes within the pancreas and the resulting autodigestion is the most important mechanism that triggers
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pancreatitis
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Classification of pancreatitisFunctional and
morphologic changesCHRONICEtOHOutcome:PainEndocrine insufficiency Exocrine insufficiency
ACUTE RECURRENTe.g. sludge, SODOutcome:
S.N.STime
ACUTEe.g. stone, EtOH Outcome:Recovery or death
Outcome:Recovery or death
Acute Pancreatitis
- Clinically severe
- Typically starts with moderate to severe abdominal pain
C li ti h ti i
S.N.S
- Complications such as pancreatic necrosis, infection, shock and multi-organ failure develop in some patients
18
Etiology of Acute PancreatitisEtiology of Acute Pancreatitis
• Autoimmune• Drug-induced
I t i
• Autoimmune• Drug-induced
I t i
OtherOther
• Iatrogenic• IBD-related• Infectious• Inherited• Metabolic• Neoplastic
• Iatrogenic• IBD-related• Infectious• Inherited• Metabolic• Neoplastic
AlcoholicAlcoholic
BiliaryBiliary
IdiopathicIdiopathic
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• Structural• Toxic• Traumatic• Vascular
• Structural• Toxic• Traumatic• Vascular
Cellular Injury through Activated EnzymesIncreased pressure
Perturbed environment
Lysosome
1. Blockage of Secretion
2. Activation of Zymogensin Lysosymes (Cathepsin B)
3. Organelle Damage and Cell
S.N.SRER
GolgiComplex
Injury by Activated Enzymes
19
Cytokines Play an Important Role in Pancreatic Injury
PancreaticAcinar CellPancreaticAcinar Cell
Systemiccomplications
Systemiccomplications
Cytokine productionCytokine
productionInsult Chemoattractionand activation
Chemoattractionand activation
Acinar CellAcinar Cell
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InflammationCell Death
InflammationCell Death
MacrophageMacrophageNeutrophilNeutrophil
Mi i l tiMi i l ti
LungsLungs
Cytokines Mediate Systemic Complications
Liver failureShock, Organ failure
ARDS
MicrocirculationMicrocirculation
PAFEndothelin
INOS
PAFEndothelin
INOSTNFαIL 1βTNFαIL 1β
ICAM-1IL-1βTNFαPAF
ICAM-1IL-1βTNFαPAF
LiverLiver
S.N.S
ProinflammatoryProinflammatoryINOS
ICAM-1INOS
ICAM-1IL-1βIL-61IL-1βIL-61
PAFPAF
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• Pancreatic and peripancreatic necrosis• Fat necrosis• Fluid loss into third space
Local effects of inflammation and pancreas injury
• Fluid loss into third space
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Chronic Pancreatitis
- Chronic disease
- Pain and malabsorption are the main symptoms
W i ht l l b d t f d id
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- Weight loss can also be due to food avoidance
21
Etiology of Chronic PancreatitisEtiology of Chronic Pancreatitis
Cystic fibrosis
Hereditary pancreatitis
Hypertriglyceridemia
Autoimmune
Cystic fibrosis
Hereditary pancreatitis
Hypertriglyceridemia
Autoimmune
Alcoholic
Idiopathic
OtherOther
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Fibrocalcific (Tropical)Fibrocalcific (Tropical)
p
CalcificationCalcification FibrosisFibrosis Decreased blood flowDecreased blood flow
Effects of Chronic Alcohol on the PancreasEffects of Chronic Alcohol on the Pancreas
Direct toxic effects
Direct toxic effects
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Cytotoxic lymphocytes
Cytotoxic lymphocytes
Altered protein synthesis
Altered protein synthesis
(unfavorable ratio of trypsinogen vs. inhibitors)
22
Hereditary PancreatitisHereditary Pancreatitis
Spink
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PANCREATITIS CLINICAL CONSIDERATONS
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23
Laboratory parameters are crucial to establish the diagnosis of acute pancreatitis
Amylase and Lipase are typically highly elevated in Acute PancreatitisLipase is more specific than Amylase and remains elevated for a longer period
ParotitisParotitis
Other causes of hyperamylasemia and hyperlipasemia:
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IMAGING DIAGNOSIS is important to judge severity and clinical course of pancreatitis
Interstitial pancreatitis Necrotizing pancreatitis
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If CT is performed within 24h of first symptoms, necrosis may not yet be present
Higher rate of complications (bacterial infection, organ failure) and mortality
24
PROGNOSIS OF ACUTE PANCREATITIS
• Age > 55 years• WBC > 16,000 mm3
• Age > 55 years• WBC > 16,000 mm3
• Hct decrease >10%• BUN increase > 5 mg/dl• Hct decrease >10%• BUN increase > 5 mg/dl
During first 48hAdmissionRanson’s severity score & mortality
• WBC > 16,000 mm• Glucose > 200 mg/dl• LDH > 350 IU/L• AST > 120 IU/L
• WBC > 16,000 mm• Glucose > 200 mg/dl• LDH > 350 IU/L• AST > 120 IU/L
100100Most patients with
BUN increase 5 mg/dl• Ca2+ < 8 mg/dl• PaO2 < 60 mm Hg• Base deficit > 4 mEq/L• Negative fluid balance > 6L
BUN increase 5 mg/dl• Ca2+ < 8 mg/dl• PaO2 < 60 mm Hg• Base deficit > 4 mEq/L• Negative fluid balance > 6L
Fat necrosis
Systemic disease
S.N.S002020404060608080
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
Acute Pancreatitis Complications
Grey-Turner signGrey-Turner sign
No epithelial lining
S.N.SARDS Obstructing PseudocystObstructing Pseudocyst
25
Infected Necrosis
Acute Pancreatitis Complications
+Treatment
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Antibiotic
Chronic Pancreatitis: Diagnostic relies on imaging and functional tests
x-ray and fecal fat have a low sensitivity to detect CP!
(EUS)(EUS)
S.N.SAmylase and Lipase are often within the normal range!!
26
Imaging FunctionalMost
sensitiveERCP/EUS Secretin test
Chronic Pancreatitis: Diagnostic tests
LesssensitiveCT
UltrasonogramFecal chymotrypsinSerum trypsinogen
Least
S.N.S
Abdominal x-ray Fecal fatBlood glucose
Least
Imaging of Chronic Pancreatitis
Abdominal X-ray Abdominal Ultrasound
S.N.SCT scan ERCP
27
Chronic Pain and Malabsorption/Malnutrition are the most common Symptoms of Chronic Pancreatitis
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Exogenous Exogenous
Exogenous proteases may not only improve maldigestion but also CCK release and pain in chronic pancreatitis
Less pain
Exogenous Proteases
Exogenous Proteases
FoodFood
CCKCCK
ProteaseProtease
S.N.S
CCK-RF cellCCK-RF cell
Proteases degrading
CCK-RF
Proteases degrading
CCK-RF
28
SUMMARY PANCREATITIS
1. ACUTE PANCREATITIS is a clinically severe disease mostly caused by EtOH and GALLSTONES
2 C O C A C A S i d l b i d2. CHRONIC PANCREATITIS causes pain and malabsorption and ist most commonly caused by EtOH
3. The diagnosis of ACUTE PANCREATITIS (but not CHRONIC Pancreatitis) is best made by detection of elevated AMYLASE and LIPASE
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4. Imaging (e.g. CT) can reveal severity of acute pancreatitis (interstitial vs. necrotic)
5. CHRONIC PANCREATITIS is diagnosed by imaging (x-Ray, Ultrasound, CT, ERCP) or functional tests (secretin, fecal fat)