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Pathophysiology of Gallstone Formation and Pancreatitis

Robert F. Schwabe

S.N.S

rfs2102@columbia.edu

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

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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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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

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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

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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.

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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 ( )

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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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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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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 %

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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

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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)

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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

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PANCREAS PHYSIOLOGY

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Pancreas macro- and microanatomy

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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

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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

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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:

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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

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- Complications such as pancreatic necrosis, infection, shock and multi-organ failure develop in some patients

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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

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GolgiComplex

Injury by Activated Enzymes

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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

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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

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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)

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Hereditary PancreatitisHereditary Pancreatitis

Spink

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PANCREATITIS CLINICAL CONSIDERATONS

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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

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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

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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!!

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Imaging FunctionalMost

sensitiveERCP/EUS Secretin test

Chronic Pancreatitis: Diagnostic tests

LesssensitiveCT

UltrasonogramFecal chymotrypsinSerum trypsinogen

Least

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Abdominal x-ray Fecal fatBlood glucose

Least

Imaging of Chronic Pancreatitis

Abdominal X-ray Abdominal Ultrasound

S.N.SCT scan ERCP

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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

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CCK-RF cellCCK-RF cell

Proteases degrading

CCK-RF

Proteases degrading

CCK-RF

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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)