Pathophysiology of Gallstone Formation and · PDF filecholecystitis) Ultrasound D Int (not er...

PathophysiologFormation an

Robert F. rfs2102@corfs2102@co

gy of Gallstone d Pancreatitis

Schwabeolumbia.eduolumbia.edu

S.N.S

- Gallbladder/Bile and Pancredigestion of food

- A large percentage of the popto 30% of people >50y) and abbillion cost/year in the US

- Gallbladder and Pancreas phgallstones cause a large percencases

as both are essential for

pulation have gallstones (up bout 700000 surgeries and $6

hysiology are linked as ntage of acute pancreatitis

S.N.S

Pancreatic secretions and bi• Bile: EmulsificaBile: Emulsifica

• Pancreatic secretions: -DigestionN t li-Neutraliz

ile are required for digestionation of fatation of fat

n of proteins, carbohydrates and fatti f th idi hzation of the acidic chyme

S.N.S

Bi

- S

- T

- S

- Rof

le

Secreted by hepatocytes

Transported through the biliary system

Stored and concentrated in the gallbladder

Released into duodenum after ingestion f food (mediated by CCK)

S.N.S

Bile comCholest

Bil S lt

Phospholipids(Lecithin)

Bile Salts(Lecithin)

12%

14%0.7%

8

mposition

Miscellaneous (Pigment, Protein)erol

H201%%

84.3%

S.N.S

Bile salts are conjugataurine to increase their

Primary bile salts

DehydroxylationSecondary bile salts

ated with glycine or r solubility at lower pH

Dehydroxylation

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Important fun

1. Emulsification of fats in

2. Cholesterol excretionBil lt t d fa. Bile salts are generated fsynthesis thus decreases

b Ch l t l i t d ib. Cholesterol is excreted in

nctions of bile

n the intestine

f h l t l d th ifrom cholesterol and their s the cholesterol pool

t bilnto bile

S.N.S

Formation and secr1. Synthesis (0.3-0.6g)

ABCholesterol

ABVarbas

Cyp7abastranpho

Bile acidsABCG11

p

ABCG11

Fecal loss 0.3-0(equals hepatic synthe

etion of bile acids2 E t h ti i l ti2. Enterohepatic circulation (5-10x daily)

ABCG11 ABCG11BC transportersABCG11 ABCG11 BC transportersrious proteins located at the solateral membrane that mediatesolateral membrane that mediate nsport of bile acids, cholesterol and ospholipids into bile

Pool =2-3gp p

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0.6g esis)

Why do we have a mechanismof bile

R b i d d liReabsorption and redelivery quickly replenish the pool ofli / llbl ddliver/gallbladder

The digestive tract is pithi l ti l h t tiwithin a relatively short time

m for enterohepatic circulation acids?

f bil id llof bile acids allows to very f bile acids in the

prepared for the next meal e.

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FXR is a sensor of bile actoxi

The Nuclear receptors FXin bile salt mBile salts are hepatoxic

CholesterolCyp7a

Bile

FXR

Bile acids

FXR

Synthetic FXRAgonists(Moschetta et al Nat Med 2004)

ABCG11 (Moschetta et al, Nat Med 2004)

cids and prevents bile acid icityXR plays an important role metabolism c at high concentrations

Hepatocyte

FXR stimulation:FXR stimulation:1. Decreased bile salt

synthesisy2. Increased bile salt

secretion

Lowers intracellular bile acid pool

increasing bile acidsecretion into bile may

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yprevent gallstone formation

Secretion of c

SR-BIHDL LDL

LDSynthesis

Ch l lCholesterol

iBiaci

ABCG5/8

cholesterol

DL-R

Export into

l

Export intoPeriphery (VLDL)

leids

S.N.S

The nuclear receptor LXRlowers intracellula

Cholesterol

CholesterolLXRCyp7a

BileacidsBile

LXR

ABCG5/8 acidsBile

acids

ABCG5/8

R is a cholesterol sensor and ar cholesterol levels

LXR stimulation:

1. Increased bile salt synthesis decreases ycholesterol

2 Increased2. Increased cholesterol secretion

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Cholesterol requires bilee salts for solubilization

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Excess cholesterol precipitacrystals and

ates to form cholesterol d stones

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Composition oC iti f

f Gallbladder bileComposition of Gallbladder Bile

H lth t lHealthy controlsPatients with Gallstones

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Where do galls

Very large stonesBile ducts:C t t fl

Very large stonesUnlikely to pass into the duct but more likely to cause local problems-Constant flow

-Bile is not concentrated

y pSmaller stonesCan pass into the duct and

Gallbladder:Sl d

cause biliary colic/cholestasis/pancreatitis

Gallbladder:-Stasis of bile-Bile is concentrated

Sludge (viscous aggregate of crystals and mucus)Can pass into the duct but is muche s co ce t atedCan pass into the duct but is much less likely to cause problems as it can easier pass the papilla

stone develop?

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Factors influencing the pAgeAgeunder 30y 1-50-60y 9-Female gender/ sex hormoneMen under 30 1-3%Women under 30 2-6%Men 50-60y 9-22%W 50 60 16 30%

Environmental and genetic fWomen 50-60y 16-30%

Female Pima Indians >25y 73Low prevalence in Asia and Africa

iObesityNon-obese women 10%

prevalence of gallstones

-6%-30%

PREGNANCYes

2. Trim 3. Trim 4-6w pp5.1% 7.9% 10.2%

factors3%a

S.N.SObese women 30%

Cholesterol stones:

- Great m- either pu(more th(more th

1 cm

M i t ib ti f tMain contributing factors:

-Decreased bile acidsIncreased biliary cholesterol

Super-Increased biliary cholesterol-Gallbladder factors allowing for stasis/

ajority of all stones in the US (>80%)ure cholesterol stones or mixed stones han 50% cholesterol content)han 50% cholesterol content)

rsaturation

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nucleation

Pigment stones:- much les- contain p

usually due to inc- or du1 cm

Main causes

Chronic HemolysisDecreased bilirubin conjugation(cirrhosis, bacterial infections)

ss common in US than Cholesterol stonespigment = bilirubin

creased hemolyisue to decreased bilirubin conjugation

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excess bilirubindecreased bilirubin solubility

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x-Ray AppearanR diRadio-opaque

27% = Cholesterol Stones73% = Pigment Stones

nce of GallstonesR di l tRadioluscent

83% = Cholesterol Stones

S.N.SS.N.S

17% = Pigment Stones

Factors Favoring Ch

SUPERSATURAT

STASIS NUCL

• Hepatic Production of Lith• Hepatic Production of LithA. Excess cholesterol secretion1 Obesity1. Obesity2. Estrogens3. Crash diet4. Genetic factors/Ethnicity (Pimas) -probably for 10% of gallstones (Nat.

holesterol Gallstones

TION

LEATION

hogenic Bilehogenic Bile

S.N.S

- Point Mutation in ABCA8 accounts Genetics 2007)

Factors Favoring Ch

• Hepatic Production of LithB D d S ti f BilB. Decreased Secretion of Bile

1. Decreased bile salt synthesis dCyp7a mutations (rare) 2. Decreased bile acid return to

• Gallbladder Factors1. Stasis (TPN, fasting, progestin2. Nucleation (increased mucopr2. Nucleation (increased mucopr

holesterol Gallstones

hogenic BileA id Acids

despite diminished pool, e.g.

liver (ileal resection)

ns)roteins)

S.N.S

roteins)

• 80% of all gallbladder stones will nevNatural History

cause symptoms

• 1-4% of gallbladder stones/year causcholecystitis)

UltrasoundUltrasoundD

IntInt(not

verof Gallstones

UltrasoundUltrasound

e symptoms (e.g. colic, pancreatitis,

ERCPERCPDilated Duct

traductal stonetraductal stonealways visible)

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Gallstones

Schematic diagram for the maGallstones

Asymptomatic

ComplicEndoscopic retrograde cholangiopancreatography (ERCP)

Follow-up

LaparoscoLaparosco

p g p y ( )

Cholecyste+/-ERCPCholecyste+/-ERCP

UrsodiolGood success with small ChVery high recurrence rate

-Visualize biliary trepancreatic ducts

-Extract stones

anagement of gallstone disease

Symptomatic

catedUncomplicated

o-

opicopicectomyectomy

Only if contraindications for surgery:•Observation

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•Ursodiol•Possibly emergency surgery

olesterol stonesee and

SUMMARY G

1. Over 80% of gallstones are CHOdysbalance between cholesterol and

2. FASTING (Gallbladder stasis), Osecretion) and ESTROGEN (increassecretion) and ESTROGEN (increasgallstone formation

3 SMALLER GALLSTONE3. SMALLER GALLSTONE pass elikely to cause symptoms (colic, pan

4. 80% of gallstones remain unsymp

5 Th f h i f i5. Therapy of choice for symtopaticcholecystectomy

GALLSTONES

LESTEROL stones caused by a d bile acids in bile

OBESITY (increased cholesterol sed cholesterol secretion) promotesed cholesterol secretion) promote

i i h d deasier into the duct and are more ncreatitis, cholecystitis)

ptomatic

ll di i l i

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c gallstone disease is laparoscopic

PANCREAS PPANCREAS PPHYSIOLOGYPHYSIOLOGY

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Pancreas macro- annd microanatomy

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Major functio

ACINUSDigestive enzyme secret

(Trypsin, Elastase, Amylase,

DUCTULEDUCTULEWater, bicarbonate secreti

onal units

tionLipase )

ion

S.N.S

HC03 concentration and pH incsecre

The increase in HC03 serves topasses into the duodenum.

160140

Meal-stimulated secr

140120100E

q/L

)

806040Io

n (m

E

4020

0

0 0.2 0.4 0.6 0.8Secretory rat

rease with increased pancreatic etion

o buffer the acidic pH of food after it

retion

8.0

pH

7.0

S.N.S

8 1.0 1.2 1.4te (ml/min)

Bicarbonate secretion is regulated thro

Cephalic phaseCephalic phase Food cues

Gastric phase

DistentionVagal Afferents

Intestinal phaseIntestinal phase

duodenalduodenalpH<4.5

pH sensitiveSecretin-releasing factor

SecretinS-cells

ough hormonal and neural mechanisms

Dorsal Vagal Complex

Vagal Efferents

Ach

Secretin

S.N.S

H20, NaHC03 CFTR

Regulation of Enzyme Secretion is

Cephalic phaseCephalic phase Food cues

Gastric phase

CCK-sensingVagal AfferentsDistention

Intestinal phaseIntestinal phaseCCK-RF

CCK(I-cells)

Proteins, AA, FA

s mediated by Neural Mechanisms

Dorsal Vagal Complex

Vagal Efferents

Ach, VIP, GRP

DigestiveEnzymes

S.N.S

Activation of pancreatic

SPINEntSPIN

TrypsinogenTrypsinogen

TrypChymotryp

ProProcarboxyp

Prophosp

2 Mechanisms to prevent autod-Trypsinogen activation occursProphosp

Pro

Trypsinogen activation occurs-Pancreatic inhibitor prevents t

enzymes in the intestine

NKterokinaseNK

TrypsinTrypsin

psinogenpsinogen

TrypsinChymotrypsin

oelastasepeptidasepholipase

ElastaseCarboxypeptidasePhospholipase

digestion:s outside of the pancreas

S.N.S

pholipaseocolipase

PhospholipaseColipase

s outside of the pancreas trypsinogen activation

PATHOGEPANCRE

Activation of pancreaticActivation of pancreaticpancreas and the resultimost important mechanpancreatitispancreatitis

ENESIS OF EATITIS

c enzymes within thec enzymes within the ing autodigestion is the nism that triggers

S.N.S

Classification oFunctional and

morphologic changes

Time

of pancreatitisCHRONICEtOHOutcome:PainEndocrine insufficiency Exocrine insufficiencyy

ACUTE RECURRENTe.g. sludge, SODOutcome:Recovery or death

ACUTEt EtOH

Recovery or death

S.N.S

e.g. stone, EtOH Outcome:Recovery or death

Acute Pan

- Clinically severe

- Typically starts with m- Typically starts with mabdominal pain

- Complications such as pinfection, shock and mulin some patientsin some patients

ncreatitis

moderate to severemoderate to severe

pancreatic necrosis, p ,lti-organ failure develop

S.N.S

Etiology of AcutEtiology of Acut

AlcoholicAlcoholicIdiopathiIdiopathi

OthOthBiliaryBiliary

IdiopathiIdiopathi

yy

te Pancreatitiste Pancreatitis

• Autoimmune• Drug induced• Autoimmune• Drug induced• Drug-induced• Iatrogenic• IBD-related

• Drug-induced• Iatrogenic• IBD-relatedcc

herher • Infectious• Inherited

Metabolic

• Infectious• Inherited

Metabolic

cc

• Metabolic• Neoplastic• Structural

• Metabolic• Neoplastic• Structural• Toxic• Traumatic

V l

• Toxic• Traumatic

V l

S.N.S

• Vascular• Vascular

Cellular Injury throug

1. Blockage of Secretion

2. Activation of Zymogensin Lysosymes (Cathepsin B)

3. Organelle Damage and CellInjury by Activated Enzymesj y y y

gh Activated EnzymesIncreased pressurep

Perturbed environment

Lysosome

GolgiGolgiComplex

S.N.SRER

Cytokines Play an Importa

PancreaticAcinar CellPancreaticAcinar Cell

CytprodCyt

prodInsult

InflaCel

InflaCel

ant Role in Pancreatic Injury

Systemiccomplications

Systemiccomplicationspp

tokine ductiontokine duction

Chemoattractionand activation

Chemoattractionand activationand activationand activation

mmationll Deathmmationll Death

MacrophageMacrophageNeutrophilNeutrophil

S.N.S

Cytokines Mediate Sys

AR

LuLuLiver failure

LiverLiver

Liver failure

ICAIL

ICAIL

ProinflaProinfla

TNFαIL-1βTNFαIL-1β

ILTP

ILTP

ProinflaProinflaIL-61IL-61

stemic Complications

RDS

ungsungs Shock, Organ failure

S

MicrocirculationMicrocirculation

PAFPAFAM-1L-1βAM-1L-1β

ammatoryammatory

PAFEndothelin

INOS

PAFEndothelin

INOS

L-1βNFα

PAF

L-1βNFα

PAFammatoryammatory ICAM-1ICAM-1

S.N.S

Local effects of inflamma

• Pancreatic and peripancreati• Fat necrosis• Fluid loss into third space

ation and pancreas injury

ic necrosis

S.N.S

Chronic Pa

- Chronic disease

- Pain and malabsorption- Pain and malabsorptionsymptoms

- Weight loss can also beg

ancreatitis

n are the mainn are the main

e due to food avoidance

S.N.S

Etiology of ChroEtiology of Chro

Alcoholic OtherOther

Idiopathic

onic Pancreatitisonic Pancreatitis

Cystic fibrosisCystic fibrosis

Hereditary pancreatitis

Hypertriglyceridemia

Hereditary pancreatitis

Hypertriglyceridemiayp g y

Autoimmune

f ( )

yp g y

Autoimmune

f ( )Fibrocalcific (Tropical)Fibrocalcific (Tropical)

S.N.S

Effects of Chronic AlcEffects of Chronic Alc

CalcificationCalcification

Cytotoxic Cytotoxic lymphocyteslymphocytes

cohol on the Pancreascohol on the Pancreas

FibrosisFibrosis Decreased bl d flDecreased bl d flblood flowblood flow

Direct toxicDirect toxicDirect toxic effects

Direct toxic effects

Altered protein synthesis

Altered protein synthesis

(unfavorable ratio of

S.N.S

trypsinogen vs. inhibitors)

Hereditary PHereditary PPancreatitisPancreatitis

SpinkSpink

S.N.S

PANCRECLINICAL CON

EATITIS NSIDERATONS

S.N.S

Laboratory parameters adiagnosis of acu

Amylase and Lipase are tin Acute PancreatitisLipase is more specific thelevated for a longer perioin Acute Pancreatitis

Other causes of hyperaelevated for a longer perio

ParotitisParotitis

are crucial to establish the ute pancreatitistypically highly elevated han Amylase and remains odamylasemia and hyperlipasemia:od

S.N.S

IMAGING DIAGNOSIseverity and clinical cy

Interstitial pancreatitisInterstitial pancreatitis

If CT is performed within 24h of first sym

IS is important to judgecourse of pancreatitisp

Necrotizing pancreatitisNecrotizing pancreatitis

Higher rate of complications g p(bacterial infection, organ failure) and mortality

S.N.S

mptoms, necrosis may not yet be present

PROGNOSIS OF ACURanson’s severity scor

• Age > 55 years• Age > 55 yearsAdmission

Ranson s severity scor

• WBC > 16,000 mm3

• Glucose > 200 mg/dl• LDH > 350 IU/L

• WBC > 16,000 mm3

• Glucose > 200 mg/dl• LDH > 350 IU/L• LDH > 350 IU/L• AST > 120 IU/L• LDH > 350 IU/L• AST > 120 IU/L

Systemic dise

8080100100

Most patients withsevere pancreatitis

Causative Treatment:- Stone extraction in severe biliary pancreat- (Cessation of Alcohol intake)

40406060%

Mortality%

Mortality

severe pancreatitis- (Cessation of Alcohol intake)

Supportive Treatment:- Enteral feeding (nasogastric tube)

002020

0 to 20 to 2 3 to 53 to 5

- Intravenous hydration- Pain medication- Intubation in case of respiratory problems

UTE PANCREATITISre & mortality

• Hct decrease >10%• Hct decrease >10%During first 48h

re & mortality

• BUN increase > 5 mg/dl• Ca2+ < 8 mg/dl• PaO2 < 60 mm Hg

• BUN increase > 5 mg/dl• Ca2+ < 8 mg/dl• PaO2 < 60 mm Hg

Fat necrosisPaO2 60 mm Hg

• Base deficit > 4 mEq/L• Negative fluid balance > 6L

PaO2 60 mm Hg• Base deficit > 4 mEq/L• Negative fluid balance > 6Lase

h stitiss

S.N.S6 to 86 to 8 9 to 119 to 11ScoreScores

Acute Pancreatit

G T iG T iGrey-Turner signGrey-Turner sign

Pancreatic Ascites:

Amylase + + +

ARDS

tis Complications

No epithelial lining

S.N.SObstructing PseudocystObstructing Pseudocyst

Acute Pancreatit

Infected N

TrTr

tis Complications

Necrosis

reatment+

reatment

Antibiotic

S.N.S

Chronic Pancreatiton imaging andg g

x-ray and fecal fat have a l

(EUS)(EUS)

y

Amylase and Lipase are ofte

tis: Diagnostic relies d functional tests

low sensitivity to detect CP!y

S.N.Sen within the normal range!!

i

Chronic PancreatitisImaging

MosensiERCP/EUS sensiERCP/EUS

LesensiCT

Ultrasonogram

Lea

Abdominal x-ray

i l

s: Diagnostic testsFunctional

ostitive Secretin testitive Secretin test

essitive Fecal chymotrypsin

Serum trypsinogen

Fecal fatast

Fecal fatBlood glucose

S.N.S

Imaging of Chro

Abdominal X-ray

CT scan

onic Pancreatitis

Abdominal Ultrasound

S.N.SERCP

Chronic Pain and Malabsmost common Symptom

sorption/Malnutrition are the ms of Chronic Pancreatitis

S.N.S

Exogenous proteases may nobut also CCK release and pbut also CCK release and p

FoodFood

Exogenous Protease

Exogenous Protease

Lesspain

Exogenous Proteases degrading

Exogenous Proteases degrading

CCKCCK

g gCCK-RFg gCCK-RF

CCK-RF cellCCK-RF cell

ot only improve maldigestion pain in chronic pancreatitispain in chronic pancreatitis

s n

S.N.S

SUMMARY PA

1. ACUTE PANCREATITIS is a ccaused by EtOH and GALLSTOy

2. CHRONIC PANCREATITIS caist most commonly caused by Eist most commonly caused by E

3. The diagnosis of ACUTE PANCPancreatitis) is best made by detPancreatitis) is best made by detLIPASE

4 I i ( CT) l4. Imaging (e.g. CT) can reveal sev(interstitial vs. necrotic)

5. CHRONIC PANCREATITIS is Ultrasound, CT, ERCP) or funct

ANCREATITIS

clinically severe disease mostly ONES

auses pain and malabsorption and tOHtOH

CREATITIS (but not CHRONIC tection of elevated AMYLASE andtection of elevated AMYLASE and

it f t titiverity of acute pancreatitis

S.N.S

diagnosed by imaging (x-Ray, tional tests (secretin, fecal fat)