Peptic Ulcer DiseasePeptic Ulcer Diseasepp

Timothy C. Wang, M.D.Chief, Digestive and Liver DiseasesColumbia University Med CenterColumbia University Med Center

(low acid)

(body/corpus)

(low acid)

(antral)

(high acid)

Simple versus Complicated P ti Ul DiPeptic Ulcer Disease

• Simple ulcers • Lifetime PUD l f 10%– Symptomatic

– Asymptomatic

prevalence of 10%• In past, DU 5X as

common as GU• Complicated ulcers

– BleedingP f ti

common as GU• Incidence of GU

increases with age– Perforation– Death

• Overall PUD has been declining

Bleedingulcer

Causes of Peptic Ulcer Diseasep• H. pylori infection *

NSAID *• NSAIDs *• Stress ulcers (Cushing’s, Curling’s, ischemia)• Increased gastrin: (Zollinger-Ellison, retained

gastric antrum, antral G-cell hyperplasia)• Increased histamine: Systemic mastocytosis,

foregut carinoid tumors, leukemia• Massive small bowel resection, renal failure,

cirrhosis, COPD

No Acid, No Ulcer• Schwarz (1910): “Ohne saueren Magensaft, kein

pepticsches Geschwur”• Hyperacidity only in some patients (e g DU ZE) but• Hyperacidity only in some patients (e.g.DU, ZE) but

acid is a factor in most patients with PUD

Role of acid (HCl) in the stomachRole of acid (HCl) in the stomach

• Helps to kill prey that is ingested liveHelps to kill prey that is ingested live• Small role in protein digestion through

activation of pepsinactivation of pepsin• Some bacteriostatic action - helps to

sterilize the gastric contentssterilize the gastric contents• Gastric juice also contains bicarbonate,

pepsinogen, intrinsic factor,pepsinogen, intrinsic factor, prostaglandins, K+, Na+, mucins, and trefoil proteins p

Effect of pH on intragastric bacteria

Intragastric pH 1.5 Intragastric pH 7

Fundamentals of acid secretion• The human stomach produces 1-1.5 liters p

of gastric juice per day• Highly acidic with pH of ~0.8 (160 mM H+)Highly acidic with pH of 0.8 (160 mM H )• Acid secreted across a concentration

gradient of 2 5 million foldgradient of 2.5 million fold• Active transport process requiring

tremendous energytremendous energy• Transport achieved by H+K+ATPase

pump

Parietal cellsParietal cells• Human stomach contains ~ 1 billion

parietal cells• Large (25 μm in diameter) oval shaped

cells located in mid region of oxyntic glands

• Major function is the secretion of acid• Three main ultrastructural features:

– numerous mitochondria– tubulovesicles– secretory canaliculi

Integrated control of acidIntegrated control of acid secretion

Three levels of regulation of acid secretion:• Neural control - acetylcholine

– cephalovagal and local intragastric reflex arcs

• Hormonal control– endocrine (gastrin) or paracrine (somatostain,

histamine)

• Local direct factors• Local direct factors– positive (+) factors - amines/amino acids, gastric

distention– negative (-) factors - increased acid or low pH

Histamine is the final common mediator of acid secretionHistamine is the final common mediator of acid secretion

Phases of gastric acid secretion•Interdigestive phase

–basal acid secretion -vagal regulation

35-40%, vagal 50%, gastrin 5%, gastrin, a.a.

Why the stomach does not digest itself

• Acid is through a mucus gel layer through narrow “viscous fingers” which g gprevent back diffusion of acid due to a change in viscosity at the lower lumenal g ypH.

Bhaskar KR et al, Nature 1992;360:458

Protective Factors

Mucous layer

Cell membrane hydrophobicityMucosal blood flowMucosal blood flowCell proliferation Mucous layer ythicknesspH gradientGlutathioneGlutathioneBicarbonate secretion

Normal GastricNormal Gastric

Acid and pepsinAcid and pepsin

Protective MechanismsProtective Mechanisms

HCLHCL

p pp pStomachStomachlumenlumenpH pH << 2 2 Protective factors:Protective factors:

all areall are PG PG dependent dependentHCLHCL

Mucous layer thicknesMucous layer thicknespH gradientpH gradient

Mucous layerMucous layerGastricGastric

epitheliumepithelium

HCOHCO33ŠŠ HCOHCO33

ŠŠ HCOHCO33ŠŠ HCOHCO33

ŠŠ

pH7pH7Cell membraneCell membranehydrophobicityhydrophobicityBicarbonate secretionBicarbonate secretion

Gastric pitGastric pit

pH7pH7

Bicarbonate secretionBicarbonate secretionMucosalMucosal blood flow blood flow

Collins, 1990.Collins, 1990.

Mechanisms of NSAID InjuryMechanisms of NSAID Injury• Topical injury

– Ion trapping: rapid, compound specific– Enterohepatic recirculation

• Prostaglandin depletion– Systemic effect

• Neutrophil Activation– Increased neutrophil vascular adherence

mediated by increased TNFα and ICAM• Combination renders mucosa vulnerable

to acid

Ion Trapping ofIon Trapping ofAcidic Acidic NSAIDsNSAIDs

Gastric LumenGastric Lumen pH = 1-2pH = 1-2 AHAH AA–– + H++ H+

pH 2pH = 2

Gastric LumenGastric Lumen pH 1 2pH 1 2 AHAH AA + H+ H

pH = 2pH = 2

AHAH AA–– + H + H++Mucous Gel LayerMucous Gel Layer

AA–– + H + H++AHAH

pH = 7pH = 7

pH = 7.4pH = 7.4Gastric EpitheliumGastric Epithelium

AHAH AA–– + H + H++BloodBlood pH = 7.4pH = 7.4

SchoenSchoen. . Am JAm J Med Med. 1989;86:449.. 1989;86:449.

Indirect Topical Exposure ViaIndirect Topical Exposure ViaEnterohepaticEnterohepaticCirculationCirculation

LiLiNSAIDsNSAIDs Excreted Excretedin Bilein BileI d h iI d th i

LiverLiver

AbsorptionAbsorptionIndomethacinIndomethacinDiclofenacDiclofenacNaproxenNaproxen

StomachStomach

Reflux (with bile)Reflux (with bile) PiroxicamPiroxicamSulindacSulindacOxaprozinOxaprozinGallbladderGallbladder

Reflux (with bile)Reflux (with bile)

ppKetorolacKetorolac

ReabsorptionReabsorption I t ti lI t ti lReabsorptionReabsorption IntestinalIntestinalDamageDamage

Pathogenesis ofPathogenesis ofPathogenesis ofPathogenesis ofNSAID-Induced UlcerNSAID-Induced Ulcer

Endothelial effectsEndothelial effects

•• stasisstasis ischemia ischemia

•• direct toxicity direct toxicity“ion trapping”“ion trapping”

Epithelial effects (due toEpithelial effects (due toprostaglandin depletion)prostaglandin depletion)

•• HClHClsecretionsecretion• __HClHClsecretionsecretion

•• ⎠⎠ mucinmucin secretion secretion

•• ⎠⎠ HCO HCO33 secretion secretion

•• ⎠⎠ surface active surface active phospholipidphospholipid secretion secretion

•• ⎠⎠ epithelial cell proliferatioepithelial cell proliferation

ULCERULCER HEALING (spontaneousHEALING (spontaneousor therapeutic)or therapeutic)

AcidAcid

EROSIONSEROSIONS

CyclooxygenaseCyclooxygenasey ygIsoenzymesIsoenzymes

��Pl t l tPl t l t ��M hM h

PhysiologicPhysiologicStimulusStimulus

InflammatoryInflammatoryStimulusStimulus

��PlateletsPlatelets

��EndotheliumEndothelium

��MacrophagesMacrophages

��LeukocytesLeukocytesCOX-1COX-1 COX-2COX-2

��StomachStomach

Kid

��FibroblastsFibroblasts

E d h li l ll

ConstitutiveConstitutive InducibleInducible

��KidneyKidney ��Endothelial cellEndothelial cell

“H k i ”“H k i ”

PGIPGI22TXATXA22 PGEPGE22 PGIPGI22 PGEPGE22

InflammationInflammation“Housekeeping”“Housekeeping” InflammationInflammation

Risk factors for serious NSAID-related Peptic Ulcer Disease

Risk factors for serious NSAID-related Peptic Ulcer DiseasePeptic Ulcer DiseasePeptic Ulcer Disease

– Age > 60 years– History of previous ulcer or GI bleeding– Concomittant use of anticoagulants or

glucocorticoids– High dose NSAID therapy– Use of multiple NSAIDs– Severity of underlying disease

• High (9%) risk of major complications if 4 or more risk factorsPPI h l i f ti t t hi h i k f NSAID l• PPI prophylaxis for patients at high risk for NSAID ulcers

H. pylori Timeline• Early 1900’s Discovery of human gastric bacteria• Early 1900 s Discovery of human gastric bacteria• 1920-1980 Rediscovery of gastric bacteria• 1982 Isolation and culture of C. pyloridispy

by Marshall and Warren• 1987 Eradication reduces DU recurrence

1989 B t i d H l i• 1989 Bacteria are renamed H. pylori• 1990’s Association of H. pylori with gastric

cancer and MALT lymphoma

Marshall

y p• 1997 Complete genome sequence of H. pylori

Marshall& Warren

Helicobacter

pylori

BJM demonstratesthat H. pylori causes gastritiscauses gastritis

Epidemiology of H. pylori• Universal in developing countries but declining in incidence in• Universal in developing countries but declining in incidence in

industrialized nations

• Cohort effect explains higher rates in older adults in the U.S.• Early childhood the major window for acquisition; low rates in

older children & adultsolder children & adults• Transmission is person-to-person

– Familial clustering (passed among siblings older-younger)g (p g g y g )– High rates in institutions with crowding & poor sanitation

• Fecal-oral versus oral-oral transmission

CagA Protein from Helicobacter pylori Is a Trojan Horse to Epithelial CellsTrojan Horse to Epithelial Cells

• Keys for survival

Type IV Secretion System

Keys for survival– Acid tolerant (urease,

UreI)M til ( lti l fl ll )– Motile (multiple flagella)

• Important attributes– Attachment (32 Hop

Src

Attachment (32 Hop adhesins, including BabA)

– Other virulence factors:

Shp-2

– Other virulence factors: VacA, picB/cagE

– Genes regulated by slipped strand mispairingslipped-strand mispairing

– Uses molecular hydrogen for energy

H. pylori: Natural HistoryChildhood Ingestion of H. pylori

(gastroenteritis/diarrhea)

Early adulthoodChronic, active gastritisChronic, active gastritis

A t ti

Fe deficiencyanemia

Asymptomatic(90%)

Duodenal

Bodygastritis

Menetrier’sHyperplastic

polyps (<1%)

Late adulthoodDuodenalulcer (5%)

G i MALTlymphoma(<1%)

Gastriculcer (3%)

Gastriccancer (0.5%)

H. pylori and gastritisALL HP INFECTIONS ARE NOT

ALIKE: HISTOLOGY IS KEY• Acute infection may result

in hypochlorhydria

H. pylori and gastritisALIKE: HISTOLOGY IS KEY

• Superficial pangastritis (mixed gastritis) without disease – Normal acid

in hypochlorhydria• Active, chronic (type B)

gastritis invariably present

• Antral predominant gastritis – Increased acid (DU)

with H. pylori• Causal relationship

established (Koch’s• Body gastritis (± atrophy)

- Decreased acid (GU, gastric cancer)

established (Koch s postulates):– Eradication of H. pylori eliminates

gastritis cancer)• Multifocal atrophy with intestinal

metaplasia – Decreased acid (gastric cancer)

g– Ingestion of H. pylori by 2

volunteers

• Mild superficial gastritis p gusually asymptomatic

H. pylori and Peptic Ulcer Di

• PUD develops in only 5-10% of HP -infected patients.

Diseasep

• In the past, HP found in 95% (DU) & 80% (GU) patients.R t U S t di d li i• Recent U.S. studies, declining prevalence of HP in PUD.

• More NSAID (+) and HP(-) / Duodenal Ulcer

NSAID (-) ulcers.• Recurrence of PUD decreased

markedly by HP eradication. G t imarkedly by HP eradication.• U.S. studies suggest that 20%

recur after HP eradication.

GastricUlcer

Eradication of Eradication of H. pyloriH. pylori in in Recurrent Duodenal UlcerRecurrent Duodenal UlcerRecurrent Duodenal UlcerRecurrent Duodenal Ulcer

• Use of triple antibiotics to eradicate Heradicate H. pylori is superior to acidsuperior to acid suppression in the prevention of recurrent D.U.

Pathogenesis of H. pylori-dependent g yduodenal ulcer disease

• Need for severe, antral-restricted gastritis• Increases in gastrin/ gastric acid g g

– Role for incompletely processed gastrins• Host genetics: noninflammatory IL-1β

genotypes• Role of Type I strains (cagA, vacAs1, babA2),

type IV secretion and dupA• Duodenal colonization by H. pylori (in areas of

gastric metaplasia)

Postulated mechanism for duodenal ulcer disease

Severe antral I d

Low levelsof IL-1β

Severe antral infection by H. pylori (type I strains)

Increasedgastrin-17

Increased acid load

H. pylori (type I strains)

Lowduodenal pH

Gastrict l i

(CagA, vacAs1, babA2)

duodenal pHmetaplasia

H pylori Active D d lH. pyloricolonization of duodenum

chronicduodenitis

Duodenalulcer

H. pylori and gastric cancer• Declining in the U.S., • 2nd leading cause of cancer-

related mortality worldwiderelated mortality worldwide.• H. pylori: odds ratio of 3- to 20-

fold.• Animal models (ferrets,

Mongolian gerbils, and mice) confirm the carcinogenicity of Type I: Polypoid Gastric Cancerconfirm the carcinogenicity of Helicobacter.

• HP classified by the IARC as a

Type I: Polypoid Gastric Cancer

HP classified by the IARC as a class I carcinogen

• Eradication may potentially d t i i kreduce gastric cancer risk.

Type II:Exophytic Gastric Cancer

Helicobacter Fox and WangNEJM 2001Helicobacter

pylori is NEJM, 2001

pya Class I

Carcinogen

H. pylori and Gastric MALT LymphomaLymphoma

• MALT = Mucosa-associated lymphoid tissuetissue

• (MALT) lymphoma of the stomach: a rare tumor strongly associated with H.

l i i f tipylori infection• H. pylori gastritis harbors the clonal B

cell that eventually gives rise to MALT lymphoma (NEJM 1998)

• Eradication of H. pylori leads to regression of early MALT lymphomas inregression of early MALT lymphomas in 60-92% of cases

• Tumors in the distal stomach and that are superficial (stage 1 T1) are mostare superficial (stage 1 T1) are most likely to respond to antibiotics

Diagnostic tests for H. pylori• Noninvasive

– Serology (ELISA, immunoblot)Serology (ELISA, immunoblot)– UBT (C13 or C14)– H pylori stool antigen (HpSA)H. pylori stool antigen (HpSA)

• Invasive (require endoscopy, minimum 3 biopsies)minimum 3 biopsies)– Rapid urease assay

Histology (Warthin Starry– Histology (Warthin-Starry, Giemsa, immunostaining

Culture PCR analysis– Culture, PCR analysis– endomicrosopy

Treatment strategies for HPg

PPI Triple Regimens - PPI plus two antibiotics (clarithromycin plus amoxicillin or metronidazole)LAC (l l / i illi / l ith i ) dLAC (lansprazole/amoxicillin/clarithromycin) dose packet most commonly used in U.S.

(in >90%)

GastrinomaGastrinomaGastrinomaGastrinoma• Described by Zollinger and

Ellison in 1955• 80-90% of tumors in

“gastrinoma triangle”– Duodenal wall - 40-50%%– Pancreas - 20-25% – Stomach and jejunum - rare– Extrapancreatic, extraintestinal -Extrapancreatic, extraintestinal

10-20%• Range from microscopic

(44%) to 20 cm(44%) to 20 cm• Ulcers often distal to

duodenal bulbDi h i 30 50%• Diarrhea in 30-50%

• GERD in 50-70%