Post on 29-Sep-2020
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%