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An Introduction to the An Introduction to the Acid-Peptic DisordersAcid-Peptic Disorders
March 17th, 2003
Regions of the gastric mucosaRegions of the gastric mucosa
HCl (acid) &HCl (acid) & pepsin I arepepsin I are produced inproduced in thethe OXYNTIC OXYNTIC GLAND AREAGLAND AREAby parietal cellsby parietal cellsand chief cells,and chief cells,respectivelyrespectively
(source of gastrin)(source of gastrin)
Oxyntic gland area: Oxyntic gland area: acid-secreting parietal cellsacid-secreting parietal cells
Activation of the parietal cell’s acid pumps Activation of the parietal cell’s acid pumps by acetylcholine (Ach) and Histamineby acetylcholine (Ach) and Histamine
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•Fusion of tubulovesicles with canaliculus, plus•Insertion of KCl symporter (conductance) into canaliculus
M3R H2R (inactive pumps)
The parietal cell’s pumpsThe parietal cell’s pumps
receptors
pump
The proton pump and its alpha The proton pump and its alpha and beta chainsand beta chains
Activated PPI site
Activation of Proton Pump Activation of Proton Pump Inhibitor (PPI) in Parietal CellInhibitor (PPI) in Parietal Cell
Basolateral Membrane
Soll’s 3-receptor parietal cell modelSoll’s 3-receptor parietal cell model
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Histamine-producing ECL Histamine-producing ECL (enterochromaffin-like) cells(enterochromaffin-like) cells
adjacent to parietal cells adjacent to parietal cells
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ParietalParietalCellCell
Gastrin stimulates parietal cells Gastrin stimulates parietal cells via neighboring ECL cellsvia neighboring ECL cells
Serum Gastrin
ECL CCKBR
Histamine
H2R (PC)
cAMP(±Ca)
Gastric Acid Secretion
CCKBR (PC)
Ca
Revised 2-Receptor Model for Revised 2-Receptor Model for Parietal Cell ActivationParietal Cell Activation
• Acetylcholine receptor:– generates Ca++ signal– major trigger is “cephalic” phase– blockers: atropine and related anticholinergics
• Histamine-2 receptor:– generates cAMP signal– major trigger is gastrin released by food protein
working via ECL cell and histamine release– blockers: cimetidine, ranitidine, famotidine, and nizatidine
note: PPIs block final step of H+ secretion and block both paths
Gastrin’s acute, intermediate, and Gastrin’s acute, intermediate, and chronic effects on ECL cellschronic effects on ECL cells
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ECLECL
HDC = histidine decarboxylase
ECL cell hyperplasia 2° to hypergastrin-ECL cell hyperplasia 2° to hypergastrin-emia in a patient with a gastrinoma (ZES)emia in a patient with a gastrinoma (ZES)
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Pathophysiology of the acid-Pathophysiology of the acid-peptic diseasespeptic diseases
AGGRESSIVE FACTORSAGGRESSIVE FACTORS
• AcidAcid• PepsinPepsin
DEFENSIVE FACTORSDEFENSIVE FACTORS
• Bicarbonate/ mucusBicarbonate/ mucus
• ProstaglandinsProstaglandins
• Clearance of acid via Clearance of acid via motor functionmotor function
• Adequate blood supply / Adequate blood supply / oxygenationoxygenation
• Cell turnover and Cell turnover and restitutionrestitution
• No inflammationNo inflammation
Strategies for therapy of Strategies for therapy of the acid-peptic diseasesthe acid-peptic diseases
AGGRESSIVE FACTORSAGGRESSIVE FACTORS
• Reduce acidity and Reduce acidity and hence peptic activityhence peptic activity– antacidsantacids
– anticholinergicsanticholinergicshistamine-2 blockershistamine-2 blockersproton pump inhibs.proton pump inhibs.
DEFENSIVE FACTORSDEFENSIVE FACTORS
• Stop NSAIDsStop NSAIDs• Prostaglandin analogProstaglandin analog• Pro-motility agentPro-motility agent• Maintain blood Maintain blood
pressure/ hi O2 sat.pressure/ hi O2 sat.• Treat inflammation Treat inflammation
when presentwhen present
The acid-peptic diseasesThe acid-peptic diseases
• GERD, and its complications– normal acid-pepsin secretion, but excessive acid
exposure to the esophageal epithelium
• PUD, and its complications– DU: acid-pepsin hypersecretion common, but not
universal; heterogeneous disease– GU: acid-pepsin secretion normal usually, implying
impaired defensive mechanisms
• Zollinger-Ellison syndrome– acid hypersecretion is massive and pathogenic
The acid-peptic diseasesThe acid-peptic diseases
• GERD– uncomplicated: heartburn– complications:
• esophageal: stricture; bleeding; adenocarcinoma
• airway: sore throat; throat clearing; laryngitis; asthma
How common is heartburn?How common is heartburn?
WOMENWOMEN
ages 25-34 48%
ages 35-44 40%
ages 45-54 47%
ages 55-64 30%
ages 65-74 40%
MENMEN
42%
53%
39%
39%
35%
( %’s refer to ANY heartburn)( %’s refer to ANY heartburn)
How common isHow common is frequent heartburn? frequent heartburn?
WOMENWOMEN
ages 25-34 16%
ages 35-44 14%
ages 45-54 22%
ages 55-64 14%
ages 65-74 20%
MENMEN
14%
26%
20%
17%
17%
(frequent means at least weekly)
Beverages and heartburnBeverages and heartburn
The 5 WORSTThe 5 WORST::– Red Wine
– Grapefruit juice
– Orange juice
– Coffee
– V8/Tomato juice
The 5 BESTThe 5 BEST::– Water
– Prune juice
– Skim milk
– Peach nectar
– Gatorade
(M Feldman, C Barnett. Gastroenterology 108:125, 1995)
Who is predisposed Who is predisposed to heartburn/GERD?to heartburn/GERD?
• Pregnant women (25% have daily heartburn)
• People with hiatal hernias
• People who smoke
• People who drink alcohol to excess
• People with acid hypersecretion (e.g., ZES)
• People who are not infected with H. pylori
Endoscopic appearance of Endoscopic appearance of reflux esophagitisreflux esophagitis
Barium esophagram of Barium esophagram of esophageal peptic strictureesophageal peptic stricture
Endoscopic appearance of Endoscopic appearance of Barrett’s esophagusBarrett’s esophagus
Gross pathologic appearance of Gross pathologic appearance of esophageal adenocarcinomaesophageal adenocarcinoma
Treatment of GERDTreatment of GERD
• Step 1: lifestyle modifications: dietary, mechanical (gravity, tight clothes, etc.)
• Step 2: over-the-counter chewable antacid tablets or liquids, H2 blockers (Pepcid, Tagamet, Zantac, Axid); or combinations of the two (Pepcid Complete)
Treatment of GERD (cont’d)Treatment of GERD (cont’d)
• Step 3: Prescription doses of H2 blockers or PPIs (Prilosec, Prevacid, Nexium, Protonix, Aciphex)
• Step 4: Add a pro-motility drug to help clear gastric contents from the esophagus, such as metoclopramide (Reglan)
Treatment of GERD (cont’d)Treatment of GERD (cont’d)
• Step 4?: New endoscopic treatments are under evaluation but long term value is ???
• Step 5: Surgery, ideally through a laparascope (minimally-invasive surgery)
The acid-peptic diseasesThe acid-peptic diseases
• GERD
• PUD, and its complications– uncomplicated: pain (“gastralgia”)– complications: bleeding, perforation, obstruction
Sir William Osler’s description Sir William Osler’s description of the pain of peptic ulcerof the pain of peptic ulcer
Pain is perhaps the most constant and distinctive feature of ulcer. It varies greatly in character; it may be only a gnawing or burning sensation, which is particularly felt when the stomach is empty, and it is relieved by taking food, but the more characteristic form comes on in paroxysms of the most intense gastralgia, in which the pain is not only felt in the epigastrium, but radiates to the back and to the sides.
THE PRINCIPLES AND PRACTICE OF MEDICINE, 1909THE PRINCIPLES AND PRACTICE OF MEDICINE, 1909
Known risk factors for PUDKnown risk factors for PUD
• Helicobacter pylori gastritis• Aspirin, even “low” cardiovascular doses*• NSAIDS*• Cigarette smoking*• Family history (genetics) • Acid hypersecretion (e.g., ZES)
* reduce mucosal prostaglandins
Benign gastric ulcer along the Benign gastric ulcer along the greater curvaturegreater curvature
UlcerUlcer
radiating radiating foldsfolds
Typical radiographic features Typical radiographic features of a benign gastric ulcer of a benign gastric ulcer
ulcer
Benign gastric ulcer along the Benign gastric ulcer along the lesser curvaturelesser curvature
UlcerUlcer
Typical radiographic features Typical radiographic features of a benign gastric ulcerof a benign gastric ulcer
ulcer
Malignant gastric ulcer Malignant gastric ulcer occurring within a massoccurring within a mass
ulcer
Pyloric outlet obstruction & Pyloric outlet obstruction & peripyloric ulcer disease peripyloric ulcer disease
Typical radiographic featuresTypical radiographic features of a duodenal ulcer of a duodenal ulcer
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Ulcer
Typical radiographic featuresTypical radiographic features of a duodenal ulcer of a duodenal ulcer
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Ulcer
Perforated duodenal ulcerPerforated duodenal ulcer
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Endoscopic view: Endoscopic view: gastric ulcergastric ulcer
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Endoscopic view of a Endoscopic view of a benign gastric ulcerbenign gastric ulcer
Endoscopic view of a gastric ulcerEndoscopic view of a gastric ulcer
Pyloric outlet obstruction Pyloric outlet obstruction & peri-pyloric ulcer disease& peri-pyloric ulcer disease
Obstructing benign gastricObstructing benign gastriculcer in pyloric channel ulcer in pyloric channel
Endoscopic view: duodenal ulcerEndoscopic view: duodenal ulcer
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Duodenal Ulcer associated with enteric-coated aspirinDuodenal Ulcer associated with enteric-coated aspirin
Bleeding gastric ulcerBleeding gastric ulcerwith “visible vessel”with “visible vessel”
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Enoscopic stigmata of Enoscopic stigmata of recent gastric ulcer hemorrhage recent gastric ulcer hemorrhage
Ulcer rebleeding rate based on Ulcer rebleeding rate based on endoscopic stigmataendoscopic stigmata
• Actively bleeding 90%
• Visible vessel 50%
• Adherent clot 10-15%
• Dots and spots 3%-5%
• Clean base 1% or less
Therapy of PUDTherapy of PUD• Eliminate H. pylori, if present• Discontinue aspirin, NSAIDs, and/or coxibs, if
applicable and if possible• Counseling and referral to smoking cessation
program, if applicable
• Proton pump inhibitor or H2-blocker
• Treat ulcer complications endoscopically (e.g., bleeding or GOO) or surgically (e.g., perforation or failure of endoscopic therapy)
The acid-peptic diseasesThe acid-peptic diseases
• GERD
• PUD
• Z-E syndrome
Zollinger-Ellison Syndrome Zollinger-Ellison Syndrome
• “Islet cell” tumor of the pancreas or of the duodenum
• Hypergastrinemia • Gastric acid hypersecretion • Consequences of acid hypersecretion :
– PUD, GERD [ with or without complications]– Diarrhea, malabsorption (see April case to be
discussed at Wed. AM Grand Rounds)
Quiz: Which disorder(s) may Quiz: Which disorder(s) may result in acid-peptic disease?result in acid-peptic disease?
• Cystic fibrosis
• Sclerosing cholangitis
• Meckel’s diverticulum
• Chronic basophilic leukemia
• None of the above