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