an introduction to the acid-peptic disorders mark feldman, md

An Introduction to the An Introduction to the Acid-Peptic DisordersAcid-Peptic Disorders

Mark Feldman, MD

Outline of talk

• Physiology

• Pathophysiology

• Clinical Features• GERD• PUD

• Therapy

Regions and gland areas of the gastric mucosaRegions and gland areas of the gastric mucosa

HCl (HCl (acidacid) &) & pepsinpepsin I are 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

Acid-pepsin interactionsAcid-pepsin interactions

Pepsinogens

hydrochloric acid

Pepsins(pepticactivity)

The proton pump of the parietal cell The proton pump of the parietal cell and its and its αα and and ββ chains chains

Activated PPI site

Activation of Proton Pump Activation of Proton Pump Inhibitor (PPI) in Parietal CellInhibitor (PPI) in Parietal Cell

Basal-lateral Membrane

apicalmembrane

basolateralmembrane

Cl-

Cl-

ATPase

K+

K+

HCO3 -

CO2 + H2O

H+ + HCO3-

CA

H+

P A R I E T A L C E L L

H2CO3

anionexchanger

cytosol

lumen

KCl symport

Histamine-producing ECL Histamine-producing ECL (enterochromaffin-like) cells(enterochromaffin-like) cells

adjacent to parietal cells adjacent to parietal cells

ParietalParietalCellCell

P ECL

G

gastrin

Antral mucosa

Hista- mine

HCl

Oxynticmucosa

2-Receptor Model for 2-Receptor Model for Parietal Cell ActivationParietal Cell Activation

• 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

• Acetylcholine receptor:– generates Ca++ signal– major trigger is “cephalic” phase– blockers: atropine and related anticholinergics

note: PPIs block final step of H+ secretion and block both paths

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

•Fusion of tubulovesicles with canaliculus, plus•Insertion of KCl symporter (conductance) into canaliculus

M3R H2R (inactive pumps)

Gastrin’s time-related effects on ECL cells Gastrin’s time-related effects on ECL cells acting via CCK-2 (CCK-B) receptorsacting via CCK-2 (CCK-B) receptors

©Copyright Science Press Internet Services

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)


Pathophysiology of the Pathophysiology of the acid-peptic diseasesacid-peptic 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

– anticholinergicsanticholinergics

– histamine-2 histamine-2 blockersblockers

– proton pump proton pump inhib- inhib- itors (PPIs)itors (PPIs)

DEFENSIVE FACTORSDEFENSIVE FACTORS

• Stop NSAIDsStop NSAIDs

• Stop smokingStop smoking

• Prostaglandin analogProstaglandin analog• Pro-motility agent Pro-motility agent (GER)(GER)

• Maintain blood Maintain blood pressure/ hi Opressure/ hi O22 sat. sat.

• Treat inflammation Treat inflammation when presentwhen present

The common acid-peptic diseasesThe common 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

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 GERD: Step Up RxTreatment of GERD: Step Up Rx

• Step 1: lifestyle modifications: dietary (food avoidance), mechanical (gravity, avoid tight clothes, etc.); weight loss if obese; smoking cessation; avoid overeating or late snacks

• 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 and safety is ???– Radiofrequency application (Stretta)

– Suturing/sewing

– Injection therapies

• Step 5: Surgery, ideally through a laparascope (minimally-invasive surgery)

Treatment of GERD: Step Down Treatment of GERD: Step Down

• Step 1: Life style modifications plus once a day PPI

• Step 2: Step up if failure; try to step down if success (but maintenance Rx usually requires dose needed to heal and induce remission)

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

Risk factors for PUDRisk factors for PUD

• Helicobacter pylori gastritis• Aspirin, even “low” cardiovascular doses*• NSAIDS*• Cigarette smoking*• Family history (genetics) • Acid hypersecretion (e.g., ZES)• Emotional distress

* reduce mucosal prostaglandins

Benign gastric ulcer along the Benign gastric ulcer along the greater curvaturegreater curvature

UlcerUlcer

radiating radiating foldsfolds

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

Endoscopic view: Endoscopic view: gastric ulcergastric ulcer


Endoscopic view of a Endoscopic view of a benign gastric ulcerbenign gastric ulcer

Endoscopic view of a gastric ulcerEndoscopic view of a gastric ulcer

Bleeding gastric ulcerBleeding gastric ulcerwith “visible vessel”with “visible vessel”


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

* Endoscopic therapy recommended

Pyloric outlet obstruction & Pyloric outlet obstruction & peripyloric ulcer disease peripyloric ulcer disease

Obstructing benign gastricObstructing benign gastriculcer in pyloric channel ulcer in pyloric channel

Pyloric outlet obstruction Pyloric outlet obstruction & peri-pyloric ulcer disease& peri-pyloric ulcer disease

Typical radiographic featuresTypical radiographic features of a duodenal ulcer of a duodenal ulcer


Ulcer

Endoscopic view: duodenal ulcerEndoscopic view: duodenal ulcer


Duodenal Ulcer associated with enteric-coated aspirinDuodenal Ulcer associated with enteric-coated aspirin

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) plus a PPI (IV or PO) or surgically (e.g., perforation or failure of endoscopic therapy)

Quiz: Which disorder(s) are risk Quiz: Which disorder(s) are risk factors for acid-peptic disease?factors for acid-peptic disease?• Cystic fibrosis

• Sclerosing cholangitis

• Meckel’s diverticulum

• Chronic basophilic leukemia

• None of the above

• All of the above

Which of the following patients should undergo EGD, and why?

• A 48 year old woman with longstanding heartburn easily controlled with life style modifications and OTC ranitidine.

• A 60 year old man with new onset dyspepsia and no “alarm” symptoms.

• A 45 year old man with dyspepsia and a duodenal bulbar ulcer on upper GI series.

• A 45 year old man with dyspepsia and a pre-pyloric gastric ulcer on upper GI series.

Gastrin stimulates parietal cells Gastrin stimulates parietal cells via neighboring ECL cellsvia neighboring ECL cells

Serum Gastrin

ECL CCK2R

Histamine

H2R (PC)

cAMP(±Ca)

Gastric Acid Secretion

CCK2R (PC)

Ca

P2

ECL2

DS

1

G

gastrin

DS

1 C C K

Antral mucosa

Duodenal mucosa

H

HCl

Oxynticmucosa

S

IS, somatostatin

Typical radiographic features Typical radiographic features of a benign gastric ulcer of a benign gastric ulcer

ulcer

Soll’s 3-receptor parietal cell modelSoll’s 3-receptor parietal cell model

an introduction to the acid-peptic disorders mark feldman, md

Documents

parietal cells acid

acidpepsin secretion

excessive acid exposure

gastric mucosahcl acid

ecl cells

heartburnhow common

gland areas

receptor model