PATHOLOC~Y ISSN:O9 12-6233
`
`TOXICOLOGIC
`Copyright 0 1988 by the Society of Toxicologic Pathologists
`
`Volume 16, Number 2, 1988
`Printed in U.S.A.
`
`The Pathophysiological and Pharmacological Basis of
`Peptic Ulcer Therapy*
`JAMES W . FRESTON
`Unisersity of Connectictrt Health Center.
`Farniington. Connectictrt 06032
`
`ABSTRACT
`Both genetic and nongenetic factors predispose to ulcer diathesis. At the mucosal level ulcers result from
`an imbalance between aggressive factors and mucosal defense. Ulcer therapy reduces aggressive forces, bolsters
`defense, or both. Gastric acid, the major aggressive factor, may have its secretion inhibited or it may be
`partially neutralized by antacids. H2 receptor antagonists competitively block histamine occupancy of H2
`receptors on parietal cells, thereby preventing stimulation of adenylate cyclase, cAMP rises, and activation
`of protein kinase and H+/K+ATPase. Prostaglandins inhibit acid secretion largely by preventing histamine-
`induced cAMP rises. Proton pump inhibitors bind H+/K+ATPase. Antimuscarinics inhibit acetylcholine
`receptors on the parietal cell, thereby blocking Ca2+ entry and subsequent activation of protein kinase and
`the proton pump.
`Mucosal defense is enhanced by certain prostaglandins, colloidal bismuth subcitrate and sucralfate. Pros-
`taglandins stimulate secretion of bicarbonate and mucus, among other effects. Colloidal bismuth and sucralfate
`bind to proteins in the ulcer base and stimulate bicarbonate and mucus secretion, partially, in the case of
`sucralfate, by increasing endogenous prostanoid synthesis. Sucralfate also binds pepsin and bile acids. Col-
`loidal bismuth temporarily eradicates mucosal colonization by Canipylobucterpylori, another putative agent
`in ulcer diathesis.
`
`INTRODUCTION
`The treatment of peptic ulcer disease (PUD) is
`best understood against a background of pathogen-
`esis and pathophysiology. Since the advent of effec-
`tive medical therapy with the introduction in 1976
`of cimetidine, the first histamine H2 receptor an-
`tagonist, there have been remarkable advances in
`our understanding of how ulcers develop. In fact,
`the availability of effective therapy stimulated in-
`terest and research in ulcer disease generally, and
`gastric physiology specifically. Thus we currently
`enjoy the advantage of having various therapeutic
`options for ulcer patients and sufficient understand-
`ing of the relevant physiology and the disease itself
`to deploy the drugs rationally.
`The purpose of this paper is to review the current
`understanding of the pathogenesis and pathophys-
`iology of ulcer disease as a prelude to a discussion
`of the mechanisms ofaction and efficacy ofthe ulcer-
`healing drugs.
`
`Presented at the Sixth International Symposium of.the So-
`ciety of Toxicologic Pathologists: “Gastrointestinal Toxicologic
`Pathology,” June 1-3, 1987 in Philadelphia, Pennsylvania.
`
`PEPTIC ULCER DISEASE
`Peptic ulcer disease appears to be a heterogeneous
`group of disorders having in common a hole in the
`gastroduodenal mucosa in the presence of gastric
`acid, but differing in the pathophysiology of ulcer-
`ation. Both genetic and non-genetic factors are in-
`volved. Regarding events at the mucosal level, new
`information has been generated by animal studies
`of acute injury induced by a variety of methods. It
`is unclear if such studies are relevant to chronic ulcer
`disease in man. This article therefore relies largely
`on studies in man.
`Genetic IqJirences. Genetic factors are involved
`in some patients, especially those with duodena1
`ulcer (DU) (39). Familial aggregation occurs and a
`positive family history is found in 20-50% of pa-
`tients, compared with 5-1 5% in controls. The prev-
`alence of PUD is increased 2-3-fold in first-degree
`relatives. Since a familial aggregation can result from
`environmental as well as genetic factors, studies in
`twins are invaluable in separating genetic and non-
`genetic influences. The concordance for ulcers in
`monozygotic twins is less than 100% but exceeds
`that of dizygotic twins. This suggests an interaction
`between genetic and environmental factors.
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`Vol. 16, No. 2, 1988
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`PEPTIC ULCER
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`26 1
`
`Several genetic markers have been identified in
`ulcer patients along with the relative risk for each
`marker. The risk is increased in individuals with
`blood group 0 and in those who do not secrete ABO
`antigens in saliva and gastric juice (“nonsecretors”).
`The relative risk for DU in those with blood group
`0 and “nonsecretor” trait is multiplicative rather
`than additive. Nearly 50% of patients with DU have
`high serum pepsinogen 1 levels, an autosomal dom-
`inant trait. People with this trait are 5 times more
`likely to have DU than those without the trait. Those
`with high serum pepsinogen 1 levels have high max-
`imum gastric acid outputs; this is a possible patho-
`physiologic link to peptic ulceration in such people.
`The hypothesis of genetic heterogeneity is con-
`sistent with observations. This hypothesis holds that
`a disease is in reality a group of disorders with a
`similar clinical expression. Both genetic and non-
`genetic factors are involved and the pathophysiol-
`ogy may vary among patients (39). Thus, ulcer pa-
`tients with a strong family history, high pepsinogen
`1 levels, and high maximum acid outputs have a
`different basis for their ulcers than those with no
`apparent familial predisposition who ingest large
`amounts of aspirin regularly. The concept also helps
`rationalize changes in ulcer pathogenesis over time;
`e.g., at one time stress may have been more im-
`portant in ulcerogenesis than aspirin ingestion.
`Nori-Getietic Factors. Various factors may in-
`crease the risk of developing an ulcer. Cigarette
`smoking is associated with an increased incidence
`of PUD, a high relapse rate, and resistance to ther-
`apy. Several physiological disturbances could ex-
`plain ulcer formation in cigarette smokers (6). Nico-
`tine reduces pancreatic bicarbonate secretion, pyloric
`sphincter pressure, and gastric mucus secretion.
`Moreover, cigarette smoking reduces gastric mu-
`cosal blood flow and gastric mucosal prostaglandin
`synthesis.
`Aspirin use and gastric ulcers (GU) are strongly
`associated (6,23). Aspirin use 4 or more days weekly
`for 3 months or more increases the incidence of
`gastric ulcers, while daily use of 1 g of aspirin for 3
`years to prevent myocardial infarction increases the
`prevalence 6-fold. Enteric-coated, but not buffered,
`aspirin reduces the risk significantly. Aspirin is di-
`rectly toxic to gastric mucosa at a pH of 3.5 or less;
`it reduces gastric mucosal synthesis of prostaglan-
`dins by inhibiting cyclooxygenase activity. Non-
`steroidal anti-inflammatory agents, including in-
`domethacin, phenylbutazone, ibuprofen, naproxen,
`and fenoprofen, inhibit prostaglandin synthesis,
`causing acute gastric erosions and ulcers in man.
`Their role in causing chronic peptic ulcer disease is
`less clear.
`The association of corticosteroids and ulcers is
`
`controversial. A review of 42 trials concluded that
`steroids are not ulcerogenic if taken for less than a
`month or in doses of less than the equivalent of 1
`g of prednisone (5). A subsequent review of 72 trials
`concluded that steroids increase the ulcer risk in a
`dose-dependent manner (29). The increased risk,
`however, is by a relatively small factor of 2.3, even
`with doses larger than the equivalent of 40 mg of
`prednisone daily.
`The influence of psychological factors in ulcero-
`genesis also is controversial. Ulcer perforations dur-
`ing air-raids (44) and occurrence of DU in people
`relocated (30,45) support an association, but there
`is no evidence that people in stressful jobs have
`more ulcers (38). People with PUD do not experi-
`ence more stressful life events than do people with-
`out ulcers (35), but they may perceive stressful life
`events more negatively (1 1). They may cope less
`well with stress and exhibit more personality dis-
`turbances, including hypochondriasis, excessive
`pessimism and dependence, immaturity, impulsiv-
`ity, and feelings of social isolation and alienation
`(1 1). Contrary to popular belief, people with ulcers
`are not more likely to be hard-driving individuals;
`no “ulcer personality” has been found.
`Although duodenal ulcers appear to be less fre-
`quent in people who consume a high fiber diet (40),
`there is no convincing evidence that diet causes ul-
`cers. Similarly, there is no convincing evidence that
`ingestion of beverages containing alcohol or caffeine
`is ulcerogenic (23).
`Event at the Miicosa in Ulceration. Peptic ulcers
`result from an imbalance between aggressive forces
`and factors responsible for maintaining mucosal de-
`fense. The most carefully studied aggressive factor
`is gastric acid. Acid secretion may be increased in
`DU patients, although it usually is within the normal
`range. In GU patients, acid secretion may be re-
`duced or normal. Thus, excessive aggressive forces
`are thought to be of greater importance in DU than
`GU.
`Increased Aggressive Factors. Several ph y sio -
`logic defects may increase acid secretion or delivery
`of acid load to the duodenum in patients with DU,
`as listed in Table I. Some patients have an increased
`rate ofgastric emtying and increased duodenal acid
`and pepsin loads. The approximate frequency of
`defects among patients with DU was recently re-
`viewed (25). The frequency of increased parietal cell
`mass varied in different parts of the world; it is about
`20% in the United States and about 50% in Wales
`and Scotland. Increased secretory drive may be due
`to rare disorders that increase serum gastrin levels,
`such as the Zollinger-Ellison Syndrome. Increased
`secretory drive may be due to increased vagus-me-
`diated secretion in about 30% of patients. Approx-
`
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`262
`
`FRESTON
`
`PATHOLOGY
`TOXICOLOGIC
`
`TABLE 1.-Some physiologic defects in acid secretion in
`patients with DU.
`
`Increased number of parietal cells
`0 Increased “drive” to secrete acid
`0 Increased parietal cell sensitivity to gastrin
`0 Increased meal-stimulated gastrin release
`Decreased acid-induced inhibition of gastrin release and
`acid secretion
`
`imately 2540% of DU patients have parietal cells
`that are abnormally sensitive to gastrin stimulation
`(1 7). Accelerated gastric emptying occurs at an un-
`known frequency in some DU patients (24); the fre-
`quency of defective feedback inhibition of acid se-
`cretion also is unknown (48). Some physiologic
`defects, such as increased parietal cell mass, en-
`hanced gastrin release by a protein meal, and rapid
`gastric emptying, appear to have a genetic basis (39).
`Pepsin, bile acids, pancreatic juice, and lysoleci-
`thin may be aggressive factors in some patients. Pep-
`sinogen is converted to pepsin by gastric acid at an
`optimum pH of 1.8-3.5. Pepsin’s proteolytic activ-
`ity could contribute to ulceration, but such an effect
`is difficult to separate from that of acid. The addition
`of pepsin to acid increases ulcerogenesis, but not to
`the extent that occurs if gastric juice is stimulated
`by secretagogues (20). This suggests either that en-
`dogenous pepsins are more injurious than is reflect-
`ed by their in vitro activity, or that additional factors
`are present in gastric juice, or both. Bile acids are
`injurious to the gastric mucosa. Ionized forms dis-
`rupt the gastric mucosal bamer to H+ by dissolving
`membrane lipids, and bile acids have other inju-
`rious effects on the bamer (8, 9). However, recent
`studies have found no difference in bile reflex into
`the stomach between normal controls and GU pa-
`tients (2, 33).
`The agent most recently incriminated in ulcero-
`genesis is Camnpylobacter pylori. This bacterium is
`cultured frequently from antral biopsies in patients
`with antral gastritis and in patients with gastric and
`duodenal ulcers (14, 28). The bacteria appear to
`occupy a protected niche below the mucus layer of
`the gastric mucosa. C. pyjori have an ultrastructure
`and fatty acid combination that differs from other
`campylobacter species. They possess a powerful
`urease, and produce large amounts of extracellular
`catalase, which may be important virulence factors.
`A cause and effect relationship appears likely for
`antral gastritis (7), but not yet for ulcers.
`Impaired Mi icosal Defense. Gas t roduoden a1 de-
`fense involves several factors (Table 11) (1 2). Mucus
`adheres to the surface of the gastroduodenal epi-
`thelia, forming an unstirred water layer through
`which H+ diffusion occurs at about one-fourth the
`
`TABLE 11.-Some factors in mucosal defense.
`
`~~~
`
`~~
`
`Mucus secretion and thickness
`0 Bicarbonate secretion
`0 Mucosal blood flow
`Mucosal repair and restitution
`0 Mucosal prostaglandins”
`0 Other factors
`a May influence other factors.
`
`rate of diffusion through unconstrained water (50).
`Within and beneath the mucus gel, hydrogen ions
`from the stomach lumen are neutralized by bicar-
`bonate ions secreted from the epithelial cells. This
`eliminates significant back diffusion of acid into ep-
`ithelial cells.
`Various defects in mucus in patients with PUD
`have been described (12). Gastric mucosal biopsies
`from patients with GU have reduced incorporation
`of precursor sugar into glycoproteins. Mucus taken
`from gastrectomy specimens of patients with GU
`contains more degraded mucus than normal, a find-
`ing also present to a lesser extent in patients with
`DU. It is not known if the mucus changes precede
`or follow peptic ulceration.
`Bicarbonate secretion by the stomach and duo-
`denum, together with mucus secretion, appears to
`be essential for mucosal protection (50). Reduced
`gastric bicarbonate secretion has not been found
`(lo), but decreased bicarbonate secretion from the
`proximal duodenum was recently reported in DU
`patients (19). This reduction may be related to de-
`fective mucosal prostaglandin synthesis or release
`(see below). Patients with DU have a smaller pH
`gradient from lumen to surface epithelial cells than
`do non-ulcer patients (37). This may be due to ab-
`normal bicarbonate secretion or other mucosal de-
`fects in DU patients. It is not known if such defects
`precede or follow ulceration.
`The role ofendogenous prostaglandins in mucosal
`defense has been clarified recently (16, 22); studies
`suggest a relationship between decreased mucosal
`prostaglandin synthesis and PUD. Prostaglandin-
`mediated mucosal defense involves several mech-
`anisms and varies with the prostaglandin employed.
`Mucus and bicarbonate secretion as well as cell res-
`iitution are strmulated by E prostaglandins, and E
`and 1 prostaglandins and some lipoxygenase prod-
`ucts enhance gastric mucosal blood flow. Duodenal
`mucosal content of PG12, PGF, (42), and PGE, (36)
`is subnormal in patients with DU, and duodenal
`prostaglandin synthesis does not rise normally in
`response to the acid load (1). Decreased synthesis
`of PGE2 has also been reported in GU patients (2 1,
`23, 52); levels may be unusually low in the region
`of the stomach containing the ulcer (2 1).
`
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`Vol. 16, No. 2, 1988
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`PEPTIC ULCER
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`263
`
`ACH
`
`HISTAMINE
`Q
`
`TABLE 111.-Drugs available for healing peptic ulcers.u
`
`Act by decreasing aggressive forces:
`H2 receptor antagonists
`cimetidine
`ranitidine
`famotidine
`Antacids
`many
`0 Antimuscarinics
`pirenzepine
`Prostaglandins
`misoprostol
`enprostol
`0 Proton pump inhibitors
`omeprazole
`Act by enliancirig riiiicosal defense:
`sucralfate
`colloidal bismuth subcitrate
`prostaglandins
`a Modified from (1 3).
`
`The efficacy of exogenous prostaglandin E com-
`pounds in healing peptic ulcers is only circumstan-
`tial evidence that mucosal prostaglandin deficiency
`is involved in peptic ulcer diathesis, since these
`agents also inhibit acid secretion at doses that con-
`vey mucosal protection. Nevertheless, available evi-
`dence supports the concept that prostaglandins are
`important in maintaining mucosal integrity and that
`they play a role in peptic ulcer disease in man. The
`precise nature of that role and its relative impor-
`tance awaits clarification.
`
`ULCER-HEALING DRUGS
`Drugs promote ulcer healing by reducing gastric
`acid, bolstering mucosal defense, or both. Table I11
`lists the drugs available for treating ulcers in the
`United States and some additional agents that are
`available in other countries. The drugs are divided
`between those that act primarily by reducing ag-
`gressive forces and those that act by bolstering de-
`fense.
`Drugs inhibit acid secretion either by blocking
`receptors on parietal cells or inhibiting intracellular
`processes of acid secretion. The apical surface of
`parietal cell contains receptors for the major phys-
`iologic stimulants of acid secretion: gastrin, hista-
`mine, and acetylcholine (Fig. 1). Activation of H2
`receptors by histamine results in formation of cyclic
`AMP (43). This presumably results from a change
`in receptor conformation which alters its interaction
`with a G protein, Gs. This protein binds the guanine
`nucleotide GTP, and then stimulates C, the catalytic
`subunit of adenylate cyclase. Cyclic AMP then ac-
`tivates specific protein kinases. The final step is the
`
`FIG. 1 .-Parietal cell events in acid secretion. Receptors
`at the apical surface recognize the major physiological
`stimulants of acid secretion. The secondary messengers
`are Ca2+, which mediates cholinergic- and gastrin-induced
`secretion, and cyclic AMP, which mediates histamine-
`induced secretion. The stimulatory G protein, Gs, and the
`catalytic subunit of GTP, C, are involved in histamine
`activation of adenylate cyclase. A KCl cotransporter must
`be inserted in the secretory membrane for the H+/
`K+ATPase to pump H+ into the gastric lumen. -
`
`insertion of a KC1-cotransporter into the apical
`membrane (4 1 , 5 l), which allows H+/K+ATPase,
`the proton pump, to exchange H+ for K+ at the
`luminal surface (4 1).
`In contrast to histamine, gastrin and cholinergic
`agents act through calcium-dependent mechanisms.
`Cholinergic agents increase Ca2+ uptake through se-
`lective receptor-activated calcium channels (32),
`which appear to differ from those present in muscle,
`nerve, and other tissues that are inhibited by cal-
`cium channel antagonists. Gastrin also increases Ca2+
`entry (31), but it is not known if this is the only
`source of raised cytosolic Ca2+ following gastrin
`stimulation. Calcium-dependent kinases are then
`activated, followed by increased activity of the pro-
`ton' pump.
`The sites of acid inhibition by drugs acting at the
`parietal cell are illustrated in Fig. 2. H2 antagonists
`inhibit the cyclic AMP pathway; antimuscarinic and
`antigastrin agents block Ca2+-mediated acid secre-
`tion. Prostaglandins block histamine-induced rises
`of cyclic AMP (4, 27, 43). This appears to result
`from an interaction between prostaglandin receptors
`on parietal cells and an inhibitory G protein, which
`binds the catalytic subunit. Omeprazole irreversibly
`binds and inactivates H+/K+ATPase (3).
`
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`264
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`FRESTON
`
`TOXICOLOGIC PATHOLOGY
`
`
`
`TABLE IV.-Efiicacy of drug regimens in healing DU.II
`% ulcers
`healed
`4
`8
`weeks weeks
`Regimen
`Dmg
`Cimetidine
`79
`800 mg/hr
`96
`300 mdhr
`Ranitidine
`84 95
`40 mg/hr
`Farnotidine
`82
`91
`95 -
`Omeprazole
`30 mg/d
`78 -
`Mylanta 110 liquid
`30 mmol7/d
`74 -
`15 mmol qid
`Link@ tablets (antacid)
`74 -
`50 mg bid
`Pirenzepine
`70 -
`35 pg bid
`Enprostol
`65 -
`400 pg bid
`Misoprostol
`75 -
`Sucralfate
`1 gqid
`74 -
`120 mg qid
`Colloidal bismuth
`a Healing rates are from representative large studies. Blanks
`indicate insufficient data available. Modified from (13).
`
`The efficacy of drugs and regimens in healing DU
`is shown in Table IV. Mosts agents heal ulcers in
`70% or more of patients after 4 weeks of treatment
`at recommended doses (1 3). Healing usually exceeds
`80% after 6 weeks and 90% after 8 weeks. Relief of
`pain is also comparable among the H2 blockers and,
`on average, slightly less rapid with sucralfate, mis-
`oprostol, and CBS (data not shown). Omeprazole
`heals duodenal ulcers in more than 90% of patients
`in 4 weeks, but the safety of omeprazole has not
`been established (26). Antacids were first shown to
`heal DUs when used in large doses, i.e., 30 ml of
`Mylanta I1 7 times daily (1,008 mmol) (34). More
`recently, small studies have shown that lower doses
`of magnesium aluminum-containing preparations
`are also effective (47, 49). Gastric ulcer healing has
`been reported with all the agents listed in Table 111.
`However, the evidence of,efficacy is well established
`in the case of the H2 antagonists and omeprazole,
`and least convincing in the case of antacids. On
`average, GUS probably heal more slowly than DUs;
`about 89% healing occurred after 12 weeks of ci-
`metidine treatment in a particularly well-designed
`study (18). Over 90% of DUs heal after just 8 weeks
`of treatment.
`
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`PROTEIN KINASES "r'
`
`FIG. 2.-Cellular mechanisms of antisecretory drugs.
`Antimuscarinic and antigastrin components block Ca2+
`entry. H2 blockers prevent intracellular rises in cyclic AMP.
`Prostaglandins prevent histamine-induced cyclic AMP
`rises by blocking a receptor, which then activates an in-
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`
`Antacids neutralize acid secreted into the gastric
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