Download drug induced injury of the gi tract

DRUG INDUCED INJURY OF THE G.I. TRACT
David A. Owen
University of British Columbia
NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
These are the most common drugs causing intestinal injury. In the majority of cases
these agents are not physician prescribed but are obtained “over the counter” from drug
stores and supermarkets etc. Their use is so widespread that patients may be assumed
to be taking them until proved otherwise. Unfortunately, information about their use is
seldom provided on patient pathology requisitions.
Advertisers’ claims that their NSAIDs are safer than the other companies NSAIDs may
or may not be correct and it is safe to assume that any NSAID may cause GI problems
The pathologic findings do not differ among the various brands available. Low-dose
preparations may also cause problems although as a general rule higher doses and
prolonged periods of administration result in greater problems. It has been estimated
that low-dose aspirin administration increases the risk of upper gastro-intestinal
bleeding by 2-4%.
In the UK it has been estimated that there are 12,000 hospital admissions annually that
are attributable to NSAID use. 2230 of these patients died.
Mechanisms of action: 1) Many NSAIDs are acidic in nature (e.g. aspirin) and are
capable of directly interfering with the mucus that covers the gastrointestinal mucosa.
This may lead to breaks in the mucous barrier. In addition, the chemical nature of the
NSAIDs themselves can directly irritate the exposed mucosa. 2) Cyclooxygenase (COX)
produces prostaglandins that are important for maintaining mucosal integrity in
gastrointestinal mucosa, particularly in the stomach where they mediate blood flow and
epithelial repair. NSAIDs inhibit COX1 and consequently prostaglandin production
resulting in neutrophil mediated damage to mucosal endothelium and ulceration.
Esophagus: NSAID damage in the esophagus produces a syndrome known as “pill
esophagitis”. Other drugs including tetracyclines, clindamycin, ascorbic acid, iron
supplements and bisphosphonates (e.g. alendronate) may also cause pill esophagitis
and the histologic changes produced are similar. The basic disease mechanism of
mucosal damage is poor swallowing and lodgement of pills at the level of the aortic arch
or in the distal esophagus. Ineffective swallowing may be promoted by ingestion of pills
when the patient is in a horizontal position or by taking inadequate amounts of water.
The contents of the pills are caustic and release of drugs from the core produces
inflammation and eventually ulceration. Endoscopically, lesions present as discrete
“punched out” ulcers with relatively little damage to adjacent mucosa. Histologically
there is neutrophil infiltration, erosions or deep ulcers. Occasionally polarizable
crystalline pill remnants can be identified.
There is some evidence that NSAIDs given in standard doses is harmful to the
esophagus and promotes esophagitis, esophageal ulcers and stricture formation.
Stomach and Duodenum: A number of gastric lesions are described in patients that
are taking NSAIDs. These include erosive gastritis, erosive duodenitis, deep ulcers
(stomach and duodenum) and reactive gastropathy. Erosive gastritis may be
hemorrhagic or non-hemorrhagic. Ulcers secondary to NSAIDs tend to be deeper and
larger than the usual type of peptic ulceration. Reactive gastropathy (also known as
chemical gastritis) probably occurs in between one third and one half of patients taking
NSAIDs. Endoscopically, it is characterized by mucosal redness. Histologically, there is
foveolar hyperplasia resulting in a corkscrew appearance. The individual cells show
cytoplasmic mucin depletion with enlarged nuclei and prominent nucleoli. The lamina
propria is congested and edematous. Small tongues of muscle from the muscularis
mucosae may extend into the lamina propria as far as the surface epithelium. The
lamina propria shows no increase in inflammatory cells. Reactive gastropathy
secondary to NSAIDs is often patchy because the pills break up into small fragments. A
more diffuse antral distribution of reactive gastropathy suggests the possibility of
duodenal reflux and increased mucosal surface cell lost secondary to the cytotoxic
properties of bile.
The underlying pathogenesis of reactive gastropathy is increased exfoliation of cells
from the mucosal surface and the mucosal hyperplasia is a compensatory reaction. If
the rate of exfoliation exceeds the rate of epithelial regeneration then an erosion will
develop. Continued use of NSAIDs will result in frank ulceration and expose the patient
to the possibility of complications such as bleeding and perforation.
Lower gastro-intestinal tract: NSAIDs may also produce ulcers in the distal small
bowel and proximal colon. The pathogenesis of small bowel ulcers is similar to that of
esophageal ulceration: local irritative effect. Bile has the effect of promoting this damage
and suppression of prostaglandins does not seem to be involved. It is interesting to note
that ligation of the bile duct prevents small intestinal damage by NSAIDs.
Multiple colonic lesions have been attributed to NSAIDs. The list includes: non-specific
colitis, erosions, ulcers, diaphragm disease, collagenous colitis, lymphocytic colitis,
pseudomembranous colitis, eosinophilic colitis and apoptotic colonopathy. They may
also exacerbate ulcerative colitis and diverticular disease. Ulceration in the colon may
be due to direct mucosal irritation by the drugs or it may be secondary to suppression of
prostaglandin production. Colonic ulcers are “non-specific” histologically and resemble
the NSAIDs induced ulcers in the stomach and esophagus. Typically they are sharply
circumscribed with dense fibrosis at the base. Inflammation is usually scanty and
confined to the immediate ulcer edge. They have some features similar to ischemic
ulceration. In older literature NSAIDs ulcers were often referred to as “solitary ulcer of
the cecum” and considered to be ischemic in etiology. This was an inappropriate
designation as the ulcers are commonly multiple and not confined to the cecum.
Diaphragm disease is a rare complication of NSAID therapy. It mainly involves the small
bowel but occasionally my affect the proximal large bowel. Histologically diaphragms
consist of a thin incomplete membrane composed of a central fibrous core and covered
by normal or attenuated mucosa. At the inner edge of the membrane there is often nonspecific ulceration. Fibrosis may extend into the submucosa of the adjacent tubular
bowel but generally the muscular component of the bowel wall is unaffected.
One common effect of NSAIDs is to promote epithelial apoptosis. In turn this leads to
increased epithelial turnover with loss of cells that could contain pre-cancerous
mutations. This is one of the proposed benefits of taking low-dose aspirin on a daily
basis. It follows therefore that biopsies from patients taking this medication may
demonstrate increased apoptosis. This change has been demonstrated in gastric and
colo-rectal biopsies.
PROTON PUMP INHIBITORS (PPIs)
Patients treated with PPIs will inevitably develop hypoclorhydria. This leads to antral G
cell hyperplasia and hypergastrinemia which in turn leads to hyperplasia and
hypertrophy of parietal cells and hyperplasia of ECL cells in the gastric body. Initially
hyperplasia of the ECL cells (histamine producing) is linear but with continued
stimulation nodularity may develop. Unlike ECL stimulation in cases of pernicious
anemia it is unusual for neuroendocrine neoplasms (micro carcinoids) to develop.
Gastrin stimulation of parietal cells leads to cytoplasmic expansion and proliferation.
Parietal cells may extend downwards to deeper levels of the mucosa where they appear
to crowd out chief cells. They may also expand upwards into the gastric foveolae.
Morphologic changes consist of gland dilatation with swelling and bulging of individual
cells (parietal cell profusion). The cells lining the gland therefore produce a serrated
rather than a smooth outline. The cytoplasm of the parietal cells becomes paler and
may ultimately become vacuolated as the canalicular system expands.
PPIs have also been associated with the development of fundic gland polyps. Polyps
are present in 17% of individuals after three months treatment and in 35% after five
months treatment. Reports suggest that the polyps will regress after PPI treatment is
stopped but will reappear when treatment is re-started. Histologically, the polyps
themselves are an exaggerated version of PPI changes in flat mucosa with parietal cell
overgrowth and cyst formation.
It is rare to be able to identify Helicobacter pylori organisms in patients who are taking
PPIs long-term. However, some authors have identified overgrowth of non-specific cocci
and bacilli. This presumable represents oral contamination with growth in the absence
of stomach acid.
INTESTINAL DISEASE SECONDARY TO CHEMOTHERAPY AND RADIOTHERAPY
The effects of cancer chemotherapy and radiotherapy on tissues are similar. Low doses
produce degenerative changes within epithelial cells that are accompanied by nonspecific lamina propria inflammation. These changes persist for about four months
following treatment after which they gradually resolve. Intermediate doses will result in
permanent damage usually in the form of atrophy. This includes loss of glands
(particularly oxyntic glands), intestinal metaplasia and crypt shortening and distortion
(small and large intestine). Larger doses may produce deep, non-healing ulcers.
Epithelial cytologic changes that accompany epithelial regeneration have to be
distinguished from dysplasia. Chemo-radiotherapy changes are characterized by: 1)
Enlarged vesicular nuclei with prominent but irregular nucleoli, 2) Cytoplasmic
degenerative changes with vacuolation and eosinophilia. 3) Syncytial change in the
surface epithelium. 4) Atypia of fibroblasts and endothelial cells. 5) Absence of atypical
mitoses, 6) Changes affect the glands and foveolae of the stomach.
In the stomach chemotherapy changes are most frequent following hepatic arterial 5FU
infusion for the treatment of primary and secondary liver cancer. In the colon
radiotherapy changes are commonly seen alongside recto-sigmoid carcinomas that
have been treated prior to total mesenteric excision. Radiotherapy changes that are
seen closely mimic chronic ulcerative colitis with dysplasia. However, the main
distinguishing feature is uniformity of changes following radiation versus patchy
dysplasia in inflammatory bowel disease.
ANTIBIOTICS
Some antibiotic tablets are large (e.g. tetracycline, doxycycline) and difficult to swallow.
They may lodge in the esophagus and cause localized inflammation with erosion and
ulceration (pill esophagitis).
Antibiotics are associated with the development of pseudomembranous colitis.
However, this is not a direct toxic effect of the drug. The normal colonic flora may be
destroyed leading to an overgrowth of cytotoxin producing Clostridium difficile. Blood
volume depletion in patients with pseudomembranous colitis may produce ischemic
changes in addition to the pseudomembranes.
Antibiotic associated hemorrhagic colitis (AAHC) may produce a clinical and pathologic
picture resembling colonic ischemia. The pathogenesis is unknown. Antibiotics primarily
implicated in causing this condition include penicillin derivatives such as ampicillin and
amoxicillin. Rarely macrolides, cephalosporin, chloramphenicol, fluroquinalones, and
tetracycline have been implicated. This condition is more commonly recognized in
Japan than in North America. This may relate to differences in normal bowel microflora.
POTASSIUM CHLORIDE
Potassium replacement may be prescribed for patients on diuretics. Many
pharmacologic preparations are designed for “slow-release” of the drug. If this does not
occur, localized damage to gastrointestinal mucosa may occur and the effects can be
very similar to those of NSAIDs. Specifically, lesions that have been identified include:
1) Pill esophagitis with or without fibrous strictures. 2) Gastric, small and large bowel
erosions, erosions, ulcers and fibrous strictures.
DRUG MEDIATED ISCHEMIC COLITIS
A wide variety of drugs have been implicated. These include: antibiotics, appetite
suppressants (phentermine), chemotherapeutic agents (taxanes and vinca alkaloids),
constipating agents (mechanism of action may be via fecal impaction), decongestants
(pseudoephedrine), digitalis (vasoconstriction of splanchnic circulation), diuretics (lower
circulating blood volume), ergot alkaloids (vasoconstriction), steroid hormones
(thrombosis), amphetamines, cocaine, interleukins, tricyclic antidepressants and
phenothiazines, (See reference Hass AJ et al for detailed information).
SODIUM PHOSPHATE ENEMAS AND LAXATIVES
Preparations used for bowel preparation prior to colonoscopy can themselves be a
cause of colitis. This is particularly true where purgatives based on sodium phosphate
are used. They may cause low-grade focal colitis and increase epithelial apoptosis
(apoptotic colopathy). Laxatives may also increase apoptosis and there is an
association between this finding and melanosis coli.
ALENDRONATE
This drug is used for treating osteoporosis and other bone disorders. Its use has been
associated with pill esophagitis and gastro-duodenal ulceration. Crystals may
sometimes be seen in the base of the ulcers.
IRON
Orally ingested iron may cause damage to the upper GI tract. Two patterns of injury are
noted: 1) Pill esophagitis with ulceration. Blackish crystalline material may be
demonstrated in the base of ulcers. 2) Gastric iron deposition within foveolae, glands
and lamina propria. In both instances histochemical stains for iron (Perl’s Prussian blue
reaction) will be positive.
KAYEXALATE
Kayexelate is an ion exchange resin which is active in the small bowel where it
exchanges sodium ions for potassium ions in the treatment of hyperkalemia. It may
cause erosions and ulcers within the esophagus, stomach and duodenum. In the base
of the ulcers non-polarizable rhomboid or triangular crystals are present. These crystals
stain red with PAS/D and acid fast stains.
COLCHICINE AND TAXOL
Taxol is an anti-cancer agent. Colchicine is used in the treatment of gout. Both drugs
interfere with tubulin and inhibit its polymerization. This causes mitotic arrest.
Histologically ring-shaped mitotic figures may be seen in the proliferation zones of the
esophagus, stomach and duodenum.
MYCOPHENOLATE
Mycophenolate is used in organ transplant patients for prevention and suppression of
acute rejection. Colonic biopsies from patients taking these drugs show changes in up
to 70% of cases. A variety of changes have been described and these may occur as
isolated findings or in combination. These include apoptosis, architectural distortion and
crypt atrophy, IBD-like changes, GVHD-like changes, ischemia-like changes and selflimited colitis-like changes.
PANCREATIC ENZYME REPLACEMENTS
This topic is of historic interest only as the drugs responsible for fibrosing colonopathy
have now been withdrawn from use. Formerly, high-strength pancreatic enzymes were
combined with methacrylic acid and caused segmental fibrous strictures particularly in
the proximal colon. Biopsies of the strictures showed increased intramucosal
eosinophils.
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DRUG INDUCED INJURY
OF THE G.I. TRACT
David A Owen
University of British Columbia
10/02/2012
NSAIDs INDUCED GI INJURY
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Pill esophagitis, ulcers and strictures
Erosive gastritis and duodenitis
Gastric and duodenal ulcers
Reactive gastropathy
Distal ileal ulcers
Proximal colonic ulcers and focal colitis
Diaphragm disease
Collagenous and lymphocytic colitis
Increased apoptosis
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PROTON PUMP INHIBITORS (PPIs)
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Hypertrophy and hyperplasia of parietal cells
Hyperplasia of ECL cells
Gland dilatation
Parietal cell “snouting”
Parietal cell cytoplasmic vacuolation
Fundic gland polyps
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CHEMOTHERAPY AND RADIOTHERAPY
• Early changes: Non-specific inflammation and
cytologic changes consisting of 1) Syncytial
change in surface epithelium 2) Enlarged
vesicular nuclei and irregular nucleoli 3)
Cytoplasmic eosinophilia and vacuolation
• Chronic changes: Mucosal atrophy and
intestinal metaplasia, non-healing ulcers,
stricture formation
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ANTIBIOTICS
• Pill esophagitis (tetracycline, doxycycline)
• Pseudomembranous colitis
• Antibiotic associated hemorrhagic colitis
(AAHC) (ampicillin, amoxicillin, macrolides,
cephalosporin, chloramphenicol,
fluoroquinolones, tetracycline.
• Histologically and clinically AAHC resembles
acute colonic ischemia
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POTASSIUM CHLORIDE
• Pill esophagitis with or without fibrous
strictures
• Gastric, small bowel, large bowel erosions,
ulcers and fibrous strictures
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DRUG MEDIATED ISCHEMIC COLITIS
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Antibiotics
Phentermine
Chemotherapeutic agents (Taxol, vinca alkaloids)
Constipating agents (fecal impaction)
Decongestants (pseudoephedrine)
Digitalis, ergotamine, cocaine (vasoconstriction)
Diuretics (lower blood volume)
Steroid hormones (thrombosis)
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ENEMAS AND LAXATIVES
• Melanosis coli
• Apoptotic colopathy
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ALENDRONATE
• Alendronate is use for treating patients with
osteoporosis or other bone disease
• May cause esophageal, gastric and duodenal
ulceration. Crystals (non-specific) may be
present in the base of the ulcers
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IRON
• Localized inflammation with ulceration
especially in esophagus, stomach and
duodenum (crystalline material present in the
base of the ulcers)
• Gastric and small bowel deposition within
epithelium, glands and lamina propria
• Ingested iron, hemosiderin and iron in
hemochromatosis will all be Prussian blue
positive
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COLCHICINE AND TAXOL
• Ischemic colitis
• Ring shaped mitotic figures may be seen in
proliferation zones in all areas of the
gastrointestinal tract
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MYCOPHENOLATE
• Mycophenolate is used to prevent and suppress
acute rejection
• Produces a colitis characterized by apoptosis,
architectural distortion, crypt atrophy, IBD-like
changes, GVHD-like changes and ischemia-like
changes
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KAYEXELATE
• Kayexalate is an ion exchange resin that is
active in the small bowel where it exchanges
sodium ions for potassium ions in the
treatment of hyperkalemia
• Kayexalate crystals are triangular or rhomboid
in configuration and are basophilic on routine
sections. They are PAS/D positive
• Apart from the presence of crystals the ulcers
are non-specific in type
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PANCREATIC ENZYME REPLACEMENTS
• Of historical interest only: Thought to be
related to high dose enzyme therapy and
methacrylic acid in the formulation (this
medication is now withdrawn)
• Changes consist of localized fibrous strictures
in the proximal colon with increased numbers
of eosinophils in overlying mucosa (fibrosing
colonopathy)
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