ARTICLE IN PRESS

Current Diagnostic Pathology (2006) 12, 239–247

www.elsevier.com/locate/cdip

MINI-SYMPOSIUM: GASTROINTESTINAL PATHOLOGY

Drug-induced pathology in the large intestine

Karel Geboes, Gert De Hertogh, Nadine Ectors

Department of Pathology, University Hospital, K.U. Leuven, Minderbroedersstraat 12, 3000 Leuven,
Belgium

KEYWORDS Summary Many drugs can cause pathology in the large intestine. Major classes
Colitis; include antibiotics, non-steroidal anti-inflammatory drugs, laxatives, anticancer
Drugs; drugs and immunosuppressive agents. The pathogenesis of the lesions caused by
Antibiotics; drugs is highly variable. Toxic injury and vascular insufficiency are probably the most
Non-steroidal anti- important mechanisms. The microscopic pattern of such lesions is generally non-
inflammatory drugs; specific. They may produce histological patterns that resemble acute infectious-type
Chemotherapy colitis, microscopic colitis, ischaemic colitis and even chronic idiopathic inflamma-
tory bowel disease. Specific features, such as the presence of crystals (Kayexalate),
pigment and diaphragms, indicating a specific diagnosis are less common. The
precise incidence of drug-induced damage to the large intestine is not known, but
the importance of the phenomenon is probably underestimated. A correct
histopathological diagnosis is difficult and requires a careful clinical history and
the consideration of the possibility of a drug-related aetiology.
& 2006 Elsevier Ltd. All rights reserved.

Introduction indeed a frequent side effect of drugs, accounting

Diarrhoea (three or more bowel movements per
day, liquid stools for longer than 1 month) is a
common symptom. In adults, its prevalence is
approximately 5%, making it a major cause of
disability.1 A small number of patients (approxi-
mately 1%) need specialized investigations or
hospitalization.2 The aetiology is highly variable
and includes, among other things, infections,
endocrine diseases, chronic inflammatory bowel
disorders, food intolerance and drugs. Diarrhoea is
Corresponding author. Tel.: +32 16 33 65 84;
fax: +32 16 33 65 48.
E-mail address: Karel.geboes@uz.kuleuven.ac.be
(K. Geboes).
for about 7% of all drug-related adverse effects.3 In
a series of 5669 patients treated with lansoprazole,
the prevalence of diarrhoea was 4.1%.4 In a series
of 11 541 patients treated with pantoprazole, the
major adverse advent and reason for stopping was
diarrhoea (106 patients).5 More than 700 drugs
have been implicated. Those most frequently
involved are antimicrobials, laxatives, magne-
sium-containing antacids, lactose- or sorbitol-con-
taining products, non-steroidal anti-inflammatory
drugs (NSAIDs), prostaglandins, colchicine, anti-
neoplastic agents, antiarrhythmic drugs and choli-
nergic agents.
The incidence of drug-induced colitis is not
precisely known. In France, 80 cases were reported

0968-6053/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cdip.2006.05.002
 ARTICLE IN PRESS
240
to the Centre de Pharmacovigilance over the period
1984–1994. Reports in the literature are usually
limited to cases or small series. These data
probably underestimate the size of the problem.
In clinical practice, drug-induced pathology of the
large intestine has two major clinical presenta-
tions: acute diarrhoea that appears during the first
few days of treatment, and chronic diarrhoea
lasting more than 3 or 4 weeks that can appear a
long time after the start of drug therapy. Both can
be severe and poorly tolerated.
The microscopic spectrum ranges from benign
diarrhoea without microscopic lesions on haema-
toxylin and eosin-stained sections through mild
oedema, to fulminant colitis with severe lesions
including extensive necrosis. Most features are non-
specific and therefore do not define a particular
aetiology.
Pathogenesis
Several mechanisms are involved in the pathogen-
esis of drug-induced diarrhoea and drug-induced
colitis (Table 1). Furthermore, some drugs may
increase or decrease the effect of other drugs.
Ciclosporin A can influence P-glycoprotein-
mediated multidrug resistance and, by this me-
chanism, increase the cytotoxicity of some drugs
such as the anticancer drug etoposide. Two or more
mechanisms are often present simultaneously. In
many situations, the exact mechanism is not clearly
established for drugs initiating colitis, because they
can act either as toxic agents or as mediators of an
immunological reaction. Predisposing factors are
local lesions such as strictures and combinations of
certain drugs (e.g. drugs that delay peristalsis such
as neuroleptics and NSAIDs).
Most of the deleterious effects of drugs are
initiated by damage to the mucosal epithelial cells,
either directly or mediated by vascular insuffi-
Table 1 Mechanisms involved in drug-induced
diarrhoea and colitis.
Diarrhoea Secretory diarrhoea
Shortened transit time
Osmotic diarrhoea
Colitis Toxic injury
Immunological injury
Allergic reactions
Impairment of cell proliferation
Vascular impairment
Promotion of infections
Bacterial overgrowth
K. Geboes et al.
ciency. Oxygen is of central importance in the
mechanisms of cell injury. Lack of oxygen causes
injury by reducing oxidative phosphorylation (de-
creased ATP levels). An excess of unused cellular
oxygen can be rendered toxic by the generation of
free radicals. This can induce lipid peroxidation,
leading to membrane injury and increased perme-
ability. Some free radicals contribute to tissue
damage indirectly by causing vascular smooth
muscle contraction and influencing mucosal blood
flow. Following membrane injury, the influx of
calcium from outside and mobilization of calcium
within the cell can accelerate membrane damage
by activating enzymes. Proteases derived from
lysosomes may attack intracellular and extracellu-
lar structural proteins and cell adhesion molecules,
and may also activate procollagenase, leading to
further cell and tissue injury. Toxic injuries are
characterized by the ability to achieve reproduci-
ble lesions in animals, by a dose-related effect and
by the development of a standard lesion. In
contrast, immunological injury is typically not
regular and not reproducible. Evidence is mounting
that most drug lesions are attributable to direct
cytotoxicity. Some drugs cause injury by a physical
event: simple entrapment of a pill in the mucosa.
This is a rare event in the colon, but it has been
observed in the presence of strictures.
Vascular lesions include haemorrhages related to
treatment with anticoagulants or drug-induced
thrombocytopenia and ischaemia because of drug-
induced (hypersensitivity) vasculitis (usually gen-
eralized) or toxic vascular injury, vascular throm-
boses due to oestrogens and progesterones, NSAIDs
or other drugs and reduced splanchnic flow caused
by cardiovascular drugs.
Many antibiotics, chemotherapeutic agents and
immunosuppressive therapies promote infections.
Type and distribution of lesions
Clinical presentation
The same drug can be responsible for different
clinical presentations, varying from mild, benign
diarrhoea without microscopic lesions to severe
disease with macroscopic lesions. Lansoprazole can
induce diarrhoea through bacterial overgrowth, as
a result of impaired gastric acid secretion or
through microscopic colitis, and in some cases no
clear lesion is found. The lesions can also be
variable in their characteristics and distribution.
They can affect the upper gastrointestinal tract
and colon, they can be limited to the small
 ARTICLE IN PRESS
Drug-induced pathology in the large intestine
intestine, or they can involve the small intestine
and colon or the colon alone.6–9 In the colon, the
lesions can be limited to the rectum or the left
colon, involve the whole colon or occur preferen-
tially in the right colon. The distribution of the
lesions depends partly on administration and drug
delivery. NSAIDs with slow-release delivery, for
instance, can preferentially affect the colon rather
than the small intestine or upper gastrointestinal
tract. Suppositories and enemas will induce distal
disease.10
Pathology
The same drug or group of drugs can also be
responsible for a variety of microscopic lesions.
Some drugs can induce an ischaemic-type disease,
a Crohn’s disease-like pattern or eosinophilic or
microscopic colitis. In other words, the pathology
induced by a specific drug can be variable.
These factors explain why diagnosis and differ-
ential diagnosis can be extremely difficult. A proper
knowledge of the clinical history of the patient,
including the drugs that he or she has been taking,
is essential. Establishing a relationship between
drug consumption and diarrhoea or colitis is,
however, difficult. When the time that has elapsed
between the start of the drug and the onset of
symptoms is long, sometimes up to several months
or years, it may be difficult to prove the relation-
ship. The relationship can be suggested when there
is a relationship in time with the start of the drug
and the onset of symptoms, and when the lesions
and symptoms regress rapidly after stopping the
drug. A challenge can prove the relationship but is
not always possible or indicated. Most lesions
induced by drugs undergo complete resolution
after elimination of the offending agent. Repeated
exposure can, however, lead to persistent lesions
such as ulcers or chronic inflammatory conditions.
Microscopic patterns
Drug-induced damage in the colon includes effects
on pre-existing disease as well as de novo disease.
With regard to pre-existing disease, NSAIDs have
been associated with complications of diverticular
disease, such as haemorrhage, perforation and
fistulous tract formation. NSAIDs have also been
linked to flares of chronic idiopathic inflammatory
bowel diseases, as well as to triggering a first
episode. Ciclosporin can promote villous transfor-
mation and epithelial regeneration in ulcerative
colitis. These histological changes may mimic
241
Table 2 Microscopic patterns of drug-induced
damage in the large intestine.
Acute colitis
Ischaemic-type colitis
Pseudomembranous colitis
Focal active colitis
Eosinophilic colitis
Microscopic colitis
Collagenous colitis
Lymphocytic colitis
Inflammatory bowel disease-like colitis
Graft-versus-host-like disease
Non-specific ulceration
Specific patterns
Diaphragm disease
Melanosis (pseudomelanosis) coli
Necrosis (Kayexalate)
Fibrosis (pancreatic enzyme supplements)
Opportunistic infections
dysplasia.11 De novo disease can show a variety of
microscopic patterns (Table 2).
Non-specific pattern
The pathology of drug-induced damage in the colon
is usually non-specific. Specific patterns are rare.
Non-specific lesions include solitary haemorrhages
in the mucosa and submucosa, erosions and ulcers,
often with normal adjacent mucosa, epithelial cell
apoptosis and inflammation. An increase in the
number of apoptotic bodies in the cryptal epithe-
lium has been observed with 5-fluorouracil, irino-
tecan, ciclosporin, colchicine, diclofenac sodium,
mefenamic acid NSAID, ticlopidine and ranitidine.2
Apoptosis of the surface epithelial cells is noted
with some laxatives (anthranoids). The inflamma-
tory infiltrate in drug-induced damage is usually
focal or patchy in distribution and less likely to be
diffuse. It is composed of neutrophils and/or
eosinophils. The intensity is often mild, especially
following NSAIDs, which are designed to limit the
inflammatory reaction. A chronic inflammatory
infiltrate is rarely observed, possibly because the
major cellular injury is toxic and not followed by an
immunological reaction unless there is, for in-
stance, an additional event like an infection.
Acute colitis
Acute colitis is a common pattern. In a prospective
study of 58 patients presenting with acute inflam-
mation, drug-induced colitis was diagnosed in 35
 ARTICLE IN PRESS
242
cases. The main drugs implicated were antibiotics
and NSAIDs.12 Antimicrobials are responsible for
25% of all cases of drug-induced diarrhoea. The
disease spectrum ranges from normal to pseudo-
membranous colitis or haemorraghic colitis. A
pattern of acute colitis has also been described
following mefenamic acid, diclofenac, naproxen
and pirprofen NSAIDs, carbamazepine, oral contra-
ceptive steroids, laxatives such as biphosphonate
enemas and bisacodyl and oral bowel prepara-
tion.13–17 Laxatives can induce flattening and
sloughing of the surface epithelium and the occa-
sional presence of neutrophils in the lamina
propria. These changes typically resolve in 1 week
and do not induce an increase in plasma cells (as
infections and IBD can do).
Saline enemas and other solutions often cause
oedema of the lamina propria but rarely damage to
the epithelium. Oral sodium phosphate can induce
aphthoid ulcers and focal active colitis in a small
number of patients. In a series of 687 consecutive
patients, aphthoid ulcers unexplained by other
diagnoses were found in 18. Focal active colitis
was present in 11 (3.5%) of 316 patients who had
biopsies but were endoscopically normal. In addi-
tion, increased cell proliferation (determined by
the MIB-1 labelling index) and increased apoptosis
are observed.18 Animal experiments show no major
difference between sodium phosphate and poly-
ethylene glycol-electrolyte bowel preparation.19
Haemorrhagic (ulcerative) colitis can be the result
of a direct toxic effect of antiseptics used for
disinfecting endoscopes (glutaraldehyde). The
characteristic feature is the occurrence of lesions
during withdrawal of the endoscope.
Ischaemic-type colitis
Colon ischaemia is a clinicopathological condition
that comprises a spectrum of disorders from
reversible and transient colitis to fulminant colitis.
The majority of patients are elderly. In this group,
predisposing factors such as aortic surgery may be
recognized. In younger (and elderly) people,
medication must seriously be considered as a
predisposing cause. Drug-induced ischaemia can
result from vasoconstriction, hypercoagulation, low
blood flow or vasculitis.
Drugs that can mimic ischaemic disease include
oral contraceptive steroids, cocaine, ergot alka-
loids, vasopressin and other vasoconstrictors, car-
diovascular drugs (alpha-adrenergic blockers,
antihypertensive drugs, diuretics, digoxin), peni-
cillin, neuroleptics, non-selective NSAIDs and
selective cyclooxygenase (COX)-2 inhibitors (rofe-
K. Geboes et al.
coxib, meloxicam), the migraine headache medica-
tion sumatriptan succinate, a serotonin-1 (5-
hydroxytryptamine1) receptor agonist alosetron
hydrochloride, a potent selective 5-hydroxytrypta-
mine3 receptor antagonist (used for the treatment
of diarrhoea-predominant irritable bowel syn-
drome) and some hormonal drugs such as flutamide
(anti-androgenic).20–26
Ergot compounds are generally safe, but in some
instances colitis with rare perforations and stric-
tures have been recorded. The frequency of colitis
induced by neuroleptics is estimated to be 1 case in
every 2000 patients. Involved classes of drug
include tricyclic antidepressants, phenothiazides
and barbiturates. The relationship between the
drug and ischaemia is not, however, always clear.
The marketing of alosetron has been suspended
after reports of colonic ischaemia. Subsequent
studies have shown that rates of colon ischaemia
among patients carrying a diagnosis of irritable
bowel syndrome are higher than in the general
population. Colon ischaemia may therefore consti-
tute a distinct part of the natural history of
irritable bowel or alternatively be a consequence
of therapy.26
The mechanism of the ischaemia induced by
drugs is also not always precisely known. Suma-
triptan may induce vasopressor responses that are
distinct from the cranial circulation. For non-
selective NSAIDs, an effect upon the isozymes
COX-1 and COX-2 has been proposed. These
isozymes catalyse the conversion of arachidonic
acid to eicosanoids, which play a role in the
platelet–vessel wall interaction. Thromboxane,
the major COX-1 product of arachidonic acid
metabolism in platelets, causes platelet aggrega-
tion and vasoconstriction. Biopsies from individuals
with drug-induced ischaemic colitis show a pattern
characterized by erosions, small shrunken abortive
crypts (microcrypts), hyaline stroma, little inflam-
mation and lamina propria haemorrhage that is
indistinguishable from other ischaemic condi-
tions.27
Eosinophilic/allergic pattern
In isolated reports, drug-induced colitis has been
noted in association with fever, rashes and eosino-
philia, and has been considered to be of allergic
origin (isotretinoin, penicillamine, clofazimine,
aciclovir, sulfasalazine). These manifestations are
generally reversible, although severe cases with
toxic megacolon have been observed. Active colitis
with a clear increase in the number of eosinophils
in the mucosa is also observed after the use of
 ARTICLE IN PRESS
Drug-induced pathology in the large intestine
psychotropic drugs (carbamazepine), aspirin, chlor-
propamide, methyldopa and ticlopidine.28,29
Microscopic colitis
The lymphocytic type of microscopic colitis has
been described following treatment with several
types of drug, including proton pump inhibitors
(lansoprazole), H2 receptor antagonists (ranitidine,
cimetidine), ticlopidine, NSAIDs, veinotonics (Cyclo
3 Fort) and others (carbamazepine, levodopa-
benserazide, ferrous sulphate, simvastatin, vinbu-
mine).3 Some drugs such as ticlopidine and Cyclo 3
Fort can even induce lymphocytic colitis and villous
atrophy in the ileum or small intestine.30–34 The
collagenous type of microscopic colitis has been
observed with the proton pump inhibitor lansopra-
zole.35 A relationship with NSAIDs has also been
proposed.
Inflammatory bowel disease-like pattern
An ulcerative colitis-like pattern has been reported
with gold salts, diclofenac NSAID and aminoglu-
tethimide (antineoplastic agent).36–38 A Crohn’s
disease-like pattern with granulomas has been
reported with diclofenac and clofazimine (a drug
used in the treatment of leprosy). A Crohn’s
disease-like pattern without granulomas has been
observed with other NSAIDs and immunosuppressive
treatment (mycophenolate mofetil).39–41 Mycophe-
nolate mofetil inhibits inositol-monophosphate
dehydrogenase, which is needed for guanine
synthesis in B- and T-lymphocytes. Experimentally,
it has been shown to impair colonic healing.42
In a series of 26 renal transplant patients treated
with mycophenolate mofetil and presenting with
chronic afebrile diarrhoea, we observed two
patterns. Thirteen patients had an infection (10
bacterial, 3 cytomegalovirus (CMV)). In the remain-
ing patients, colonic biopsies showed focal archi-
tectural changes and focal active cryptitis with a
loss of Ki67 epithelial staining (Fig 1).43 A graft-
versus-host like pattern has also been described
with mycophenolate mofetil.44
Non-specific ulceration
Extensive non-specific colonic ulceration can be
observed following NSAIDs, as well as with anti-
neoplastic agents (methotrexate). The use of ergot
drugs in suppositories can cause localized ulcers of
the rectum and anal canal that resemble those seen
in solitary ulcer syndrome, but the lesions heal
promptly after stopping the drug. Similar ulcers as
243
Figure 1 Microphotograph showing a colonic biopsy from
a renal transplant patient presenting with chronic
diarrhoea. The crypt architecture is markedly disturbed
(variability in diameter), and the lamina propria cellu-
larity is mildly increased. The patient was treated with
mycophenolate mofetil. The pattern has been called
Crohn’s-like because of the focal nature of the abnorm-
alities (H&E 250  ).
well as strictures can be observed with supposi-
tories containing analgesics (dextropropoxyphene,
paracetamol).
Infective colitis
Steroids and other immunosuppressive agents
might unleash opportunistic infections such as
CMV in immunodeficient patients (transplants) and
in predisposed patients (inflammatory bowel dis-
ease). Gold salts might have a similar effect in
predisposing to CMV infection.45 Neutropenic colitis
or enterocolitis, ileocaecal syndrome and typhlitis
are all labels for a syndrome with bowel wall
necrosis that occurs during the treatment of
haematological malignancies as well as during
aplastic anaemia and cyclic neutropenia. It is in
fact usually an infection occurring in a patient with
neutropenia.46,47
Specific patterns
It is generally very difficult to recognize with
certainty drug-induced colitis. Increased crypt
epithelial apoptosis may be a marker that is
common for different types of drug-induced coli-
tis.2 A challenge with the drug might induce or
reinduce the typical apoptotic lesions.48 Some
lesions can, however, be highly suggestive of a
specific drug-related aetiology, as described below.
 ARTICLE IN PRESS
244 K. Geboes et al.

Melanosis coli

Melanosis coli or pseudolipofuscinosis coli is the

result of the long-term use and abuse of anthro-
quinone-containing laxatives. This is a common
asymptomatic condition that is characterized by
the presence of a lipofuscin-type pigment in the
macrophages of the lamina propria of the large
bowel. The laxative drugs belong to the contact
laxatives. The active compound is released in the
caecum by bacteria. Therefore, the small intestine
is never involved, and the accumulation of pig-
mented macrophages starts in the right colon.
When the intake of the drug is prolonged, the Figure 2 Microphotograph showing the mucosa from the
whole colon will gradually be involved. The colon from a patient with renal insufficiency treated with
pigmentation is reversible. Kayexalate. The surface is covered with characteristic
The active drug binds to surface epithelial cells crystals (H&E 250  ).
and promotes the apoptosis of these cells, in
contrast to many other drugs, which affect the
crypt epithelium. The cell remnants (with the drug
metabolites) are engulfed by the macrophages, and With acid-fast stains, Kayexalate crystals are more
this produces the typical colour. The epithelial cell maroon, whereas Questran is more pink.50
damage is usually associated with mild mucosal
inflammation.
NSAIDs

Kayexalate-sorbitol Diaphragm disease is believed to be a pathology

Kayexalate-sorbitol (sodium polystyrene sulpho-
nate) is given as an enema or orally for the
treatment of hyperkalaemia. It has been reported
to induce intestinal necrosis in uraemic patients.
Necrosis is the common lesion observed in endo-
scopic and surgical specimens of the stomach, small
intestine and colon. The mechanism of the mucosal
damage is unclear. Experimental evidence suggests
that the sorbitol component of the drug, rather
than Kayexalate itself, is involved in the pathogen-
esis underlying the necrosis. Sorbitol is metabolized
by colonic bacteria to short-chain fatty acids. If the
concentration of these acids exceeds the patient’s
absorption capacity, there is an osmotic entrance of
fluid into the gastrointestinal lumen, with subse-
quent necrosis. It has indeed been shown that rats
receiving enemas of Kayexalate in water developed
no lesions, whereas 6 of 10 rats receiving sorbitol
enemas showed transmural colonic necrosis. Never-
theless, the lesions induced by Kayexalate can be
recognized through the presence of characteristic
Kayexalate crystals (Fig. 2).9,49
It must be remembered that other resins besides
Kayexalate are used clinically. For instance, Ques-
tran (cholestyramine) is an orally administered
resin that binds to bile acids. The histology induced
by Questran is very similar to that of Kayexalate,
except that Questran tends to be more opaque.
that is pathognomonic of damage by NSAIDs. It was
documented first in the small intestine but has
been identified mainly in the right colon, especially
in patients taking sustained-release preparations of
NSAIDs. Biopsy pathology is usually non-specific.
The diagnosis relies mainly on gross examination.
The pathophysiology of the lesion is probably
related to the healing of a drug-induced annular
ulcer, resulting in a purse-string effect. The lesion
represents a striking picture but is, overall, a rare
complication for NSAIDs users.51
Colchicine
Colchicine is an alkaloid with antimitotic activity.
Pathology results from a loss of cellular renewal
coupled with a selective depression of intestinal
enzyme activity. Metaphase mitoses, epithelial
pseudostratification and loss of polarity have been
described in colchicine toxicity.7 Lesions are more
common in patients with renal failure and are
usually not limited to the gastrointestinal tract.
Pancreatic enzyme supplements
Fibrosing colonopathy, strictures and increased
colonic wall thickness are observed in children
with cystic fibrosis and adults exposed to large
 ARTICLE IN PRESS
Drug-induced pathology in the large intestine 245

doses of high-strength pancreatic enzyme supple-

ments.52

Clofazimine

Clofazimine can induce crystal-storing histiocyto-

sis. The crystals are red in frozen sections and
appear as clear spaces in routinely processed
sections.

Major classes of aetiological agents

Antimicrobial drugs and antibiotics

Some products can be directly toxic and induce

ulcerative enteritis or colitis (flucytosine) or
haemorrhagic colitis (no major necrosis). Colitis is
also described with ampicillin, tetracycline, iso-
niazid and chloramphenicol. Other agents are
occasionally responsible for diarrhoea through
interference with the enteric nervous system or
the smooth muscle (erythromycin being a motilin
agonist). The major injurious effect is Clostridium
difficile-associated colitis.
NSAIDs
NSAID-induced colitis is a significant clinical pro-
blem. Patients are usually elderly. Symptoms can
develop after 2 months up to 5 years. Patients
present with abdominal cramps, diarrhoea and
blood loss. The mechanism of action is related to
a decreased production of COX-2, leading to a
decrease in mucosal prostaglandins. Lesions are
characterized by epithelial injury, minimal inflam-
mation and often loss of the muscularis mucosae
(Fig. 3).
Enemas, laxatives and oral bowel
preparations
Several laxatives can induce a reversible deposition
of pigmented macrophages in the lamina propria. A
mild and reversible proctitis has been noted after
enemas containing Fleet’s solution and bisacodyl.
Most preparatory solutions induce only oedema.
Oral bowel preparations can induce focal active
colitis.
Chemotherapy
Irinotecan hydrochloride (CPT-11), a drug used for
the treatment of solid tumours because of its
inhibition of DNA topoisomerase I, may cause two
Figure 3 (a) Higher magnification from an NSAID-induced
colitis: the mucosa shows marked architectural abnorm-
alities, mucin preservation and only mild inflammation
(H&E 250  ). (b) Non-steroidal anti-inflammatory drug
(NSAID)-induced transmural necrosis of the colon. The
muscularis propria is severely involved (H&E 100  ).
types of diarrhoea: an early secretory diarrhoea
that is cholinergic in nature, and a delayed
diarrhoea. In animal studies, it has been shown
that irinotecan causes increased apoptosis and
crypt hypoplasia in the small and large intestine,
most probably responsible for the delayed diar-
rhoea.53
Many other chemotherapeutic agents have a
direct toxic effect on actively replicating gastro-
intestinal epithelial cells. As a result, apoptosis and
marked reactive epithelial changes with cellular
atypia, erosions and ulcerations can occur. The
occurrence of similar changes in the stromal cells
may be a helpful clue to the aetiology of such
lesions. The small intestine is the most sensitive
region, but colitis is not uncommon. Toxic mega-
colon has been reported following methotrexate,
and colonic perforation has been noted with
paclitaxel. In terminally ill patients, intestinal
pathology may be the result of a combination of
factors including ischaemia and shock, radiation
therapy, infections and drugs.
 ARTICLE IN PRESS
246
Immunosuppressive agents
Opportunistic infections as well as ischaemic injury,
diffuse ulceration and mucosal architectural dis-
tortion with inflammatory pseudopolyps can be
observed. Two cases of colitis in patients receiving
ciclosporin have been published, with a positive
rechallenge in one case.3
Steroid hormones
Oestrogens and progesterone compounds can cause
ischaemic lesions of the small intestine and colon,
although the incidence of this is low. Lesions are
more common in older patients. They develop in
patients who have taken 0.5 g of the drug per day
for more than 1 year.
Heavy metals
Gold salts, which are used in rheumatoid arthritis,
can induce lesions of the small intestine and colon.
The condition is rare and is usually seen in women.
The lesions start typically within 3 months of
commencing drug therapy. Patients present
with abdominal pain, fever and diarrhoea (watery
or haemorrhagic), often in association with a
rash.
Conclusion
Drug-induced colitis is difficult to diagnose because
of problems with clinical correlation and the large
number of drugs that may induce lesions, which can
in turn be variable in appearance. Antibiotics and
NSAIDs are the two major classes of drug respon-
sible for drug-induced pathology of the large
intestine.
Practice points
 Many drugs can induce pathology in the
large intestine. Major classes involved are
antibiotics, NSAIDs and anticancer drugs.
 The microscopic lesions are usually non-
specific. The most common patterns are
acute (infectious-type colitis), ischaemic
colitis, microscopic colitis and focal active
colitis. Specific patterns can be observed
with anthranoid laxatives, occasionally with
NSAIDs and with Kayexalate.
 The diagnosis involves a careful clinical
history and consideration of the possibility
of a drug-related aetiology.
K. Geboes et al.
Research agenda
 The influence of drugs upon the small and
large intestine needs more investigation.
 The pathogenesis of drug-induced pathology
in the large intestine needs clarification.
 The incidence of drug-induced pathology in
the large intestine needs clarification.
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