iatrogenic pathology of intestines

REVIEW

Iatrogenic pathology of the intestines

Aoife J McCarthy,1 Gregory Y Lauwers2 & Kieran Sheahan11Department of Histopathology, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland, and 2Department of

Pathology, Massachusetts General Hospital, Boston, MA, USA

McCarthy A J, Lauwers G Y & Sheahan K

(2015) Histopathology 66, 15–28. DOI: 10.1111/his.12598

Iatrogenic pathology of the intestines

Many drugs and chemical agents can cause enteritisand colitis, producing clinical gastrointestinal sideeffects, the most common of which are diarrhoea,constipation, nausea and vomiting. Significant histo-logical overlap exists between some patterns of medi-cation or chemical injury and various disease entities.A particular medication may cause multiple patternsof injury and may mimic common entities such ascoeliac disease, Crohn’s disease, infectious enteritis

and colitis. Thus, given the common absence of spe-cific histopathological features, the diagnosis oftenrelies upon thorough clinicopathological correlation.This review concentrates on selected examples ofmedication-induced injury of the intestinal tract inwhich the pathology can be recognized, particularlyon biopsies, with a focus on newly described medica-tion-induced gastrointestinal effects.

Keywords: colon, damage, drug-induced, gastrointestinal tract, iatrogenic, injury, large intestine, medication-induced, side effects, small intestine

Introduction

Although many drugs or chemical agents produceclinical gastrointestinal (GI) side-effects, the mostcommon of which are diarrhoea, constipation, nau-sea and vomiting, drug-associated enteritis and colitisare probably underestimated. From a histologicaldiagnostic viewpoint, it is important to keep in mindthat significant overlap exists between some patternsof medication or chemical injury and various diseaseentities. Given the common absence of specific histo-pathological features, the diagnosis relies upon aclose clinicopathological exercise. It is difficult inpractice to establish a strict correlation between acompound and a specific pattern of injury. The opti-mal establishment of a temporal relationship, andimprovement with withdrawal or rechallenge of asuspected agent is rarely available and not practical

when dealing with a single patient.1 Thus, the role ofthe pathologist is, in many cases, to offer a strongindex of suspicion concerning possible drug-relatedpathology, after ensuring that no underlying diseaseis present.Microscopic patterns of injury associated with drug

reactions are protean and may mimic common enti-ties such as coeliac disease, Crohn’s disease, infectiousenteritis and infectious colitis. Similarly, the unwarypathologist ought to remember that a particular med-ication may cause multiple patterns of injury(Table 1).This review concentrates on selected examples of

those entities in which the pathology can be recog-nized, particularly on biopsies, with a focus on newlydescribed medication-induced GI effects. We will focuson intestinal damage, and medication-induced injuryof the oesophagus and stomach will not be reviewedspecifically. Similarly, we will not cover surgical orradiological-associated complications (e.g. pouchpathology or drug-eluting bead transarterial chemo-embolization therapy effect). We highlight someadverse drug effects (olmesartan, mycophenolate and

Address for correspondence: Prof. K Sheahan, Consultant Histopa-

thologist, Department of Histopathology, St Vincent’s University

Hospital, Elm Park, Dublin 4, Ireland. e-mail: k.sheahan

@st-vincents.ie

© 2015 John Wiley & Sons Ltd.

Histopathology 2015, 66, 15–28. DOI: 10.1111/his.12598

tumour necrosis alpha inhibitors) not encounteredprior to a number of excellent relatively recentreviews in the literature.2,3

Mimics of coeliac disease and otherenteropathies

Some therapeutic agents can cause villous atrophy,in addition to significant intraepithelial lymphocyto-sis, with or without epithelial damage. In addition, avariety of agents used predominantly for their

immunosuppressive or antineoplastic effects inducevarious types of injuries, predominantly apoptosis,dilated, damaged crypts and mucosal erosions.

O L M E S A R T A N

Olmesartan is one of several angiotensin II receptorantagonists/blockers used for the management ofhypertension. In 2012, Rubio-Tapia and colleaguesreported a case series supporting an associationbetween severe sprue-like enteropathy and olmesar-

Table 1. Patterns of injury and drugs most commonly associated with them

Pattern of injury Drug

Focal active colitis Ipilimumab, NSAIDs, sodium phosphate

Chronic colitis Mycophenolate, ipilimumab, TNF-inhibitors, NSAIDs, rituximab

Apoptosis excess Ipilimumab, mycophenolate, antimetabolites, TNF-inhibitors,colchicine, taxane, NSAIDs, sodium phosphate enema

Dilated damaged crypts andapoptosis

Mycophenolate, sodium phosphate enema, 5-FU

Small intestinal villous atrophy(coeliac disease-like)

Olmesartan, mycophenolate, ipilimumab, colchicine,azathioprine, NSAIDs

Microscopic colitis Olmesartan, ipilimumab, NSAIDs, lansoprazole, ranitidine,ticlopidine, simvastatin, paroxetine, carbamazepine, penicillin,flutamide, cyclo3 fort, sertraline

Increased mitoses Colchicine, taxane

Erosions/ulcers NSAIDs, KCl, kayexalate

Diaphragms/stenosis NSAIDs

Ischaemic colitis NSAIDs, kayexalate, cocaine, diuretics, sumatriptan,dopamine, methysergide, amphetamines, oestrogens,ergotamine, alostron, digitalis, pseudoephedrine, vasopressin, interferon

Pseudomembranous colitis Antibiotics, proton pump inhibitors

Crystal deposition Kayexalate, kalimate, sevelamer, cholestyramine, bisphosphonates

Strictures KCL, pancreatic enzymes

Pseudomelanosis coli Laxatives

Sigmoid diverticular perforation Corticosteroids

Hypereosinophilia NSAIDs, oestrogen-progesterone drugs, plavix

Malakoplakia Corticosteroids

Epithelial atypia i.v. cyclosporin

NSAIDs: Non-steroidal anti-inflammatory drugs; TNF inhibitors: tumour necrosis factor alpha inhibitors; 5-FU: fluorouracil;KCL: potassium chloride; i.v.: intravenous.

© 2015 John Wiley & Sons Ltd, Histopathology, 66, 15–28.

16 A J McCarthy et al.

tan.4 The authors first suspected the associationwhen two consecutive patients, referred to their insti-tution for evaluation of presumed refractory coeliacdisease, had unexplained clinical improvement duringhospitalization (antihypertensive medications werewithheld due to hypotension), but prompt relapse fol-lowing hospital discharge (antihypertensive medica-tions were restarted). In their series, they describe theclinical manifestations of 22 patients during a 3-yearperiod with unexplained sprue-like enteropathy thatimproved clinically after discontinuation of olmesar-tan. All 22 patients presented with chronic diarrhoea(for at least 4 weeks), in addition to weight loss,while taking olmesartan. Additional symptomsincluded nausea and vomiting, abdominal pain, bloat-ing and fatigue. Most of the patients were taking40 mg/day of olmesartan (range 10–40 mg/day) forseveral months or years before the onset of diarrhoea.The cause of their enteropathy could not be estab-lished after a systematic diagnostic evaluation(including investigation for disorders associated withnon-responsive coeliac disease5), and they improvedclinically after discontinuation of olmesartan.In all patients, baseline intestinal biopsies demon-

strated villous atrophy (VA) with variable degrees ofmucosal inflammation. Total villous blunting wasobserved in 15 patients, partial VA in seven patientsand a thick band of subepithelial collagen depositionin seven patients. Colonoscopy with random colonicbiopsies was performed in 13 patients (59%), showingmicroscopic colitis in five patients (two had lympho-cytic colitis and three had collagenous colitis). Biop-sies of the stomach were available in 14 patients(64%), showing lymphocytic gastritis in five patients,collagenous gastritis in two patients and chronic gas-tritis in seven patients. Of note, a gluten-free diet didnot resolve symptoms. However, following suspensionof olmesartan, clinical response was observed in all22 patients.At the time of publication, follow-up intestinal

biopsies had been performed in 18 patients (82%)after a mean of 242 days from the date of stoppingolmesartan. Histological recovery of the duodenumwas documented in 17 patients, implying that thesechanges were triggered by olmesartan.4

In contrast, a larger study [the Randomised Olme-sartan and Diabetes Microalbuminuria Prevention(ROADMAP) study] showed a lack of excess adverseeffects relating to the GI system in individualsenrolled into the study, half of whom were treatedactively with olmesartan.6 More specifically, noassociation was detected between a prescription of40 mg of olmesartan once daily and the occurrence

of intestinal adverse effects in 2232 diabetic patientstreated for a median of 3.2 years. The ROADMAPstudy concluded that the association of olmesartanand severe small intestinal mucosal damage is proba-bly rare. Nonetheless, the association described in theRubio-Tapia publication is compelling, and theauthors of this review paper have encountered anumber of these cases recently (Figure 1). Furtherinvestigation is warranted to elucidate the specificmechanism of olmesartan-associated enteropathy andto determine whether other drugs in the angiotensinII receptor antagonists/blockers family class canresult in a similar adverse reaction. Interestingly,human leucocyte antigen (HLA)-DQ2/8 maypredispose to olmesartan-associated enteropathy.4

A

B

Figure 1. A, Olmesartan-induced enteropathy: a low-power view of

duodenal mucosa with villous blunting and increased cellularity of

the lamina propria. B, A higher-power view highlighting the villous

blunting and increased lamina propria cellularity, in addition to

increased numbers of intraepithelial lymphocytes. [Case courtesy of

Professor C E Connolly, Galway, Ireland]


Iatrogenic pathology of the intestines 17

Drug effects characterized by increasedapoptosis, abnormal mitotic forms andnuclear atypia possibly mimicking dysplasia

A P O P T O T I C E N T E R O P A T H Y

Apoptosis in the deep portions of the crypts is consid-ered abnormal, as apoptotic cells are found only rarelyin normal intestinal mucosa. When present in normalintestinal mucosa, they are usually confined to the sur-face epithelium due to normal cell turnover.7 Increasedcrypt apoptosis (variably defined as either one apopto-tic body per biopsy8 or more than five apoptotic bodiesper 100 crypts9) should prompt pathologists to look foradditional histological changes (e.g. acute or chronicinflammation, mucin depletion, crypt loss, cryptitisand Paneth cell metaplasia), which may help in attrib-uting the findings to a particular aetiology. Clinicalhistory, with particular focus on drug intake, is essen-tial for the identification of the cause for an increase inapoptosis in the colon.10

It is pertinent for pathologists to be aware of theexpanding spectrum of drugs [mycophenolate, ipi-limumab,11 antimetabolites and tumour necrosisfactor alpha inhibitors, as well as non-steroidal anti-inflammatory drugs (NSAIDs)12 and sodium phos-phate-containing bowel preparation formula] thatcan cause apoptotic enteropathy.

MycophenolateMycophenolate (MPA) is an immunomodulator usedto prevent rejection in solid organ transplant, includ-ing heart, kidney and liver. It inhibits the enzyme i-nosine monophosphate dehydrogenase and preventsthe conversion of inosine monophosphate into guano-sine monophosphate, decreasing purine synthesis andarresting the cell cycle. This affects the production ofT and B lymphocytes, resulting in immunosuppres-sion.13,14 MPA also alters GI epithelial cell replica-tion, leading to villous atrophy, malabsorption anddiarrhoea.15 Two formulations are available, myco-phenolate mofetil (MMF) and mycophenolate sodium(MPS),16 commonly marketed under the trade namesCellCept (Roche Pharmaceuticals,) and Myfortic (Nov-artis Inc.,), respectively. MMF is absorbed in the stom-ach while MPS is absorbed in the small intestine.Common GI side effects of MPA (affecting up to

45% of patients17) include diarrhoea, nausea, vomit-ing and abdominal pain, and range from mild (inter-mittent nausea or diarrhoea) to life-threatening(colonic necrosis or perforation) complications.18 Upto 40% of patients taking MMF complain of dyspepticsymptoms,19 but the effects on the upper gastrointes-

tinal tract (GIT) are considered to be minor whencompared with the lower GIT.Diffuse colitis has been reported as an endoscopic

feature of MMF use.20,21 Endoscopy showing segmen-tal mucosal injury, similar to ischaemic colitis, hasalso been described.20

Histological abnormalities in the upper GIT reflectlocal mucosal irritation, similar to that induced byNSAIDs,19 and include ulcerative oesophagitis, reac-tive gastropathy-type changes and duodenal ulcers.10

Coeliac disease-type changes have also beenreported. The first histological description of duodenalMPA-associated injury was documented in 1998,when villous blunting and crypt hyperplasia weredescribed in a renal transplant patient on MMFtherapy.22

Striking apoptosis has been identified in colonicbiopsies in patients on MPA therapy,9,14,23 and therehave also been reports of similar features in the duo-denum, where more than two apoptotic bodies/100crypts have been defined as increased.10 In fact,increased epithelial cell apoptosis has been reportedto be the hallmark for the diagnosis of MMF-relatedcolitis.23 Other morphological features indepentlyassociated with MMF include the presence and quan-tity of lamina propria eosinophils and endocrine cellaggregates, and the presence and quantity of apopto-tic microabscesses, hypereosinophilic degeneratedcrypts and crypt distortion23,24 (Figure 2).Other pathological effects of MPA in the lower GIT

include graft-versus-host disease (GVHD)-like coli-tis,7,10,13,25 inflammatory bowel disease-like fea-tures24,26 and ischaemia-like colitis.13,20,27 Althoughthere is no definitive way to distinguish microscopi-cally between MPA toxicity and GVHD in the lowerGIT,17 the latter usually occurs soon after transplan-tation and is often accompanied by other features,such as cutaneous involvement. Furthermore, it isunlikely for GVHD to develop after solid organ trans-plant (occurs in fewer than 5% of cases).28 Star andcolleagues emphasized that increased eosinophils,endocrine cell aggregates in the lamina propria andapoptotic microabscesses are the most useful featuresto help differentiate MMF from GVHD-inducedcolitis.29

Recent studies have shown an association betweenMMF and CMV infection.30 The European Mycophen-olate Mofetil Cooperative Study reported thatcytomegalovirus (CMV) infection occurs in as manyas 36% of patients assigned to receive 3000 mg ofmycophenolate per day,31 with CMV colitis occurringin 6.5–11% of these patients.32–34



CMV colitis causes a broad range of lesions in thesetting of MMF therapy, and can clinically mimic idi-opathic inflammatory bowel disease (IBD),32 ischae-mic colitis, intestinal pseudo-obstruction, toxicmegacolon and colon carcinoma.35 Any patient beingtreated with MMF, presenting with fever, nausea,vomiting, diarrhoea, with leucopenia and/orincreased liver enzymes, should undergo endoscopyand biopsy to assess the possibility of CMV enteritis,as failure to identify and treat enteric CMV at anearly stage could allow spread to critical organs (e.g.lung and liver) and perforation of the infected viscuswith potentially disastrous consequences.36 Thus, ahigh degree of suspicion must be employed andbiopsy taken to confirm CMV infection.

IpilimumabRecently, the use of CTLA-4 (ipilimumab), a fullyhuman monoclonal antibody directed against cyto-toxic T lymphocyte antigen-4, has been shown tooffer durable objective therapeutic responses inpatients with metastatic malignant melanoma andrenal cell carcinoma.37

However, this regimen is associated with numerousimmune-mediated toxicities, including enterocolitis,dermatitis, hypophysitis, uveitis, hepatitis and nephri-tis.37–41 Major toxicity has been reported to be mostfrequently seen in the GIT (in 20% of patients receivingipilimumab).42 Furthermore, a 5% mortality rate hasbeen reported in patients who develop ipilimumab-associated colitis with significant risk for colonic perfo-ration.41,43

Recently, Oble and colleagues reported their obser-vations of five patients who developed severe GI toxic-ity affecting the gastric, small intestinal and colonicmucosa.11 Endoscopic findings were variable, rangingfrom normal to diffusely erythematous and ulceratedmucosa. On histology, villous blunting was present inileal and duodenal mucosa. There was a lymphoplas-macytic expansion of the lamina propria with anincrease in intraepithelial lymphocytes, and increasedepithelial apoptosis was also a distinctive feature.Thus, ipilimumab-associated enteritis demonstrateshistology resembling coeliac disease and autoimmuneenteropathy.Other histological findings of ipilimumab-associated

colitis include neutrophilic and plasma cell infiltrationin the lamina propria and focal neutrophilic and lym-phocytic cryptitis39 (Figure 3). Foci of crypt abscesses,glandular destruction and erosions of the mucosalsurface are usually evident, with occasional ulcera-tion. These inflammatory changes are often diffusethroughout the colon. An increased number of intra-epithelial lymphocytes and apoptotic activity in en-terocytes is usually noted. Histological evidence ofchronicity (namely crypt architectural distortion,basal plasmacytosis, granulomata, Paneth cellmetaplasia or pyloric metaplasia) is usually absent.The colitis associated with ipilimumab has features

similar to GVHD as well as IBD, including acute andchronic inflammatory changes and patchy areas ofinflammation (skip lesions).39 GVHD is usually histo-logically distinct, characterized by prominent epithelialcell apoptosis and glandular destruction, which are lessprominent in ipilimumab-associated colitis. Unlike Cro-hn’s disease or ulcerative colitis, ipilimumab-relatedcolitis involves the descending colon more than the sig-moid colon, ascending colon or rectum44 and does notdemonstrate features of chronicity.39

A

B

Figure 2. A, Mycophenolate-associated colitis: a medium-power

view of colonic mucosa with markedly increased numbers of eosin-

ophils in the lamina propria, as well as a crypt abscess. B, A high-

power view of colonic mucosa highlighting the increased numbers

of eosinophils in the lamina propria, as well as an apoptotic micro-

abscess and cryptitis.



A N T I M E T A B O L I T E S A N D T N F - a A N T A G O N I S T S

Recently, Soldini and colleagues45 described fourpatients who developed watery diarrhoea due todrug-induced apoptotic enteropathy after intake ofantimetabolites (methotrexate and capecitabine)and/or tumour necrosis alpha inhibitors (etanerceptand infliximab). The diarrhoeal illness was tempo-rally related to the patients’ drug intake. On endos-copy, normal colonic mucosa was seen in twopatients, while there were focal ulcerations in theother two patients (in an ileo-anal pouch and inthe sigmoid colon). Histological changes reportedinclude increased apoptosis of basal crypts, cysticallydilated cysts, lined by flattened and degeneratedepithelium containing apoptotic debris with few

neutrophils, and architectural distortion. The tempo-ral association between drug initiation and/or doseincrease, and onset of diarrhoea led the authors tobelieve that these drugs can cause clinical endo-scopic and histological changes of apoptotic enterop-athy.

A B N O R M A L P R O L I F E R A T I O N

Colchicine (an alkaloid with antimitotic ability) andPaclitaxel (Taxol) (an agent used in the therapy oflung, breast and oesophageal cancers) can producedistinctive changes throughout the GIT.

Colchicine (also described below)Colchicine is used to treat a variety of medical condi-tions, such as gout. Colchicine toxicity may causeerosions of the small intestine (the site most severelyaffected) and the stomach (antrum). Toxicity is usu-ally confined to patients with renal failure and clini-cal manifestations of colchicine toxicity.46

On histology, this diagnosis should be suspected bythe presence of numerous mitotic figures and, partic-ularly, ring mitoses47 (also described in ‘Mimics ofdysplasia’).

TaxaneThe changes due to taxanes occur early during thecourse of the therapy and are related to the timeelapsed since medication intake.48 The oesophagus isthe site that shows the most striking abnormalities(namely florid apoptosis shortly after the formationof ring mitoses49), but ulceration and perforation ofthe colon, caused by taxanes, have also beenreported.48

Mimics of dysplasia

Colchicine toxicity, intravenous cyclosporin and radi-ation may all lead to epithelial atypia that mimicsdysplasia.

C O L C H I C I N E ( A L S O D E S C R I B E D A B O V E )

In colchicine toxicity, histology can demonstrate ringmitoses, accompanied by an increase in glandular cellapoptosis and epithelial cell pseudostratification.46

These changes are found typically in the mid crypt inthe small intestine, and in the deep crypts in thelarge intestine. The irregular arrangement and hyper-chromatism of the nuclei, in addition to the increasein mitotic figures, can mimic dysplasia.47

A

B

Figure 3. A, Ipilimumab-associated colitis: a low-power view of

colonic mucosa showing increased cellularity of the lamina propria;

increased epithelial apoptosis is seen at this low power. B, A high-

power view of colonic mucosa confirming the presence of a plasma

cell infiltrate in the lamina propria and several apoptotic bodies.



I N T R A V E N O U S C Y C L O S P O R I N

Intravenous (i.v.) cyclosporin is used in the treatmentof severe ulcerative colitis (UC). Hyde and colleaguescompared 23 colectomy specimens from patients withUC who had been treated with i.v. cyclosporin andsteroids, with 10 colectomy specimens from patientswith UC who had been treated with steroids alone.50

They found that, although villous transformation andepithelial regeneration mimicking dysplasia may beseen in UC, they are more frequent and more severe inthose patients who received i.v. cyclosporin and i.v. ste-roids, compared to controls who received i.v. steroidsalone. Increased awareness of this potential mimic ofdysplasia is crucial for appropriate patient management.A helpful clue to exclude dysplasia in this setting is thepresence of nuclear maturation with increasingamounts of cytoplasm toward the surface of the mucosa.In addition, true dysplasia in UC is more focal, while theepithelial atypia induced by cyclosporin is diffuse.

R A D I A T I O N ( A L S O D E S C R I B E D I N ‘ R A D I A T I O N -

I N D U C E D I N J U R Y ’ , B E L O W )

Acute-phase radiotoxicity classically demonstratessevere mucosal inflammation, crypt disarray, surfaceand crypt epithelial damage and crypt abscesses. Acuteulceration and mucosal sloughing may be present. Thelamina propria is typically oedematous and hasincreased cellularity due to inflammatory cells, oftenwith a prominent eosinophilic infiltrate (Figure 4). Tel-angiectasia is usually observed, and vascular fibrinoidnecrosis and mild vascular fibrosis may be seen.51,52

Enterocyte nuclear abnormalities (atypia and loss ofpolarity), in conjunction with mucin depletion andapoptosis, can be present, and may mimic malignancy.However, nucleomegaly and a low nuclear:cytoplasmicratio, in tandem with the other histological featuresdescribed above, and recent history of radiation sup-ports the diagnosis of radiation-induced injury.

Crystal deposition (non-absorbable drugs)

Various non-absorbable drugs can be associated witha wide spectrum of mucosal and mural alterations.These drugs are characterized by detectable micro-scopic crystals, with distinctive shapes and colours.

C A T I O N - E X C H A N G E R E S I N S

Sodium polystyrene sulphonate (Kayexalate; SPS) isused routinely to treat hyperkalaemia (by binding and

excreting potassium through the GIT), mainly inpatients with end-stage renal disease (ESRD) but also inthose with hyperkalaemia resulting from other diseases.Seventy per cent sorbitol was included in the origi-

nal formulations of SPS, and was implicated in theearly reports of necrosis and ischaemia of the termi-nal ileum and colon. However, the absence of sorbitolin other formulations failed to eliminate the ischae-mic side effects.52,53 Calcium polystyrene sulphonate(Kalimate) is another of these cation-exchange resins.Cases of ischaemic colitis related to these resins

have been reported, associated with significant mor-bidity and a mortality rate of 36%.54–57 The vastmajority of these cases occurred postoperatively, inthe critically ill, in patients with ESRD and in thosewith uraemia.54–57 However, a recent study of 11patients with intestinal necrosis suspected to be sec-ondary to SPS in sorbitol described patients who wereminimally ill at admission, leading the authors toconclude that non-postoperative patients and patientswithout significant vascular compromise were alsopotentially at risk for this complication.58

Histological features of cation-exchange resin-induced injury include transmural necrosis andulcerations containing resin crystals that can also bepresent in the lumen, or on the serosal surface if perfo-ration occurs.59 The microscopic appearance of Kayex-alate and Kalimate crystals is the same. They havenarrow, rectangular ‘fish scales’, are violet/lightlybasophilic on haematoxylin and eosin (H&E) and arerefractile but not polarizable.60 The crystals stain redwith periodic acid-Schiff (PAS) stain and Ziehl–Neelsenstain, and display a characteristic crystalline mosaic

Figure 4. Radiation colitis: a low-power view of rectal mucosa with

oedema of the lamina propria, increased cellularity of the lamina

propria due inflammatory cells and prominent telangiectasia.



pattern (that distinguishes them from cholestyraminecrystals).61 Of interest, rectal stenosis due to foreignbody response to Kayexalate has also been reported.57

S E V E L A M E R

Sevelamer (Renvela) is a polyamine gel that bindsphosphate, and is used in the treatment of hyper-phosphataemia in dialysis patients. These broad,curved and irregularly spaced ‘fish-scale’-type crystals(with a variably eosinophilic to rusty brown colour onH&E and a violet colour on periodic acid–Schiff–dia-stase (PAS-D) stain60) have been identified predomi-nantly in the colon, but also in the small intestine.60,62

Rarely, associated mucosal abnormalities include acuteinflammation, chronic mucosal damage, inflammatorypolyps, extensive ulceration, ischaemia and necrosis.60

C H O L E S T Y R A M I N E

Other types of crystals that can be observed are chole-styramine crystals, which are not typically associatedwith mucosal injury.60 Cholestyramine crystals aremore opaque and have a more homogeneous appear-ance than SPS crystals, lack internal ‘fish scales’ of se-velamer, are bright orange on H&E, are PAS-positiveand are variably grey or hot pink on PAS-D.59,60

B I S P H O S P H O N A T E S

Bisphosphonates (BPs) inhibit bone resorption andare used in the management of Paget’s disease ofbone and osteoporosis. Ingestion of BPs has beenassociated with oesophagitis and oesophageal ulcers,gastric ulcers and duodenal ulcers. BP-induced ulcer-ation can be suspected when crystals are identified inan ulcer bed. These crystals are pale yellow in colour,are refractile under polarized light and may beaccompanied by multinucleated histiocytes and epi-thelial giant cells.47

Ulcerative pattern of injury

Various drugs can present with an ulcerative mucosalinjury pattern, the most common of which are NSA-IDs.

N S A I D S

NSAIDs are used widely for the treatment of manyconditions, including arthritis, and they act by block-ing cyclo-oxygenases 1 and 2 (COX-1 and COX-2).The incidence of adverse effects with NSAIDs has

been reported to be up to 70% with long-term treat-ment,63 the most common side effects being dyspep-sia, nausea and vomiting. The major pathologycaused by this group of drugs in the small intestine isulceration and haemorrhage, more likely with highdoses and prolonged use.64 Primary mucosal ulcera-tion is, in the majority of cases, entirely non-specifichistologically. However, a discrete ulcer, with normalmucosa on either side, should raise the suspicion ofan iatrogenic origin (although not specifically NSA-IDs).3 In most cases, the correct diagnosis will dependupon careful clinicopathological correlation ratherthan on the histology alone.3

Recently, there have been an increasing number ofreports of similar pathological changes in thecolon,65,66 which has led to increased awareness ofNSAID-induced colopathy.

NSAID-induced enteropathyAlthough common, the real prevalence of NSAID-induced enteropathy has been underestimated.67

Using new technologies (such as balloon-assistedendoscopy and video capsule endoscopy) to visualizethe small intestinal mucosa,68–70 recent studies haveshown that more than 50% of patients taking NSA-IDs have some mucosal damage in the small intes-tine.71

Clinically, NSAID enteropathy can manifest itselfwith ulceration, occult bleeding and subsequent heal-ing with stricture formation. The endoscopic appear-ance of NSAID-induced enteropathy is protean andincludes mucosal erythema, erosions, shallow roundulcers, punched-out ulcers, ring ulcers, irregularlyshaped ulcers, longitudinal ulcers, perforation ulcers,membranous stenosis and diaphragm-like strictures(described in ‘Diaphragm disease’, below).71,72 Thehistological features of NSAID-associated ulcers arenot specific, although typically they are not associ-ated with abundant chronic inflammatory cells. Eo-sinophils may predominate in the inflammatoryinfiltrate, but this is a general feature of drug pathol-ogy rather than one specific to NSAIDs.

NSAID-induced colopathyIn the large intestine, NSAIDs induce a broad spec-trum of damage63 and, due to the increased use ofcoated and slow-release preparations, NSAID-inducedcolopathy is becoming more frequent.73

The endoscopy may be normal or reveal only non-specific erosions. Caecal mucosal ulcers and those ofthe ascending colon, characterized by sharply demar-cated ulcerations (at the crest of a mucosal web, withadjacent normal mucosa), are said to be characteris-



tic of sustained release preparations.74 Although thepredilection to the right side has been attributed tohigher concentrations of the drug in the proximalcolon,75 the rectum and distal colon may also beinvolved.Pathological findings reported in NSAID-induced

colitis include focal active and chronic colitis (resem-bling infectious colitis or Crohn’s disease) (Figure 5),collagenous or lymphocytic colitis and non-gangre-nous ischaemic colitis. In addition, eosinophilic colitisand pseudomembranous colitis have been reported insingle reports as a consequence of NSAIDs.3,76–79 Sol-itary, or a limited number of ulcers located from cae-cum to rectum, are the most common pathology andthe greatest diagnostic problem, as the appearance isnon-specific and other causes of limited colonic ulcer-ation must be considered, e.g. solitary caecal ulcera-tion, ulceration secondary to a diverticulum, localischaemia, stercoral ulceration and solitary rectalulcer syndrome.3 Typically, NSAID-induced colitis ischaracterized by a low content of inflammation,without architectural distortion. To distinguishNSAID-induced colitis from chronic inflammatorybowel disease, and particularly Crohn’s disease, it isimportant that a history regarding NSAID ingestionis obtained in every patient.

Diaphragm diseaseAlthough the first cases of diaphragm-like lesions(lesions pathognomonic of NSAIDs) were described inthe small intestine,3,80 similar lesions have also beennoted in the colon,81,82 especially in patients takingsustained-release preparations.75

These lesions consist of thin septal-like diaphragms,with or without well-circumscribed ulcers or superfi-cial ulcerations at their margins, and with normalintervening mucosa.83 Although diaphragm disease isessentially an endoscopic diagnosis, it can berecognized histologically by submucosal fibrosis and achaotic arrangement of smooth muscle fibres, andvascular, neural and ganglion elements.72,84 It canprogress to significant strictures with long-termNSAID use (usually more than 1-year duration), andmay necessitate therapeutic intervention (endoscopicballoon dilatation or even a segmental colectomy63).The reason for the development of diaphragm-likestrictures remains obscure.83

Pseudomembranous colitis

Antibiotics (most commonly penicillins, clindamycin,cephalosporins and trimethoprim–sulphamethoxaz-ole85) render the bowel susceptible to colonization by

Clostridium difficile by altering the bowel flora. C. diffi-cile infection is one of the most common infections inthe hospital environment, particularly in an elderlypopulation.Recently, Dial and colleagues86 published convinc-

ing epidemiological evidence suggesting that protonpump inhibitor (PPI) use is associated with commu-nity-acquired C. difficile colitis. Therefore, PPIs shouldalso be considered an important potentiator ofpseudomembranous colitis.Damage by the toxins of this organism result in a

characteristic appearance both endoscopically and his-tologically.87 On endoscopy, discrete yellow plaquesare seen on the colorectal mucosal surface, which arepathognomonic of pseudomembranous colitis. On

A

B

Figure 5. A, Non-steroidal anti-inflammatory drug (NSAID)-

induced colitis: a low-power view showing colonic mucosa with

chronic colitis, characterized by architectural distortion, crypt

shortening and subcryptal lymphoplasmacytic inflammation. B, A

higher-power view showing colonic mucosa with focal active colitis

(cryptitis).



histology, a dilated cluster of crypts capped byinflammatory cells and debris disrupts each plaque.

Ischaemic-pattern colitis

Ischaemic-pattern colitis has been reported inassociation with a variety of drugs, including oral con-traceptives,88–90 ergotamine derivatives,91 cocaine92–94 and, potentially, sumatriptan [a serotonin-1 5-hydroxytryptamine (5-HT 1) receptor agonist] over-use.95 Rare cases of ischaemic colitis associated withinterferon-alpha (IFN-a) treatment for chronic hepati-tis C (HCV) infection and metastatic cancer have beenreported.96–98 There have been isolated reports of is-chaemic colitis associated with various other drugs,including alosetron,99–101 pseudoephedrine,102 dopa-mine, methysergide and NSAIDs.2 Drugs, such as digi-talis and diuretics, may predispose to ischaemic colitisin elderly patients in a state of low blood flow, oftendue to heart failure.85 The diagnosis of ischaemic coli-tis in a young person should always raise the possibil-ity of drug involvement (particularly oestrogens,cocaine and ergotamine).90

Radiation-induced injury

Radiation therapy is utilized commonly as a majorcomponent in the treatment of pelvic malignancies(colorectum, prostate, cervix). Secondary toxicity tothe lower GIT can occur, most commonly affectingthe rectum, although injuries to the colon and smallintestine are not uncommon.103 Toxicity is related tothe total dose, the frequency at which it is given andthe total volume of tissue irradiated. The effects canbe acute (within 3 months; described in ‘Radiation’,above), related to cell toxicity or can be chronic(occurring many years after completion ofradiotherapy), related to a progressive vasculitis andischaemia.103

Endoscopy can reveal granularity and friability,erythema, pallor or prominent submucosal telangiec-tasias. In the chronic phase, telangiectasia of capillar-ies, lymphangiectasia, platelet thrombi formation andnarrowing of hyalinized arterioles are accompaniedby lamina propria fibrosis. Atypical ‘radiation’ fibro-blasts, with enlarged, hyperchromatic nuclei andbasophilic cytoplasm, are typically present in the lam-ina propria. Features of chronicity, with variablecrypt distortion and atrophy, loss of goblet cells andPaneth cell metaplasia, may be seen. Marked hyalini-zation of submucosal vessels can be present, alongwith neuronal proliferation.52,104,105

Microscopic-type colitis

Although some scepticism may remain, given thatthe association has only ever been based on uncon-trolled case reports or case series, an ever-increasinglist of drugs has been reported to be associated withmicroscopic colitis; i.e. lymphocytic and collagenouscolitis. These include, for example, lansoprazole (aPPI) that can lead to either lymphocytic (strongerassociation) or collagenous colitis.106 Others includeNSAIDs [collagenous colitis and lymphocytic coli-tis (LC)107], 3-hydroxy-3-methylglutaryl-coenzyme(HMG-CoA) reductase inhibitors (statins, e.g. simvast-atin – LC), ticlopidine (LC), ranitidine (LC), flutamide(LC), acarbose (LC), carbamazepine (LC), penicillin(LC) and selective serotonin re-uptake inhibitors(SSRIs, e.g. sertraline – LC).106,108–111

A recent study from St Vincent’s University Hospi-tal, Dublin, Ireland112 of 222 patients with micro-scopic colitis revealed that patients were taking avariety of medications at diagnosis thought to beassociated with the microscopic colitis, includingNSAIDs (22%), aspirin (19%), statins (15%), PPIs(19%) and SSRIs (10%).

Pneumatosis coli

Publications in the Japanese literature have reportedthat alpha-glucosidase inhibitors, a new class ofantidiabetic agents (e.g. miglitol, acarbose, voglibose),can cause pneumatosis coli, a rare condition consistingof minute pneumocysts in the submucosa or the subse-rosa of the colon and occasionally in the pericolic softtissue.113–116 The mechanism is unclear, however.

Conclusion

Iatrogenic-induced gastrointestinal histopathologicalabnormalities are often non-specific and mimic manyforms of colitis, including inflammatory bowel disease,ischaemic colitis, microscopic colitis and coeliac dis-ease. Although there are some histological clues thatare helpful in the diagnosis, correlation with the clini-cal history and specific medication history is essentialto improve diagnostic accuracy. The pathologist playsan integral role in recognizing new medication-induced. Understanding the mechanisms of injurymay also contribute to future attempts to minimizeiatrogenic injury to the intestine.Close corroboration between the clinician and the

pathologist is essential in the diagnosis of medication-induced injury.



Conflict of interests

The authors have no competing interests to declare.

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