Chapter 5 – Drug-Induced Gastrointestinal Disease


An ever increasing number of drugs are known to cause gastrointestinal injury. The histological features are often non-specific and a single drug can induce many different patterns, necessitating close collaboration between pathologists and clinicians to reach a correct diagnosis. However, there may be some histological clues that are helpful in the diagnosis of drug-induced injury.

Chapter 5 Drug-Induced Gastrointestinal Disease

Aoife McCarthy and Kieran Sheahan


The number of medications that can cause gastrointestinal (GI) injury continues to grow. Drug formulation, dosage, length of treatment, pre-existing conditions, intrinsic host sensitivity, and interaction with other medications can all influence the degree of pathological injury.1 Because of the GI tract’s limited repertoire of morphological responses to injury, it is not surprising that significant histological overlap exists between some patterns of medication-induced injury and other disease entities. Likewise, a single medication can often cause multiple patterns of injury. Therefore, collaboration between the treating clinician and the pathologist is essential for the diagnosis of medication-induced injury.

Upper Gastrointestinal Tract

The upper GI tract (oesophagus, stomach, and small intestine) serves a critical role in food digestion and nutrient absorption and is thus vulnerable to medication-induced injuries.2 Although the number of drugs that can damage the upper GI tract is large, these drugs produce a limited number of injury patterns (Table 5.1). Some of these patterns are non-specific and generate a differential diagnosis, which may be resolved by clinical history.3 Occasionally, a specific drug can be suspected based on the findings within the biopsy.3

Table 5.1 Medication-induced damage to the oesophagus

Histological pattern of injury Drug
‘Pill oesophagitis’

  • Antibiotics (e.g. tetracycline, doxycycline, clindamycin)

  • NSAIDs

  • Potassium chloride

  • Iron supplements

  • Ascorbic acid

  • Bisphosphonates (e.g. alendronate)

Sloughing oesophagitis Caustic chemicals
Mitotic arrest

  • Paclitaxel (Taxol)

  • Colchicine

NSAIDs, non-steroidal anti-inflammatory drugs.


Injury Patterns

‘Pill Oesophagitis’

Pill oesophagitis’ occurs secondary to caustic injury to the oesophagus, caused by the retention of a pill within the oesophagus. This is often associated with failure to consume adequate amounts of liquid with tablet or capsule medications, and with taking these medications in the supine position before bedtime.3 Elderly patients and female patients are most often affected.4

Most patients present with odynophagia, retrosternal pain, and dysphagia. The usual sites of involvement are the mid oesophagus, at the level of the aortic arch (at 22–24 cm), and, in patients with left atrial enlargement, the distal oesophagus (at 30–35 cm).3 Endoscopic findings include erythema, mucosal denudation, discrete ulcers, or erosions and strictures.3 Histological evaluation often shows the usual features of oesophagitis: acute inflammation, erosions or ulcers, and granulation tissue. Polarisable crystalline material may be an important clue to the diagnosis of ‘pill oesophagitis’, although it is not present in all cases.3

The most commonly reported agents causing pill oesophagitis include non-steroidal anti-inflammatory drugs (NSAIDs; the most common offending drug by far),4 antibiotics (particularly clindamycin, doxycycline, and tetracycline), potassium chloride, iron supplements, and ascorbic acid and alendronate (a bisphosphonate).5

Sloughing Oesophagitis

Sloughing oesophagitis (see also Chapter 11) describes corrosive injury of the oesophagus and may be caused by the ingestion of chemicals, such as lye (also known as sodium hydroxide or caustic soda).6 This type of injury is common in children,7, 8 who typically ingest caustic substances accidentally. A subset of all caustic ingestions represents suicide attempts. These patients are at lifelong risk for squamous cell carcinoma of the oesophagus.9 The characteristic feature of caustic injury is superficial mucosal necrosis that produces white plaques or membranes on endoscopic examination (‘oesophagitis desiccans superficialis’). This type of injury affects the mid and distal oesophagus most profoundly.10

Microscopically, the superficial epithelium shows coagulative necrosis, with separation of the superficial epithelium from the basal layer (Figure 11.7). An associated intraepithelial inflammatory infiltrate is usually seen.10

Table 5.1 summarises patterns of oesophageal pathology that may occur as a result of medications.

Oesophagus-Specific Drugs


Patients may receive oral iron supplements, most commonly in the form of ferrous sulphate tablets, for the treatment of iron deficiency anaemia. There is no doubt that iron has the capacity to cause corrosive injury in the upper GI tract,10 and many patients on oral iron complain of upper GI symptoms including dyspepsia and nausea.11 The endoscopic appearance of iron-related pathology varies from superficial erosions to frank ulceration.11

Iron pill–associated upper GI pathology is increasingly recognised by pathologists (Fact Sheet 5.1; see also Chapter 13).11 Mucosal erosion or ulceration may occur in the oesophagus and/or the stomach. Biopsy specimens typically display iron deposition, characterised by luminal crystalline iron (detectable on routine haematoxylin and eosin [H&E] stains), adjacent to the surface epithelium or admixed with a fibrino-inflammatory exudate (Figure 13.18).11 Crystalline iron deposition can also be apparent in the lamina propria, either covered by an intact epithelium, subjacent to small superficial erosions, or admixed with granulation tissue. Iron may be deposited in lamina propria histiocytes and rarely in glandular epithelial cells. The presence of intracellular iron deposits (particularly in epithelial cells of deep glands), in the absence of a significant inflammatory component, is more suggestive of haemosiderosis or haemochromatosis than iron pill–associated mucosal injury.12

Fact Sheet 5.1 Histological Features of Iron Pill–Associated Mucosal Injury

  • Mucosal erosion and/or ulceration

  • Luminal crystalline iron (detectable on H&E)

  • Crystalline iron in lamina propria

  • Pitfalls (for misdiagnosis of malignancy)

  • Regenerative epithelial changes

  • Pseudoepitheliomatous epithelial hyperplasia

  • Exuberant proliferation of reactive fibroblasts

Occasionally, an exuberant proliferation of reactive fibroblasts and regenerative epithelial changes is present near oesophageal ulcers that contain iron crystalline material. These changes can be so striking that they raise the differential of a malignant process.10 Pseudoepitheliomatous (‘pseudocarcinomatous’) epithelial hyperplasia may also appear in areas of reparative squamous oesophageal mucosa, causing initial alarm.10


Bisphosphonates (e.g. alendronate sodium) are effective in the treatment of osteoporosis, Paget’s disease, and hypercalcaemia of malignancy, in order to prevent osteoclast-mediated bone reabsorption.13 Ingestion of alendronate sodium (Fosamax) and related medications is associated with both oesophagitis and oesophageal ulcers.14, 15 Patients may develop erosive/ulcerative oesophagitis during alendronate therapy.5

Oesophageal biopsies of the ulcer site show a characteristic inflammatory exudate with granulation tissue. Polarisable, crystalline, foreign material may be present (pale yellow crystals), and multinucleated giant cells within the inflammatory exudate may be found near the crystalline foreign material.1 Adjacent squamous epithelium typically shows active inflammation with reactive/regenerative epithelial changes, characterised by epithelial cells with enlarged, hyperchromatic nuclei.


Injury Patterns

Reactive/Chemical Gastropathy

Reactive/chemical gastropathy/gastritis represents the second most common diagnosis made on gastric biopsies, after Helicobacter pylori–associated gastritis.16 It is regarded as a non-specific response to a variety of gastric irritants,17 the most common of which are NSAIDs, bile reflux, and alcohol.

The histological features of reactive/chemical gastropathy include (Fact Sheet 5.2) hyperplastic foveolar epithelium with a ‘corkscrew’ appearance (tortuosity of gastric pits), surface epithelial degeneration with cuboidal change of the foveolar glandular cells (nuclear enlargement and hyperchromasia), lamina propria oedema, dilated capillaries, and vascular congestion in the lamina propria, a paucity of inflammatory cells, and smooth muscle splaying in the lamina propria with vertical orientation of the muscle fibres (see also Chapter 13).18 Foci of pseudopyloric or intestinal metaplasia are common and may reflect ulcer repair.18

Fact Sheet 5.2 Histological Features of Chemical/Reactive Gastropathy

  • Foveolar hyperplasia

  • Tortuosity of gastric pits and a corkscrew appearance

  • Cuboidal change in foveolar epithelial cells, with nuclear enlargement and hyperchromasia

  • Superficial mucosal oedema

  • Dilated capillaries in lamina propria

  • ‘Tongues’ of smooth muscle fibres extending from the muscularis mucosae upward into the lamina propria

Ulceration or Perforation

Numerous drugs, most commonly NSAIDs, can cause erosions or ulcers in the stomach.19 Other drugs associated with GI ulcers include corticosteroids, alendronate, doxycycline, colchicine, chemotherapy, iron, and Kayexalate.

Mucosal Deposits

OsmoPrep is a tablet form of bowel preparation.20 The active ingredient in OsmoPrep is sodium phosphate, which functions as an osmotic laxative. It is a colon preparatory agent that is used infrequently, primarily because of the associated risk of acute phosphate nephropathy.20 Patients may be prescribed this form of colon preparation if they cannot tolerate the large volume of chalky fluid that constitutes the more commonly prescribed liquid sodium phosphate agent.20

OsmoPrep-associated gastritis is characterised by marked reactive epithelial changes, associated with purple to black inorganic deposits in the superficial lamina propria of gastric antral biopsies.20 The gastric mucosa associated with the deposits typically demonstrates prominent mucin loss and nuclear hyperchromasia, without significantly increased inflammation, producing changes compatible with reactive gastropathy. The deposits have been described as irregular in contour, of varying sizes (typically <100 mm), and generally having the appearance of crushed pill fragments. Histochemical special stains show that the deposits are Perls iron stain negative and von Kossa stain positive.20 The histological differential diagnosis includes mucosal calcinosis and iron pill gastritis.20

Table 5.2 summarises patterns of gastric pathology that may occur as a result of medications.

Table 5.2 Medication-induced damage to the stomach (see also Table 12.6)

Histological pattern of injury Drug
Reactive/chemical gastropathy/gastritis

  • NSAIDs

  • Alcohol


  • NSAIDs

  • Corticosteroids

  • Alendronate (a bisphosphonate)

  • Doxycycline

  • Colchicine

  • Chemotherapy (FUDR, mitomycin C, paclitaxel)

  • Iron

  • Kayexalate

Dysplasia-like atypia

  • Chemotherapy (FUDR, mitomycin C, paclitaxel)

  • Radiation

Mitotic arrest

  • Paclitaxel (Taxol) toxicity

  • Colchicine


  • Gastric mucosal calcinosis

Mucosal deposits OsmoPrep

See also Table 12.6.

FUDR, 5-fluoro-2-deoxyuridine; NSAIDs, non-steroidal anti-inflammatory drugs.

Stomach-Specific Drugs


Mucosal changes are observed only when this alkaloid reaches toxic levels (typically in patients with renal failure or hepatic failure).21 The histological changes reflect, in part, the inhibition of tubulin polymerisation.17 The gastric epithelium frequently shows nuclear pseudo-stratification and loss of polarity.21 Numerous mitotic figures arrested in metaphase are seen, with the chromosomes often arranged as ‘ring’ mitoses.21 Apoptoses can also be prominent, and apoptotic bodies are typically located either in the proliferative region of the gastric crypt or of the gland neck.17

Aluminium-Containing Antacids or Sucralfate

Gastric mucosal calcinosis is seen most frequently in orthotopic transplant patients (varied organs) and in chronic renal failure patients who have been prescribed either aluminium-containing antacids or sucralfate.17 Gastric mucosal calcinosis describes the presence of small, deeply pink, and partially calcified refractile crystals, that characteristically reside beneath the surface epithelium of the gastric antrum.17 Typically, some degree of foveolar hyperplasia and mucosal oedema are also present.22


Gastric mucosal injury may be seen following radiation therapy for upper abdominal neoplasia or in bone marrow transplant (BMT) recipients.17 Radiation gastritis is diagnosed less commonly than radiation enteritis (see also Chapter 3).

Early changes (8–10 days post-irradiation) are characterised histologically by nuclear karyorrhexis and cytoplasmic eosinophilia of the gastric pit epithelium (Fact Sheet 5.3). During the subsequent days, mucosal oedema and congestion develop, together with submucosal collagen bundle swelling, fibrin deposition, and telangiectasia. Inflammation is usually insignificant. Characteristic radiation-induced nuclear atypia follows. If damage is extensive, ulceration and haemorrhage may occur. Possible late radiation effects include endothelial proliferation and fibrinoid necrosis of blood vessel walls. Recovery usually begins during the third week after radiation injury and is complete within 2–3 months.17

Fact Sheet 5.3 Histological Features of Radiation Gastritis

Early Changes (8–10 days post-irradiation)

  • Nuclear karyorrhexis

  • Cytoplasmic eosinophilia of gastric pit epithelium

Subsequent Changes

  • Mucosal oedema and congestion

  • Telangiectasia

  • Fibrin deposition

  • Submucosal collagen bundle swelling

  • Epithelial atypia

Late Effects

  • Endothelial proliferation

  • Fibrinoid necrosis of blood vessel walls

If Damage Is Extensive

  • +/− ulceration

  • +/− haemorrhage

Yttrium-90–Microsphere Selective Internal Radiation

Selective internal radiation therapy (SIRT) (see also Chapter 3) with biocompatible resin-based yttrium-90 (Y-90)-emitting microspheres, administered via hepatic artery branches, is a method used to deliver internal radiation therapy selectively to inoperable/unresectable primary and secondary (particularly colorectal liver metastases) hepatic malignancies.23, 24 As the overwhelming majority of the tumour blood supply is derived from the hepatic artery (while the normal parenchyma is largely supplied by the portal vein), this method allows selective delivery of effective doses of radiation to liver lesions without compromising normal liver parenchyma.25Thus, it is a form of loco-regional radiation therapy.

However, selective internal radiation therapy has the potential to cause extrahepatic adverse effects if the microspheres are inadvertently delivered to arteries supplying the stomach or duodenum or other organs.25 The reported incidence of GI complications of this therapy varies from 3% to 24%.26 Radiation ulcers are a recognised complication, situated mostly in the gastric antrum, pylorus, and duodenum23, 26 and occur as a consequence of indirect irradiation or direct deposition of Y-90 microspheres.23

The presence of round, purple microspheres on histological examination of biopsy specimens is diagnostic of direct deposition of Y-90 microspheres (Figures 3.14 and 6.1B).23, 27 The microspheres are 20–30 μm in diameter and this size allows them to lodge preferentially in the microvasculature of the tumour as well as in the microvasculature of the GI tract, leading to direct radiation toxicity.23, 26, 27 Even small quantities of microspheres caught in the gastric and/or duodenal capillary bed may lead to ulceration, bleeding, and perforation.24 Other changes that may be appreciated histologically include apoptosis, epithelial flattening, glandular cystic dilatation, nuclear atypia, capillary ectasia, and prominent endothelial cells.25 The lack of lamellations differentiates the spheres from psammoma bodies.23

Chemotherapeutic Agents

Most reports of chemotherapy-related GI injury describe gastroduodenal inflammation and ulceration in patients undergoing hepatic arterial infusion chemotherapy (HAIC) for the treatment of primary or metastatic hepatic carcinomas.28 The chemotherapeutic agents implicated most often are 5-fluoro-2-deoxyuridine (FUDR) and mitomycin C. Following HAIC, patients may have erosions and ulcers on endoscopy, usually in the antro-pyloric region of the stomach and less often in the duodenum and oesophagus.29

Histological examination may show marked epithelial atypia in the region of the ulcer that can be mistaken for dysplasia or carcinoma. Features that assist in the distinction of this reactive atypia from carcinoma include the following (Fact Sheet 5.4)30: (1) preservation of mucosal architecture; (2) bizarre atypia (exceeding that usually seen in carcinoma); (3) cytological resemblance to radiation effect; (4) preservation of low nuclear/cytoplasmic ratio; (5) prominent cytoplasmic eosinophilia, often with vacuolisation; (6) atypia limited to, or accentuated towards, the basal part of the gastric crypts; (7) few or no mitotic figures; (8) absence of intestinal metaplasia in the adjacent gastric epithelium; and (9) similar atypia within endothelial cells and fibroblasts.

Fact Sheet 5.4 Histological Features Distinguishing Chemotherapy-Related Reactive Atypia from Carcinoma

  • Preservation of mucosal architecture

  • Bizarre atypia (exceeding that usually seen in carcinoma)

  • Cytological resemblance to radiation effect

  • Preservation of low nuclear/cytoplasmic ratio

  • Prominent cytoplasmic eosinophilia +/− vacuolisation

  • Atypia limited to the basal part of the gastric crypts

  • Few or no mitotic figures

  • Absence of intestinal metaplasia in adjacent gastric epithelium

  • Similar cytological atypia within endothelial cells and fibroblasts

Systemic chemotherapy for oesophageal carcinoma has also been reported to cause dysplasia-like atypia in the stomach.31 Paclitaxel (Taxol; taxane chemotherapeutic agent) toxicity can be associated with mitotic arrest, similar to the effects of colchicine. This particularly affects the oesophagus, but may also involve the stomach or small intestine.32 Similar to colchicine (described earlier), Taxol induces this change by binding to microtubules, thus promoting polymerisation and inhibiting depolymerisation.33 Electron microscopy shows a central core of polymerised microtubules surrounded by dispersed chromatin, resulting in a ‘ring’ structure during metaphase.32

Small Intestine

Endoscopic exploration of the small intestine is now a widespread technique. As a consequence, the detection of drug-induced injury has increased (Table 5.3).34

Table 5.3 Medication-induced damage to the small intestine

Pattern Drug
Duodenal villous atrophy

  • Mycophenolate

  • Olmesartan and other ARBs

  • Ipilimumab

  • Azathioprine

  • Colchicine

  • NSAIDs

  • PD-1/PD-L1 inhibitors

Duodenal lymphocytosis

  • Olmesartan and other ARBs

  • NSAIDs

  • PPIs

Apoptotic enteropathy

  • Mycophenolate

  • Ipilimumab

  • Anti-metabolites and TNF-alpha inhibitors

  • NSAIDs

  • Sodium phosphate-containing bowel preparation formula

  • PD-1/PD-L1 inhibitors

Crystal deposition Kayexalate

ARBs, angiotensin II receptor antagonists/blockers; NSAIDs, non-steroidal anti-inflammatory drugs; PD-1, programmed cell death protein 1 (PD-1); PD-L1, programmed death-ligand 1; PPIs, proton pump inhibitors; TNF, tumour necrosis factor.

Injury Pattern

Duodenal Villous Atrophy

Some therapeutic agents can cause villous atrophy in addition to significant intraepithelial lymphocytosis, with or without epithelial damage (Fact Sheet 5.5).

Fact Sheet 5.5 Medications Causing Small Intestinal Villous Atrophy

Duodenal Lymphocytosis

The upper limit of intraepithelial lymphocytes (IELs) in the duodenum is reported to be 20–25 IELs/100 epithelial cells.35 A greater density of IELs is seen in the crypts and, normally, there is a decrease in the number of IELs from the villous base towards the tip.36 Thus, counting IELs at the tips of the villi and observing a lack of decrescendo from crypts to tips have been recommended as the most useful methods of confirming a duodenal lymphocytosis.36

Duodenal lymphocytosis has been observed in up to 7% of patients undergoing upper GI endoscopy and small intestinal biopsy.37 Causes of duodenal lymphocytosis (with normal villous architecture) include gluten-related disorders, non-gluten food hypersensitivity, infections, bacterial overgrowth, immune deficiency and dysregulation, lymphocytic and collagenous colitis, and, of course, drugs.38 Duodenal lymphocytosis has been noted frequently in patients taking NSAIDs37, 39 and proton pump inhibitors (PPIs) (Fact Sheet 5.6).

Fact Sheet 5.6 Medications Causing Duodenal Lymphocytosis (with Normal Villous Architecture)

Olmesartan can lead to significant lymphocytosis; it is commonly also associated with various degrees of villous blunting.40

Apoptotic Enteropathy

Apoptosis in the deep portions of the crypts is considered abnormal, as apoptotic cells are found only rarely in normal intestinal mucosa. When present in normal intestinal mucosa, they are usually confined to the surface epithelium due to normal cell turnover.41 Increased crypt apoptosis (variably defined as either 1 apoptotic body per biopsy fragment42 or more than 5 apoptotic bodies per 100 crypts43) should prompt pathologists to look for additional histological changes (e.g. acute or chronic inflammation, mucin depletion, crypt loss, cryptitis, and Paneth cell metaplasia), which may help in attributing the findings to a particular aetiology. Clinical history, with a particular focus on drug intake, is essential for identification of the cause of an increase in apoptosis in the intestine (Fact Sheet 5.7).44

Table 5.3 summarises patterns of small intestinal pathology that may occur as a result of medications.

Fact Sheet 5.7 Medications Causing Apoptotic Enteropathy

Specific Drugs


Mycophenolate (MPA) is an immunomodulator used to prevent rejection in solid organ transplant, including heart, kidney, and liver. Two formulations are available, mycophenolate mofetil (MMF) and mycophenolate sodium (MPS),45 commonly marketed under the trade names CellCept (Roche Pharmaceuticals) and Myfortic (Novartis), respectively. MMF is absorbed in the stomach while MPS is absorbed in the small intestine.46 MPA inhibits the enzyme inosine monophosphate dehydrogenase and prevents the conversion of inosine monophosphate into guanosine monophosphate, decreasing purine synthesis and arresting the cell cycle. This in turn affects the production of T and B lymphocytes, resulting in immunosuppression.47, 48 Common GI side effects of MPA (affecting up to 45% of patients49) include nausea, vomiting, diarrhoea and abdominal pain, and range from mild (intermittent nausea or diarrhoea) to life-threatening (colonic necrosis or perforation) complications.50

Histological abnormalities in the upper GI tract of patients treated with MPA reflect local mucosal irritation, similar to that induced by NSAIDs,51 and include ulcerative oesophagitis, reactive gastropathy-type changes, and duodenal ulcers.44 Coeliac disease–type changes in duodenal biopsies may also occur in patients treated with MPA. The first histological report of duodenal MPA-associated injury appeared in 1998, when villous blunting and crypt hyperplasia were described in a renal transplant patient on MMF therapy.52

Increased epithelial cell apoptosis has been identified as a hallmark feature for the diagnosis of MPA-related colitis.53 Striking apoptosis in duodenal and colonic biopsies from patients on MPA therapy has been described.43, 44, 48, 53 Other morphological features independently associated with MMF include the presence and quantity of lamina propria eosinophils and endocrine cell aggregates, and the presence and quantity of apoptotic microabscesses, hypereosinophilic degenerated crypts, and crypt distortion53, 54 (Figure 5.1; Fact Sheet 5.8).

(A) A medium-power view of colonic mucosa with markedly increased numbers of eosinophils in the lamina propria, and a crypt abscess.

(B) A high-power view of colonic mucosa with increased numbers of eosinophils in the lamina propria and an apoptotic microabscess with cryptitis.

Figure 5.1 Mycophenolate-associated colitis.

Fact Sheet 5.8 Gastrointestinal Tract Histological Changes Associated with Mycophenolate

Site in GI tract Microscopic feature
Oesophagus Ulcerative oesophagitis
Stomach Reactive gastropathy-type changes
Small and large intestines

  • Duodenal ulcers

  • Villous blunting (small intestine)

  • Crypt hyperplasia (small intestine)

  • Striking apoptosis

  • Lamina propria eosinophils

  • Lamina propria endocrine cell aggregates

  • Apoptotic microabscesses

  • Hypereosinophilic degenerated crypts and crypt distortion

GI, gastrointestinal.


Olmesartan is one of several angiotensin II receptor antagonists/blockers (ARBs) used for the management of hypertension. In 2012, Rubio-Tapia and colleagues published a case series supporting an association between severe sprue-like enteropathy and olmesartan.40 In their series, they described the clinical manifestations of 22 patients during a 3-year period with unexplained sprue-like enteropathy that improved clinically after discontinuation of olmesartan. All 22 patients presented with chronic diarrhoea (for at least 4 weeks), in addition to weight loss, while taking olmesartan (range 10–40 mg/day). All patients had dramatic improvement, with resolution of their diarrhoea, following the cessation of olmesartan. Since then, there have been several other series and case reports of olmesartan-associated enteropathy.5558

Histologically, duodenal biopsies from patients with olmesartan-associated enteropathy demonstrate villous atrophy (total villous blunting or partial villous atrophy) (Figure 5.2), often with a concomitant increase in intraepithelial lymphocytes (Fact Sheet 5.9). Variable degrees of lamina propria chronic inflammation, acute inflammation, and increased eosinophils are present. A thick band of subepithelial collagen deposition may develop. Biopsies from the stomachs of patients with olmesartan-associated enteropathy may demonstrate lymphocytic gastritis, collagenous gastritis, or non-specific chronic gastritis. Random colonic biopsies from these patients may show microscopic colitis (lymphocytic colitis or collagenous colitis) (Fact Sheet 5.9).

(A) A low-power view of duodenal mucosa with villous blunting and increased cellularity of the lamina propria.

(B) A higher power view of duodenal mucosa highlighting villous blunting and increased lamina propria cellularity, in addition to increased numbers of intraepithelial lymphocytes.

(Case courtesy of Professor C E Connolly, Galway, Ireland.)

Figure 5.2 Olmesartan-induced enteropathy.

Fact Sheet 5.9 Histological Changes in the Gastrointestinal Tract Associated with Olmesartan

Site in GI tract Microscopic feature
Small bowel

  • Villous atrophy (total or partial)

  • Increase in intraepithelial lymphocytes

  • Thick band of subepithelial collagen deposition

  • Variable degrees of mucosal inflammation


  • Lymphocytic gastritis

  • Collagenous gastritis

  • Non-specific chronic gastritis

Large bowel Microscopic colitis (lymphocytic or collagenous colitis)

Coeliac disease can be excluded by negative serology tests (absence of IgA tissue transglutaminase antibodies, absence of IgA endomysial antibodies) and the absence of a clinical response to a gluten-free diet.59

Case reports of patients taking other ARBs demonstrating a profound sprue-like enteropathy also exist,60 implicating irbesartan,60, 61 valsartan,62 telmisartan,61 and eprosartan.35


Ipilimubab, a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4, has been shown to offer durable objective therapeutic responses in patients with metastatic malignant melanoma and renal cell carcinoma.63 However, this regimen is associated with numerous immune-mediated toxicities, including enterocolitis, hepatitis, nephritis, dermatitis, hypophysitis, and uveitis.6367 Major toxicity appears to affect the GI tract most frequently, occurring in up to 20% of patients receiving ipilimumab.68 A 5% mortality rate has been reported in patients who develop ipilimumab-associated colitis, with a significant risk of colonic perforation.64, 69 Endoscopic findings in patients suffering from severe ipilimumab-associated GI toxicity can be variable, ranging from normal mucosa to diffusely erythematous and ulcerated mucosa.70

Histologically, ipilimumab-associated enteritis demonstrates features in ileal and duodenal biopsies resembling coeliac disease or autoimmune enteropathy, namely villous blunting, an increase in intraepithelial lymphocytes, and an expansion of the lamina propria by a lymphoplasmacytic infiltrate (Fact Sheet 5.10). Increased epithelial apoptosis is often a distinctive feature (Figure 5.3).

Fact Sheet 5.10 Histological Changes in the Gastrointestinal Tract Associated with Ipilimumab

Site in GI tract Microscopic feature
Small bowel

  • Villous blunting

  • Increase in intraepithelial lymphocytes

  • Lymphoplasmacytic infiltrate in lamina propria

  • Increased epithelial apoptosis

Large bowel

  • Lamina propria neutrophilic and plasmacytic infiltrate

  • Focal neutrophilic and lymphocytic cryptitis

  • Mucosal erosions and/or occasional ulceration

  • Crypt abscesses

  • Glandular destruction

(A) A low-power view of colonic mucosa with increased cellularity of the lamina propria and increased epithelial apoptosis.

(B) A high-power view of colonic mucosa with a plasma cell infiltrate in the lamina propria and several apoptotic bodies.

Figure 5.3 Ipilimumab-associated colitis.

Histological findings of ipilimumab-associated colitis include an inflammatory infiltrate in the lamina propria comprising neutrophils and plasma cells, and focal neutrophilic and lymphocytic cryptitis (Fact Sheet 5.10).66 Foci of crypt abscesses, glandular destruction, and erosions of the mucosal surface are usually evident, with occasional ulceration. These inflammatory changes are often diffuse throughout the colon.

The colitis associated with ipilimumab has histological features similar to those of colorectal graft-versus-host disease (GvHD) as well as to those of inflammatory bowel disease (IBD) (see also Chapter 22, including acute and chronic inflammatory changes and patchy areas of inflammation (skip lesions).66 GvHD is usually histologically distinct, being characterised by prominent epithelial cell apoptosis and glandular destruction. These features are less prominent in ipilimumab-associated colitis. Unlike Crohn’s disease or ulcerative colitis, ipilimumab-related colitis involves the descending colon more than the sigmoid colon, ascending colon or rectum71 and does not usually demonstrate features of chronicity.66

Crystal Deposition (Non-absorbable Drugs)

Various non-absorbable drugs can be associated with a wide spectrum of mucosal and mural alterations in the small intestine. These drugs are characterised by microscopically detectable crystals, with distinctive shapes and colours.

Crystal Deposition: Kayexalate

Sodium polystyrene sulphonate (Kayexalate; SPS) is used routinely to treat hyperkalaemia (by binding and excreting potassium through the GI tract), mainly in patients with end-stage renal disease (ESRD) but also in those with hyperkalaemia resulting from other diseases.1 SPS may cause ischaemic necrotising lesions in any segment of the intestine (especially in the small intestine and colon) that can appear within hours and up to 11 days after intake.72

Histological features of cation-exchange resin-induced injury include transmural necrosis and ulcerations containing resin crystals that can be present in the lumen, or on the serosal surface if perforation occurs.72 Kayexalate crystals have narrow, rectangular ‘fish scales’, are violet/lightly basophilic on H&E and are refractile but not polarisable (Figure 5.4).73 The crystals stain red with periodic acid–Schiff (PAS) and Ziehl–Neelsen (ZN) stains, magenta with periodic acid–Schiff diastase (PASD) and display a characteristic crystalline mosaic pattern (Table 5.5).74

Figure 5.4 Kayexalate crystals have narrow, rectangular ‘fish scales’, are lightly basophilic, and are refractile but not polarisable.

(Courtesy of Dr Laura Lamps, University of Michigan, USA.)

Large Intestine

Injury Patterns

Focal Active Colitis

Focal active colitis (FAC) is the term used to describe the isolated finding of neutrophilic crypt injury (focal acute inflammation of the crypt epithelium) of the colorectal mucosa, diagnosed in colorectal biopsies, in the absence of any other significant microscopic abnormality (Fact Sheet 5.11).75, 76 This descriptive term encompasses a spectrum of histological changes, ranging from a single focus of cryptitis or a single crypt abscess to multiple discrete foci of cryptitis or crypt abscesses within a series of colorectal biopsies.75

Fact Sheet 5.11 Medications Causing Focal Active Colitis

Studies on adult populations with FAC have suggested that the majority of cases of FAC are due to drugs (especially NSAIDs) and self-limiting colitis⁄infection.75, 77, 78 Drugs that have often been implicated include antibiotics, PPIs, steroids, NSAIDs(mefenamic acid, diclofenac, naproxen), and immunosuppressive medication.78, 79 However, drugs that have been reported to cause FAC are numerous, and also include the following: ipilimumab, bisoprolol, furosemide, amiodarone, thyroxine, simvastatin, Asacol, fluoxetine, Sanomigran, pirprofen, carbamazepine, oral contraceptive steroids, laxatives (such as bisphosphonate enemas and bisacodyl) and oral bowel preparation.79 Please see Table 5.4.

Table 5.4 Medication-induced damage to the large intestine

Pattern Drug
Focal active colitis

  • NSAIDs

  • Antibiotics

  • PPIs

  • Steroids

  • Immunosuppressive medications

  • Others

  • PD-1/PD-L1 inhibitors

Mucosal ulcerations, erosions and strictures

  • NSAIDs

  • Methotrexate

  • Non-absorbable drugs, e.g. colesevelam, colestipol, cholestyramine, kayexalate, sevelamer

Ischaemic colitis

  • Cocaine

  • Ergotamine

  • Oestrogens

  • Progesterones

  • Sodium polystyrene

  • Pegylated alfa interferon

  • Ribavirin

  • PD-1/PD-L1 inhibitors

Eosinophilic colitis

  • NSAIDs

  • Clozapine

  • Carbamazepine

  • Rifampicin

  • Tacrolimus

  • Gold

Microscopic colitis

  • NSAIDs

  • PPIs

  • SSRIs

  • Others

  • PD-1/PD-L1 inhibitors

Mimics of dysplasia

  • IV cyclosporin

  • Colchicine

  • Taxol

Pseudomembranous colitis

  • Antibiotics

  • PPIs

Pneumatosis coli

  • α-Glucosidase



Crystal deposition

  • Sevelamer

  • Cholestyramine

‘Paradoxical’ new-onset IBD

  • Etanercept

  • Infliximab

  • Adalimumab

  • Rituximab

EGFR-TKI, epidermal growth factor receptor–tyrosine kinase inhibitor; IV, intravenous; NSAIDs, non-steroidal anti-inflammatory drugs; PPIs, proton pump inhibitors; SSRIs, serotonin reuptake inhibitors; VEGF-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitors.

Ischaemic Colitis

More than 90% of patients with non-iatrogenic causes of ischaemic colitis are in their seventh decade of life or older. Occasionally, ischaemic colitis occurs in younger patients as a result of comorbidities or medications. There is a well-established association between ischaemic colitis and illicit drugs, such as cocaine,8082 and prescription drugs, such as ergotamine,83 oestrogens,8486 progesterones,87 and sodium polystyrene. Psychotropics, particularly neuroleptics, gold, and beta-blockers, are other possible risk factors for ischaemic colitis.8890 Phenothiazine, clozapine, and tricyclic antidepressants are the most frequently reported anti-psychotics thought to cause ischaemic colitis.9194

A probable correlation between a wide range of drugs (including alosetron, interferon-a, digitalis, dopamine, epinephrine or norepinephrine, amphetamines, methylsergide, NSAIDs, pseudo-ephedrine, vasopressin, barbiturates, cyclosporine, danazol, diuretics, flutamide, glycerin enema, and phospho-soda solution) and ischaemic colitis has been reported.88 In addition, isolated case reports have described ischaemic colitis as a possible consequence of cyclo-oxygenase 2 (COX2) inhibitors, triptans, chemotherapy, tegaserod, clinasetron, phentermine, voglibose, RhinAdvil, vinorelbine, combination therapy with peginterferon and ribavirin (described in more detail in the text that follows), oral laxatives, and barium enema.88

Eosinophilic Colitis

A consensus on the diagnostic criteria for eosinophilic colitis does not currently exist, although many pathologists use a diagnostic threshold of 20 eosinophils per high-power field (hpf).95 However, normal values for tissue eosinophils vary widely between different segments of the colon, ranging from <10 eosinophils per hpf in the rectum to>30 eosinophils per hpf in the caecum.96 Therefore, the location of the biopsy is critically important for the interpretation of findings.97 Drug-induced eosinophilic colitis has been described in response to a variety of drugs, including NSAIDs,98 clozapine,99101 carbamazepine,102 rifampicin,103 tacrolimus,104 and gold.105

Microscopic-Type Colitis

Microscopic colitis is a common cause of chronic diarrhoea, especially in the elderly.106 A diagnosis of microscopic colitis (lymphocytic or collagenous colitis) is based upon histological abnormalities of colonic mucosa in patients with chronic diarrhoea and macroscopically normal or near normal colonic mucosa (see Chapter 20).107 Although the pathophysiology of microscopic colitis is not well understood it is probably multifactorial and related to an abnormal immune reaction to luminal antigens in predisposed hosts.108 Recent research has highlighted the potential role of drugs in inducing microscopic colitis.107 Identifying such drugs is important, considering the associated disease burden.

NSAIDs (can be associated with collagenous colitis or lymphocytic colitis),109, 110 PPIs (e.g. lansoprazole; can lead to either lymphocytic [stronger association] or collagenous colitis),109, 111 and serotonin reuptake inhibitors (SSRIs; e.g. sertraline, associated with lymphocytic colitis) are among the medications that are very likely to induce microscopic colitis.112115 However, an ever-increasing list of drugs is associated with microscopic colitis and includes 3-hydroxy-3-methylglutaryl-coenzymeHMG-CoA reductase inhibitors (statins, e.g. simvastatin), ticlopidine, ranitidine, flutamide, acarbose, carbamazepine, penicillin, and aspirin.111, 116120 Drug-induced microscopic colitis is an important condition to recognise, as removal of the causative agent can result in resolution of diarrhoea and avoid the cost and potential side effects of specific pharmacotherapy for microscopic colitis.114, 121

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Sep 2, 2020 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 5 – Drug-Induced Gastrointestinal Disease

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