Pill esophagitis

Pill esophagitis refers to oesophageal injury secondary to contact between ingested pills and the oesophageal mucosa. Patients are often elderly and common symptoms include odynophagia, chest pain, sudden dysphagia, and vomiting. A minority of patients present with haematemesis.1 A number of medications have been associated with pill esophagitis including doxycycline, non-steroidal anti-inflammatory drugs (NSAID), fluoxetine, lansoprazole, aspirin, clindamycin, diltiazem hydrochloride, potassium chloride and alendronate.1–4 The middle third of the oesophagus is preferentially affected and endoscopic findings include erythema, circumferential deep ulcers, oedematous, nodular, or fragile mucosa, superficial ulcers, ‘kissing ulcers’ (ulcers facing each other), or strictures.1 Tablets may get lodged in the oesophagus or in epiphrenic or Zenker's diverticula, where they may cause local mucosal injury and bleeding.5

The histologic features associated with pill-induced esophagitis are non-specific and have not been well described, except those associated with the use of bisphosphonates, specifically with alendronate (Fosamax). Abraham and colleagues reported 10 patients who experienced erosive/ulcerative esophagitis with alendronate ingestion.6 The authors found that biopsies from all patients showed inflammatory exudates and inflamed granulation tissue with or without polarisable crystalline foreign material (figure 1A,B). Multinucleated giant cells may be seen in the inflammatory exudate and associated with the foreign material. Adjacent squamous epithelium typically shows active inflammation and reactive changes with enlarged, hyperchromatic nuclei.

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Figure 1

Select medication injury patterns of the oesophagus. (A, B) Pill esophagitis. Pill fragments are variably polarisable and refractile; some are bright pink with a Periodic Acid-Schiff special stain. (C, D) Sodium polystyrene sulfonate is violet on H&E and black on acid fast bacillus (AFB). (E, F) Sevelamer is two-toned on H&E with bright pink linear accentuations and a rusty yellow background; it is magenta on AFB. Both sodium polystyrene sulfonate and sevelamer have regular internal demarcations (‘fish-scales’). (G, H) bile acid sequestrants (BAS) are eosinophilic on H&E and dull yellow on AFB. They are uniform or glassy in texture: they lack an internal ‘fish-scale’ pattern.

Regardless of the appearance, finding foreign material in association with oesophageal injury should prompt consideration of pill-induced esophagitis. Affected individuals are typically treated conservatively with proton pump inhibitors (PPI), removal of the offending agent, or behavioural modification, such as tablet ingestion with increased fluids while maintaining an upright posture. Patients usually experience uneventful recoveries.1

Doxycycline

Doxycycline is a member of the tetracycline family; it acts by inhibiting bacterial protein synthesis.7 It is commonly used to treat a wide spectrum of bacterial infections, such as those associated with acne, rosacea, respiratory tract and genitourinary infections, malaria, and Lyme disease. It is generally orally administered and related injuries are most prominent in the oesophagus (and stomach).8–10 Characteristic presentations include severe chest pain shortly after tablet ingestion, which may relate to underlying nerve or vascular injury. Endoscopic abnormalities include erosions, ulcerations, friability, and circumferential white ‘coated’, ‘hard-to-peel-off’ lesions.9–11 Consequently, biopsies of these white, plaque-like lesions may be submitted with a clinical concern for Candidiasis or ‘sloughing oesophagitis’. Histologic findings include erosions, ulcerations, and necrosis. More recently, experts have proposed doxycycline may specifically cause vascular injury.8–10 So-called ‘perivascular halos’ describe the characteristic doxycycline lesion of the oesophagus with perivascular zones of oedema, reactive myofibroblasts, and lymphoblasts. These lesions have been reported surrounding damaged small-sized and medium-sized arterioles subjacent to deep oesophageal ulcers.9 A similar process has been described in gastric mucosal biopsies consisting of reactive gastritis with capillary vascular wall degeneration and microthrombi in a process termed ‘toxic-ischaemic pattern’ (TIP).8 ,10 TIP shares some overlap with gastric antral vascular ectasia (GAVE): clues favouring GAVE include a ‘striped watermelon’ endoscopic image and antral restricted disease.

Resins

Resins are non-absorbable medications that serve as platforms for ion exchange in the GIT. They are typically orally ingested and their colourful crystal forms can be seen anywhere along the tubular GIT. The resins include sodium polystyrene sulfonate, sevelamer, and the bile acid sequestrants (BAS). Confidence in discriminating between these resins is essential because the first two are associated with GIT injury. Sodium polystyrene sulfonate-related mucosal injury, for example, is a medical emergency that can result in ischaemic necrosis and perforation, necessitating immediate clinician contact to ensure close patient monitoring or medication adjustments. Resins can usually be confidently identified on H&E with more challenging cases helped by an acid fast bacillus (AFB) special stain (figure 1C–H), a quick chart review, and awareness of pertinent clinical clues (table 1).

Sodium polystyrene sulfonate (Kayexalate)

Sodium polystyrene sulfonate lowers potassium levels in patients with chronic kidney disease. Initially, it was administered in an aqueous vehicle, but constipation and life-threatening bezoar formation resulted in its delivery in a hyperosmotic sorbitol solution, which itself has been linked to severe ulceration and ischaemia.12–18 To avoid sorbitol-related complications, today orally administered sodium polystyrene sulfonate is emulsified directly into food or drink. Nevertheless, sodium polystyrene sulfonate-related injury persists; some suggest the resins themselves can directly inflict GIT injury.14 Histologically, sodium polystyrene sulfonate displays an internal ‘fish-scale’ pattern, is violet on H&E, and black on AFB (figure 1C, D).

Sevelamer

Sevelamer is a relatively new medication; it lowers phosphate in patients with chronic kidney disease. The sole morphologic description found a dose-dependent relationship between sevelamer and mucosal injury, suggesting sevelamer may cause mucosal injury, particularly in patients with dysmotility or tablet impaction.19 Like sodium polystyrene sulfonate, sevelamer also displays an internal ‘fish-scale’ pattern. It has a two-toned colour on H&E with bright pink linear accentuations and a rusty yellow background (figure 1E); sevelamer is magenta on AFB (figure 1F).

Bile acid sequestrants

BAS were initially introduced to treat hypercholesterolaemia.20 They form strong complexes with bile acids in the intestinal lumen, forcing their elimination into the faeces and depleting the endogenous reservoir of bile acids. As a result, the hepatobiliary system compensates by synthesising more bile acids from cholesterol precursors, thereby lowering serum cholesterol levels. Additional applications include the treatment of bile acid-mediated diarrhoea,21 bile acid-mediated pruritus,22 and improved glycemic control in adults with type 2 diabetes mellitus.23–26 Despite these diverse clinical uses, BAS are infrequently administered. Drawbacks include their non-specific sequestration of other essential medications and water-insoluble vitamins, sometimes severe triglyceride elevations, and sometimes intolerable nausea, constipation and bloating.26–28 Histologically, BAS are presumed innocuous with no established capacity for direct GIT mucosal injury.26 They are included in this discussion because they are often misdiagnosed as sodium polystyrene sulfonate or sevelamer. The BAS, however, are all eosinophilic on H&E, dull yellow on AFB, and they lack an internal ‘fish-scale’ pattern (figure 1G, H). As such, the various BAS resins are histologically indistinguishable from each other; a specific diagnosis as colesevelam, colestipol, or cholestyramine always requires correlation with the medication list.

Iron

Iron supplemental therapy is used to treat iron deficiency anaemia; iron pigment is seen in up to 3.8% of upper tract biopsies.29–33 In a study of 500 gastric biopsies, the deposition was demonstrated in three generalised patterns. Pattern A was the most common (‘non-specific gastric siderosis’, 2.2%), and was associated with prior mucosal injury. The subtle depositions were predominantly within lamina propria macrophages and stromal cells (figure 2A, B). Pattern B was specifically associated with ferrous sulfate therapy (‘iron pill gastritis’, 0.8%). The deposition was coarse, crystalline, and predominantly identified in the luminal or extracellular space (figure 2C, D). The background mucosa can show a reactive gastritis pattern with erosions, ulcerations, fibrino-inflammatory exudate, and can display marked atypia. The mechanism of iron pill injury is poorly understood; it is unclear if the iron tablet has a direct caustic effect on the GIT, or if the iron deposits simply colonise previously injured mucosa.32 Pattern C was associated with iron overload settings, such as hereditary haemochromatosis and multiple blood transfusions (‘gastric glandular siderosis’, 0.6%). The characteristic deposits were subtle, uniform and identified in the deep antral and oxyntic glands (figure 2E, F). Iron is an important morphologic red flag that should prompt (1) careful scrutiny for nearby mucosal damage (Patterns A and B); (2) a note suggesting behavioural modification, such as tablet ingestion with increased fluids to prevent further injury (Pattern B) and (3) consideration of an iron overload evaluation (Pattern C). In challenging cases, iron can be easily highlighted with a Prussian blue iron special stain.

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Figure 2

Select medication injury patterns of the stomach. (A, B) Pattern A (‘non-specific gastric siderosis’) refers to subtle iron depositions within lamina propria macrophages and stromal cells (arrowheads); it is linked to prior mucosal injury and haemorrhage. (C, D) Pattern B (‘iron pill gastritis’) refers to crystalline mineralisation that is predominantly luminal and extracellular; it is associated with ferrous sulfate therapy. (E, F) Pattern C (‘gastric glandular siderosis’) refers to uniform pigment in the deep antral and oxyntic glands (arrowheads); it is associated with iron overload syndromes. A Prussian blue special stain highlights iron blue (B, D, and F). (G, H) Mucosal calcinosis is a black-purple pigment that is usually superficial and extracellular (arrowheads). (H) A von Kossa special stain highlights calcium black. (I, J) ⁹⁰Yttrium-labelled microspheres are uniform, 30 to 40 μm in diameter, and basophilic; they are used in the targeted treatment of unresectable primary and metastatic hepatic malignancies.

Calcinosis

Mucosal calcium deposition is classified as metastatic, dystrophic, or idiopathic.34–37 Metastatic calcinosis is the most common subtype and refers to calcium deposition in normal tissues in the setting of calcium dysregulation. Clinical clues may include a history of hyper-parathyroidism, osseous destruction, vitamin D disorders, and renal failure. Less common causes include excessive ingestion of calcium or calcium containing antacids. Dystrophic calcification refers to calcium deposition in damaged tissues in the setting of normal serum calcium. Endoscopically, mucosal calcinosis appears as small white flecks, plaques, or nodules. Histologically, the coarse black-purple pigment is usually superficial and extracellular (figure 2G). On histologic grounds alone, calcium can be difficult to distinguish from iron. Additionally, patients could be on dual iron-calcium therapy, emphasising the usefulness of ordering a von Kossa special stain for calcium (calcium appears black, figure 2H) and a Prussian blue special stain for iron (iron appears blue, figure 2B, D, F). Recognition is important because ‘metastatic calcinosis’ indicates the patient may be at risk for fatal cardiac calcium deposits.

⁹⁰Yttrium-labelled microspheres

⁹⁰Yttrium-labelled microspheres are used in the targeted treatment of unresectable primary and metastatic hepatic malignancies, a process termed ‘selective internal radiation therapy’. The microspheres are delivered via catheter into the hepatic artery to preferentially target the neoplastic cells (the non-neoplastic hepatocytes derive the majority of their blood supply from the portal vein). Theoretically, this targeted delivery allows for a higher dosage of radiation than would be ordinarily tolerated, and minimises the toxic effects of the radiation to uninvolved organs. However, when the ⁹⁰Yttrium-labelled microspheres inadvertently enter the arteries supplying the oesophagus, stomach, duodenum, gallbladder, or pancreas, they can cause unintended radiation damage to non-targeted organs at relatively high doses.38–41 Histologically, radiation injury consists of lamina propria hyalinisation, damaged-ectatic vessels, and atypical stromal and endothelial cells. The microspheres are uniformly 30–40 μm in diameter and basophilic (figure 2I, J). They have a maximum penetration of 11 mm, a half-life of 2.5 days, and emissions can occur as far out as 14 days postdelivery.39 ,40

Taxanes (Taxol or Paclitaxel; and Taxotere or Docetaxel) and colchicine

Taxanes are chemotherapeutic agents used in the treatment of breast, ovarian and lung cancer, as well as Kaposi sarcoma.42 ,43 Their mechanism of action involves microtubule stabilisation, resulting in mitotic ring forms and mitotic arrest. Colchicine administration can result in identical mitotic ring forms; it is used to prevent gout attacks. Whereas mitotic ring forms with taxane indicate medication effect, the identical findings with colchicine indicate toxicity, requiring immediate clinician notification.43 Colchicine is classified as a biotoxin by the Centers for Disease Control because it can be fatal in low doses, leading to multiple organ failure, bone marrow suppression, respiratory dysfunction, disseminated intravascular coagulopathy, cardiac dysfunction, intestinal obstruction, neuromuscular abnormalities, sepsis and metabolic disturbances.

Pseudomelanosis enteri

Like its colonic counterpart (pseudomelanosis coli), the name ‘pseudomelanosis’ enteri is an unfortunate misnomer. The pigment is not melanin but, instead, represents iron with variable amounts of calcium, lipofuscin, magnesium, aluminium, potassium, silica and sulfur.44–46 The coarse, brown-black pigment is identified within the cytoplasm of macrophages at the villous tips (figure 3A), and can usually be highlighted with special stains for iron (83%) or calcium (24%).47 Clinical clues to pseudomelanosis enteri include a history of hypertension, gastrointestinal bleeding, renal failure, diabetes, and particular medications, such as iron and antihypertensive medications (hydrochlorothiazide, atenolol, lisinopril/quinapril, and irbesartan).47 ,48

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Figure 3

Select medication injury patterns of the small intestine. (A) Pseudomelanosis enteri refers to the brown-black pigment within the cytoplasm of macrophages, usually at the villous tips. (B) Biopsy of the duodenum from a patient with olmesartan-induced injury shows a ‘sprue-like’ pattern with marked villous atrophy and intraepithelial lymphocytosis. (C) Diaphragm disease is associated with non-steroidal anti-inflammatory drugs injury and refers to web-like luminal protrusions of fibrotic mucosa that narrow the lumen of the small intestine or colon. (D) Mycophenolate mofetil (MMF) injury is characterised by increased crypt apoptosis with a background of eosinophils >15 per 10 High Power Field, an absence of endocrine cell aggregates, and an absence of apoptotic microabscesses.

Olmesartan (Benicar)

The antihypertensive medication olmesartan, an angiotensin II receptor inhibitor, is associated with lymphocytic gastritis, collagenous gastritis and collagenous enteritis.49–54 These patterns of injury may occur singly or in combination with intraepithelial lymphocytosis and villous atrophy (figure 3B). This medication reaction has been described as ‘sprue-like’ both in its clinical and histologic presentation, resulting in progressive diarrhoea and weight loss which can be severe enough to warrant in-patient treatment. While the biopsies can be indistinguishable from those of coeliac disease, patients lack serologic evidence of coeliac disease, and symptoms are non-responsive to a gluten-free diet. Complete clinical and histologic resolution occurs following cessation of olmesartan use.

Non-steroidal anti-inflammatory drugs

NSAIDs are notorious for causing non-specific inflammatory injury throughout the GIT. They non-selectively inhibit the cyclo-oxygenase isoenzymes, resulting in decreased production of mucosal protectant products, such as prostaglandins, mucin, bicarbonate and dampened microcirculation.55 Within the small intestine, NSAIDs most frequently affect the duodenum (preferentially the duodenal bulb) and distal ileum. Mucosal injury is characterised by acute inflammation, erosions, ulcerations, and reactive epithelial changes. In general, prominent chronic inflammation is uncommon. Diaphragm disease is another adverse event of NSAIDs and consists of web-like luminal protrusions of fibrotic mucosa that narrow the lumen of the small intestine or colon. As a result, patients can present with obstructive symptoms. Although diaphragm disease is most easily appreciated during gross exam, histologic features include columns of fibrosis, often eroded at their tips, extending from the mucosa into deeper regions of the submucosa with variable amounts of smooth muscle, ganglion cells, and vessels (figure 3C).

Mycophenolate mofetil (CellCept)

Mycophenolate mofetil (MMF) is an immunosuppressant used to prevent allograft rejection in solid organ transplantation, to prevent graft-versus-host disease (GVHD) in stem cell transplantation, and to treat autoimmune and inflammatory diseases, such as psoriasis, lupus nephritis, myasthenia gravis, among others. It prevents T-cell and B-cell proliferation by inhibiting inosine monophosphate dehydrogenase, an enzyme in purine synthesis. It also inhibits leukocyte recruitment to inflammatory sites. Reported side effects include diarrhoea, nausea, vomiting, abdominal pain, malabsorption, and bleeding. MMF-associated injury can affect the entire GIT, and manifests endoscopically as ulcers and erosions. The severity of injury varies from mild to life-threatening and is associated with both short-term and long-term exposure. Treatment usually entails dose reduction or complete medication cessation. A change to mycophenolic acid, a delayed release MMF formulation with a lower GI side-effect profile, is sometimes beneficial for patients with mild symptoms. Histologically, increased crypt apoptosis is the hallmark of MMF injury (figure 3D), a feature also seen in graft-versus-host disease and cytomegalovirus (CMV) infection.56 ,57 Although distinguishing MMF injury from GVHD is challenging, accurate distinction is critical since both can be fatal and the treatments are distinct: MMF injury is cured with medication cessation, and GVHD is treated with immunosuppression. Recent case control studies report that features favouring MMF injury include a triad of eosinophils >15 per 10 HPF, an absence of endocrine cell aggregates, and an absence of apoptotic microabscesses (degenerating crypts with luminal apoptotic, necrotic, and inflammatory debris).58 Features favouring GVHD including apoptotic microabscesses, endocrine cell aggregates, hypereosinophilic degenerating crypts, architectural distortion, and a lack of eosinophilia. Others have reported similar findings.59 ,60 CMV immunostains are recommended in all cases of apoptotic prominence.

Ipilimumab (Yervoy)

Ipilimumab is one of an emerging field of chemotherapeutic agents that enhance immune-mediated destruction of tumours.61 Briefly, ipilimumab is a monoclonal antibody that targets the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). By inhibiting CTLA4's suppressive effects, ipilimumab results in enhanced T-cell-mediated tumour destruction (figure 4). As an unintended consequence of stimulating the immune system, up to 60% of patients report immune-related adverse effects within 11–14 days from the first dose.61–63 The GIT is the most common site of involvement, followed by the skin.64 The diarrhoea is described as watery and culture-negative. Common endoscopic findings range from normal to marked ulcerations. Histologic sections show active chronic injury with increased intraepithelial lymphocytes, apoptotic bodies, granulomata, eosinophilia, and lymphoplasmacytic expansion of the lamina propria (figure 5A). Small intestine biopsies can also show villous blunting with prominent intraepithelial lymphocytosis, mimicking a malabsorption pattern of injury. Ipilimumab injury is treated with medication cessation or heightened concomitant immunosuppression. Death and perforation attributed to immune-related adverse events are rare (1%) but are only seen in those cases with delayed diagnosis or failed recognition, underscoring the importance of recognising ipilimumab-associated injury.61 ,64 While the most common clinical clue is a history of metastatic melanoma, ipilimumab is also under active study for its potential role in treating prostate, lung, renal, pancreatic cancers and lymphoma.

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Figure 4

(A) Normally, T-cell activation results from a stimulatory interaction between B7 on the antigen presenting cell and CD28 on the cytotoxic T-cell. (B) Following sufficient immune stimulation, T-cell activation is dampened, in part, by a CTLA4-dependent process. CTLA4 is translocated from the cytoplasm to the cell membrane where it disrupts the stimulatory B7-CD28 interaction by preferentially binding B7, eventually leading to T-cell inactivation. (C) Ipilimumab is a monoclonal antibody directed against CTLA4. Through binding and neutralising CTLA4's suppressive effects, ipilimumab results in enhanced T-cell mediated tumour destruction.

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Figure 5

Select medication injury patterns of the colon. (A) Ipilimumab colitis can show active chronic colitis; a history of metastatic melanoma is a common clinical clue. (B) The ischaemic colitis pattern is characterised by surface epithelial injury, epithelial mucin loss, atrophic microcrypts, and lamina propria hyalinisation with or without overlying pseudomembranes. (C) The collagenous colitis pattern consists of surface epithelial damage, increased intraepithelial lymphocytes (arrowheads), an expansion of the lamina propria inflammatory cells, and a markedly thickened and irregular subepithelial collagen table that entraps capillaries and inflammatory cells. (D) Lymphocytic colitis also has an expanded lamina propria with increased intraepithelial lymphocytes, but the subepithelial collagen table is of normal thickness. Microscopic colitis can be caused by non-steroidal anti-inflammatory drugs and proton pump inhibitors. (E, F) Pseudomelanosis coli refers to coarse, brown-black pigment in the cytoplasm of the colon's resident macrophages and is associated with laxatives.

Iatrogenic injury associated with an ischaemic pattern (various drugs)

The ischaemic colitis injury pattern encompasses surface epithelial injury, epithelial mucin loss, atrophic microcrypts, and lamina propria hyalinisation with or without overlying pseudomembranes (figure 5B). Additional common findings can include striking cytologic atypia with hyperchromatic-enlarged nuclei, atypical mitoses, and loss of nuclear polarity. Common causes, particularly in the elderly, include atherosclerotic mesenteric vascular disease, amyloidosis, neoplasms, non-specific medication injuries, and infections. An ischaemic injury pattern in a younger patient, however, should invoke consideration of recreational drugs (cocaine), non-recreational medications, coagulopathies, and extreme athleticism. Cocaine-induced vasospasm, in particular, can precipitate impressive ischaemic colitis, preferentially in the left colon and even in the richly vascularised rectum.65 Patients are typically younger and have a significantly higher mortality rate and need for surgical intervention compared to those with other causes of ischaemic colitis.66

Many medications, over the counter and prescribed, may be implicated in the ischaemic colitis pattern. Exogenous hormonal use (oral contraceptives, hormone replacement therapy) has long been implicated in the development of ischaemic colitis. Oestrogen induces a hypercoagulable state,67 an effect that is exacerbated by smoking. The process is usually reversible and typically involves the left colon: sigmoid, descending, splenic flexure and distal transverse colon, in descending order of frequency.68 Small intestine involvement has also been described.69 Over-the-counter medications are additional considerations, such as herbal remedies, weight loss products, and NSAIDs (see also table 2 for a comprehensive list).

Non-steroidal anti-inflammatory drugs

As discussed in the small intestine section, the histologic changes associated with NSAID injury spans a spectrum of morphologic changes.70 ,71 NSAID-induced colonic injury typically affects the right side of the colon. Endoscopic findings may include ulcerations, erythema, and webs, and histologically a non-specific active inflammation and or ischaemic injury pattern can be seen. With chronic NSAID injury, additional features of chronic mucosal injury can be seen. Deshpande et al72 reported such chronic changes can include patchy crypt architectural distortion (crypt shortening and variation in crypt size) and basal plasmacytosis with a sheet-like arrangement of plasma cells at the crypt bases. Plasma cells may or may not be seen infiltrating the muscularis mucosae and submucosa. NSAIDs have also been associated with the collagenous colitis injury pattern.73 ,74 Although most clinicians are aware of this association, it is worthwhile to consider NSAID-related injury before diagnosing idiopathic collagenous colitis.

Proton pump inhibitors

More recently, PPIs have been associated with microscopic colitis, specifically lansoprazole, esomeprazole and omeprazole.75 ,76 Though the literature is limited to case reports, case series, and case-control studies, PPIs-related injuries should at least be considered when encountering a microscopic injury pattern, since PPIs withdrawal can be curative. While the endoscopic appearance is normal in microscopic colitis, a subset of PPIs-related colitis may present with linear mucosal defects,77–81 friability, bleeding,78 ,82 and a decreased vascular pattern.82 PPIs injury is more strongly linked to collagenous colitis than lymphocytic colitis.83

The histologic appearance of PPIs-related microscopic colitis is identical to that of idiopathic microscopic colitis. The collagenous colitis pattern consists of surface epithelial damage, increased intraepithelial lymphocytes, an expansion of the lamina propria chronic inflammatory cells, and a markedly thickened and irregular subepithelial collagen table that entraps capillaries and inflammatory cells (figure 5C). Lymphocytic colitis also has an expanded lamina propria with increased intraepithelial lymphocytes, but the subepithelial collagen table is of normal thickness (figure 5D). Both may show prominent eosinophilia. Some cases show mixed features of collagenous and lymphocytic colitis patterns; some of these may evolve into definitive collagenous or lymphocytic colitis with time. It is our practice to mention the possibility of medication injury (NSAID or PPIs) in cases of the microscopic colitis pattern.