Drug-Induced Disorders of the Gastrointestinal Tract

Pill Esophagitis

Pill esophagitis occurs secondary to caustic injury caused by retention of a pill in the esophagus. This is often associated with failure to swallow an adequate amount of liquid with the tablet or capsule and swallowing these medications in the supine position before bedtime. The most commonly reported agents that can cause pill esophagitis include antibiotics (particularly doxycycline, tetracycline, and clindamycin), NSAIDs, potassium chloride, iron supplements, ascorbic acid, quinidine, emepronium bromide, and alendronate. ^{, ,} The mechanism by which these drugs cause esophagitis differs depending on the particular agent involved. Tetracyclines, ascorbic acid, and ferrous sulfate produce acidic solutions when dissolved in water, suggesting that they produce acid burns, whereas phenytoin produces an alkaline solution and possibly alkaline burn. ^, Production of local hyperosmolarity by potassium chloride and intracellular poisoning after mucosal uptake by doxycycline and NSAIDs may be the mechanism of injury of these agents. ^{, ,}

Women and older patients are more often affected. ^{, ,} However, the age range is wide. Different drugs are consumed by different age groups. In a review of 650 reported cases, the average age of patients who had quinidine-related esophageal injury was 60, whereas the average age of patients injured by oral antibiotics was 30. Most patients present with odynophagia, retrosternal pain, and dysphagia ^{, ,} and do not have a history of esophageal dysmotility. ^, Complications of pill esophagitis include esophageal strictures, hemorrhage, esophageal perforation, and even death. ^{, , , ,}

Endoscopic findings include erythema, mucosal denudation, discrete ulcers or erosions, and strictures. ^{, , , , , , ,} The squamous epithelium may exfoliate, forming an intraluminal cast, a condition known as esophagitis dissecans superficialis. ^, Sloughing esophagitis with longitudinal sloughing of the middle to distal esophagus is characteristic of esophagitis secondary to dabigatran, a thrombin inhibitor. Quinidine-induced esophageal injury occasionally manifests with exuberant exudates that mimic carcinoma. ^, Remnants of the pill may also be seen. The usual sites of involvement are the midesophagus at the level of the aortic arch (22 to 24 cm) and, in patients with left atrial enlargement, the distal esophagus at 30 to 35 cm. ^{, ,} However, distal involvement with stricture may easily be mistaken for reflux esophagitis. ^, Histological evaluation shows the usual features of esophagitis, with acute inflammation, erosions or ulcers, and granulation tissue. ^, Polarizable crystalline material may be an important clue to the diagnosis ( Fig. 12.1 ) although it is not present in all cases. Multinucleation of squamous epithelial cells has been reported in association with alendronate-associated esophageal injury. ^, Perivascular edema has been described in the ulcers secondary to doxycycline. ^, Esophageal strictures have been described in patients taking potassium chloride, doxycycline, tetracycline, acetylsalicylic acid, ascorbic acid, phenytoin, and quinidine.

Reactive Gastropathy

Reactive gastropathy was a condition initially thought to be specifically related to gastric mucosal injury caused by reflux of duodenal contents into the stomach and was also known as alkaline gastritis or bile reflux gastritis. ^, This distinctive histological entity is now considered a nonspecific response to a variety of gastric irritants, of which bile is only one. NSAIDs and alcohol are also common causes. The features of reactive gastropathy (or “chemical gastritis”) include foveolar hyperplasia with a “corkscrew” appearance to the pits, surface epithelial degeneration with cuboidalization of the foveolar glandular cells and mucin depletion, lamina propria edema, vascular congestion, a paucity of inflammatory cells, and smooth muscle hyperplasia in the lamina propria. The muscle fibers are typically oriented perpendicular from the muscularis mucosae toward the mucosal lumen ( Fig. 12.2 ). ^, Small foci of atrophy with pseudopyloric or intestinal metaplasia are common and may reflect ulcer repair.

Celiac Disease–Like Enteropathy

Increasingly, a celiac disease–like enteropathy secondary to medications has been reported. Villous atrophy, variable lymphocytic exocytosis, and variable crypt apoptoses may mimic celiac disease, and clinical circumstances, including onset of symptoms related to initiation of the suspected medication, severe presentation, and absence of response to gluten withdrawal, may be clues to the correct diagnosis. Olmesartan and other sartans are the most widely known agents that cause this, but other agents can produce a similar picture, such as ticlopidine, idelalisib, checkpoint inhibitors, and mycophenolate mofetil.

Colitis

Drugs may cause patterns of injury that mimic virtually every other known type of colitis. The patterns of colitis that suggest particular agents are listed in Table 12.1 . Eosinophilic colitis ( Fig. 12.3 ) is associated with numerous drugs, including NSAIDs, gold compounds, and carbamazepine hypersensitivity. In one series of patients undergoing colonoscopy for probable drug colitis, increased eosinophils were found in the left colon of patients taking NSAIDs, antiplatelet agents, or estroprogestinic agents, regardless of colonoscopic findings. NSAIDs are associated with increased lymphocytes and scattered neutrophils in the lamina propria, or an appearance similar to that of lymphocytic colitis. Alpha methyldopa and NSAIDs may cause a neutrophilic colitis, mimicking infection. Amoxicillin and levofloxacin have been implicated in cases of pseudomembranous colitis. Chemical colitis from glutaraldehyde, alcohol, or hydrogen peroxide can mimic ischemic colitis. Checkpoint inhibitor therapy, rituximab, mesalamine, and etanercept can cause colitis that resembles ulcerative colitis, can trigger IBD, or can exacerbate preexisting IBD.

Microscopic Colitis

Several drugs have been implicated in the development of lymphocytic and collagenous colitis, including NSAIDs, lansoprazole, selective serotonin reuptake inhibitors (SSRIs), ticlopidine, ranitidine, simvastatin, flutamide, carbamazepine, sertraline, and penicillin V. ^, Checkpoint inhibitor colitis may resemble either lymphocytic or collagenous colitis.

Ischemic Enteritis/Colitis

The clinical presentation of drug-induced ischemia varies depending on the offending agent, the mesenteric vessels involved, the interval between exposure of the drug and clinical presentation, and the general status of the patient. Segmental involvement is typical. The histology is identical to that of ischemia due to other causes. It may reveal ulceration, necrosis, edema, and fibrosis, depending on the stage of injury. Drugs associated with ischemic colitis include antibiotics, NSAIDs, chemotherapeutic agents such as the taxanes, nasal decongestants, constipation-inducing medications, laxatives, vasopressor agents, cocaine, ergotamine, serotonin agonists/antagonists including sumatriptan, oral contraceptives, amphetamines, digitalis, diuretics, and immunomodulators such as interleukin-2. ^, The mechanisms by which drugs cause ischemia vary. For instance, estrogens may result in vascular thromboses, ergotamine may cause vascular spasm leading to proctitis with the development of shallow ulcers, cocaine is a potent sympathomimetic mesenteric vasoconstrictor that produces severe intestinal ischemia, diuretics may cause extracellular fluid volume changes that favor peripheral circulation over mesenteric circulation, and antibiotics may cause hypersensitivity vasculitis. Chemical colitis, such as from glutaraldehyde or alcohol enemas, can also appear histologically indistinguishable from ischemic colitis.

Focal Active Colitis

Focal active colitis (FAC) is defined as cryptitis that involves one or a few crypts, and is associated with epithelial injury and often a surrounding mononuclear infiltrate in an otherwise unremarkable colonic biopsy ( Fig. 12.4 ). It is historically associated with Crohn’s disease. In a 1997 study involving patients without a prior history of IBD, Greenson et al. found that most symptomatic patients with FAC had acute self-limited or infectious colitis, whereas FAC in asymptomatic patients carried no clinical significance. None developed Crohn’s disease. However, 19 of 42 patients in this study were taking NSAIDs, leaving open the possibility that NSAIDs were the cause of FAC. Subsequently, FAC was reported by Driman et al. in patients given oral sodium phosphate as a bowel prep regimen, and they suggested that the idiopathic cases in Greenson’s report may have been due to bowel prep.

Pseudo-obstruction

Drug-induced pseudo-obstruction, or paralytic ileus, rarely comes to the attention of surgical pathologists, because the usual treatment is discontinuation of the offending agent. However, complications such as megacolon or perforation may ensue, necessitating surgical intervention. Many drugs can damage the myenteric plexus, causing loss of neurons and schwannosis. Narcotics, phenothiazines, tricyclic antidepressants, anthraquinone laxatives, anti-Parkinson’s drugs, clonidine, calcium channel blockers, and vincristine are associated with pseudo-obstruction.