Esophageal Disorders Caused by Medications, Trauma, and Infection


Medication-Induced Esophageal Injury

Medication-induced esophageal injury occurs at any age and from a variety of commonly used medications. Nevertheless, medication-induced esophageal injury is likely underdiagnosed in clinical practice for several reasons. First, common and more serious problems such as acute coronary syndrome and pulmonary embolism might be considered initially because of the severe chest pain, often pleuritic in nature, associated with pill-induced esophagitis. Second, patients may be assumed to be having a severe episode of acid reflux, a far more common condition than a medication-induced esophageal ulceration. Third, several of the medications that cause medication-induced esophagitis are over-the-counter medications (e.g., NSAIDs) or may have been taken safely for years (e.g., tetracycline) without injury and therefore not considered by patients to be a possible contributor to their symptoms. Fourth, because it is not routinely reported or recognized, medication-induced esophageal injury is considered to be uncommon. This under recognition can be problematic as failure to recognize this entity can lead to failure to discontinue the offending agent and lead to extensive and erroneous evaluation and treatment of other conditions. Under recognition may lead to failure to provide the patient proper instruction to avoid injury as well, because this chapter provides a detailed overview of medication-induced esophageal injury, with particular attention to suspecting this entity both by its symptoms and by the medications that are potentially culpable.

Mechanisms

Medications cause esophageal injury through several mechanisms. These can initially be divided into those that cause direct injury to esophageal mucosa because of their caustic nature or by facilitation of injury through other mechanisms such as induction of acid reflux (e.g., calcium channel antagonists). Medications directly damage the esophageal mucosa through 1 of 4 known mechanisms: (1) production of a caustic acidic solution (e.g., ascorbic acid and ferrous sulfate); (2) production of a caustic alkaline solution (e.g., alendronate); (3) creation of a hyperosmolar solution in contact with esophageal mucosa (e.g., potassium chloride); and (4) direct drug toxicity to the esophageal mucosa (e.g., tetracycline). For many medications, the mechanism of esophageal injury does not fall into any of these known categories. Other factors may influence the toxicity of the pill, particularly contact time, pills coated with gelatinous material, sustained-release formulations, and a wax matrix form of the drug. Cellulose fiber and guar gum pills may swell and lodge in the esophagus, causing complete obstruction because of their water-absorbing capacity. Finally, medications may cause esophageal injury through induction of a systemic reaction that affects the esophagus.

It is commonly assumed that a predisposition to medication-induced esophageal injury is due to an anatomic or motility disorder of the esophagus or that the medication was taken incorrectly, in either case allowing for prolonged exposure of the medication to esophageal mucosa. For example, studies have shown that patients with left atrial enlargement, esophageal strictures, esophageal dysmotility, and esophageal diverticula (either Zenker or epiphrenic diverticula) have greater risk of pill-induced injury. Similarly, in the patient with normal esophageal function, the site of drug-induced injury most commonly occurs where there are areas of normal hypomotility or extrinsic compression, such as in the trough zone of the esophagus (where the smooth and skeletal muscle overlap) or at the level of the aortic or left bronchial impression on the esophagus. These locations of relative stasis allow for a pill, when taken incorrectly, to cause injury. However, any part of the esophagus may be involved. Methods of taking a medication incorrectly that predispose to injury include ingesting a pill without enough water or assuming a recumbent position or sleeping immediately after pill ingestion, or both. The latter 2 factors are particularly problematic, by eliminating the help of gravity in esophageal transit and by reducing saliva production and frequent swallowing, which occur normally while awake. Importantly, however, many, if not most, patients who suffer pill-induced esophageal injury presumably have normal esophageal function and do not necessarily ingest their medication in a faulty manner. That pill-induced esophageal injury can occur under “normal” conditions is supported by data demonstrating prolonged radiographic retention of capsules in the esophagus by normal subjects even when taken with water in the upright position. Capsules may have longer esophageal retention times than tablets.

Clinical Features and Diagnosis

Patients typically note an acute onset of chest pain, which may radiate over the central chest and to the back. The pain is commonly accentuated with inspiration and may be accompanied by severe odynophagia, even to small sips of liquids. Some patients may complain of a severe acute onset of heartburn-type symptoms. This set of symptoms associated with ingestion of a potentially injurious medication taken incorrectly (particularly just before bedtime without enough water) strongly suggests the diagnosis. If objective confirmation of the diagnosis is necessary, endoscopy or radiography can be used, although endoscopy is considered more sensitive. Findings range from discrete ulcers to diffuse severe esophagitis with pseudomembranes, as may be seen with bisphosphonates or with sodium polystyrene sulfonate suspension (Kayexalate), mimicking candidal esophagitis. A diffuse sloughing appearance of the mucosa, also known as esophageal dissecans superficialis , may also be identified. Occasionally, severe inflammatory reactions causing stenoses and tumor-like appearances occur. Similar findings may be seen radiographically, particularly when double-contrast radiography is used. The range of findings described on esophagography may also include solitary or multiple ulcers; small or large ulcerations; ulcers with punctate, ovoid, linear, serpiginous, or stellate collections of barium; confluent ulcers; or areas of normal-appearing mucosa separating ulcers ( Fig. 45.1 ). The occurrence of multiple esophageal septa has also been described. Rarely, severe complications of medication-induced injury occur such as esophagorespiratory fistula, esophageal perforation, hemorrhage secondary to ulceration, and chronic stricture formation. Pathologically, esophageal biopsies in affected areas reveal dilated intercellular spaces and a predominance of T lymphocytes and eosinophils in a pattern different from other causes of esophagitis.

Fig. 45.1, A, Barium esophagogram showing esophageal ulceration secondary to tetracycline, with the ( arrow ) pointing to an area of ulcerations. B, Endoscopic image of a tetracycline-induced esophageal burn.

Prevention, Treatment, and Clinical Course

No specific treatments have been shown to be beneficial in altering the course of medication-induced injury. Treatment is aimed at symptom control, prevention of superimposed injury from acid reflux, maintenance of adequate hydration, and removal of the offending medication. Symptom control may be achieved topically by local anesthetics such as viscous lidocaine solution. Occasionally, narcotics are necessary. Prevention of superimposed reflux is best achieved with a twice-daily PPI, although no data show that prevention of acid reflux hastens symptomatic or pathologic improvement of pill-induced injury. For patients who have severe odynophagia prohibiting adequate oral intake, IV hydration may be necessary for a few days. Removal of the cause of injury is self-evident, although this is not always easily achieved. This is particularly true in clinical situations in which there may not be an adequate substitute such as in aspirin prophylaxis for cardiovascular disease, bisphosphonates for severe osteoporosis, or high-dose NSAIDs for pain from chronic inflammatory arthritides. No data address the question of whether rechallenge with a pill that induced prior esophagitis poses higher risk of recurrent injury if the pill is taken with better caution, with the possible exception of bisphosphonates. It is also unclear if patients with a theoretical underlying risk (e.g., esophageal dysmotility) have a greater risk of esophagitis with rechallenge. In the absence of stricture formation or catastrophic presentation, most patients have clinical resolution of symptoms within 2 to 3 weeks, and radiographic resolution has been described in 7 to 10 days.

Because no treatment has been proved effective, it is hoped that proper administration of potentially injurious medications will help avoid occurrence of esophageal injury. On the basis of the sometimes normally slow transit of medications through the esophagus, particularly for gelatin capsules and larger tablets, the following recommendations are made: (1) medications should be swallowed with at least 8 ounces of a clear liquid; (2) patients should remain upright for at least 30 minutes following ingestion of the medication; and (3) in patients with potential underlying increased risk for pill-induced injury (e.g., inability to follow the previous instructions, poor esophageal motility, anatomic compromise of the esophageal lumen), one should search for alternative safer medications or carefully weigh the risks and benefits of this medication against the disease for which this medication is necessary.

Specific Medications

Several broad categories of medication types cause esophageal injury. These include antibiotics, antivirals, NSAIDs, specific antiarrhythmic drugs, vitamins, and miscellaneous isolated drugs from varied categories .

BOX 45.1
Medications Commonly Associated with Esophagitis or Esophageal Injury

  • Antibiotics

    • Clindamycin

    • Doxycycline

    • Penicillin

    • Rifampin

    • Tetracycline

    • Cloxacillin

  • Antiviral agents

    • Nelfinavir

    • Zalcitabine

    • Zidovudine

  • Bisphosphonates

    • Alendronate

    • Etidronate

    • Pamidronate

  • Chemotherapeutic agents

    • Bleomycin

    • Cytarabine

    • Dactinomycin

    • Daunorubicin

    • 5-Fluorouracil

    • Methotrexate

    • Vincristine

    • Crizotinib

  • NSAIDs

    • Aspirin

    • Ibuprofen

    • Naproxen

  • Other medications

    • Ascorbic acid

    • Ferrous sulfate

    • Lansoprazole

    • Multivitamins

    • Potassium chloride

    • Quinidine

    • Theophylline

Antibiotics ( Box 45.1 )

Tetracycline, doxycycline, and their derivatives are by far the most common causes of pill-induced esophagitis, with almost as many cases reported as all other cases combined. Its commonality of injury may be more a reflection of how frequently these drugs are used rather than a strong propensity of tetracycline to produce such injury. This relatively low incidence of esophageal ulceration from tetracycline for all users is suggested by a lack of any cases of esophageal injury seen in a recent survey of 491 Gulf War veterans treated with doxycycline. The mechanism of injury is felt to be corrosive damage, because tetracycline dissolved in water produces a solution with a very low pH. Symptoms may be acute in onset and typically last several days to several weeks. Ulcerations may vary in appearance but are typically small and superficial, may have a “kissing” appearance, are located in the mid-esophagus just above the aortic arch or left mainstem bronchus, and have a burn-like appearance (see Fig. 45.1 ). Stricture formation is uncommon.

Injury from other antibiotics is uncommon and mostly documented in case reports. These include clindamycin, rifampin, ciprofloxacin, penicillins, and cloxacillin but the incidence is still exceedingly low given their common use. If a history is compatible with pill-induced esophageal injury, any antibiotic currently being used should be considered a possible culprit, although rare.

Antiviral agents, particularly those used for treatment of HIV, also have been reported to cause medication-induced esophageal injury. These include zalcitabine, zidovudine, and nelfinavir.

Bisphosphonates

The most rapidly emerging category of medication-induced esophagitis has been those injuries secondary to bisphosphonates used to treat osteoporosis. This class of medications has in fact become the most prevalent cause of medication-induced esophagitis.

To date, injury has been reported mostly with alendronate, but also with etidronate and pamidronate. Although the overall incidence of injury is probably low (<100 cases reported) when considering the millions of patients using the medication, injury can be serious and even fatal. Unfortunately, reflux-type symptoms are common and can be difficult to distinguish from medication-induced mucosal injury. Risedronate has low potential for causing esophageal injury, if at all. Part of this might be explained by the rapid esophageal transit and subsequently minimal contact time of the drug with esophageal mucosa. In 1 study prospectively following 255 patients treated with risedronate and undergoing endoscopy 8 and 15 days later, no patients developed esophageal ulceration. This study also underscored the overall safety of bisphosphonates in general in that only 3 of 260 patients receiving alendronate developed esophageal ulceration.

Diagnosis is best made endoscopically, where marked exudates and inflammation are seen. Biopsies show an intense inflammatory exudate and granulation tissue that may contain polarizable crystals and multinucleated giant cells. Stricture formation occurs in up to one third of patients, and life-threatening hemorrhage, Zenker diverticulitis (due to pill trapping), and esophageal perforation have been reported. Patients who sustain injury are described commonly to take the bisphosphonate not in accordance with directions (i.e., in the upright position with at least 8 ounces of beverage, remaining upright for at least 30 minutes). Still, as with other pill-induced esophagitides, patients taking the medication correctly may sustain esophageal injury. One question frequently answered anecdotally, but not clearly addressed scientifically, is whether patients with a history of GERD should avoid bisphosphonates. Furthermore, if GERD is a risk factor, it is unclear what degree of reflux constitutes risk. The decision should weigh the severity of osteoporosis and risk of fracture against the risk of esophagitis. Patients with GERD that predisposes to stasis, such as those with stricture or severe ineffective esophageal motility, should be particularly cautious.

NSAIDs

NSAIDs are another common cause of pill-induced esophageal injury. Similar to the other common causes of medication-induced esophageal injury, they occur in a small fraction of all NSAID users. Aspirin, naproxen, indomethacin, and ibuprofen account for the majority of cases, but most other NSAIDs have been reported to cause esophageal injury in case reports. Not surprisingly, hemorrhage, which may be severe, is a common complication of these esophageal ulcers, especially when compared with other medication causes of esophagitis. Bronchoesophageal fistula has also been reported. Notably, it is over-the-counter use of NSAIDs that is most commonly associated with injury, in keeping with their more commonly used venue.

In a study of 1122 patients hospitalized for GI bleeding, any dose of aspirin, including a low dose, was associated with increased risk of developing esophagitis. Other studies have also identified NSAIDs in general as a risk factor for erosive esophagitis. Whether the esophagitis in these studies is all directly due to these medications or whether they act synergistically with reflux-induced injury is unclear, although one study has suggested that aspirin makes the esophageal mucosa more sensitive to acid and pepsin.

Other Medications

Potassium chloride (KCl) pills have been associated with esophageal injury. Injury can be severe, as documented by reports of esophageal stricture formation or of perforation into the left atrium, bronchial artery, or mediastinum. Patients who sustain esophageal injury from KCl pills commonly report associated conditions such as cardiac (including left atrial) enlargement or prior cardiac surgery. Whether these processes truly predispose to pill stasis and injury because of extrinsic esophageal compression by the heart or because patients using KCl pills have a high prevalence of cardiac disease is unclear.

Quinidine is another medication with the potential for severe esophagitis. Endoscopically, quinidine may be associated with findings ranging from mild ulceration to a marked inflammatory response with edema suggesting carcinoma. Ferrous sulfate, theophylline, oral contraceptives, ascorbic acid, mycophenolic acid, and multivitamins have caused esophageal ulceration. Numerous other medications have been reported to cause esophageal ulceration in single case reports. Examples include sildenafil, phenytoin, warfarin, glyburide, lansoprazole, valproic acid, chlorazepate, captopril, foscarnet, deferasirox, dabigatran, paracetamol, and throat lozenges.

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