Case 7 -

"Iron Pill Esophagitis" Elizabeth Montgomery, MD Johns Hopkins Medical Institute

Clinical history: Female, 70-year-old, This biopsy was obtained from an area of "esophagitis" with scleroderma. Case 7 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer "Iron Pill Esophagitis" In our patient population, mucosal iron (ferrous sulfate) is found in about 1% of patients undergoing upper tract endoscopic biopsies. Iron is well-recognized for its capacity to cause corrosive injury in the esophagus but in a hospital population, it is not uncommon to find iron associated with an esophageal ulcer or erosion. While it can be argued that such a phenomenon is a result of a prior injury in which an iron tablet becomes embedded, the corrosive and toxic nature of iron itself suggests that the iron pill has caused the injury. Regardless, it is still worth learning to recognize "iron pill esophagitis" as the patient can then be encouraged to ingest the medication in a crushed form with a soft food (such as applesauce or yogurt]. Using Johns Hopkins material, Abraham et al [1] have studied the clinical and histologic features of 36 upper gastrointestinal tract biopsies from 33 patients (24 gastric, 9 esophageal, 1 gastroesophageal junction, and 2 duodenal) containing characteristic brown crystalline iron material, and evaluated the amount and tissue distribution of the iron. They also investigated the prevalence of iron-associated mucosal injury on the endoscopic examinations. The biopsies typically displayed luminal crystalline iron adjacent to the surface epithelium or admixed with luminal fibrinoinflammatory exudates. Most biopsies (83%) showed crystalline iron deposition in the lamina propria, either covered by an intact epithelium, subjacent to small superficial erosions, or admixed with granulation tissue. Three biopsies (8%) demonstrated iron-containing thrombi in mucosal blood vessels. Erosive or ulcerative mucosal injury was present in the majority of biopsies (83%). The amount of iron accumulation in cases with mucosal injury was greater than in cases without mucosal injury. Iron medication (usually ferrous sulfate) was confirmed in 25 of 33 patients (76%). However, as an argument for iron causing injury as a secondary event, half of the patients (17 of 33, 51%) also had underlying infectious, mechanical, toxic, or systemic medical conditions that could have initiated or exacerbated tissue injury. In any biopsy in which there has been injury to the mucosa, reactive fibroblasts can be a component. At times, these can proliferate exuberantly and have atypical (probably hypoxic) features. Pseudoepitheliomatous epithelium may appear in the area of the repairing mucosa. Other Drugs/Agents Known To Cause Mucosal Injury Kayexalate The use of Kayexalate (sodium polystyrene sulfonate) for the management of hyperkalemia was approved for use in the United States in 1975. Kayexalate is a cation-exchange resin that can be instilled into the lower gastrointestinal tract as an enema preparation or into the upper gastrointestinal tract either orally or by nasogastric tube. When administered orally or by nasogastric tube, sodium cations are first released from the resin and exchanged for hydrogen ions in the acidic milieu of the stomach. As the resin passes through the intestines, hydrogen is exchanged for potassium, which is then eliminated in the feces along with the remainder of the altered resin, thereby lowering the serum potassium concentration. In the early use of Kayexalate, the resin was typically administered as a suspension in water. Although generally well tolerated, some patients were reported to develop gastric and bowel opacifications as a result of concretions of crystalline resin. It therefore became increasingly popular to administer Kayexalate in a suspension with hypertonic sorbitol, which reduces the frequency of Kayexalate bezoar formation and colonic impaction by promoting an osmotic diarrhea. In 1987, Lillemoe et al. [2] reported five uremic patients who developed colonic necrosis temporally associated with the use of Kayexalate in sorbitol and contributed to death in four of the five patients. That study also provided experimental evidence implicating sorbitol as the agent responsible for colonic necrosis in a rat model. More recently, it has become apparent that kayexalate can be associated with severe mucosal injury in the upper GI tract as well, and a series of such cases has been reported by Abraham et al [3] . In most instances, kayexalate is easy to recognize in endoscopic biopsies and the clinician can be alerted if there is associated ischemic GI tract disease or erosive lesions. Kayexalate crystals are lightly basophilic on hematoxylin and eosin stain, red on PAS/Alcian blue and acid-fast stains, and blue on Diff-Quik staining. The crystals display a characteristic crystalline mosaic pattern that resembles fish scales and is faintly present in many cases on routine hematoxylin and eosin stain, but is better demonstrated on acid-fast, PAS/Alcian blue, and Diff-Quik stains. It is this mosaic pattern that allows the distinction from between kayalexate crystals and histologically similar cholestyramine crystals. Kayexalate crystals are refractile but not polarizable. Taxol, Colchicine Taxol, an antineoplastic agent with a novel mechanism of action, can be associated with striking mitotic arrest associated with epithelial necrosis and ulceration the esophagus [4] . The mitotic arrest is associated with bundling of intermediate filaments secondary to accumulation of polymerized microtubules. Thus the histologic correlate is the presence of arrested mitoses with ring forms. With taxol, the findings tend to be striking in the esophagus, whereas, in colchicine toxicity, the small bowel is more likely to be severely altered. Fosamax The bisphosphonates (BPs) are a relatively new class of drugs which prevent osteoclast mediated bone reabsorption and have therefore been found effective in the treatment of osteoporosis, Paget's disease and the hypercalcemia of malignancy [5] . Ingestion of alendronate sodium (Fosamax) and related medications by osteoporotic patients has been associated with esophagitis and esophageal ulcer [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18] . Alendronate can damage the esophagus both by toxicity from the medication itself and by nonspecific irritation secondary to contact between the pill and the esophageal mucosa ("pill esophagitis"). Abraham and colleagues reported 10 patients who experienced erosive/ulcerative esophagitis while ingesting alendronate [9] . Biopsies from all patients showed inflammatory exudate and inflamed granulation tissue as characteristic of any ulcer site. Polarizable crystalline foreign material was present in six of 10 biopsies (60%). Multinucleated giant cells within the inflammatory exudate were near the crystalline foreign material in three of 10 biopsies (30%). Adjacent squamous epithelium typically showed active inflammation and a reactive appearance with enlarged, hyperchromatic nuclei. Multinucleated squamous epithelial giant cells were present in two of 10 cases (20%). Microorganisms were unusual; scattered fungi and/or viral inclusions were present in only two of 10 biopsies (20%). The key is that there is no specific histolgic finding, but it is worthwhile to be aware of this complication of such medicines so concern can be relayed appropriately to the clinician. However, it is now known that modifications in dosing schedules of this medication [19] can reduce mucosal injury and it is less likely to be encountered in practice. These agents should be avoided in patients with achalasia and other motility disorders of the esophagus, esophageal stricture or preexisting severe reflux esophagitis. However, patients with reflux disease can probably be treated with a proton pump inhibitor (PPI) and then safely have biphosphonate therapy with continued concomitant use of the PPI. "Thermal Injury" We have occasionally observed a pattern of injury in our biopsy material which we believe may be a reflection of thermal injury (?taking hot beverages after heating them microwave ovens?). Biopsies showing a "thermal injury" pattern display an unaltered basal layer and "mummification" of the superficial squamous epithelium such that there are "ghost" nuclei and the mucosa sloughs. Corrosive Ingestion (e.g. Lye, Bleach) Like the esophageal injury associated with fosamax, corrosive injury does not result in a specific pattern of injury (although saponification may accompany lye ingestion) and cannot be identified directly (like iron or kayexalate). However, it can usually be correlated with an ingestion history in a pediatric patient or a psychiatric setting. Endoscopically, severe ulceration is seen and endoscopists have described a strong bleach-like odor even when the patient has ingested lye. Microscopically, extensive necrosis is found. Those who survive are likely to have severe stricturing disease with all its complications. The key with such patients is that they require lifetime follow-up as they are prone to develop squamous cell carcinoma [20] . References Abraham SC, Yardley JH, Wu TT. Erosive injury to the upper gastrointestinal tract in patients receiving iron medication: an underrecognized entity. Am J Surg Pathol. 1999;23(10):1241-7. 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