Rodger C. Haggitt Slide Seminar: Lesions of Esophagus, Stomach, and Duodenum
Moderators: Dr. Cecilia Fenoglio-Preiser and Dr. Wendy Frankel
Case 7 -
"Iron Pill Esophagitis"
Elizabeth Montgomery, MD
Johns Hopkins Medical Institute
Female, 70-year-old, This biopsy was obtained from an area of "esophagitis" with scleroderma.
Case 7 - Slide 1
"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  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
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
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.  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
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  . 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, an antineoplastic agent with a novel mechanism of action, can be associated with striking
mitotic arrest associated with epithelial necrosis and ulceration the esophagus  . 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.
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  .
Ingestion of alendronate sodium (Fosamax) and related medications by osteoporotic patients has been
associated with esophagitis and esophageal ulcer
. 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  . 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 
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.
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  .
- 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.
- Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery. 1987;101(3):267-72.
- Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT. Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings. Am J Surg Pathol. 2001;25(5):637-44.
- Hruban RH, Yardley JH, Donehower RC, Boitnott JK. Taxol toxicity. Epithelial necrosis in the gastrointestinal tract associated with polymerized microtubule accumulation and mitotic arrest. Cancer. 1989;63(10):1944-50.
- Lanza F. Bisphosphonate mucosal injury--the end of the story? Dig Liver Dis. 2003;35(2):67-70.
- Peter CP, Handt LK, Smith SM. Esophageal irritation due to alendronate sodium tablets: possible mechanisms. Dig Dis Sci. 1998;43(9):1998-2002.
- Wallace JL. Upper gastrointestinal ulceration with alendronate. Dig Dis Sci. 1999;44(2):311-3.
- Dobrucali A, Tobey NA, Awayda MS, et al. Physiological and morphological effects of alendronate on rabbit esophageal epithelium. Am J Physiol Gastrointest Liver Physiol. 2002;283(3):G576-86.
- Abraham SC, Cruz-Correa M, Lee LA, Yardley JH, Wu TT. Alendronate-associated esophageal injury: pathologic and endoscopic features. Mod Pathol. 1999;12(12):1152-7.
- Bauer DC, Black D, Ensrud K, et al. Upper gastrointestinal tract safety profile of alendronate: the fracture intervention trial. Arch Intern Med. 2000;160(4):517-25.
- Lowe CE, Depew WT, Vanner SJ, Paterson WG, Meddings JB. Upper gastrointestinal toxicity of alendronate. Am J Gastroenterol. 2000;95(3):634-40.
- Lanza FL, Hunt RH, Thomson AB, Provenza JM, Blank MA. Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women. Gastroenterology. 2000;119(3):631-8.
- Graham DY, Malaty HM. Alendronate and naproxen are synergistic for development of gastric ulcers. Arch Intern Med. 2001;161(1):107-10.
- Sharpe M, Noble S, Spencer CM. Alendronate: an update of its use in osteoporosis. Drugs. 2001;61(7):999-1039.
- Levine J, Nelson D. Esophageal stricture associated with alendronate therapy. Am J Med. 1997;102(5):489-91.
- Colina RE, Smith M, Kikendall JW, Wong RK. A new probable increasing cause of esophageal ulceration: alendronate. Am J Gastroenterol. 1997;92(4):704-6.
- de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med. 1996;335(14):1016-21.
- Graham DY, Malaty HM. Alendronate gastric ulcers. Aliment Pharmacol Ther. 1999;13(4):515-9.
- Lanza F, Sahba B, Schwartz H, et al. The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study. Am J Gastroenterol. 2002;97(1):58-64.
- Csikos M, Horvath O, Petri A, Petri I, Imre J. Late malignant transformation of chronic corrosive oesophageal strictures. Langenbecks Arch Chir. 1985;365(4):231-8.