Iron Mettle: Unveiling an Unusual Incidental Case Report of Esophageal Ulcer

Abstract

Introduction

Erosive damage to the upper gastrointestinal (GI) tract caused by therapeutic oral iron supplements is relatively uncommon. While such injuries are frequently linked to overdoses of oral iron, they can also occur with doses within the standard therapeutic range. Cases have highlighted GI complications caused by iron, predominantly involving the stomach and sometimes the esophagus. During absorption, iron is initially processed as ferrous iron, which, when bound to proteins, can lead to cellular injury. Additionally, ferric iron exerts a corrosive effect on the GI mucosa and disrupts cellular processes by generating free radicals and triggering lipid peroxidation.

Case Presentation

A 55-year-old female with dysphagia, pain, and anorexia showed linear to circumferential ulcers covered with white slough extensively around central esophagus with thickened and erythematous mucosa with focal erosions on esophagogastroduodenoscopy.

Conclusion

This case highlights a rare case report of iron-induced esophageal ulcer found incidentally and the significance of acknowledging that iron preparations can harm the esophageal mucosa, especially in an Indian population where anemia is fairly predominant.

Introduction

Medication-induced esophageal injury is well-known but relatively uncommon clinical condition, with an annual incidence of 4 per 100,000 population. Studies have reported that erosive mucosal injury from therapeutic iron therapy occurs in approximately 0.7% of gastrointestinal (GI) mucosal biopsies [1, 2]. Esophageal injury caused by standard therapeutic oral iron has a very rare occurrence unlike stomach and duodenum. Literature suggests that approximately 1 in 1,000–1 in 10,000 patients who take iron supplements may experience esophageal injury, though the numbers can vary depending on individual risk factors such as pre-existing GI issues, dosage, and the type of supplement [2].

Patients with esophageal dysmotility, obstruction, or structural abnormalities are at a heightened risk for medication-induced esophagitis. Common culprits include antibiotics, nonsteroidal anti-inflammatory drugs, potassium chloride, quinidine preparations, iron supplements, and bisphosphonates. Symptoms frequently reported are retrosternal chest pain, heartburn, painful swallowing (odynophagia), and difficulty swallowing (dysphagia). Medication-induced esophagitis is thought to result from either disruption of the protective barrier by reducing prostaglandin-mediated production of the mucosal lining in the stomach and esophagus or through direct irritation of the esophageal tissue [2, 3]. In contrast to solid iron tablets, liquid iron formulations have not been associated with esophageal injury, likely due to their reduced concentration on the mucosal surface. Inorganic iron forms a brown-black crystalline layer on the epithelial tissue, resulting in mucosal erosion. Furthermore, iron contributes to thrombosis, which can exacerbate necrosis and inflammation, potentially delaying ulcer healing and leading to the formation of strictures.

Case Presentation

A 55-year-old woman presented with pain during swallowing, difficulty swallowing (dysphagia), and loss of appetite (anorexia). Esophagogastroduodenoscopy revealed linear to circumferential ulcers in the central esophagus, extensively covered with white slough. The mucosa appeared thickened, erythematous and exhibited focal erosions (Fig. 1a, b). There was no stricture, varices, hiatus hernia, or growth. Stomach and duodenum showed normal distensibility with no obvious ulceration or growth. Laboratory parameters were within normal limits. Biopsy was taken from base of the ulcer. Histopathological examination revealed an ulcer showing fibrinopurulent exudate with occasional degenerated epithelial cells, typical of ulcer base. Additionally, orange-ophilic amorphous deposits were observed (Fig. 2a, b). There were no malignant findings or obvious findings of cytomegalovirus inclusions, fungal elements, which were ruled out by periodic acid-Schiff and Grocott’s methenamine silver stain. A strong suspicion of esophageal mucosal damage due to pill was raised. On interrogating the patient, it was found that the patient had been taking iron supplements in the form of 100 mg of iron as ferrous fumarate prescribed twice daily dose for 4 weeks and was relieved of symptoms subsequently.

Fig. 1.

a Esophagogastroduodenoscopy (EGD) showing linear to circumferential ulcers covered extensively with white slough around the central esophagus (b) thickened and erythematous mucosa with focal erosions.

Fig. 2.

Iron-induced esophageal ulceration. a Histopathology: an ulcer showing a fibrinopurulent exudate with occasional degenerated epithelial cells (hematoxylin and eosin. ×40). b Orange-ophilic amorphous deposits (black arrow) within the necro-inflammatory tissue (hematoxylin and eosin. ×40). c Prussian blue staining highlighting presence of iron (Perls Prussian blue. ×400).

Prussian blue staining was done, which confirmed the presence of iron (Fig. 2c). We rendered a diagnosis of iron-induced esophageal ulceration. The patient was advised to discontinue iron tablets and is currently on close follow-up. Repeat esophagogastroduodenoscopy is scheduled subsequently after 1 month.

Discussion

Erosive damage to the upper GI tract caused by therapeutic oral iron supplements is an uncommon phenomenon. While such injuries are more frequently associated with iron overdoses, case studies suggest that localized necrosis can occur due to the direct corrosive effect of crystalline iron, particularly when a single tablet becomes lodged in the esophagus. This is contrasted by the lack of similar injuries with liquid iron supplements, likely due to their rapid clearance from the stomach. The stomach is the most commonly affected site, followed by the duodenum, with the esophagus being rarely involved. The injury resembles a chemical burn and, on biopsy, appears as erosions containing brown-black crystalline material within the ulcer slough. Microscopically, iron appears as brown, granular, or fibrillary crystalline material that is refractile but nonpolarizable under routine hematoxylin and eosin staining. Prussian blue histochemical staining is typically used to confirm the presence of iron, staining it a bright blue. Normally, ferrous (Fe²⁺) iron is absorbed into duodenal enterocytes via the energy-dependent divalent metal transporter-1 (DMT-1). However, at high concentrations, iron can also be absorbed through a concentration-dependent mechanism, explaining the intracellular accumulation of ferric and ferrous ions in the stomach. These ions generate reactive oxygen species and lipid peroxidation, leading to necrosis and inflammation. In cases of iron pill-induced injury, iron is often observed coating the mucosal surface, embedded within granulation tissue in areas of erosion, within glandular lumens, or in the lamina propria, including within microthrombi. These findings are sometimes associated with a giant cell reaction. Mucosal damage from iron tablets can occur at doses as low as one-third of the standard prescription amount, with endoscopic and histological changes detectable within 5 days of initiating therapy. Factors such as the drug formulation, dosage, duration of treatment, preexisting conditions, individual sensitivity, and interactions with other medications can significantly influence the severity of the GI effects [4, 5].

In a study by Kaye et al. [6], it was found that 16.1% of patients using iron supplements had detectable iron on routine hematoxylin and eosin stains of upper GI tract biopsies. Patients with longer durations of iron pill supplementation tend to exhibit more pronounced visual gastric endoscopic abnormalities. To the best of our knowledge, there has not been a single case of iron-induced ulcer in esophagus reported in India even though use of iron medication is prevalent and common for patients with anemia.

The pattern of iron distribution in tissue from iron pill injury differs from that seen in conditions like iron overload or hemochromatosis, where finer intracellular deposits of iron (as hemosiderin) accumulate deeper within the mucosa. To distinguish iron pill effects from other siderotic conditions, Marginean et al. [7] outlined three patterns of gastric iron deposition: the first pattern involves iron accumulation in the stroma and macrophages, typically due to gastric inflammation, ulcerations, or previous hemorrhages and only rarely associated with iron medications. The second pattern shows extracellular iron deposition, which is often linked to the use of iron supplements. The third pattern, glandular siderosis, is associated with iron overload or conditions like portal hypertension and cirrhosis, where portocaval shunting exposes gastric cells to high concentrations of iron [7].

An imperative takeaway is the need to understand that even therapeutic doses of iron supplementation can cause problems and also that oral iron supplements should be kept in differential diagnosis of erosive mucosal disorders affecting upper GI tract, especially in countries like India [8]. A crucial factor in distinguishing drug-induced esophagitis from other causes, such as eosinophilic esophagitis, herpes esophagitis, infectious esophagitis (such as esophageal candidiasis), malignancy, gastroesophageal reflux disease, peptic ulcer disease, achalasia, esophageal motility disorders, and acute necrotizing esophagitis (black esophagus) in the elderly, is the patient’s medication history. Drug-induced esophagitis is a self-limiting disease with a good prognosis following conservative treatment. Esophageal injury from iron supplementation may result from both the direct corrosive effects of the tablet and the systemic impact of iron overload. These factors contribute to tissue damage, with the severity depending on the amount of iron ingested, how the tablet is taken, and individual susceptibility to toxicity. Proper administration can reduce risks [9, 10].

Treatment for iron-induced esophageal injury is similar to other medication-induced injuries: discontinue the medication, and if iron is still necessary for patients who present with severe, albeit rare, symptoms such as hematemesis, dysphagia, melena, or abdominal pain, consider using a liquid or injectable preparation [9, 10].

Conclusion

In summary, esophageal mucosal injury caused by iron pills is a rare but significant complication that is often underrecognized. Individuals with a history of ulcers or esophageal dysmotility may benefit from transitioning to liquid iron supplements to reduce the risk of such injuries. Endoscopy is typically required to describe morphology; however, biopsy is considered the gold standard for evaluating drug-induced esophagitis. Use of special stains can aid in making an accurate diagnosis [9].

All members of the interprofessional team must remain vigilant and collaborate to promptly identify drug-related esophagitis, preventing it from becoming a more serious issue and undermining patient pharmacotherapy due to non-compliance. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000544108).

Statement of Ethics

This study protocol was reviewed and the need for approval was waived by Dr. D.Y. Patil Vidyapeeth Institutional Ethics Committee. A written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors declared no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Funding Sources

The authors received no financial support for the research, authorship, and/or publication of this article.

Author Contributions

Dr. Akshi Raj: conceptualization, data curation, formal analysis, investigation, methodology, validation, writing – original draft, and writing – review and editing; Dr. Mangesh Londhe: validation and review; Dr. Madhuri Singh: data curation, formal analysis, and methodology; Dr. Yogesh Bade and Dr. Charusheela Gore: investigation and discussion; and Dr. (Major) Anuj Sharma: conclusion and references.

Funding Statement

The authors received no financial support for the research, authorship, and/or publication of this article.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.