Bisphosphonate-induced Esophagitis Dissecans Superficialis: A Rare Case Report

Abstract

Esophagitis dissecans superficialis (EDS), also referred to as “sloughing esophagitis,” is an uncommon benign condition characterized by the desquamation of the superficial layer of the esophageal squamous mucosa. It is often underdiagnosed due to its rarity and nonspecific clinical presentation. Although several factors such as caustic ingestion, thermal injury, autoimmune disorders, and mechanical trauma have been implicated, medication-induced mucosal injury remains one of the most significant causes. Among these, bisphosphonates – a class of drugs widely prescribed for osteoporosis and other bone-related disorders – have been identified as a potential offending agent. We report the case of a 66-year-old woman with no significant comorbidities who presented with persistent retrosternal burning and pain for 2 months. There was no associated dysphagia, odynophagia, vomiting, hematemesis, weight loss, or history of nonsteroidal anti-inflammatory drug use. Physical and systemic examinations were unremarkable. Despite treatment with double-dose esomeprazole for 8 weeks, her symptoms persisted. Upper gastrointestinal endoscopy revealed a large area of whitish sloughed-off mucosa overlying a superficial ulcer with regular margins, extending from 26 cm to just above the gastroesophageal junction. A detailed drug history subsequently revealed the use of bisphosphonate gel for osteoporosis. Histopathological analysis demonstrated sloughed squamous epithelium with the features of superficial mucosal necrosis, confirming the diagnosis of EDS secondary to bisphosphonate-induced chemical injury. Discontinuation of the bisphosphonate and continuation of proton-pump inhibitor therapy led to complete symptom resolution within 2 weeks. This case underscores the importance of considering drug-induced esophageal injury in patients with refractory retrosternal pain unresponsive to acid suppression therapy. Bisphosphonates, although highly effective in osteoporosis management, may cause significant mucosal damage when not used properly. Clinicians should maintain a high index of suspicion for bisphosphonate-induced EDS, as timely recognition and withdrawal of the offending agent usually result in rapid clinical and endoscopic improvement.

INTRODUCTION

Esophagitis dissecans superficialis (EDS) is a rare, benign, desquamative disorder of the esophagus that is characterized by sloughing and shedding of the superficial squamous mucosal layer into the esophageal lumen. Although first described decades ago, it remains an under-recognized entity, largely due to its infrequent occurrence and nonspecific presentation. The true incidence of EDS is not well established; however, studies suggest it accounts for <0.03% of all upper gastrointestinal (UGI) endoscopies.[1,2]

Clinically, EDS can present with a wide range of manifestations – from being completely asymptomatic to causing symptoms such as retrosternal discomfort, odynophagia, dysphagia, or upper abdominal pain. In some cases, patients may even vomit whitish mucosal casts that resemble esophageal tissue. The nonspecific nature of these symptoms often leads to misdiagnosis or delayed diagnosis, especially in cases where more common conditions like gastroesophageal reflux disease (GERD) or peptic ulcer disease are suspected.[3,4]

The etiology of EDS is multifactorial. It may occur idiopathically or as a result of chemical, thermal, or mechanical mucosal injury. Commonly implicated agents include medications such as bisphosphonates, potassium chloride, nonsteroidal anti-inflammatory drugs (NSAIDs), iron supplements, and psychoactive drugs. Other associated factors include caustic ingestion, autoimmune blistering diseases (such as pemphigus vulgaris), celiac disease, and prolonged mucosal irritation due to reflux or infections.[5,6]

Bisphosphonates, in particular, are well-documented to cause esophageal irritation and ulceration due to their caustic properties. These drugs, often prescribed for osteoporosis and metastatic bone disease, can cause localized mucosal injury when they come into prolonged contact with the esophageal lining, especially if not swallowed with adequate water or when used in topical or gel formulations. The pathophysiology involves direct chemical injury leading to necrosis of the superficial epithelial layer, resulting in sloughing and ulcer formation.[7,8]

Endoscopically, EDS is characterized by the presence of long, whitish, or grayish sloughed mucosal sheets lining the esophagus, often overlying a hyperemic or ulcerated mucosa. Histologically, it shows separation of the superficial epithelium from the underlying viable mucosa, without significant inflammatory infiltration or dysplasia.

Given its self-limiting nature, EDS often resolves spontaneously once the offending agent is discontinued. However, its recognition is important to prevent unnecessary invasive procedures or prolonged use of inappropriate medications. Here, we present a case of bisphosphonate-induced EDS in an elderly woman who presented with persistent retrosternal pain, emphasizing the need for careful drug history and awareness of this rare but significant adverse drug effect.

CASE REPORT

A 66-year-old postmenopausal woman presented to the outpatient department with complaints of retrosternal burning sensation and intermittent dull pain in the central chest region for the past 2 months. The pain was described as nonradiating, moderate in intensity, and not related to meals or posture. There was no history of dysphagia, odynophagia, vomiting, hematemesis, regurgitation, or heartburn prior to this episode. She denied any history of weight loss, anorexia, or melena. The patient had no known history of diabetes mellitus, hypertension, ischemic heart disease, or chronic liver or kidney disease.

She reported no history of chronic medication use, alcohol intake, or tobacco consumption. There was no history suggestive of reflux symptoms or any prior gastrointestinal disorder. Importantly, she denied taking any NSAIDs, corticosteroids, or potassium supplements. There was no history of caustic ingestion or radiation exposure.

On general physical examination, she was afebrile, with stable vital parameters. Her nutritional status was adequate, and no signs of anemia, dehydration, or systemic illness were present. Systemic examination of the cardiovascular, respiratory, and abdominal systems was unremarkable.

A clinical diagnosis of refractory GERD or nonulcer dyspepsia was initially considered. She was started on a double-dose proton-pump inhibitor (esomeprazole 40 mg twice daily) for 8 weeks, along with dietary modifications and lifestyle advice. Despite strict adherence to the prescribed regimen, the patient reported no significant improvement in her symptoms.

Due to persistence of pain, she was referred for an UGI endoscopy. Endoscopic evaluation revealed a striking finding [Figure 1] – a large segment of whitish, thick sloughed-off mucosal sheets extending longitudinally along the lower esophagus, with an underlying superficial ulceration exhibiting regular margins and a smooth base. The lesion began approximately 26 cm from the upper incisors and extended distally up to just above the gastroesophageal (GE) junction. There was mild surrounding mucosal erythema but no evidence of nodularity, strictures, or mass lesions. The stomach and duodenal mucosa appeared normal. The endoscopic appearance was suggestive of sloughing esophagitis or EDS.

Figure 1.

Upper gastrointestinal endoscopy

Biopsy specimens were obtained from the affected region, including both the sloughed mucosa and the ulcer base, for histopathological examination. Meanwhile, a detailed review of the patient’s medical history was undertaken to identify the possible etiological factors. On careful re-evaluation, the patient revealed that she had been applying a topical bisphosphonate gel preparation on her gums and oral mucosa for the management of osteoporosis-related dental sensitivity over the past 3 months. She had not previously disclosed this detail, as she considered the gel a “local vitamin preparation” and not a medication relevant to her esophageal symptoms.

Histopathological examination [Figure 2] of the biopsy revealed the fragments of necrotic squamous epithelium with surface sloughing, acantholysis, and separation of the superficial epithelial layer from the underlying mucosa. The lamina propria showed minimal inflammatory infiltrate without evidence of fungal elements, viral cytopathic changes, or malignancy. These features were consistent with EDS, likely secondary to chemical injury from bisphosphonate exposure.

Figure 2.

Histopathology. The arrow revealed the the fragments of necrotic squamous epithelium with surface sloughing, acantholysis, and separation of the superficial epithelial layer from the underlying mucosa. The magnification value was low to intermediate that 40x to 100x

Following the histopathological confirmation, the bisphosphonate gel was immediately discontinued. The patient was advised to continue once-daily esomeprazole (40 mg) and avoid any chemical or topical oral preparations. She was counseled about adequate hydration and proper medication administration techniques.

On follow-up after 2 weeks, the patient reported the complete resolution of retrosternal pain and burning. A repeat endoscopic examination was not deemed necessary given the complete symptomatic relief. The patient remained asymptomatic on subsequent monthly follow-ups for 3 months.

This clinical course, characterized by a strong temporal association between bisphosphonate use and symptom onset, endoscopic evidence of sloughed mucosa, and complete recovery upon discontinuation, confirmed the diagnosis of bisphosphonate-induced EDS.

DISCUSSION

EDS, also known as “sloughing esophagitis,” is a rare, benign condition characterized by the desquamation of the superficial layer of the esophageal squamous epithelium. Although the condition is uncommon, with a reported prevalence of <0.03% in endoscopic series,[1] it is likely underdiagnosed due to its nonspecific presentation and spontaneous resolution in many patients. EDS is usually identified incidentally during UGI endoscopy performed for unrelated complaints.

The exact pathogenesis of EDS remains unclear; however, mucosal injury due to chemical or mechanical insult is thought to play a central role. Various drugs have been implicated, including bisphosphonates, potassium chloride, NSAIDs, iron supplements, and certain psychoactive medications such as sertraline and methotrexate.[2,3] Other causative factors include ingestion of caustic substances, hot beverages, thermal injury, and autoimmune conditions such as pemphigus vulgaris and bullous pemphigoid.

Bisphosphonates, particularly alendronate and risedronate, are well known to cause esophageal irritation and ulceration. Their mechanism of injury involves direct mucosal toxicity due to the compound’s acidic pH and chelating properties. Bisphosphonates can adhere to the esophageal mucosa and, upon dissolution, cause localized chemical burns and necrosis of epithelial cells.[4,5] The resulting epithelial sloughing corresponds histologically to the characteristic findings of EDS – detachment of the superficial squamous layer from the basal zone with minimal inflammatory response. The risk of esophageal injury is significantly increased with improper administration (e.g., inadequate water intake, lying down soon after ingestion, or, as in this case, topical contact with mucosa through a gel formulation).

Clinically, EDS presents with a broad spectrum of symptoms ranging from mild retrosternal discomfort and heartburn to odynophagia, dysphagia, or even vomiting of esophageal casts.[6] In many cases, however, patients remain asymptomatic. Because symptoms overlap with more common conditions such as GERD, esophageal candidiasis, or peptic ulcer disease, diagnosis is often delayed or missed.

Endoscopic appearance is diagnostic in most cases. The hallmark feature is sloughed, whitish, or grayish mucosal sheets, often described as “membranous” lesions that can be peeled off, leaving behind a smooth or mildly erythematous surface. In severe cases, the mucosa may appear ulcerated or friable. In this patient, endoscopy revealed an extensive segment of sloughed mucosa with underlying superficial ulceration extending up to the gastroesophageal junction, consistent with the classical description of EDS.

Histopathological examination confirms the diagnosis and distinguishes EDS from other forms of esophagitis. The typical features include detachment of the superficial squamous epithelium, acantholysis, necrosis, and minimal inflammatory infiltrate in the lamina propria.[7] In this case, biopsy demonstrated necrotic sloughed squamous cells with minimal inflammation, ruling out infectious, reflux, or neoplastic causes.

Differential diagnosis

The differential diagnosis of EDS includes the several other causes of esophageal mucosal injury:

Pill-induced esophagitis

Commonly caused by tetracyclines, potassium chloride, or NSAIDs, pill esophagitis usually presents with discrete ulcers rather than diffuse mucosal sloughing.

Infectious esophagitis

Candida, cytomegalovirus, and herpes simplex virus infections produce characteristic endoscopic and histological findings, including pseudomembranes, viral inclusions, or fungal hyphae, none of which were present in this case.

Corrosive or caustic ingestion

Typically presents with circumferential deep ulceration and fibrosis, often associated with stricture formation.

Autoimmune bullous disorders

Diseases such as pemphigus vulgaris and bullous pemphigoid can cause esophageal desquamation but are usually associated with cutaneous or oral lesions and positive immunofluorescence findings.[8]

Management and prognosis

The treatment of EDS primarily involves the identification and removal of the inciting factor. In drug-induced cases, discontinuation of the offending agent leads to rapid symptom resolution, as observed in this patient. Supportive management with proton pump inhibitors aids mucosal healing and provides symptomatic relief.[9] Corticosteroids or immunosuppressive agents are reserved for autoimmune-associated cases.

The prognosis of EDS is excellent. Most cases resolve completely without complications once the causative agent is withdrawn. Recurrence is rare unless re-exposure occurs. In our patient, cessation of bisphosphonate gel use led to the complete symptom relief within 2 weeks, confirming the causal association.

Review of literature

Several reports in the literature have described bisphosphonate-induced esophageal injury, but cases presenting specifically as EDS are rare. Purdy and Appelman[10] first described the condition as a distinct endoscopic and histologic entity. Carmack et al.,[1] in their analysis of 21 cases, noted that approximately one-third was associated with medication use, with bisphosphonates being one of the most common culprits. A more recent review by Ebigbo et al.[11] reiterated that bisphosphonate-induced EDS tends to occur in elderly women using oral or topical preparations and typically resolves with drug discontinuation and acid suppression therapy.

Our case adds to this growing body of evidence, emphasizing that not only oral ingestion but even topical bisphosphonate preparations can lead to mucosal injury through inadvertent esophageal exposure. Awareness of such atypical presentations is crucial to prevent misdiagnosis and unnecessary invasive procedures.

CONCLUSION

This case highlights the importance of a detailed medication history in all patients presenting with refractory retrosternal pain or atypical endoscopic findings. Bisphosphonate-induced EDS, although uncommon, should be considered in the differential diagnosis of esophageal ulceration, particularly in elderly women on osteoporosis therapy. Early recognition and prompt discontinuation of the offending agent can lead to complete recovery and prevent recurrence.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.