Esophageal Mucosal Injuries From Drugs, Radiation, and Caustic Agents

Article information

Korean J Helicobacter Up Gastrointest Res. 2025;25(2):126-133

Publication date (electronic) : 2025 June 4

doi : https://doi.org/10.7704/kjhugr.2025.0023

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Corresponding author Younghee Choe, MD Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 56 Dongsu-ro, Bupyeong-gu, Incheon 21431, Korea E-mail: ychoe@catholic.ac.kr

Received 2025 March 27; Revised 2025 May 16; Accepted 2025 May 20.

Abstract

Various factors can lead to esophageal mucosal injury. A thorough patient history is crucial to accurately diagnose esophageal injuries caused by drugs, radiation, and caustic agents. These conditions are often identifiable based on characteristic clinical features, concomitant diseases, and endoscopic findings and do not necessarily require histological confirmation through biopsies. Regardless of the underlying cause, avoiding or minimizing the offending agent is essential for preventing further mucosal damage. In cases where this is unavoidable, such as radiationinduced esophageal injuries, careful adjustment of the radiation dose, field, and frequency is necessary. Additionally, the use of mucosal protective agents and adherence to a soft diet can help regenerate the mucosal epithelium. Esophageal mucosal injuries can cause chronic complications, such as esophageal strictures; therefore, they require close monitoring. Notably, injuries induced by caustic agents carry an increased risk of progression to esophageal cancer, underscoring the importance of long-term surveillance.

Keywords: Caustics; Chemically-induced disorders; Esophagitis; Gastrointestinal endoscopy; Radiation injuries

INTRODUCTION

Esophageal mucosal injuries have a wide range of causes. The most common etiology of esophageal mucosal injury is gastroesophageal reflux or infection. In recent years, eosinophilic esophagitis has emerged as a significant cause of esophagitis, particularly in Western countries. In addition to these causes of esophagitis, various others are known to result in esophageal mucosal injuries, including drug-induced esophagitis, radiation esophagitis, corrosive esophagitis, and esophagitis secondary to systemic diseases. This review focuses on esophageal mucosal injuries caused by drugs, radiation therapy, and caustic agents. These types of esophageal mucosal injuries can often be diagnosed without histological confirmation based on a detailed clinical history and characteristic endoscopic findings. Although drug-induced esophagitis is common, it is frequently underrecognized in clinical practice. Radiation-induced esophagitis inevitably occurs after radiation therapy for esophageal or lung cancers, and many studies have aimed to reduce its frequency or predict its occurrence. Caustic esophagitis is a clinically relevant condition encountered in various settings.

This review aimed to provide a comprehensive discussion of the clinically essential causes of esophageal mucosal injuries, focusing on categorization by etiology. Herein, we discuss the clinical manifestations, pathophysiology, endoscopic findings, and approaches used for the treatment or prevention of each disease.

DRUG OR PILL-INDUCED ESOPHAGEAL MUCOSAL INJURIES

Drug-induced esophageal mucosal injuries occur when a drug is of significant size or remains in the esophageal mucosa for a long time, causing direct (chemical) damage to the esophageal mucosa. After oral administration, the esophagus is the first organ to encounter the ingested drug, making it more directly exposed to certain medications than other parts of the gastrointestinal tract are. Moreover, because many medications are taken in solid form, such as tablets or capsules, the esophageal mucosa is more susceptible to direct physical irritation and injury from prolonged contact with these formulations. Drug-induced esophageal mucosal injuries are not well recognized despite the frequency at which they occur. Furthermore, they can be caused at any time, and even by drugs that have been safely administered for a long period. Common medications associated with esophageal injuries include bisphosphonates, tetracyclines, nonsteroidal anti-inflammatory drugs, potassium supplements, and iron preparations (Table 1). Recently, bisphosphonates, which are used to treat osteoporosis, have been identified as the most common causative drugs [1]. Although alendronate is the most commonly reported, etidronate and pamidronate have also been reported [2,3].

Table 1.

Drugs reported in two or more papers to cause changes in the esophageal mucosa

Pathophysiology

Drug-induced esophageal injury can result from several pathophysiological mechanisms. Certain medications cause direct mucosal damage due to their corrosive properties. Similar to ascorbic acid and bisphosphonates, these medications can damage the esophageal mucosa by generating an acidic solution and promote cell apoptosis by generating an alkaline solution, respectively. Potassium supplements can cause necrosis of mucosal cells by altering the osmotic pressure. Commonly encountered nonsteroidal anti-inflammatory drugs exhibit reduced mucosal protection and direct toxicity through cyclooxygenase-1 inhibition. Studies have reported that aspirin makes the esophageal mucosa more sensitive to acid and pepsin [4]. Tetracyclines are also known to directly damage the mucosa because they are acidic in nature (Table 2) [5,6]. They can also cause indirect injuries through other mechanisms, such as inducing acid reflux.

Table 2.

Mechanisms and drugs that can cause esophageal mucosal injuries

Prolonged contact time, sustained-release formulations, gelatin coating, and capsule-type tablets accelerate mucosal injuries during ingestion, and in some cases, the drug coating ingredients absorb water, swell, and become lodged. In some cases, drug flow may be impeded due to anatomical abnormalities, such as left atrial enlargement or esophageal stricture, and esophageal motility disorders may prevent drug excretion [7]. Drugs may stagnate in areas with typical structures and functions, such as where smooth and skeletal muscles overlap, or in areas with external compression, such as the aorta or left bronchus; however, the possibility of drug-induced esophageal mucosal injuries exists in any location. They can also occur when a drug is swallowed without sufficient water or taken immediately before going to bed.

Clinical manifestations and diagnosis

The most common symptoms include chest pain and dysphagia [8]. In some cases, pain occurs even after drinking water, and in others, it is expressed as heartburn. In cases occurring after chemotherapy, oral and oropharyngeal mucositis is usually accompanied by severe dysphagia. Severe dysphagia has been reported in the case of vincristine [9,10].

Diagnosis can be made when an ulcer or erosion in the form of a kissing ulcer is observed during esophagogastroduodenoscopy (EGD), along with a history of drug use (Fig. 1) [11,12]. It can also observed in the form of esophageal epithelium sloughing and occurs more frequently in the elderly, those taking many other drugs simultaneously, and those taking psychoactive agents [13-15]. Drug-induced mucosal injuries can also be estimated via double-contrast radiography or esophagography, but the results are not as accurate as those obtained through EGD. Endoscopically, prominent exudate and inflammation can be observed, and in cases where drug-induced esophageal mucosal injuries are advanced, bleeding, esophageal ulceration, and stricture may occur [16]. In severe cases, these injuries may resemble esophageal cancer [17]. Rarely, complications that include esophageal perforation or esophagobronchial fistula may occur [18].

Fig. 1.

Endoscopic findings of drug-induced esophageal mucosal injuries. A: A 64-year-old male with rectal cancer who had discontinued FOLFOX chemotherapy due to severe neuropathy underwent esophagogastroduodenoscopy (EGD), revealing sloughing esophagitis. The patient reported only mild odynophagia. B: A 72-year-old female with dysphagia underwent EGD. She had been taking multiple medications for underlying conditions, including hypertension, diabetes, cardiovascular disease, and arthritis.

Treatment and prevention

The primary approach to managing drug-induced esophageal mucosal injuries involves discontinuing the offending agent or switching to an alternative formulation. Acid-suppressive therapy, such as the use of proton pump inhibitors and mucosal protective agents, may aid in symptom relief and mucosal healing. In cases of severe esophageal ulceration with active oozing, oral intake may need to be temporarily restricted, and parenteral nutrition may be required for several days. If complications, such as stricture, occur after ulcer healing, endoscopic dilatation may be considered.

Preventive strategies include taking medications with at least 200 mL water and avoiding their intake immediately before bedtime. Maintaining an upright position for at least 30 min after drug administration is recommended.

RADIATION-INDUCED ESOPHAGEAL MUCOSAL INJURIES

Radiation-induced esophageal mucosal injuries usually occur after radiation therapy for esophageal, gastroesophageal junction, and lung cancers. The risk of radiation-related adverse effects increases with exposure to higher radiation doses and larger treatment fields [19,20]. Preexisting comorbidities are also significant risk factors for the development of radiation-induced mucosal injuries. As the gastrointestinal tract is a continuously functioning organ system, there are inherent limitations to the maximum radiation dose that can be tolerated. Excessive radiation in a localized area can lead to functional impairment of the entire organ due to its integrated physiological activity.

Pathophysiology

Radiation therapy generates free radicals that cause DNA double-strand breaks in esophageal mucosal cells, leading to cell death (apoptosis) and inflammation [21]. The rate of apoptosis is dose-dependent and increases with higher radiation exposure. Radiation also upregulates the expression of p53 in epithelial cells. It activates a cascade of cytokines, including transforming growth factor-beta, contributing to the inflam-matory response [22]. In the acute phase, mucosal edema and erosion occur, whereafter the epithelium becomes thin and falls off.

Vascular endothelial injury contributes to tissue ischemia, further promoting fibrotic changes [21,23]. In addition to chronic inflammatory conditions, such as diabetes, lifestyle-related factors— notably tobacco use and alcohol consumption—can exacerbate chronic mucosal irritation and significantly increase the risk of progressive esophageal fibrosis [24-26]. It may take 3–24 months for the epithelium to fully recover from the effects of radiation [27,28].

Clinical manifestations and diagnosis

Symptoms usually include odynophagia, dysphagia, and retrosternal chest pain. When radiation therapy is administered concurrently with chemotherapy, the toxic effects can be amplified, which significantly increases the incidence and severity of esophageal mucosal injuries [29,30]. In addition, hyperfractionation, which involves dividing radiation therapy into two or more doses per day, also increases treatment-related toxicity. Dysphagia usually occurs due to stricture and may be accompanied by changes in motility due to fibrosis or motility changes and neural damage. Abnormal peristalsis is typically reported 1–3 months after the completion of treatment, and stricture can occur 4–8 months later. Endoscopic findings vary and include erythema, erosion, mucosal sloughing, and ulceration (Table 3) [31]. Several key features, such as congested mucosa, telangiectasia, ulceration, stricture, and necrosis, are used in scoring systems to assess late mucosal damage caused by radiation therapy (Fig. 2) [32].

Table 3.

Progress of esophageal mucosal injuries over time after radiation therapy

Fig. 2.

Endoscopic findings of radiation-induced esophageal mucosal injuries. A 72-year-old female with esophageal squamous cell carcinoma (cT2–3N1) underwent esophagogastroduodenoscopy due to severe chest pain following neoadjuvant concurrent chemoradiotherapy (45 Gy over five weeks). A: Edema, erythema, and erosions were observed throughout the esophagus. B: Tumor size had decreased; however, ulcers, ulcer scars, and friable mucosa were noted around the lesion.

Treatment and prevention

The initial management of radiation-induced esophagitis includes pain control with oral analgesics or topical anesthetics, acid suppression using proton pump inhibitors, and the use of prokinetic agents to enhance esophageal motility. If coexisting infections, such as esophageal candidiasis, are present, concurrent treatment is advisable. Dietary modifications also play a key role in symptom management. Patients are advised to avoid irritating foods and consume soft or pureed diets. Avoiding smoking, alcohol, coffee, carbonated beverages, acidic foods, and high-fat meals is recommended. Nutritional support using high-calorie supplements may be beneficial [33]. Moreover, liquids at room temperature are generally better tolerated than extremely hot or cold foods are. Tube feeding or parenteral nutrition may be required in severe cases of dysphagia. If esophagitis progresses to a severe or refractory state, modification or discontinuation of cancer therapy may need to be considered [34]. When esophageal strictures develop, endoscopic dilation using bougies or balloon catheters can be attempted. Esophageal stenting or surgical intervention may be required in patients with perforations or esophagobronchial fistulas.

In a study conducted in patients with lung cancer, accelerated radiotherapy was associated with a lower incidence of acute esophageal mucosal injuries than concomitant chemoradiotherapy was. Notably, the two significant predictors of acute esophageal mucosal injuries were the volume of the esophagus receiving >38 Gy and the mean esophageal dose [35].

The maximum radiation dose or intensity of fractionated radiotherapy with an acceptably low risk of complications is called the tolerance dose (TD) [36,37]. The TD5/5, the dose that can cause a 5% risk of severe adverse effects within five years after radiotherapy, is estimated to be 60 Gy when one-third of the length of the esophagus is irradiated [38]. Maintaining the cumulative average dose to the esophagus below 34 Gy is recommended, as well as to limit the treated portion of the esophagus to ≤60 Gy [19,39].

Radioprotective agents have also been investigated as potential preventive strategies. Oral glutamine supplementation has been associated with a lower incidence of radiation-induced esophagitis in several studies [40,41]. Additionally, compounds such as soy isoflavones, which possess radioprotective effects, have been studied for their potential benefits in this setting [42].

CAUSTIC AGENT-INDUCED ESOPHAGEAL MUCOSAL INJURIES

Caustic esophagitis occurs after the ingestion of acidic or alkaline substances, which can cause acute or chronic injury to the esophagus and other parts of the gastrointestinal tract. These substances are often accidentally ingested by children and used for suicide or mental health reasons in adults. Alkaline substances include detergents and bleach, which contain sodium or potassium hydroxide. They are usually tasteless and odorless; therefore, the accidental ingestion of large quantities poses a potential risk.

Pathophysiology

The degree of damage varies depending on the substance and amount ingested, as well as the length of time in which the gastrointestinal tract is exposed. In the acute phase, a risk of mucosal necrosis, ulceration, and perforation exists, whereas stricture and esophageal cancer can occur in the chronic phrase.

The esophagus is most affected by alkaline ingestion. Ingestion of alkaline substances quickly causes liquefactive necrosis, which can penetrate deep into the mucosa and damage the muscle layer. Vascular thrombosis can occur after necrosis [43]. In the acute setting, transmural necrosis can lead to life-threatening complications, such as perforation, mediastinitis, or peritonitis, particularly within 24–72 h after ingestion. Perforation usually occurs within 24–72 h. Subsequently, ulceration, extensive granulation tissue, fibroblast activity, and collagen deposition can occur within 14–21 days, and chronic stricture can occur over several weeks to years.

In contrast, acidic substances cause coagulative necrosis, which further damages the surface layer when ingested. Acidic agents are more likely to damage the stomach than the esophagus. Acidic agents tend to be consumed in smaller amounts than alkaline agents are because they usually have unpleasant tastes, cause immediate pain, and tend to cause less overall damage than alkaline agents do [44].

Clinical manifestations and diagnosis

Affected individuals typically complain of oropharyngeal, chest, and upper abdominal pain, as well as dysphagia. If the oropharynx is damaged, drooling may occur; if the larynx or upper respiratory tract are damaged, hoarseness, stridor, and dyspnea may occur. In addition, if chest or back pain is persistent, esophageal perforation or mediastinitis may occur, and severe abdominal pain could indicate gastric perforation and peritonitis. When such perforation occurs, chest or abdominal X-ray images can be used to confirm this; however, the results are typically not helpful. If perforation is suspected, computed tomography of the chest, abdomen, or neck should be performed; if perforation is confirmed, emergency surgery rather than EGD is necessary.

However, in most cases, EGD is performed within 24–48 h after caustic ingestion to assess the extent of esophageal mucosal injuries (Fig. 3) [45,46]. The degree of mucosal injuries observed in the endoscopic findings can be graded, which can be used to predict the prognosis (Table 4) [44]. Grades 1 and 2A can be cured without sequelae, but grades 2B and higher cause esophageal stricture, and grade 3 is associated with necrosis. Grade 4 with perforation significantly increases the mortality rate [44,47].

Fig. 3.

Endoscopic findings of esophageal mucosal injuries from caustic agents. A: Zagar Grade 1: a 42-year-old asymptomatic male presented after alkali ingestion. Esophagogastroduodenoscopy (EGD) revealed mild mucosal edema and erythema. B: Zargar Grade 2A: a 20-yearold female underwent EGD immediately after acid ingestion, which revealed friability, hemorrhages, and erosions. C: Zargar Grade 2B–3A: a 57-year-old male presented to the emergency room after ingesting 10% hydrochloric acid in a suicide attempt. EGD showed multiple ulcers and areas of necrosis. D: Zargar Grade 3B: gastric findings from EGD following ingestion of a large volume of acid revealed extensive mucosal necrosis.

Table 4.

Common classification of caustic-induced gastrointestinal injuries and prognoses

Treatment and prevention

Initial management should focus on airway protection, breathing, and circulation, particularly on significant oropharyngeal and respiratory tract involvement. In Grade 1 or 2A injuries, the use of neutralizing agents, such as sodium bicarbonate or activated charcoal, is contraindicated, as they may exacerbate tissue injury through exothermic reactions. In mild cases, patients may begin with a nothing-by-mouth status and gradually reintroduce oral intake once symptoms improve. In more severe injuries, prolonged fasting and parenteral nutrition may be required to allow mucosal healing. The role of corticosteroids in preventing stricture formation remains controversial, and current evidence does not support their routine use. If esophageal strictures develop, endoscopic dilation can be an effective therapeutic option [48,49]. Caustic esophageal mucosal injuries increase the risk of esophageal cancer; therefore, lifelong surveillance is recommended for patients with a history of severe injury.

CONCLUSION

The esophagus, which is first encountered during EGD, is susceptible to mucosal injuries of various etiologies. Due to its relatively thin mucosal layer and proximity to vital mediastinal structures, even minor injuries can have significant clinical consequences. Herein, we discussed drug-, radiation-, and caustic agent-induced esophageal mucosal injuries, which are clinically important but not well recognized. Unlike infiltrative esophagitis due to chronic disease, a biopsy is not necessarily required, and medical history and endoscopic findings are important for assessing the current status and prognosis. All three types of esophageal mucosal injuries have different causes; however, endoscopic findings can lead to erythema, erosion, ulceration, and even stricture or perforation. In severe cases, fasting for several days or endoscopic treatment may be necessary, and understanding how to prevent this would be useful.

Distinguishing the causes of esophageal mucosal injuries frequently encountered during EGD is essential. Notably, esophageal mucosal injuries may be complex and not result from a single cause. The most important aspect is to clearly understand the clinical features and concomitant diseases of patients through a detailed medical history. This approach would enable a more accurate identification of the underlying type of esophagitis involved, facilitate appropriate management strategies, and help improve the quality of life while reducing the risk of chronic complications.

Notes

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.

Conflicts of Interest

Younghee Choe, a contributing editor of the Korean Journal of Helicobacter and Upper Gastrointestinal Research, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.

Funding Statement

None

Acknowledgements

The authors thank Professor Jin Lee of Inje University for his assistance with this paper.

Authors’ Contribution

Conceptualization: Younghee Choe. Data curation: Hyung Jin Bae, Younghee Choe. Investigation: Hyung Jin Bae, Younghee Choe. Project administration: Younghee Choe. Resources: Hyung Jin Bae, Younghee Choe. Supervision: Younghee Choe. Visualization: Younghee Choe. Writing— original draft: Hyung Jin Bae, Younghee Choe. Writing—review & editing: Hyung Jin Bae, Younghee Choe. Approval of final manuscript: all authors.

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Pharmacologic class	Drugs cited in literature
Antibiotics	Amoxicillin, ciprofloxacin, clindamycin, metronidazole, tetracyclines (e.g., doxycycline)
Bisphosphonates	Alendronate, etidronate, pamidronate
Chemotherapeutic agents	Bleomycin, cytarabine, dactinomycin, 5-fluorouracil, methotrexate, vincristine
NSAIDs	Aspirin, ibuprofen, indomethacin, naproxen
Psychoactive agents	SNRIs, SSRIs
Other medications	Acetaminophen, ascorbic acid, ferrous sulfate, phenytoin, potassium chloride, quinidine

Mechanisms	Drugs
Acidic solution production	Ascorbic acid, ferrous sulfate
Alkaline solution production	Bisphosphonates (e.g., alendronate)
Hyperosmotic solution production	Potassium chloride
Direct drug toxicity	Tetracyclines (e.g., doxycycline), NSAIDs

Time after radiation	Pathophysiology	Clinical features	Endoscopic findings
Immediately to 2 weeks	Free radical generation, DNA damage, cytokine release (e.g., TGF-β), p53 activation	Mild odynophagia, retrosternal pain	Erythema, mild edema
2–6 weeks	Apoptosis, inflammation, epithelial sloughing	Odynophagia, dysphagia, chest pain	Mucosal sloughing, erosions, superficial ulcers
1–3 months	Fibroblast activation, early submucosal fibrosis	Worsening dysphagia, abnormal motility	Ulceration, beginning stricture formation
4–8 months	Chronic fibrosis, ischemic damage, neural injury	Progressive dysphagia (stricture predominant)	Strictures, deep ulcers, telangiectasia
>8 months	Late complications, possible necrosis/fistula	Refractory dysphagia, rare fistula symptoms	Necrosis, severe strictures, esophagobronchial fistula (rare)

Grade	Prognosis	Prognosis
0	Normal	Complete recovery
1	Edema and erythema	Complete recovery
2A	Friability, hemorrhage, and superficial ulcerations	Stricture unlikely
2B	Deep ulcerations (either discrete or circumferential), in addition to friability, hemorrhage, and superficial ulcerations	High risk of stricture, low risk of perforation
3A	Small, scattered areas of necrosis	High risk of stricture, greater risk of perforation than with grade 2B injury
3B	Extensive necrosis	High risk of perforation and strictures
4	Perforation	Often fatal