Drug-Induced Esophagitis

Etiology

There are reports of more than 30 medications as a cause of drug-induced esophagitis.[4] More commonly reported drugs as a cause of drug-induced esophagitis are listed below. Still, it may also be true that any medication can cause drug-induced esophagitis as the mechanism of injury also takes certain other patient-related factors such as inadequate water intake and recumbent position while taking pills.[1][2] Other patient-related factors include reduced saliva production, which may be due to the ingestion of anticholinergics or other diseases such as Sjogren syndrome etc. Rarely, drug-induced esophagitis can occur due to an anatomical factor or underlying esophageal disorder, for example, undiagnosed vascular ring, scleroderma, etc.

• Antibiotics: One of the most common causes of drug-induced esophagitis. These include tetracyclines, especially doxycycline. Other antibiotics that can cause esophagitis include clindamycin, amoxicillin, metronidazole, ciprofloxacin, rifaximin, etc.
• Non-steroidal anti-inflammatory drugs (NSAIDs): aspirin and aceclofenac can lead to esophageal mucosal injury[3].
• Bisphosphonates: alendronate, ibandronate. Risedronate seems to be slightly safer than alendronate in terms of gastrointestinal side effects[5].
• Ascorbic acid
• Potassium chloride and ferrous sulfate
• Acetaminophen
• Warfarin
• Chemotherapeutic regimens: dactinomycin, daunorubicin, bleomycin, methotrexate, 5-fluorouracil, cytarabine, and vincristine cause esophagitis perhaps due to oropharyngeal mucositis.
• Thoracic irradiation • Other medications: anti-hypertensives, quinidine, glimepiride, tiropramide, pinaverium bromide, esomeprazole, etc.

Epidemiology

According to a Swedish survey of 700000 patients at medical institutions conducted for four years, the estimated incidence of drug-induced esophagitis is 3.9 per 100000 population per year. Drug-induced esophagitis is more common in females and elderly patients. It is also common in patients using a capsule form of the drug.[1][2] Another estimate suggested 10000 cases per year in the United States. Other data estimate more than 20 cases in the pediatric population. Among them, the youngest child having drug-induced esophagitis was three years of age.[6][7]

Pathophysiology

The pathogenesis of medication-induced esophagitis involves a direct irritant effect and disruption of cytoprotective barriers.[8] Researchers hypothesize that prolonged contact of irritants with the esophageal mucosa can lead to mucosal damage.  Some mechanisms have been proposed by which a drug causes esophageal mucosal injury, which includes factors related to both medications and the patient itself.

Drugs related factors

Local acid burn and hyperosmolar properties of a medicine can cause esophageal mucosal injury. A clinical and experimental study which included 40 patients who were taking tetracyclines and developed esophageal ulcer showed similar appearance on endoscopy. The study demonstrated the corrosive effect of tetracycline on the esophagus of a cat in the experimental part of the study.[9] Low PH medicines such as doxycycline, ferrous sulfate, and ascorbic acid cause drug-induced esophagitis with a similar mechanism. Reports also exist of hyperosmolar property-related local tissue destruction and vascular injury of the esophagus as a cause of potassium chloride-induced esophagitis.[10] Sustained-release drugs have higher chances of causing esophagitis as compared to other preparations. Likewise, gelatin capsules are more likely to cause esophagitis because of their hygroscopic nature. They become sticky and adhere to the esophageal wall, probably due to mechanical pressure on the wall of the esophagus or by chemical injury to the mucosa once the drug gets released from the capsule.[11][4][12][2][6]

Aspirin and other nonsteroidal anti-inflammatory drugs can cause drug-induced esophagitis, albeit with a different mechanism by disrupting the cytoprotective prostaglandin barrier of the esophagus.

Patient-related factors 

Patient-related reasons mainly include factors that cause prolonged transit time of medications in the esophagus. Geriatric-related low saliva production, altered esophageal anatomy, taking a medication just before sleeping, and motility disorder can all result in increased esophageal transit time for drugs, as demonstrated in several studies.[13][14][15] The other and probably most important factor is medication ingestion with insufficient water and in the recumbent position. In one study, healthy volunteers showed delayed esophageal transition (defined if transit time is greater than 90 seconds) in subjects taking medications in the recumbent position and with less than 100 ml water. Many preparations stuck to the esophageal mucosa and disintegrated in the lower part of the esophagus. Difficulty in swallowing was reported with one or more medications by sixty percent of the volunteers. The study concluded that patients should take medications with at least 100 ml of water in a standing position to avoid the risk of drug-induced esophagitis, and liquid formulation should be considered in bedridden patients and in patients with swallowing difficulty.[13]

In drug-induced esophagitis, an upper gastrointestinal endoscopy usually reveals pathology in the middle third of the esophagus.[2] Areas of esophageal anatomical narrowing are commonly involved. Mid-esophagus may get externally compressed by the aortic arch or an enlarged left atrium (as in mitral valve disease), thus making it more prone to drug-induced injury. It can also occur at the gastroesophageal junction. Likewise, patients having hiatal hernia are more predisposed to drug-induced esophagitis. The pathology includes erosions, ulcers, mucosal friability, edema, or inflammation. Sometimes pill residues, impacted drugs, or drug coating can also be seen. Endoscopy may show complications like strictures or thickening of the esophageal wall. Other endoscopic findings include bleeding ulcers or kissing ulcers.[11][4][12][2]

Histopathology

Histologically, drug-induced esophagitis may show intraepithelial eosinophilic infiltration. Reflux esophagitis and eosinophilic esophagitis also can have similar findings, and the diagnostic basis is on the clinicopathological picture.[7]

History and Physical

Patients with drug-induced esophagitis typically present with retrosternal chest pain or heartburn, dysphagia, or odynophagia. A retrospective study that included 78 patients with pill-induced esophagitis observed the frequency of chest pain (71.8%), odynophagia (38.5%), and dysphagia (29.5%).[2] The symptoms are generally of sudden onset, intermittent, and self-limiting. Symptoms can develop with hours to 10 days after taking the drug and can be severe enough to cause difficulties even in swallowing saliva. Patients rarely may have melena due to esophageal ulcer related bleeding. The sudden onset of symptoms is probably because the drug releases chemical contents, which then damages the mucosa. There is a history of not taking the medication with an adequate amount of water or taking the medication in the recumbent position. Patients may be taking pills just before going to sleep with little or no water.[1][12][2]

Drug-induced esophagitis in children: Children with symptoms of dysphagia, retrosternal chest pain, odynophagia, and vomiting should raise suspicion for drug-induced esophagitis if there is any recent medication administration history. Drug-induced esophagitis can occur in children who take capsules or tablet formulations of medicines. Inadequate water intake and medication administration at bedtime are usually the risk factors associated with children. Severe complications are rare in children having drug-induced esophagitis, but morbidity and mortality have correlated with iron and potassium preparations. Children generally have an uneventful clinical course in drug-induced esophagitis.[16]

Evaluation

It is imperative to make the correct diagnosis to avoid repeated injuries to the esophagus and thus preventing related complications. The determination of drug-induced esophagitis has its basis in both clinical presentation and endoscopic findings. Patients presenting with retrosternal chest pain, dysphagia or odynophagia, and recent history of taking medicines which are known to cause drug-induced esophagitis are diagnosable with history only.

Blood tests, including complete blood count, is not usually needed unless there is an associated history of hematemesis or melena. If a patient presents with severe symptoms including vomiting and unable to swallow, then a metabolic panel also should be done to check for any electrolyte imbalance and to ensure adequate replacement.

Endoscopy usually confirms the diagnosis and remains the gold standard for the evaluation and management of drug-induced esophagitis. It is usually necessary for patients who have either persistent symptoms after discontinuation of culprit medicine for one week or presentation with severe but rather rare symptoms of hematemesis, difficulty swallowing, melena, and abdominal pain. The most commonly observed endoscopic findings in patients with the diagnosis of drug-induced esophagitis are as follows in decreasing frequency[2][17]:

• Esophageal mucosal erythema and erosion
• Ulcer and Ulcer with bleeding 
• Coating with drug material 
• Impacted pill fragments 
• Stricture 
• Kissing ulcers 

Histopathology may not be necessary for diagnosing drug-induced esophagitis, but it would exclude the possibility of malignancy.[1][2][12]

A barium swallow study is not much useful in evaluating medication-induced esophagitis but usually gets done in the process of evaluation of dysphagia, which can be one of the presenting symptoms at the time of presentation. 

Treatment / Management

Drug-induced esophagitis management involves the discontinuation of culprit medicine and other supportive treatment and lifestyle modification to protect the esophagus from further injury. 

• Discontinuation of the causative drug - When possible, discontinue potentially caustic oral medications. If possible, the medication preparation should change to a liquid formulation
• Short-term treatment with proton pump inhibitors (PPIs) and antacids. PPIs are found to be very useful with their acid-inhibiting properties as gastric acid reflux may contribute further to the worsening of esophageal injury.
• Oral sucralfate - It forms a local protective barrier and has cytoprotective effects.[1][2]
• Clinical features may persist for weeks to months in some patients. They can receive a topical application of lidocaine to alleviate symptoms.
• In patients with difficulty swallowing, parenteral nutrition for a short duration can be considered but usually is not needed.
• Avoid irritating food such as very hot or cold or acidic items.
(B2)

Preventive Measures

• Take medication with an adequate amount (at least 200 to 250 ml) of water.
• Avoid the prone position while taking the drug.
• Take pills at least 30 minutes before going to bed.
• Eat a meal after taking medicine.

Medication-induced esophagitis is usually transient and improves in 1 to 2 weeks after discontinuing culprit medication. In a study, when patients were followed up after two days to 2 months with endoscopy, they showed normal esophageal findings or well-healed scars in the esophagus.[18][11][4][12](B3)

Differential Diagnosis

Because retrosternal chest pain and dysphagia or odynophagia are common symptoms shared by many other diseases, differential diagnosis is usually broad. Usually, medication history is vital information in most cases, which helps in differentiating drug-induced esophagitis from other causes. 

• Eosinophilic esophagitis: Eosinophilic infiltration presents in drug-induced esophagitis as well as eosinophilic esophagitis. The two are separated based on the clinical picture and pathological diagnostic criteria.
• Herpes esophagitis: It most commonly presents in immunocompromised patients, such as acquired immune deficiency symptoms (AIDS). Esophagogastroduodenoscopy may show lesions such as small erosions or ulcers in the distal or mid esophagus. Twenty-six percent of the cases involve the entire esophagus. Diagnosis requires biopsies and a viral culture of the lesion.[19]
• Infectious esophagitis such as esophageal candidiasis
• Malignancy
• Gastroesophageal reflux disease and peptic ulcer disease
• Achalasia and esophageal motility disorder
• Acute coronary syndrome with atypical chest pain
• Acute necrotizing esophagitis (black esophagus) in the elderly[1][18][2]

Prognosis

Drug-induced esophagitis is a self-limiting disease with a good prognosis following conservative treatment. Patients are generally symptom-free within a week of stopping the causative drug and start of symptomatic therapy. Esophageal mucosa also recovers within this time. In most cases, repeat endoscopy or any additional measures are not necessary.[1][4][12][16]

Complications

• Gastrointestinal bleeding
• Stenosis and esophageal strictures
• Esophageal perforation
• Intramural esophageal hematoma  
• Mediastinitis