Take a Systematic Approach to Evaluating Seronegative Enteropathies

Seronegative enteropathies, characterized by small bowel villous injury with negative celiac serologies, are a common cause of malabsorption, yet many patients go undiagnosed. This can lead to serious health consequences, including severe malnutrition. Physicians should take a systematic approach to evaluating patients in order to correctly diagnose their condition for individualized treatment, says gastroenterologist Alberto Rubio-Tapia, MD, Director of the Celiac Disease Program at the Cleveland Clinic.

Pathology, serologic testing, endoscopic evaluation, medications and even the patient’s travel history should all play a role in narrowing down the diagnosis. A team approach with experienced specialists is key to recognizing the multiple clinical presentations of seronegative enteropathies, including seronegative celiac disease, as well as mimickers like medication-related enteropathy, tropical sprue, CVID enteropathy and autoimmune enteropathy, he adds.

“Seronegative enteropathy diagnosis requires clinical suspicion and attention to details in terms of clinical presentation and expert pathology evaluation of the biopsy,” Dr. Rubio-Tapia said. “It is a diagnostic challenge because you need to think beyond the common disorders to make an individualized plan for the patient.”

Dr. Rubio-Tapia was the lead author of the American Gastroenterological Association’s 2021 clinical practice update on the evaluation and management of seronegative enteropathies. He presented on the topic at the American College of Gastroenterology’s annual meeting in October.

Common Mistakes in Evaluating Patients

Clinicians regularly make three serious mistakes when evaluating villous atrophy with negative celiac serologies, says Dr. Rubio-Tapia, starting with the assumption that negative celiac serologies mean that celiac disease is not possible. In fact, seronegative celiac disease is still the most common cause of seronegative enteropathy.

The primary way to distinguish true seronegative celiac disease from other causes of villous atrophy is to test for the celiac gene: a negative result rules out celiac disease.

Other clues that should prompt clinicians to start thinking beyond celiac include a lack of response to a gluten-free diet, he adds.

“Pathology evaluation of intestinal tissue by an expert GI pathologist is also very important, because sometimes the pathologist can identify the specific reason for the enteropathy,” he says.

A second common mistake made by clinicians is neglecting to review the patient’s medications in detail. Dr. Rubio-Tapia notes that one of the most common causes of non-celiac villous injury is sprue-like enteropathy associated with the use of Olmesartan or similar angiotensin II receptor blockers.

Finally, he notes that clinicians may miss important clues if they fail to ask about the patient’s travel history. This can be especially relevant for individuals living in or visiting areas where tropical sprue is endemic, including Central America, India and Southeast Asia, Northern Australia, and Central African countries.

Case study: Patient with chronic diarrhea and weight loss

A patient presented with chronic diarrhea and weight loss of around 60 pounds over eight months.

During the initial visit, Dr. Rubio-Tapia asked about the medications the patient was taking. The patient revealed taking losartan, an ARB in the same class as olmesartan, which the patient had been using for hypertension management over several years. At Dr. Rubio-Tapia’s suggestion, the prescription was switched to a different class of blood pressure medication.

“Just four weeks after the change, the diarrhea is gone, and the patient started recovering weight,” Dr. Rubio-Tapia says. “The patient was extremely happy and couldn’t believe that the medication had not been stopped earlier.”

The importance of a multidisciplinary approach

Dr. Rubio-Tapia noted that Cleveland Clinic has a dedicated celiac disease program with a multidisciplinary approach, making it a world leader in the diagnosis and treatment of celiac disease and seronegative enteropathies. Clinicians see hundreds of patients with celiac disease or celiac mimics each year.

The program’s success is largely thanks to its collaborative approach, including specialized GI pathologists, state-of-the-art imaging, molecular diagnostics, and a multidisciplinary team of specialists such as expert dietitians, he adds.

Dr. Rubio-Tapia says the biggest challenge for clinicians in evaluating patients with seronegative enteropathy remains establishing a specific diagnosis so that treatment can be tailored to the correct condition.

“I really enjoy seeing these patients, because with a good diagnosis you can make a big difference in their health and lives,” he says.