Improving celiac disease diagnosis

Celiac disease should be part of the differential diagnosis for several classic clinical presentations, but atypical symptoms, including constipation, can cause doctors to overlook some patients.

While an estimated 1% of the U.S. population has celiac disease, many more may not know of it.

“There's a lot of celiac disease out there, and still it remains an underdiagnosed condition,” said Rupa Mukherjee, MD, an assistant professor of medicine at Harvard Medical School in Boston and medical director of the Celiac Center at Lexington, part of Beth Israel Deaconess Medical Center. “One thing that contributes to that is just not having it on the radar.”

Celiac disease should be part of the differential diagnosis for several clinical presentations, explained Amy Oxentenko, MD, FACP, a gastroenterologist and vice dean of practice at Mayo Clinic in Rochester, Minn. Classic presentations include chronic diarrhea or bloating, as well as weight loss or features of malabsorption; however, patients with celiac disease can also report baseline constipation. “If people wait for the patient with very classic or typical symptoms, they are going to overlook a lot of patients who have celiac disease,” she said.

Kofi Clarke, MD, FACP, a gastroenterologist and division chief of gastroenterology and hepatology at Penn State Health Milton S. Hershey Medical Center in Hershey, Pa., agreed, noting that fewer than half of patients with celiac disease have characteristic GI symptoms. “You can imagine that if someone is not thinking outside of the box, they might not even consider celiac disease as a diagnosis,” he said.

Celiac disease also has other non-GI manifestations, such as iron deficiency anemia. Any patient with iron deficiency should be screened for celiac disease, Dr. Oxentenko said, though this is often skipped or overlooked in women of reproductive age because the anemia is attributed to menstruation. Clinicians should also consider the diagnosis in those with early bone loss that is not otherwise explained, unexplained infertility, abnormal liver biochemistries, and vitamin or mineral deficiencies, she said.

Dr. Clarke noted that unexplained fatigue and certain skin rashes should also get clinicians thinking about celiac disease. Further complicating matters, about 20% of patients are completely asymptomatic, said Nielsen Fernandez-Becker, MD, PhD, director of the Celiac Disease Program at Stanford University in California.

Though celiac disease can develop at any time as an immune reaction to a gluten-containing diet, clinicians should be alert to some groups at higher risk, said Dr. Mukherjee, including patients with type 1 diabetes, autoimmune thyroid disease, Down syndrome, or Turner syndrome. Individuals with rheumatoid arthritis, Sjögren's disease, and lupus are at moderately increased risk, Dr. Mukherjee said. In addition, the American College of Gastroenterology's (ACG) guidelines for the evaluation and management of patients with celiac disease, published Jan. 5 by the American Journal of Gastroenterology, recommend that clinicians consider testing when a first-degree family member has biopsy-confirmed disease.

Diagnostic workup

If there is suspicion of celiac disease because of symptoms, laboratory abnormalities, or family history, a clinician should make the diagnosis based on results of serology and biopsy testing, experts said.

The diagnostic approach to celiac disease in adults using histological and serological data in the 2023 ACG guidelines is the same as in its 2013 guidelines. The first step is antibody testing with a serum tissue transglutaminase antibody (tTG) test, as well as a serum IgA assay. Since the tTG is an IgA-based test, it is important to test for IgA deficiency to make sure that the tTG results will be reliable. If the patient has IgA deficiency, they should be assessed for celiac disease using a deamidated gliadin peptide IgG assay (DGP-IgG). All diagnostic testing should be conducted when patients are on a gluten-containing diet, Dr. Mukherjee said.

An elevated level on antibody testing does not equate to a diagnosis of celiac disease, but it does raise the level of suspicion even more, according to Dr. Fernandez-Becker. These patients should be referred for duodenal biopsy, the ACG guidelines state. In addition, while celiac disease is unlikely in those with negative results on antibody testing, they may still have celiac disease. Clinicians should refer patients who have a family history or symptoms suggestive of celiac for biopsy via upper endoscopy regardless of their antibody results, Dr. Fernandez-Becker said.

There's been some controversy about whether biopsy is necessary for all adult patients, even those with highly elevated antibody levels and clear clinical celiac symptoms, Dr. Oxentenko said, and whether serology, history taking, and physical exam may sometimes be adequate. While the ACG guidelines recommend multiple duodenal biopsies for confirmation of the diagnosis, they also suggest that in symptomatic adults unwilling or unable to undergo upper GI endoscopy, high-level tTG antibody IgA (>10 times the upper limit of normal) with a positive endomysial antibody in a second blood sample are reliable tests for diagnosis of likely celiac disease.

Dr. Oxentenko said biopsy also provides a useful baseline. “It's helpful to get that baseline histology, not just to confirm the diagnosis but then to have something to compare it to a year or two later if that patient still has ongoing symptoms or when we assess the response to treatment,” she said. “Is this improved compared to how it was before?”

While the gluten-free diet is highly effective patients can be inadvertently exposed to gluten when they eat new foods or dine outside the home Image by Rawpixelcom
While the gluten-free diet is highly effective, patients can be inadvertently exposed to gluten when they eat new foods or dine outside the home. Image by

Mucosal healing in celiac disease after starting a gluten-free diet takes time and is incomplete or absent in a substantial number of patients diagnosed in adulthood, according to the ACG guidelines. Clinicians could consider follow-up biopsy to assess mucosal healing in adults in the absence of symptoms after two years of starting a gluten-free diet following shared decision making with the patient, the guidelines state. The guidelines suggest setting a goal of intestinal healing as an end point of gluten-free diet therapy, as well as individualized discussion of goals of the gluten-free diet with the patient beyond clinical and serological remission.

NCGS and genetic testing

Symptom reduction or resolution on a gluten-free diet is not considered diagnostic of celiac disease, Dr. Mukherjee cautioned. “Some patients who don't have celiac disease but have nonceliac gluten sensitivity (NCGS) can feel much better on a gluten-free diet but not actually have celiac disease,” she said.

Patients with NCGS have negative results on both serology and biopsy but experience symptoms when eating gluten-containing foods. If NCGS is suspected, be sure to rule out conditions with similar symptoms such as irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth, Dr. Clarke advised. It is also helpful to make a clear connection between the timing of ingestion of gluten and the onset of symptoms in order to be more confident about the diagnosis of NCGS, he said.

One of the biggest challenges in making the diagnosis of celiac disease is that many patients are already on a gluten-free diet when they come to the office, Dr. Oxentenko said.

While they may feel better on the diet, they may also continue to have symptoms or want confirmation that they have celiac disease. But since the patient has already removed gluten from their diet, neither antibody testing nor endoscopy may yield a reliable result, based on how long or how strictly they have been gluten free, she explained. “That's where it really requires a dialogue with the patient to ask if they are willing to reintroduce gluten into their diet for us to definitively make a diagnosis of celiac disease or not,” she said.

For those patients who are already on a gluten-free diet, genetic testing may help assess risk, Dr. Fernandez-Becker said. A blood test can see if the patient carries human leukocyte antigen (HLA)-DQ2 or DQ8 haplotypes, which are present in the vast majority of patients who have celiac disease and play a key role in its pathogenesis. About 30% to 40% of the population carries these celiac genetic markers, but fewer than 5% go on to manifest the illness. In addition to HLA-DQ2 and DQ8, other patients may have HLA DQ A1*05, Dr. Clarke said.

HLA testing may be helpful in the context of serology-histology discrepancy and is central to the approach to testing in individuals who have already started a gluten-free diet, according to the ACG guidelines. In the presence of a celiac disease-compatible haplotype, clinicians can offer a gluten challenge; if negative, they can rule out celiac disease, the guidelines said.

Appropriate counseling is required before starting a gluten challenge, which typically lasts up to eight weeks, Dr. Oxentenko said. “Some people think that they have to eat nothing but gluten for eight weeks, and that's not true. It takes very little, usually the equivalent of a slice of bread per day—just enough to stimulate their immune system if they do have celiac disease.”

Making the right diagnosis is critical because the treatment for celiac disease is a gluten-free diet for life. “It's a lifelong commitment and very socially isolating,” Dr. Clarke said. “The gluten-free diet is also significantly more expensive than regular foods.”

Conversely, a false-negative diagnosis can leave patients with various nutritional deficiencies, bone loss issues, and other adverse outcomes. “It is important to know what the diagnosis is, one way or another, if it's practical,” Dr. Mukherjee said.

Follow-up, management, next steps

To see if the gluten-free diet is having an effect, Dr. Oxentenko suggests that antibody testing be repeated at four to six months after diagnosis, with additional testing at one year and then annually from that point forward. A repeat biopsy of the small bowel at two years is also helpful to assess the patient's progress. In addition, be sure to assess bone density at the time of diagnosis, unless the patient had it measured previously, she said.

Patients may continue having symptoms after starting a gluten-free diet, but true refractory celiac disease is rare. A recent clinical practice update on the topic from the American Gastroenterological Association walks clinicians through the recommended ways to determine whether a patient has true refractory disease or if their continuing symptoms are due to inadvertent ingestion of gluten, other concurrent or associated GI conditions, or misdiagnosis of their original symptoms. For those with refractory disease, corticosteroids, open-capsule budesonide, or, if unavailable, prednisone, are first-line therapy, said the update, which was published by Gastroenterology on Sept. 18, 2022.

To increase the chances that a gluten-free diet will stick, patients with a new diagnosis should see a dietitian up front for advice and counseling, Dr. Oxentenko said. She refers patients to a GI dietitian initially, then again in three to six months when they have more targeted questions.

“That's a much better approach for patients than sending them out into the abyss of the internet,” she said. “They oftentimes become much more restrictive than they need to be in their diet because of things they find on the internet.”

While the gluten-free diet is highly effective, patients can be inadvertently exposed to gluten when they eat new foods or dine outside the home. Researchers are looking to mitigate this issue by developing agents that could prevent injury from incidental gluten exposure.

One type of agent currently in clinical trials is a glutenase, which is a cocktail of enzymes that would degrade gluten before it hits the small intestine and activates the immune system, said Dr. Mukherjee. “The idea is that patients would take this medication if they felt they may have been exposed to gluten, when eating at a restaurant, for instance, or prior to an event where they may not have access to reliably gluten-free food,” she said. However, this type of agent would not replace the gluten-free diet.

Another potential medication in development targets the tight junctions between cells in the small intestine that, when exposed to gluten, separate slightly, allowing gluten to enter. These tight junction modulators, now in clinical trials, are aimed at closing those junctions to prevent gluten from making it to the small intestine, Dr. Mukherjee explained.

“There are multiple therapeutics for celiac disease that are actively being investigated, with a few coming down the pipeline,” she said.