Maggie McCombs had been gluten free for about five years without a celiac disease diagnosis, when at age 23, with the rest of her life and big changes ahead, she needed answers.
“I realized how much work I was already putting into the diet, but I needed to know if it was for a good reason,” she says.
Traditionally, a biopsy would be key to getting an answer. For decades specialists have considered a biopsy the gold standard for diagnosing celiac disease. But debate about the absolute need for a biopsy is emerging among experts, with some saying there are times when the invasive test is not needed.
Blood tests have become more accurate in identifying antibodies associated with the autoimmune reaction. Until recently tests could only provide preliminary evidence, needing confirmation of celiac disease from a biopsy. But some celiac disease researchers say there are cases when blood tests provide enough proof.
McCombs had adopted the diet at 17 when her brother was diagnosed with Type 1 diabetes and celiac disease, the autoimmune disorder triggered by gluten protein in wheat, barley and rye. McCombs’ brother had undergone a biopsy to look for characteristic tissue damage in his small intestine prior to getting a final celiac disease diagnosis.
“I feel as though my brother was a guinea pig in many ways,” says McCombs, now 25 and a content marketer in Lexington, Kentucky. “He had the multiple blood tests, the follow-up visits, the endoscopy.
“After his diagnosis, my mother immediately suspected that I also had the disease due to my stomach pain complaints and itchy rashes spreading across my hands and face,” McCombs says. She started to research celiac disease and felt all her symptoms suddenly made sense.
“I’d experienced severe depression, anxiety, confusion: all hidden neurological symptoms of celiac disease. Admittedly I was both in denial of the possibility and deathly afraid of needles. So I evaded the blood tests and started adapting to the diet,” she says.
Though her health improved, she had trouble maintaining the gluten-free diet at college.
“Initially part of my problem was not knowing for sure that I had celiac disease, so I’d talk myself into sneaking some gluten-filled meals and snacks,” she admits. “Naysayers insisted that the disease was all in my head.”
After graduation she wanted to know for sure and decided to take the blood test recommended years earlier by her brother’s doctor. Celiac disease cannot be diagnosed in someone when they’re on a gluten-free diet, so McCombs had to start eating gluten again—called a gluten challenge.
“Instead of looking forward to eating anything I wanted, I actually dreaded cramming my body with my favorite foods,” she recalls. “My stomach ached. I had itchy red rashes spreading all over my hands and face. Although the doctor asked for a full month of eating as much gluten as I could tolerate, I was so sick that I had to get the test a week early.”
When McCombs’ tests came back, her doctor told her the antibody levels were the highest he had seen since her brother’s. “Any other tests would be superfluous. I had celiac disease,” she says.
Unlike her brother, McCombs received a diagnosis without undergoing an endoscopy and biopsy, a procedure in which a gastroenterologist inserts a narrow tube down the throat, through the stomach and into the small intestine, allowing a visual inspection. But more importantly, small samples taken from the lining are examined to determine if there is damage from celiac disease.
RoByn Thompson, 51, of Paterson, New Jersey, was also recently diagnosed with celiac disease after a blood test. Her doctor didn’t suggest a biopsy, but Thompson says she probably would have decided against it.
“I’m a cancer survivor and have had too much surgery already,” she explains, adding she’s confident in the diagnosis. “I’m symptom free when I avoid gluten.”
A few specialists believe it’s time to move beyond the biopsy as the gold standard. Geoffrey Holmes, M.D., emeritus consultant gastroenterologist at Royal Derby Hospital in Derby, U.K., is advancing the case for blood tests.
“Endoscopic biopsy is generally safe, but it is invasive and unpleasant and often requires sedation, so why do it if it is unnecessary?” he asks.
Holmes was seeing patients with high antibody levels and started to ask the question, “What could this be other than celiac disease and why do I need to perform a biopsy which is certain to confirm it?”
Though many doctors were already making diagnoses without biopsy and putting patients on gluten-free diets, Holmes says he wanted to address the question from a scientific basis.
The most valuable blood test relies on tissue transglutaminase (TTG), an enzyme that occurs in the gut and interacts normally with gluten protein. Meanwhile the immune system produces a class of antibodies called immunoglobulin A (IgA) to fight infection. But people with celiac disease produce particular IgA antibodies that bind with their own TTG.
Holmes thought there must be a high level of IgA anti-TTG that could predict celiac disease 100 percent of the time. His research found that antibody levels at least 10 times the upper limit of normal were sufficient, so a biopsy was unnecessary to confirm diagnosis. He and his colleague published these findings in 2008.
Previous research has suggested that 20 to 30 percent of patients with celiac disease can safely be diagnosed without biopsy. However recent work by Holmes and colleagues pushes the number much higher, to 78 percent. In practice, he claims about half of celiac disease patients in Derby are diagnosed without biopsy.
In 2012 the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) published new guidelines for diagnosis, based partly on Holmes’ work. The society affirmed that in a child showing 10 times the normal anti-TTG, an additional test for IgA endomysial antibodies (EMA) could be used in follow-up. If this second test was positive, the child could be placed on a gluten-free diet. If this produced beneficial results and the child’s antibodies returned to normal, celiac disease could be considered proven.
The EMA test was discovered when researchers were studying a painful skin form of celiac disease, dermatitis herpetiformis. Certain IgA antibodies appeared in connective tissue under the skin. This led to the revelation that EMAs also occur in celiac disease without the skin manifestation. In fact almost 100 percent of people who test positive for EMA have celiac disease.
But the EMA test gives a few false negatives, not showing up in 5 to 10 percent of patients. TTG doesn’t miss as many. EMA is also more difficult and expensive to perform, demands specialized training for the pathologist, and is not widely available in North America.
Not everyone agreed with the ESPGHAN’s protocol and movement away from biopsy.
In 2013 the American College of Gastroenterology (ACG) weighed in, recommending that an endoscopy with biopsy is a “critical component” in evaluating patients and should be used to confirm the diagnosis. While affirming the value of blood tests, the group does not recommend use of EMA. British Society of Gastroenterology guidelines published in 2014 also insist that a biopsy is always necessary.
Joseph Murray, M.D., of the Mayo Clinic in Minnesota, is a strong proponent of biopsy. He acknowledges the ESPGHAN guidelines can lead to an accurate diagnosis, but only if followed correctly.
“Unfortunately what we’re seeing is people not following the guidelines,” says Murray.
Clinical antibody tests are recommended as a starting point by physicians, but some patients don’t take that step before starting a gluten-free diet.
Jill Wirth’s daughter Kaiya is an example. At 2 years old, Kaiya was “almost at the failure-to-thrive weight,” says Wirth, 38, a technical sales professional in Cambridge, Ontario, Canada.
“As a baby she cried more often than what I would consider normal. She didn’t want to be held or fed. She had very little interest in food. She was not what I would call a happy baby by any means,” Wirth recalls. “Our general practitioner had suggested [putting] 35 percent cream in her bottle and to put sugar on her food to try to entice her to eat it.”
After dissatisfying results, Wirth took Kaiya to a holistic nutritionist who tested her for food sensitivities and celiac disease. Results from an over-the-counter test for celiac disease were positive so Wirth immediately put Kaiya on a gluten-free diet.
Murray says store-bought tests like the one used to diagnose Kaiya are available in Canada but have not been approved by the U.S. Food and Drug Administration. The tests can give accurate results, according to Murray, but that depends on the test and who does it. And patients are advised to seek further testing to confirm results before undertaking a gluten-free diet.
Kaiya’s doctor did order a blood test, which also came up slightly higher than normal. Finally Wirth asked for a referral to a gastroenterologist.
“We decided with the specialist that we would not put our daughter through having to be glutened for an extended period of time in order to go for a measurable biopsy,” she says. “Since we had seen such a positive change in weight, behavior and mental wellness, we would not put her back on a diet that included gluten.”
Kaiya, now 5, “responded incredibly,” Wirth says, “a complete transformation.” She adds that she and her husband are completely confident in the diagnosis.
“If there is any doubt about the celiac disease, there is certainly no doubt that this sweet young girl should not be consuming gluten. I guess the biopsy would only confirm the extent of the damage the gluten creates in Kaiya’s body, not whether or not she should consume gluten,” Wirth explains.
Blood tests for diagnosis include several alternatives suited for specific circumstances. IgA deficiency, a rare condition affecting a few people with celiac disease, causes undetectable IgA anti-TTG. This can call for an IgA deficiency test and alternate tests for celiac disease based on immunoglobulin G (IgG). However, their accuracy is less well known.
Genetic tests for celiac disease are now being commonly used. The human leukocyte antigen (HLA) gene codes for an agent in the immune system. Two forms, HLA-DQ2 and HLA-DQ8, occur in about 40 percent of the population. Only people who carry these genes can develop celiac disease: Still, the vast majority never will.
Some celiac disease experts have found the problem with HLA tests is that patients and many doctors interpret a positive result as strong evidence for a diagnosis, which it is not. It indicates only that the patient has a higher risk for celiac disease. The ESPGHAN guidelines recommend including it with other blood tests in reaching diagnosis, even though genetic testing is inconclusive and relatively expensive to perform.
A negative HLA result is helpful in ruling out celiac disease in the majority of cases. The ACG recommends this as a first step for patients who have already adopted a gluten-free diet without diagnosis. A negative result indicates the diet is unnecessary. However the genetics of celiac disease are not entirely understood, and about 1 percent of patients have none of the gene types so far identified. These rare individuals would get a negative HLA result.
The ACG strongly recommends that people with a positive HLA seek appropriate diagnosis beginning with a gluten challenge and appropriate antibody tests, instead of continuing a gluten-free diet.
Some doctors won’t understand these nuances, says Murray. He discourages the practice of sending patients for a panel of blood tests. “The problem when you combine tests is they reduce to the lowest common denominator of accuracy. I frequently have patients come to me who’ve had four tests, one out of the four was positive, and they were told they had celiac disease when it’s obvious they don’t.”
Murray says the first step after a positive anti-TTG test should always be referral to a gastroenterologist.
“One of the hardest things I do in my practice is, when someone comes to me who has been committed to being on a gluten-free diet for two or three years, I have to tell them, ‘You don’t have celiac disease.’ It is a life-long diagnosis with a life-long, life-altering treatment,” Murray says. “Many people choose to go gluten free, but that’s very different from the burden on a patient, who must go gluten free. It affects every time you eat, buy food, eat out or travel. That applies to children as well as adults, and with children it’s imposed on them, so I think there’s a higher bar for certainty.”
Ivor Hill, M.D., medical director of Nationwide Children’s Hospital Celiac Disease Center in Columbus, Ohio, says he has had cases where the symptoms were very typical, the TTG was very high, and the parents were reluctant to have their child undergo a biopsy.
“I’ve felt comfortable in those cases saying we’ll put them on the diet and monitor the response. They all had a good response and their [antibody] numbers came down, so in retrospect I’m pretty sure they have celiac disease,” Hill says. “Do we have the same level of confidence with a non-biopsy diagnosis? Hopefully we’ll get there someday but right at the moment, maybe not.”
He discusses the implications of making a positive diagnosis with the parents. “I want to be 100 percent sure that the child has celiac disease because if they’re going to go gluten free, it’s for life,” Hill explains.
Alessio Fasano, M.D., chief of the division of pediatric gastroenterology and nutrition at Massachusetts General Hospital for Children in Boston and director of the Center for Celiac Research and Treatment, says patients who have been diagnosed based on blood tests alone tend to comply poorly with the gluten-free diet over time, compared with people who have received a picture of their damaged intestine.
Previously a supporter of diagnosing without biopsy in some cases, Fasano says he now has reservations because endoscopy can reveal important information that would otherwise be missed. For example a patient may have other related conditions such as reflux.
“In a large number of people who go on the gluten-free diet, once their symptoms have gone and their antibodies go back to normal, after a year when we repeat the endoscopy, we see [a significant] number of these individuals that still have damage,” Fasano says. “So that’s another reason why we are skeptical at this point.”
Holmes argues that while biopsy remains useful, its status as the gold standard is becoming hard to defend. Celiac disease may be the correct diagnosis if the intestinal lining is typically flattened, but some cases are more uncertain.
Reading the biopsy
Biopsy has its limitations. Damage from celiac disease may be spotty, with some tissue still appearing healthy. Specialists recommend collecting at least five or six samples from different parts of the small intestine of each patient. Studies have shown gastroenterologists performing the procedure do not always take enough samples to detect celiac disease in every patient.
The tissue samples must then be correctly preserved and oriented so the damage is visible. They are sent to a lab where trained pathologists look for telltale damage. The earliest sign of damage is an increase in a certain kind of white blood cells in the tissues. However this can occur in other conditions, too.
Next comes an increase in the number of cells in depressions lining the intestine, a condition called crypt hyperplasia. This is thought to occur in response to tissue damage.
The third and most significant change is flattening of the villi, minute hair-like projections that normally line the gut, increasing its surface area. Celiac disease blunts them or flattens them completely, so the body has a hard time absorbing enough nutrients. This is the damage pathologists look for to confirm a diagnosis. It may occur in a few other conditions, but they’re very rare.
Inconsistencies in how tissue samples are collected and prepared raise concerns even among biopsy advocates. Holmes says typical flattening may provide a clear diagnosis, but with moderate damage the cause is uncertain.
“Often the villi are reported as slightly shortened or blunted. Is this celiac disease? It may or may not be, and here serology can come to the rescue,” he says.
The right diagnosis
Meanwhile, McCombs says she is confident in her celiac disease diagnosis.
“I was determined to get a definitive answer, so I definitely would have gotten a biopsy if needed,” she reflects. “Honestly I would have undergone almost any procedure to get diagnosed and end the misery of the gluten challenge.”
Two years later she is learning to cook at home, asking more questions in restaurants and looking for a follow-up with a new doctor in the area where she moved to start a career.
“I’m still so thankful to know what’s wrong with me. Most days I don’t even mind the gluten-free diet because I see it as a cure,” she says. “Changing my diet improved my health, but changing my attitude improved my entire way of life.”
Van Waffle, who has a bachelor’s degree of science in biology, is research editor for Gluten-Free Living. A resident of Ontario, Canada, he also contributes regularly to Edible Toronto and blogs about nature, gardening and local food at vanwaffle.com.
This article was originally published in our March/April 2015 issue. All information was correct at time of publication.