Coeliac Disease – pitfalls in monitoring adherence to a gluten free diet
I want you to consider that everything we’re doing is wrong. This was the opening statement made by a Professor of Gastroenterology presenting at a UK symposium last year. The topic of discussion was how we monitor coeliac disease. With adherence rates reported to be between 42 and 92%, it is true that many coeliacs are at risk of developing complications. These are such as lymphoma, ulcerative jejunitis, osteoporosis, infertility, and nutritional deficiencies. In children signs of non-adherence include faltering growth and delayed puberty. To reduce the incidence of comorbidity we must have the right tools to detect gluten exposure. There are a variety of methods used in practice to assess adherence to a gluten free diet – validated scores, questionnaires, ask the patient, request a dietitian review and of course serology. Healthcare professionals like numbers, and biomarkers give us quick reassurance; until they don’t.
Long term follow-up in coeliac disease remains controversial. Currently there are no effective non-invasive markers of gluten free diet adherence, with point-of-care testing, dietary adherence questionnaires and serology all having poor sensitivity for the detection of villous atrophy. Serological response is often used as a surrogate for histological recovery however. A recent survey reported 65% of Gastroenterologists in Canada used bloods including serology as a monitoring tool. Overall however serology was performed less frequently in adults than children in favour of routine intestinal biopsy, showing a trend towards the use of the gold standard assessment.
There are inherent difficulties in using coeliac serology as a monitoring tool. In order to obtain clinically meaningful endpoints, it is essential that patients are eating a certain amount of gluten prior to testing. Guidelines vary on the amounts and duration with one institution saying gluten in more than one meal daily for 6 weeks, and another recommending 1-3 slices of bread daily for 1-3months before testing. Once you can be sure the patient is adequately prepared for a test there are a few other serological anomalies to consider.
It is reported that 1.7%–5% of coeliacs are affected by seronegative coeliac disease (SNCD). This is a rare and still poorly defined form of coeliac disease, presenting with negative serology, villous atrophy, genetic compatibility, with or without symptoms of malabsorption and who demonstrate clinical and histological response to a gluten free diet. A further 2% of coeliacs have IgA deficiency. This is a separate entity to seronegativity.
In this case, if not done automatically by the lab, you need to order IgG antibodies as an alternative to IgA antibodies. According to a recent meta analysis, sensitivity of the anti-tissue transglutaminase (tTg) antibody for ongoing villous atrophy was only 43.6%. So even if well considered and accurately prepared there appears to be a limit to how much serological testing can tell us about mucosal healing. It is like flipping a coin. There is a 50% chance of persistent villous atrophy with a negative IgA tTg result.
If you decide to pursue biopsy as a method of assessment and find persistent villous atrophy there are caveats here too. There are many mimics of villous atrophy including NSAIDs or olmesartan use, Helicobacter pylori gastritis, giardiasis, collagenous or microcytic colitis to name but a few. The timeframe for biopsy must also be selected carefully. Villous atrophy improves on a gluten free diet but it may take 2-3 years so be careful not to repeat the biopsy too early. It has been suggested that immune tolerance is possible over time.
A recent study showed that neither occasional nor voluntary dietary gluten intake was associated with the onset of clinical, serological, histologic, or endoscopic changes in a group of coeliac patients. Interestingly no association was found between histological alterations and the amount of gluten intake following diagnosis. This means the traditional advice of a strict gluten free diet for all warrants further investigation and review. The tolerable amount of gluten is still contended and this casts a shadow over current dietary advice.
Perhaps there is a subset of patients where a more relaxed approach can be considered but we need the monitoring tools to allow that to happen in a safe way. Dietetic assessment of adherence also has limitations. Targeted dietetic intervention through removal of identified gluten sources or avoidance of trace amounts of gluten led to resolution of persistent villous atrophy in only 50% of patients studied.
In summary, serology appears to be a poor surrogate marker for mucosal recovery and dietary assessment may fail to uncover a potential gluten source in some patients with ongoing villous atrophy. This could be explained by non-disclosure or under reporting of dietary intake but warrants further investigation Although current clinical guidelines do not recommend routine repeat biopsy, it appears to be the surest way to monitor mucosal healing and response. Although such a change in clinical practice would have financial implications, the cost of non-adherence has a clear impact on the health of individuals. Equally an overly strict gluten free diet can affect quality of life. In the meantime we need more accurate non-invasive markers of mucosal damage in children and adults with coeliac disease who are following a gluten free diet.
Perhaps novel biomarkers such as Gluten Immunogenic Peptide (GIP) might have the ability to increase detection rates of non-adherence. This convenient urine test checks for gluten exposure. There has been criticism of false negatives but researchers say testing over a number of days is a pragmatic approach. According to one study, 3 negative urine tests from three different days revealed a 97% possibility of no villous atrophy. New biomarkers are promising and will add to our understanding of gluten metabolism and, with additional studies, could be used as a supplemental tool in the future management of our patients.
In conclusion, current methods fall short in detecting rates of non-adherence in coeliac disease leading to comorbidities that are largely preventable. Long term monitoring is not as straightforward as we once thought and requires more thorough consultation. Do not rely on serology alone. Serology, dietary adherence and mucosal remission do not have a perfect relationship. The only way to know for sure if your patient is responding to diet therapy is to repeat biopsy. So back to my opening line, please consider everything you’re doing is wrong.
References available on request
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