Putting celiac disease in perspective: Pathogenesis, comorbidity and transition of care

With the many advances in serological diagnosis and increased awareness, celiac disease (CD) is now appreciated to affect patients throughout all of Europe, the Middle East, South Asia, and North Africa. The prevalence of CD has increased in the USA and worldwide. The clinical expression has also changed over time. In the past century, CD was an overt malabsorptive condition with diarrhea, a low body mass index, bone disease, malnutrition, infertility and anemia, but atypical CD is now more common, with non-gastrointestinal presentations including neurological problems, depression and migraines. Some patients also lack an overt clinical manifestation—the so-called “silent” CD, which is often detected during screening of first degree relatives and other at-risk patients.

Advances in the understanding of CD pathogenesis have occurred over the past few decades with better understanding of the role of the host genotype, the mode of gluten delivery, the type of feeding, the time of feeding and, possibly, the contribution of antibiotics that modulate the microbiome. The DQ2 genes are necessary but were insufficient to explain the development of CD. About 40% of the burden of CD is related to the HLA-DQ2.2, 2.5 and 8 genes. In spite of many genome-wide association studies, no specific key molecules have been identified that play a significant role in causing the disease to date. The average age of diagnosis of CD currently is someone in their mid-40 s who has been eating gluten all their life, so it is not clear why and when people develop CD. Studies implicating the association of enteric infections and CD may explain why genetically susceptible individuals that are exposed to gluten from childhood do not all develop the disease in early childhood. The concept of enteric infection being a trigger has been postulated, possibly by modulating the immune system, causing breaches in the mucosal barrier, or skewing of the microbiome. A study recently published in Science supports the role of reovirus as a trigger for CD¹ and results from the TEDDY study group published in Clinical Gastroenterology and Hepatology suggest that rotavirus vaccination could reduce CD in susceptible children.²

A recent report in Science Advances demonstrated that patients within hours of oral or intradermal gluten exposure experienced gastrointestinal symptoms that were associated with elevated serum cytokines, particularly IL-2, IL-8 and IL-10.³ In the February issue of the United European Gastroenterology Journal, high-sensitivity cytokine assessment differentiated CD from self-reported gluten sensitivity (SR-GS) in subjects on a gluten-free diet who were given a gluten challenge.⁴ This finding was partially validated by the absence of cytokine responses in a separate cohort of SR-GS individuals after a dietary challenge. These findings are potentially important in understanding the contribution of the immune system to so-called “non-celiac” gluten sensitivity. Clinically relevant findings in SR-GS could stem from fructose or fructans in wheat starch (FODMAPs) that lead to symptoms similar to irritable bowel syndrome or other functional gastrointestinal disorders. Testing for non-celiac gluten or wheat sensitivity is difficult as the mechanisms are unknown, and thus prevalence cannot be established. Directly evaluating the immune response to a gluten challenge may prove useful.

However, the results reported using this approach cannot change the practice of medicine just yet. First, the magnitude of cytokine induction was relatively modest in most cases with some not changing while most were <1–2 pg/ml. Validating these results with a biologically independent approach, for example, by identifying the mucosal cells responsible for the release and documenting the assay was specific, would help. Additional work will be needed to determine if the sensitivity and specificity of serum IL-2 induced by a gluten challenge is helpful in distinguishing between CD and SR-GS.

This issue includes an article from Laura Kivelä and colleagues on factors that affect transition from childhood to adulthood in CD.⁵ I had the opportunity with colleagues in Europe and America to participate in “Transition from childhood to adulthood in coeliac disease: the Prague consensus report”. Transit-CeD disk is a promising tool for patients and families, pediatricians and gastroenterologists that scores a patient’s knowledge of CD, their ability for self-management, their dietary compliance and their quality of life.⁶ As such, some objective assessment of these issues could guide a physician in tailoring their care in an age-appropriate manner. In North America, primary physicians often provide care for patients with CD, and such a tool could be quite helpful.

Finally, a retrospective study was reported that investigated the prevalence of CD associated with other immune-mediated conditions in the Republic of Ireland.⁷ This study included 749 CD patients. Total coexistent immune-mediated conditions were 31.1%. The comorbidity with autoimmune thyroidal diseases over the past 50 years was 19.9%. Other autoimmune diseases are cited as well. Although this association of comorbidities is interesting, they noted that autoimmune thyroidal diseases became less frequent over time. There are currently no unifying hypotheses to explain why they may happen together. The combination of genes associated with these different disorders, along with the optimal environmental conditions, may account for the comorbidities. Additional studies are needed to fully understand the potential overlap in the pathogenesis of this disease or what it may mean for diagnosis and treatment.