People with celiac disease have increased risk of dying prematurely, despite increased awareness of the disease in recent years and better access to gluten-free food.
This is according to a new study from Karolinska Institutet in Sweden and Columbia University in the U.S. published in the journal JAMA. Celiac disease was linked to increased risk of death from cardiovascular disease, cancer and respiratory disease.
Previous studies have demonstrated a modest but persistent increased risk of premature death in patients with celiac disease.
However, in recent years, more people with milder disease have been diagnosed and gluten-free food is widely available.
It has therefore been hypothesized that celiac disease may no longer be associated with an increased risk of death.
Using nationwide data from Sweden’s pathology departments, linked to national healthcare registers, researchers at Karolinska Institutet and Columbia University examined almost 50,000 patients with celiac disease and their risk of death.
Compared with controls, overall mortality was increased by 21 percent in those with celiac disease.
The relative increase in mortality risk was present in all age groups and greatest in those diagnosed in the age range of 18 to 39 years old.
“We have known that celiac disease can cause a number of long-term complications that can impact life expectancy, but this study examines an entire population in the most recent era, at a time when awareness of celiac disease and access to gluten-free food is widespread,” says Benjamin Lebwohl, Director of Clinical Research at the Celiac Disease Center at Columbia University and first author of the study.
“Despite this, we found that celiac disease is associated with long-term consequences.”
Individuals with celiac disease were at increased risk of death from cardiovascular disease, cancer and respiratory disease.
Compared with controls, the overall mortality risk was greatest in the first year after diagnosis but the risk increase persisted beyond 10 years after diagnosis.
The increased risk was present also in patients diagnosed during recent years (2010-2017).
“Celiac disease is characterized by inflammation, which is generally bad for your health,” says corresponding and last author, Jonas F Ludvigsson, senior paediatrician at Örebro University Hospital and professor of clinical epidemiology at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet.
“I am therefore not surprised that we found an increased mortality for a number of causes of death in individuals with celiac disease.”
The fact that the relative risks were highest in the first year of follow-up can have several explanations, says Jonas F Ludvigsson.
“The intestinal inflammation is often most intense around diagnosis, and before a gluten-free diet has had an effect on mucosal healing.
Another possible explanation is that the celiac diagnosis may have been made in patients who were very ill from other causes.”
In separate analyses, the authors adjusted for socioeconomic status and comorbidity but the increased mortality risk for people with celiac disease remained.
The research was funded by the Swedish Research Council, the Celiac Disease Foundation and the Louis and Gloria Flanzer Philanthropic Trust. Jonas F Ludvigsson has previously coordinated another study that received funding from the pharmaceutical company Janssen. No other potential conflicts of interest are reported in the paper.
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. A
dditional 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.
- Bouziat R, Hinterleitner R, Brown JJ, et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 2017; 356: 44–50. [PMC free article] [PubMed] [Google Scholar]
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- Goel G, Tye-Din JA, Qiao SW, et al. Cytokine release and gastrointestinal symptoms after gluten challenge in celiac disease. Sci Adv 2019; 5: eaaw7756–eaaw7756. [PMC free article] [PubMed] [Google Scholar]
- Tye-Din JA, Skodje GI, Sarna VK, et al. Cytokine release after gluten ingestion differentiates coeliac disease from self-reported gluten sensitivity. United European Gastroenterol J 2020; 8: 108–118.
- Kivelä L, Hekkala S, Huhtala H, et al. Lack of long-term follow-up after paediatric-adult transition in coeliac disease is not associated with complications, ongoing symptoms or dietary adherence. United European Gastroenterol J 2020; 8: 157–166.
- Ludvigsson JF, Agreus L, Ciacci C, et al. Transition from childhood to adulthood in coeliac disease: the Prague consensus report. Gut 2016; 65: 1242–1251. [PMC free article] [PubMed] [Google Scholar]
- Dominguez Castro P, Harkin G, Hussey M, et al. Prevalence of coexisting autoimmune thyroidal diseases in coeliac disease is decreasing. United European Gastroenterol J 2020; 8: 148–156.
More information:JAMA (2020). DOI: 10.1001/jama.2020.1943