Autoimmune Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease

doi:10.1016/j.cgh.2015.01.026

Clinical Gastroenterology and Hepatology

Volume 13, Issue 7, July 2015, Pages 1271-1277.e2

https://doi.org/10.1016/j.cgh.2015.01.026 Get rights and content

Background & Aims

First-degree relatives of individuals with celiac disease are at increased risk for this disorder, but little is known about their risk for other autoimmune diseases. We assessed the risk of nonceliac autoimmune disease in first-degree relatives and spouses of people with celiac disease.

Methods

We identified individuals with celiac disease by searching computerized duodenal and jejunal biopsies, collected from 1969 through 2008, at 28 pathology departments in Sweden. Celiac disease was identified based on biopsy reports of villous atrophy (equal to Marsh grade 3; n = 29,096). Individuals with celiac disease were matched with up to 5 controls (people without celiac disease) for sex, age, county, and calendar year (total, 144,522 controls). Through Swedish health care registries, we identified all first-degree relatives (fathers, mothers, siblings, and offspring) and spouses of individuals with celiac disease (n = 84,648) and controls (n = 430,942). We used Cox regression analysis to calculate hazard ratios (HRs) for nonceliac autoimmune disease (Crohn’s disease, type 1 diabetes mellitus, hypothyroidism, hyperthyroidism, psoriasis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, or ulcerative colitis) in these groups.

Results

During the follow-up period (median, 10.8 y), 3333 of the first-degree relatives of patients with celiac disease (3.9%) and 12,860 relatives of controls (3.0%) had an autoimmune disease other than celiac disease. First-degree relatives of people with celiac disease were at increased risk of nonceliac autoimmune disease, compared with controls (HR, 1.28; 95% confidence interval, 1.23–1.33), as were spouses (HR, 1.20; 95% confidence interval, 1.06–1.35). Risk estimates for nonceliac autoimmune disease did not differ between first-degree relatives and spouses of individuals with celiac disease (interaction test: P = .11). HRs for nonceliac autoimmune disease were highest in the first 2 years of follow-up evaluation.

Conclusions

First-degree relatives and spouses of individuals with celiac disease are at increased risk of nonceliac autoimmune disease. In addition to genetic factors, environmental factors and ascertainment bias might contribute to the increased risk of autoimmunity in first-degree relatives of individuals with celiac disease.

Section snippets

Collection of Biopsy Data

Data regarding CD were collected in 2006 to 2008 through computerized duodenal/jejunal biopsies performed at all Swedish Pathology Departments between 1969 and 2008. CD was defined as having a biopsy specimen classified with villous atrophy equal to histopathology, stage Marsh III,¹⁴ with date of first pathologic biopsy as the date of diagnosis and study entry. In total, there were 29,096 celiac individuals identified. Taking small intestinal biopsy samples is the clinical routine in Sweden,¹⁵

Background Data

We obtained data on 84,648 unique celiac FDRs and 430,942 control FDRs (Table 1). The majority of FDRs were male (61.1% in celiac FDRs vs 61.4% in control FDRs), which was expected because most CD patients are female. There were 3333 unique events of any nonceliac autoimmune disease in celiac FDRs compared with 12,860 in the control relatives; for spouses, the corresponding figures were 323 for the celiac FDRs and 1353 for the control relatives (Table 1). Own celiac disease was more prevalent

Discussion

In this nationwide, population-based longitudinal cohort study we examined the risk of nonceliac autoimmune disease in celiac FDRs. All outcomes were more common in celiac FDRs than in control FDRs, and hence we found a significantly increased risk of our composite measure “any included nonceliac autoimmune disease” in celiac FDRs. The highest HRs were observed for SLE, T1DM, and sarcoidosis. Although these diseases have been linked to CD, the HRs in individuals with CD have been substantially

Conclusions

We found an increased risk of nonceliac autoimmune disease in FDRs and celiac spouses. This risk probably represents a mixture of genetic, environmental, and ascertainment bias mechanisms.

Acknowledgments

This project (2006/633-31/3) was approved by the Research Ethics Committee of the Karolinska Institutet, Sweden, on June 14, 2006.

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Cited by (29)

Celiac disease
2024, Medicine (Spain)
La enfermedad celíaca (EC) se define como una enteropatía autoinmune crónica desencadenada por la ingesta de gluten que afecta a individuos genéticamente predispuestos. Su prevalencia ha aumentado en los últimos años (se estima en torno a un 1%), debido principalmente a la mayor implantación del cribado de individuos de riesgo y a la mejora de las herramientas diagnósticas. Las manifestaciones clínicas de la EC tienen un amplio espectro, con síntomas de presentación muy variados, tanto digestivos como extradigestivos. Como herramientas diagnósticas fundamentales ante la sospecha clínica disponemos de la determinación de serología (elevada sensibilidad y especificidad), junto con el estudio genético y posterior confirmación histológica con biopsia duodenal. El único tratamiento efectivo en la EC es la retirada completa del gluten en la dieta. Es muy importante una correcta labor formativa y educativa por parte de los profesionales sanitarios para asegurar una buena adherencia a la dieta sin gluten y evitar complicaciones asociadas a largo plazo como EC refractaria o desarrollo de linfoma intestinal.
Celiac disease (CD) is defined as a chronic autoimmune enteropathy triggered by gluten intake that affects genetically predisposed individuals. Its prevalence has increased in recent years (it is estimated to be around 1%), mainly due to increased implementation of screening of at-risk individuals and improved diagnostic tools. There is a broad spectrum of clinical manifestations of CD, with a wide variety of presenting symptoms, both digestive and extra-digestive. When there is a clinical suspicion, the available diagnostic tools include a serology determination (high sensitivity and specificity) together with a genetic study and later histological confirmation with a duodenal biopsy. The only effective treatment for CD is the complete elimination of gluten from the diet. Proper training and education by healthcare professionals is very important in order to ensure good adherence to a gluten-free diet and to avoid associated long-term complications such as refractory CD or the development of intestinal lymphoma.
Sarcoidosis and its relation to other immune-mediated diseases: Epidemiological insights
2023, Journal of Autoimmunity
Several epidemiological studies show a co-occurrence of sarcoidosis with other immune-mediated diseases (IMD). There are many similarities between sarcoidosis and IMDs in their geographical distribution and risk factors. Understanding these similarities and identifying the differences can help us to better understand sarcoidosis and put it into context with other IMDs. In this review, we present the current knowledge about the overlap between sarcoidosis and other IMDs derived from epidemiological studies. Epidemiologic methods utilize study design and statistical analysis to describe the patterns in data and, ideally, identify causal relationships between an exposure and a health outcome. We discuss how study design and analysis may affect the interpretation of epidemiological studies on this topic and highlight some theories that attempt to explain the relation between sarcoidosis and other IMDs.
Comorbidities associated with celiac disease, dermatitis herpetiformis, and nonceliac gluten sensitivity
2021, Gluten-Related Disorders: Diagnostic Approaches, Treatment Pathways, and Future Perspectives
Celiac disease is common so that many disorders will occur in association. Diabetes mellitus was the earliest disorder to be described in a child with celiac disease in 1925 (Poynton FJ, Cole LB. A case of celiac disease with glycosuria. Br J Child Dis. 1925;22:30–6) and in an adult in 1956 (Finlay JM, Wightman KJR. Modern treatment of the malabsorption syndrome in adults. Ann Intern Med. 1956;45:191–206). Since then the number of recognized comorbidities has mushroomed. Interest in this aspect of celiac disease has not diminished, and many reports continue to be published. Many disorders also occur in conjunction with dermatitis herpetiformis and nonceliac gluten sensitivity. Relatives of patients with celiac disease may develop specific comorbidities. Those involved in providing care for patients need to be aware of these associations so that optimal support can be given. Some comorbidities will simply be chance occurrences whereas others will have a statistically valid link, while yet others can be regarded as complications of celiac disease. This review is not designed to be comprehensive because the number of publications is now very extensive so will concentrate mainly on more recent reports. Earlier literature has been summarized in detail (Lewis NR, Holmes GKT. Risk of morbidity in contemporary celiac disease Exper Rev Gastroenterol Hepatol. 2010;4(6):767–80; Lewis NR, Holmes GKT. Morbidity and mortality associated with celiac disease. In: Rampertab SD, Mullin GE, editors. Celiac disease. New York: Humana Press; 2014. p. 209–43). There are currently no reports of comorbidities occurring with wheat allergy or gluten ataxia.
Wheat - An Exceptional Crop: Botanical Features, Chemistry, Utilization, Nutritional and Health Aspects
2020, Wheat - An Exceptional Crop: Botanical Features, Chemistry, Utilization, Nutritional and Health Aspects
Prevalence and Morbidity of Undiagnosed Celiac Disease From a Community-Based Study
2017, Gastroenterology
Citation Excerpt :
Moreover, we found some laboratory measures, including cholesterol and ferritin levels, were lower in individuals with undiagnosed celiac disease than in matched controls. These findings are partly consistent with results from a previous study19 showing that undiagnosed celiac disease is associated with an increased risk of comorbid conditions in older adults, as well as findings of other studies of patients with clinically detected celiac disease.43,44 Furthermore, we found the difference of laboratory parameters between those with and without positive serology.
Little is known about the prevalence and burden of undiagnosed celiac disease in individuals younger than age 50. We determined the prevalence and morbidity of undiagnosed celiac disease in individuals younger than age 50 in a community.
We tested sera from 31,255 residents of Olmsted County, Minnesota (<50 y), without a prior diagnosis of celiac disease assay using an assay for IgA against tissue transglutaminase; in subjects with positive test results, celiac disease was confirmed using an assay for endomysial IgA. We performed a nested case–control study to compare the proportion of comorbidities between undiagnosed cases of celiac disease and age- and sex-matched seronegative controls (1:2). Medical records were abstracted to identify potential comorbidities.
We identified 338 of 30,425 adults with positive results from both serologic tests. Based on this finding, we estimated the prevalence of celiac disease to be 1.1% (95% confidence interval, 1.0%–1.2%); 8 of 830 children tested positive for IgA against tissue transglutaminase (1.0%; 95% confidence interval, 0.4%–1.9%). No typical symptoms or classic consequences of diagnosed celiac disease (diarrhea, anemia, or fracture) were associated with undiagnosed celiac disease. Undiagnosed celiac disease was associated with increased rates of hypothyroidism (odds ratio, 2.2; P < .01) and a lower than average cholesterol level (P = .03) and ferritin level (P = .01). During a median follow-up period of 6.3 years, the cumulative incidence of a subsequent diagnosis with celiac disease at 5 years after testing was 10.8% in persons with undiagnosed celiac disease vs 0.1% in seronegative persons (P < .01). Celiac disease status was not associated with overall survival.
Based on serologic tests of a community population for celiac disease, we estimated the prevalence of undiagnosed celiac disease to be 1.1%. Undiagnosed celiac disease appeared to be clinically silent and remained undetected, but long-term outcomes have not been determined.
No increased mortality in 109,000 first-degree relatives of celiac individuals
2016, Digestive and Liver Disease
Citation Excerpt :
The mortality ratio in FDRs was substantially lower than in individuals with CD in our earlier study of Swedish individuals with biopsy-verified CD [13]. Earlier studies [22,33] have found an increased risk of both lymphoproliferative malignancy and autoimmune disease in FDRs to individuals with CD and that may have contributed to the excess mortality. Mortality ratios were very similar in different FDRs (Table 2), ranging from 0.99 in brothers to 1.04 in offspring where sons were at no increased risk but daughters demonstrated a 10% increased mortality.
Several studies have shown an excess mortality in individuals with celiac disease (CD). However, it is unknown if also first-degree relatives (FDRs) to celiac patients are at increased risk of death.
We aimed to assess mortality in FDRs to celiac patients.
Individuals with CD were identified through biopsy reports (equal to Marsh grade III). Each celiac individual was matched on sex, age, county and calendar year with up to five control individuals. Through Swedish healthcare registries we identified all FDRs (father, mother, sibling, offspring) of CD individuals and controls. Through Cox regression we calculated hazard ratios (HRs) for mortality (all-cause death, circulatory, cancer and other).
We identified 109,309 FDRs of celiac individuals and 549,098 FDRs of controls. Overall mortality was increased in FDRs to celiac individuals (HR = 1.02, 95%CI = 1.00–1.04, p = 0.03). This corresponded to an excess risk of 5.9 deaths per 100,000 person-years of follow-up. When limiting follow-up to time since celiac diagnosis in the index individual, we found no increased risk of death (HR = 1.01; 95%CI = 0.98–1.03).
FDRs to individuals with CD are at increased risk of death. This excess risk is however minimal and unlikely to be of any clinical importance to the individual.

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: Conflicts of interest The authors disclose no conflicts.

: Funding This study was funded by the Swedish Research Council.

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Original articleAlimentary tractAutoimmune Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease

Background & Aims

Methods

Results

Conclusions

Section snippets

Collection of Biopsy Data

Background Data

Discussion

Conclusions

Acknowledgments

Lancet

Gastroenterology

J Autoimmun

Clin Gastroenterol Hepatol

Gastroenterology

J Autoimmun

Gastroenterology

Clin Gastroenterol Hepatol

The first large population based twin study of coeliac disease

Gut

Celiac disease

N Engl J Med

Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes

Aliment Pharmacol Ther

Celiac disease and autoimmunity

J Pediatr Gastroenterol Nutr

Mapping of immune-mediated disease genes

Annu Rev Genomics Hum Genet

Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study

Arch Intern Med

Original article
Alimentary tract
Autoimmune Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease