On a small island off the coast of Portugal, researchers tested family members of 39 children diagnosed with celiac disease at the island’s only hospital. This study, which was highly representative of the island’s entire population, investigated the prevalence of celiac disease in untested family members. NFCA is committed to helping untested family members get diagnosed through our Family Talk program, and this study has reaffirmed our drive to raise more awareness in this area.
The researchers took blood samples from 95 first-degree relatives of the children they originally surveyed, and tested for IgA-tTG antibodies. Five of these first-degree relatives had elevated IgA-tTG antibodies, so they underwent genetic testing. HLA-DQ2 was found in three of the relatives, and two were HLA-DQ2 incomplete. In other words, those who were HLA-DQ2 incomplete only presented with one chain of the gene. Interestingly, most of the relatives experienced symptoms associated with celiac disease. Looking at these results, it is clear that it is important for first-degree relatives to be screened for celiac disease even in the absence of symptoms. The results of this study may have other implications on family testing as well.
To get answers to our most pressing questions about this study, we turned to the corresponding author, Dr. Joana Raquel Henriques Oliveira from the pediatric department at Dr. Nélio Mendonça Hospital, Madeira.
Q. First and foremost, can you please explain what it means to be “HLA-DQ2 incomplete”?
A. The principal determinants of genetic susceptibility for celiac disease are the DQA and DQB genes coded in the short arm of chromosome 6. More than 95% of celiac disease patients share the HLA-DQ2 heterodimer (two chains of the gene), and most of the remainder have the HLA-DQ8.
The presence of only one chain of the DQ2 heterodimer (DQA1*05 or DQB1*02, but not both) accounts for an increased risk of celiac disease. Patients in this situation are said to have “half DQ2 gene,” or HLA-DQ2 incomplete.
Q. After testing for antibodies and genetic typing, four of the five relatives who were at a high risk of having celiac disease underwent intestinal biopsy to confirm a diagnosis. However, one participant chose not to have a biopsy done to confirm his diagnosis, even after being informed of the complications linked to untreated celiac disease.
A. In cases such as these, when relatives refuse to undergo testing despite knowing that they are at a higher risk for celiac disease, what information would you suggest using to persuade someone that this invasive procedure is necessary for their health and wellbeing?
Despite the fact that the intestinal biopsy still is the gold standard for celiac disease diagnosis, it is an invasive test and is understandable that some refuse to do it. For this reason serologic tests and HLA typing have an important role in screening potential patients. However, if these tests are positive, it is important to confirm the diagnosis by intestinal biopsy, considering that celiac disease is a lifelong disorder with the need for adherence to a restrictive and demanding diet.
Recent population-based studies have confirmed that patients with diagnosed celiac disease are at increased risk of mortality and increased risk of gastrointestinal cancer. There is also some evidence suggesting that a gluten free diet may reduce the risk of lymphoproliferative malignancy. The confirmation of the diagnosis is important to start a gluten free diet in order to prevent complications and improve the quality of life of individuals with celiac disease.
Q. One participant had elevated antibodies and had the presence of HLA-DQ2, but her intestinal biopsy was normal. When test results indicate that someone does not have biopsy-confirmed celiac disease, but is at a higher risk for developing it down the road because of a positive genetic test and elevated antibodies, what are the next steps for follow-up and further testing?
A. If a seropositive asymptomatic at risk person does not have any conclusive evidence for celiac disease after the extended evaluation of biopsies it is advised to follow such a person on a normal gluten-containing diet, and re-evaluate them at regular intervals, because the disease may still develop later in life.
Q. Two of the first-degree relatives who underwent genetic typing had incomplete HLA-DQ2 genes. Can you explain what it means to have an incomplete gene, and if there are any implications for further treatment of these individuals?
A. Having either a complete or incomplete DQ2 gene accounts for a higher risk of celiac disease, so the follow-up is advised in both situations.
Q. With a 3.15% prevalence of celiac disease in first-degree family members, prevalence on Madeira Island is much higher than in Portugal, which you note has a prevalence of 0.7%. You suggest that this may be because of a “lower genetic variability in island inhabitants.” Can you explain this phenomenon a little further? What implications may this have for other island or smaller country populations?
A. In small populations, the risk of inbreeding and crossing with genetically similar elements, increases the occurrence of all genetically mediated diseases. So, we believe that this factor may have contributed for the higher prevalence of celiac disease in our island.
Q. Only three out of five of the relatives studied experienced symptoms related to celiac disease. It can be very difficult to ask family members to be tested for celiac disease due to the cost and invasiveness of the procedure, as you mentioned in your study. It becomes even more difficult when they do not experience any symptoms that affect day-to-day activities. How can doctors overcome these barriers when evaluating a patient’s risk of having celiac disease because of their family history?
A. When symptoms are absent, it is harder to get the message of the need for diagnosis and management of this disease. A doctor-patient healthy and reliable relationship, based on communication and continuous information is required. In most cases, when the patient is informed of the risks involved in untreated celiac disease, they will agree to perform the tests, even without symptoms.
Q. As the celiac disease field looks to identify best practices in increasing the diagnosis rate, what are your recommendations for physicians and researchers looking to adopt a strategy for testing among at-risk family members?
A. Among at-risk family members, genetic HLA testing as the first course of action is probably cost effective because a significant proportion of the patients do not harbor DQ2 or DQ8 genes, and can be excluded from further follow up studies.
However, if HLA testing is not feasible, the screening procedure may start with celiac disease specific antibody testing (anti-TG2 and serum total IgA determination). If IgA anti-TG2 is negative and IgA deficiency is excluded, celiac disease at the present time is very unlikely. However, the disease may still develop later in life. Therefore serological testing should be repeated at regular intervals.
If anti-TG2 antibodies are positive, signs related to celiac disease should be searched for (anemia, elevated liver enzymes, etc.). Even in the abcense of such signs, if anti-TG2 concentration is >3 times upper limit of normal, the patient should be referred to a specialist (gastroenterologist or pediatric gastroenterologist) for endoscopy with intestinal biopsies.
If you or a loved one has been diagnosed with celiac disease, please talk to your family members about the importance of being tested. Visit our website at http://www.beyondceliac.org/Resources/Talk-to-Your-Family/740/ to get more information on how to talk to your family members about getting tested, how loved ones should talk to their doctor about their risk of developing celiac disease, and many more useful resources.
Source: Oliveira, J. R. H., Cabral, A. J., Ferreira, E., Capelinha, F., Spínola, H., & Gonçalves, R. (2014). Celiac disease in children from Madeira Island and its prevalence in first degree relatives. Arquivos de gastroenterologia, 51(2), 151-154.