A Large Multicenter Study, Arch Intern Med. 2003; 163:286-292

Reviewed by Lynn Rainwater

A Memo to the Celiac Community was posted on the Internet in April 1997 announcing a fund raising campaign kickoff for a US celiac prevalence study. Alamo Celiac shared this memo with you in our June newsletter that year. The memo asked “How can celiacs in the US get the necessary attention of the medical, business, and governmental communities we so desperately seek?”

In answer to this question the memo explained: “A few short years ago many European countries were experiencing the same frustrations. Today, things are dramatically better. Most have gluten-free products readily available; doctors are knowledgably looking for celiac disease in patients; school children are being tested for celiac disease when they first enroll in school; McDonald's sells gluten-free Big Macs. What made the difference was a series of serological screening studies. They concluded, beyond a reasonable medical doubt, that 1 of every 300 in the general population is a celiac. These tests showed that there was a lucrative market in celiac disease; and money speaks.”

The memo reasoned “Since celiac disease is genetic, those of us in the US of European descent should test to the same ratio.” It noted that “The technology used by the Europeans to do these studies is even more reliable today.”

Then came the big news: “University of Maryland School of Medicine has established the Center for Celiac Research, with Drs. Alessio Fasano and Karoly Horvath, Medical Directors. They have set up a design for a comprehensive study, in cooperation with several medical centers throughout the US, to establish the prevalence rate of celiac disease in this country.”

In February 2003, the details of the study that resulted from the proposal in that groundbreaking memo were published. The results of the study are: “In at-risk groups, the prevalence of CD was 1:22 in first-degree relatives, 1:39 in second-degree relatives, and 1:56 in symptomatic patients. The overall prevalence of CD in not-at-risk groups was 1:133. All the EMA-positive subjects who underwent intestinal biopsy had lesions consistent with CD.”

Who was tested?

A total of 13,145 people were tested, 9,019 at risk and 4,126 not at risk for celiac disease. Of these, 57% were female. Participants were from all age groups:

• 0 to 19 years: 27.3%
• 20 to 44 years: 38.0%
• 45 to 59 years: 20.1%
• 60 years or older: 14.6%

The study report notes that “At-risk subjects were either relatives of patients with CD or were patients who presented with CD-associated symptoms (diarrhea, abdominal pain, and constipation) or with CD-associated disorders (type 1 diabetes mellitus, Down syndrome, anemia, arthritis, osteoporosis, infertility, and short stature). A total of 4,508 first-degree and 1,275 second-degree relatives of patients with biopsy-proven CD (as established by either medical records or verbal reports) were recruited during CD support group meetings…In addition, 1,326 children and 1,910 adults with either CD-associated symptoms or CD-associated disorders were enrolled.”

The not-at-risk groups tested included blood donors, schoolchildren, and patients seen in outpatient clinics for routine checkups as follows:

• Red Cross blood bank blood donors: 2,000
• West Virginia schoolchildren: 1,119
• Tested during routine visits to health care providers or during CD support group meeting: 1,007 adults and children

What were the results?

• 350 (2.7%) of 13,145 tested were EMA positive
• Of the 350 EMA-positives, 143 (41%) were asymptomatic
• Intestinal biopsies were performed on 116 (33%) of the EMA-positives, and in all cases a lesion compatible with the diagnosis of CD was found
• Only 40 (34%) of the EMA-positives tested showed classic subtotal or total villous atrophy
• Of the remaining 234 EMA-positives, 56 chose to go on the gluten-free diet without confirming the diagnosis by biopsy, 55 remained on an unrestricted diet, 71 had requests for a biopsy denied by either their physician or health care insurance company, and 52 were undecided.
• The prevalence of CD was relatively similar across all age groups
• The results suggest that CD is as frequent among adolescents as among younger children
• Among relatives of patients with CD, 205 first-degree relatives and 33 second-degree relatives tested positive
• Of the newly diagnosed at-risk pediatric cases, 40% were symptomatic
• Of the newly diagnosed at-risk adult cases, 59% were symptomatic
• Abdominal pain, diarrhea, and constipation were among the most frequently reported symptoms
• Only 35% of the newly diagnosed had chronic diarrhea
• The prevalence of CD was as high in asymptomatic first– and second-degree relatives of patients with CD as in relatives with symptoms, highlighting the importance of genetic predisposition as a risk factor
• In non-relatives, the presence of symptoms significantly increased the risk of CD
• A high prevalence was found among those with numerous common disorders, including type 1 diabetes, anemia, arthritis, osteoporosis, infertility, and Down syndrome, even in the absence of gastrointestinal symptoms
• In not-at-risk patients, the prevalence of CD was significantly higher in adults at 1:105 than in children at 1:320, suggesting a correlation between the duration of gluten exposure and the development of an immune response to gluten in genetically susceptible individuals

Discussion

The researchers ask “If CD is as common in the United States as our study suggests,” why “is it not diagnosed more frequently?” They feel that “Foremost among the possible explanations is that if physicians believe that CD is rare, they are less likely to test for it. A failure by physicians to appreciate that many individuals with the disease initially present without gastrointestinal symptoms is another reason why CD testing may not be performed. Use of only the more widely known but less sensitive and less specific AGA serologic test instead of EMA and tTG tests could also result in missed diagnoses. Even when gastrointestinal symptoms are present and a gastrointestinal endoscopy is performed, endoscopists do not always obtain intestinal biopsy specimens that could demonstrate the presence of CD. Finally, failure by pathologists to recognize early features of CD “…could be a significant problem in the United States.”

Moreover, the authors feel that “Our study suggests that a minority of patients (34%) will have the classic flat mucosa, while most have various degrees of partial villous atrophy that could be misinterpreted by those unfamiliar with the architectural changes found in the early stages of the disease.”

What was really surprising was that for 21% of the EMA positive individuals, physicians or insurance companies denied payment for an intestinal biopsy, claiming that the costs of this procedure were not justified by the symptoms. As the protocol for diagnosis of CD calls for intestinal biopsy to be performed when the blood tests are positive, this is inexcusable. The researchers are of the opinion that “This attitude probably reflects the lack of appreciation of the magnitude of the problem in the United States and the potential consequences of a delayed diagnosis.” With such shortsightedness so common, no wonder “…the average gap between the onset of symptoms and the time CD diagnosis was confirmed” is 11 years.

Conclusions

The authors conclude that “Our results suggest that CD occurs frequently not only in patients with gastrointestinal symptoms, but also in first- and second-degree relatives and patients with numerous common disorders even in the absence of gastrointestinal symptoms. The prevalence of CD in symptomatic patients and not-at-risk subjects was similar to that reported in Europe. Given the high morbidity and mortality related to untreated CD and the prolonged delay in diagnosis in the United States, serologic testing of at-risk patients (ie, case finding) is important to alleviate unnecessary suffering, prevent complications, and improve the quality of life of a multitude of individuals with CD.”

Author Information

From the Center for Celiac Research (Drs Fasano, Fornaroli, and Horvath, Mr Drago, and Mss Thorpe and Kryszak), Division of Pediatric Gastroenterology and Nutrition (Drs Fasano and Horvath, Mr Drago, and Mss Thorpe and Kryszak), and Center for Vaccine Development (Dr Wasserman), University of Maryland School of Medicine, Baltimore; Istituto per l'Infanzia Burlo Garofalo, Trieste, Italy (Drs Berti, Gerarduzzi, Not, and Ventura); Division of Pediatric Gastroenterology and Nutrition, University of Vermont, Burlington (Dr Colletti); Division of Pediatric Gastroenterology and Nutrition, Marshall University, Huntington, WV (Dr Elitsur); Division of Gastroenterology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY (Dr Green); Section of Pediatric Gastroenterology, Hepatology, and Nutrition, and University of Chicago Celiac Disease Program, University of Chicago, Chicago, Ill (Dr Guandalini); Division of Pediatric Gastroenterology and Nutrition, Wake Forest University School of Medicine, Winston-Salem, NC (Dr Hill); Division of Pediatric Gastroenterology and Nutrition, Children's Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles (Dr Pietzak); and Mayo Clinic, Rochester, Minn (Dr Murray).