Alessio Fasano, MD
Carlo Catassi, MD
Celiac disease (CD) is an autoimmune disorder characterized by damage of the small intestine mucosa occurring in genetically predisposed individuals, and triggered by the ingestion of dietary gluten 1. Gluten is the major protein component of wheat and other cereals (barley and rye). The genetic predisposition to CD is related to some HLA-related haplotypes, i.e. the DQ2 and the DQ8 heterodymers. HLADQ2 or –DQ8 are needed for CD development, but are not a sufficient cause, as they may be found in many not-CD healthy subjects (approximately 30% of the general population) 1. The development of the CD enteropathy is paralleled by the appearance of serum autoantibodies, e.g. IgA class anti-transglutaminase (TTG) and anti-endomysial (EMA) antibodies, which are a highly specific marker of the disease. CD presents with a wide spectrum of clinical manifestations at any age. Typical CD manifests with intestinal complaints such as chronic diarrhea, weight loss, malnutrition and abdominal distension. Atypical CD is characterized by lack of malabsorption and either intestinal (recurrent abdominal pain, irritable bowel-like symptoms, recurrent aphtous stomatitis) or extra-intestinal manifestations (e.g. isolated increase of serum aminotransferase level, iron deficiency anemia, short stature, delayed puberty or chronic fatigue) 1. Since the introduction of serological tests, “silent” (apparently symptomless) CD has been increasingly recognized because of occasional screening. This is often the case in subjects with a family history of CD, patients with associated autoimmune (e.g. type 1 diabetes) or genetic (Down, Turner or Williams syndromes) disorders 1. Finally, potential CD is characterized by positivity for anti-tTG and EMA antibodies in subjects with a normal intestinal mucosa or subtle histological abnormalities, such as an increased number of intraepithelial lymphocytes (IEL) (so called type 1 lesion). Patients with potential CD can either be free of symptoms or have intestinal symptoms which may respond to a gluten-free diet (GFD). Over time, they may develop a flat mucosa. Treatment of CD is based on the lifelong exclusion of gluten-containing cereals from the diet (1). In many areas of the world, including North America and Europe, gluten-rich products, such as bread and pasta, are part of the staple diet. Gluten-containing food therefore makes a substantial contribution to daily energy intake and is enjoyable to eat. The changes needed to begin and maintain a GFD are substantial and have a major impact on daily life.
CD is one of the most common lifelong disorders in countries populated by individuals of European origin, affecting approximately 1% of the general population. In the early 90’s researchers in Italy launched the new “era” of CD epidemiology 2. Using blood samples from 17,201 healthy Italian students in 1996, it was shown that CD is much more common than previously thought, and that most atypical cases remain undiagnosed unless actively searched for by blood tests. The prevalence of active CD in screened subjects was 4.77 per 1,000 or 1 in 210 subjects 2. The overall prevalence of CD, including diagnosed individuals, was 5.44 per 1,000 or 1 in 184 subjects. The ratio of previously diagnosed to undiagnosed CD cases was as high as 1 to 7 2. Quite surprisingly at that time, most newly diagnosed patients with CD showed only modest complaints such as anemia or chronic fatigue or no symptoms at all 2.
A recently published large international, multicenter study investigated a wide population sample of more than 28,000 children and adults in four different European countries by screening with the serum IgA anti-TTG test (3). On average, the overall prevalence of CD was 1%, with large variations between countries (2.0 % in Finland, 1.2 % in Italy, 0.9 % in Northern Ireland, and 0.3 % in Germany) 3. This study confirmed that many CD cases would remain undetected without active serological screening.
In the past, CD was generally perceived to be less common in North America than in Europe. This misconception was corrected in 2003 by a U.S. prevalence study conducted by the University of Maryland Center for Celiac Research that included 4,126 subjects sampled from the general population 4. The overall prevalence of CD in this U.S. population sample was 1 in 133, actually overlapping the European figures 4.
Similar disease frequencies have been reported from developed countries populated mainly by individuals of European origin, e.g. from Canada, Australia, New Zealand, Brazil and Argentina 5-8. The frequency of CD in other parts of the world is still largely unknown. However recent reports indicate that CD is a common disorder wherever gluten-containing cereals are a staple food, e.g. in Northern Africa, Middle East and part of the Indian continent 9-12.
The epidemiology of CD is efficiently conceptualized by the iceberg model. The overall number of CD cases is the size of the iceberg, which is not only influenced by the frequency of the predisposing genotypes in the population, but also by the pattern of gluten consumption. Typical CD cases are usually diagnosed because of suggestive complaints. They make up the visible part of the celiac iceberg, in quantitative terms expressed by the incidence of the disease. In developed countries, however, for each diagnosed case of celiac disease, an average of 5 cases remain undiagnosed (the submerged part of the iceberg), usually because of atypical, minimal or even absent complaints. These undiagnosed cases remain untreated, leaving individuals exposed to the risk of long-term complications, such as infertility, osteoporosis or cancer. Currently the best approach to improving the CD diagnostic rate is a process of case-finding focused on at-risk groups, a procedure that minimizes costs and is ethically appropriate 13. Increased awareness of the many clinical faces of CD, coupled with a higher inclination for using blood tests, could efficiently uncover a large portion of the submerged celiac disease iceberg. The primary care physician’s office would provide the most natural setting for selective screening to first identify individuals at risk for CD who need referral for definitive diagnosis.
In a recent and rather puzzling development, the prevalence of CD seems to be on the rise in developed countries (Figure 1). The total prevalence of CD has doubled in Finland during the last two decades (1.05% in 1978–80 and 1.99% in 2000–01) 14, and the increase cannot simply be attributed to a better rate of detection.
Figure 1. Trend of Celiac Disease diagnosis in USA since the CFCR 2003 epidemiology study. So far ~180,000 patients out of the 3,000,000 projected cases have been diagnosed. This increase is the combination of increased awareness and, therefore, increased diagnostic rate, and true increase in celiac disease prevalence over time.
To learn more about the natural history of CD and to further investigate the changes in CD prevalence over time, we recently tested blood samples from an American cohort of 3,511 residents from Washington County, Maryland 15. The group has been followed since 1974 for CD autoimmunity. Blood samples were first tested for IgA anti-tTG antibodies. Samples with borderline or elevated anti-tTG antibodies were subsequently tested for the more specific serum IgA class endomysial antibody to improve the diagnostic process. We found CD autoimmunity in 7 subjects in 1974 and in an additional 9 subjects (total 16 cases) in 1989 15. Our study indicated that celiac disease autoimmunity within an American population doubled between 1974 (1 every 501 subjects) and 1989 (1 every 219 subjects). This trend apparently continued in the following years. In a different sample of the adult American population in 2001, we reported a CD prevalence of 1 in 105 4. During the last 30 years the prevalence of CD among adults in the U.S. increased by 5-fold, doubling approximately every 15 years. Remarkably, this study showed that loss of gluten tolerance may occur at any time in life, for reasons that are currently unclear. The implications of this discovery could have a wide-ranging effect on the diagnosis and treatment of CD in elderly patients.
A steady rise in the incidence of autoimmune disorders as well as allergic disorders has been registered in industrialized countries during the last few decades. Both in Europe and the U.S., Type 1 diabetes (T1D) showed a stable and relatively low incidence during the first half of the 20th century, followed by a sharp increase that began some time after the middle of the century. According to the “hygiene hypothesis,” the cleaner environment found nowadays in Western countries led to lower frequency of early childhood infections and differences in the spectrum of microrganisms populating the gut. These changes could modify the immune response and be responsible for higher risk of different autoimmune disorders. However, the rising prevalence of adult onset of CD that we observed in the U.S. study can hardly be explained by hygienic changes occurring in childhood. The amount and the quality of ingested gluten, the type and duration of wheat dough fermentation, the spectrum of intestinal microorganisms and how they change over time, intestinal infections, and stressors in general are all possible switches of the tolerance/immune response balance 16. However, more research is needed to determine if and how these factors can cause loss of gluten tolerance. Researchers could use the results of these studies to determine how to prevent not only the onset of CD but other autoimmune disorders as well.