Celiac Disease (CD)

Celiac Disease (CD)
By Ahmet Aybar, MD, FAAP

Celiac Disease (CD) is one of the autoimmune disease processes affecting susceptible individuals with gluten sensitivity. Ingestion of gluten containing grains, especially the gliadin fraction of wheat gluten triggers the intestinal damage.  This eventually causes a spectrum symptoms ranging from a silent disease to full blown CD.

The typical intestinal damage is seen in the duodenum and upper jejunum, but the extent of this mucosal damage is highly variable and may involve the entire small bowel in some rare cases.  The other characteristic finding is that the intestinal involvement may be patchy.

The intestinal damage is characterized by loss of absorptive surface of the small intestine that in turn causes variety of nutritional deficits in the affected individuals. However, these mucosal changes completely resolve upon elimination of gluten from the patient’s diet.

It is now evident that CD is the result of an inappropriate T cell-mediated immune response against ingested gluten. In normal conditions, the intestinal surface serves as the main barrier to passage of large molecules such as gluten.  However, in CD, this barrier can no longer serve its function and an immune response to environmental antigens (i.e., gluten) may develop.

There have been tremendous amount of research and discoveries reported on CD within the past 15 years.  One example of this is discovery of the tissue transglutaminase (tTG). In 1997, Dieterich et al demonstrated that one of the targets of the autoimmune response in CD is the tTG. The demyelinating activity of this enzyme seems to generate gliadin peptides that bind to DQ2 to be recognized by disease-specific intestinal T cells.

Once considered as a rare disorder, Celiac disease (CD) used to be affecting individuals of European origin.  In the past, the diagnosis was made based on symptoms of the disease and subsequent confirmation by duodenal biopsy.  However, with emergence of newer diagnostic tools that are highly sensitive and specific there is a surge of clinically atypical or even silent forms of CD.  These serologic tests such as antiendomysium (EMA) and the antitransglutaminase (tTG) antibodies used in number of studies confirmed that CD is one of the commonest, lifelong disorders affecting humanity all over the world. 

CD is not only frequent in developed countries, but is increasingly reported in developing or underdeveloped countries in North Africa, the Middle East, and Asia.  CD contributes substantially to childhood morbidity and mortality in these countries.

In the past 3 decades, a number of epidemiologic studies have been conducted in Europe to establish the frequency of CD. One of the oldest of these studies conducted in 1950 established that the cumulative incidence of the disease in England and Wales was 1/8000, whereas an incidence of 1/4000 detected in Scotland. The diagnosis at that time was difficult due to variable symptoms and confirmed by nonspecific tests. The awareness of the disease greatly increased in 1960s when tests that are more specific became available. Consequently, in the mid 1970s the incidence was being reported in the neighborhood of 1/450-500 in studies from Ireland, Scotland, and Switzerland. This sudden jump in the number of CD cases prompted changes in the dietary habit, based on the assumption that delayed exposure to gluten could prevent the onset of the disease.  After a late introduction of gluten in infant diet, in the UK and Ireland, the incidence of CD decreased.  Unfortunately, this decrease was subsequently counterbalanced by the increase of atypical forms of CD occurring in older children or in adults.

As more sensitive diagnostic serologic tests have become available, it is now possible to evaluate the prevalence of CD (number of affected persons, including silent cases, in a defined population at a certain point in time).  The prevalence of CD throughout the world seems to be more homogeneous.  Furthermore, these screening tests showed that CD is one of the most frequent genetically based diseases occurring in 1 of 130-300 in the European population. Another interesting observation is that despite similar genetic backgrounds and environmental factors, the clinical presentation of CD may greatly diverge in neighboring countries. One example of this is Denmark, where the incidence of CD was thought to be 1/10000. This was almost 10-fold less than Finland, and 30-fold less than Sweden who share similar genetic background. Subsequent studies later on suggested that actually CD was as frequent in Denmark as other Scandinavian countries with reported prevalence of 1/500 and most cases in Denmark were undiagnosed due to lack of typical clinical symptoms. Factors such as type of cow’s milk formulas, breast feeding, age at gluten introduction, quantity of gluten and quality of cereals, and quantity of wheat gluten may all influence the clinical presentation of the disease.

There were only limited number of scientific papers published in the US in the 30 year period from 1965-1995 and based on them, CD was thought to be a rare with the prevalence of ~1: 10000. These studies were based on strict guidelines such as presence of classic gastrointestinal symptoms of CD, dermatitis herpetiformis, and positive biopsy findings. Unfortunately, by focusing on specific symptoms, these studies failed to consider the protean clinical manifestations of CD, the submerged part of the so-called Celiac Iceberg. Recently, a series of epidemiologic studies conducted using more appropriate experimental designs and powerful screening tools showed that CD is as frequent in the US as in Europe.

CD is the result of interaction between genetic (both HLA and non-HLA associated genes) and environmental factors (gluten-containing grains), therefore if one evaluates the world distribution of these 2 factors, areas at risk can be identified. We already confirmed that Europe is a high risk region. By the same token, there have been limited epidemiologic studies coming from the regions where CD has been considered rare. In fact, recent studies have shown that areas that are known to be at risk such as South America, North Africa, and Asia, CD was indeed underdiagnosed.

A seen in Europe the clinical presentation of CD varies greatly in neighboring countries which may explain the difference in prevalence previously reported. This difference stems from the fact that CD with typical gastrointestinal findings (in the intestine) is 15 times less common than CD with atypical findings (out of the intestine); therefore making the diagnosis more challenging.

The epidemiology of CD is efficiently conceptualized by the Iceberg Model, originally introduced in 1991. The prevalence of CD can be conceived as the overall size of the iceberg, which is both influenced by the genetic makeup of the population and by the pattern of gluten consumption. In many countries the prevalence of CD is in the neighborhood of 0.5-1 % of the general population. These cases make up the visible part of the iceberg. In developed countries, for each diagnosed case of CD, and average of 5-10 cases remain undiagnosed (the submerged part of the iceberg), because of atypical or unusual complaints as described above. The importance of this lies in the fact that the undiagnosed cases remain at risk for long term complications of CD. The line separating this iceberg, so called “the waterline” is dynamic and mostly depends on the physician’s intuitiveness in CD diagnosis and utilization of serologic CD markers. The availability of such diagnostic tests or lack there of, is a major problem in large areas of the world, e.g., North Africa, the Middle East, and India, where the frequency of CD is currently underestimated. Because of the variable relevance of these factors, the waterline is much more unstable than the overall size of the iceberg, thereby explaining the reported wide fluctuations of CD incidence. The intriguing question at present is whether environmental variables can influence the prevalence of CD, therefore assessing the fascinating possibility of primary prevention of this disorder.

-Ahmet Aybar, MD, FAAP