Overview of Biomarkers for Diagnosis and Monitoring of Celiac Disease

Ignazio Brusca1    Department of Clinical Pathology, “Buccheri La Ferla” Hospital, Palermo, Italy
1 Corresponding author: email address: ignbr@libero.it

1 Introduction

Wheat is one of the principal components of the human diet among diverse populations around the world. There is a widespread perception of wheat as an ancient and healthy food, associated with positive emotions. Wheat-based foods are used in advertisements to evoke a sense of tranquility, peace, and well-being. Like all foods, however, wheat is capable of causing a wide range of adverse reactions. Of these, celiac disease (CD) is the longest studied and best-known pathology.

The recently issued guidelines of the European Society of Pediatric Gastroenterology and Nutrition (ESPGHAN) define CD as an immune-mediated systemic disorder, elicited by gluten and related prolamins in genetically susceptible individuals [1]. This pathology is characterized by a number of variable signs and symptoms, the presence of specific autoantibodies, the genetic haplotype DQ2 or DQ8, and enteropathy [1]. These concepts are expressed in other recent publications on CD; “The Oslo definitions for coeliac disease-related terms” and “Spectrum of gluten-related disorders: consensus on new nomenclature and classification” [2,3]. The key points highlighted in these recent consensus documents are: (a) the presence of the principle pathology of enteropathy (i.e., villous atrophy), (b) the presence of heterodimers DQ2 or DQ8, and (c) an association between clinical manifestation and gluten consumption.

Gluten is an alcohol-soluble fraction of wheat, principally made up of gliadin and glutenin, which are storage proteins. Prolamins similar to gliadin are present in other seeds grown for human consumption, notably barley and rye. In subjects who have the haplotypes DQ2 or DQ8, deamidated fractions of gliadin presented to the immune system can induce an autoimmune reaction that causes small bowel mucosal damage. The consumption of gluten elicits the symptoms, and the elimination of this food from the diet has a positive effect, not only clinically but also on histological mucosal damage and on serology.

A recent International Consensus [3] has defined three categories of adverse effects caused by wheat ingestion: (1) the autoimmune reaction classified as CD, dermatitis herpetiformis (DH) and gluten ataxia, (2) allergic reactions, and (3) non-celiac gluten sensitivity (NCGS).

Allergic reactions to wheat can be induced by certain agents, other than gluten, which are also present in food. The most frequent clinical manifestations of these are baker's asthma, usually induced by sensitization to the alpha amylase, and wheat-dependent exercise-induced anaphylaxis, in which the most frequent allergen responsible is omega-5-gliadin. Tri a14, a Lipid Transfer Protein, is also present in wheat, but it has a low cross-reaction with the LTPs of other allergenic foods that most frequently cause allergic reactions to foods in the Mediterranean region.

NCGS can present with a wide range of symptoms, often not distinguishable from CD. The serology findings typical of CD (anti-transglutaminase and -endomysial autoantibodies) are negative. Minimal intestinal damage is possible. The heterodimer DQ2/DQ8 is present in about 50% of these cases, and IgG anti-gliadin antibodies (AGA) are present in the same percentage of subjects. A test that could have been a good candidate for the diagnosis of this condition was the basophil activation test [4,5], but the recent commercialized formulation is unable to detect this condition [6]. The diagnosis is therefore principally made through a gluten-free diet and then a food challenge.

2 Epidemiology

The first epidemiological studies of CD expressed the belief that this disorder prevailed among European and North American white individuals, but progress in diagnostic procedures, and later studies, have completely revolutionized our knowledge of the actual frequency and distribution of the disease around the world [7,8]. The worldwide distribution of CD reflects the consumption of cereals by populations and their migratory flows. Genetic background information has enabled us to conclude that Middle-Eastern populations, who commonly cultivated wheat and rye in the region denominated the “Fertile Crescent,” migrated to the Mediterranean region and central and western Europe about 10,000 years ago, and then continued with their process of expansion towards Northern Europe [9]. Where there was once thought to be a low incidence of the disease, it is now believed that this was because of under diagnosis [10]. The epidemiological studies published so far are not homogeneous: some are based only on serology results, some take into account serology and small bowel biopsy, and a few study serology, biopsy, and response to a gluten-free diet as well. Nonetheless, it is already common knowledge that the epidemiology of CD can be represented by an iceberg, in which the cases diagnosed are symbolized by the part above water level, and all the other cases lie below the water level [11].

From a gender point of view, the male/female ratio is 1:2.8. Men with CD are usually diagnosed at an older age than women [12–14]. Presently it is estimated that the prevalence of CD in western countries is between 1:100 to 1:300 [15,16], and the trend is rising when compared with the numbers detected in previous decades [17–20]. In Europe as a whole, the frequency is the same as in other western regions, but in Northern Europe, it is probably higher. In fact, some studies have reported a 1.5% prevalence [8,16,21–31]. Figure 1 shows the prevalence of CD in the principle regions of the world, based on data obtained by screening populations randomly. Studies done in the USA show the prevalence of CD between 1:33 to 1:200 in non risk groups [32–34]. In South America, with the exception of Argentina, the prevalence of the pathology is generally thought to be inferior to the other western regions, but with substantial variations in various studies. In Brazil, it varies between 1:105 and 1:681, with a higher prevalence in children [35–39]. In Argentina, the prevalence detected in 2000 subjects was equal to 1:167, probably connected to the elevated frequency of haplotype HLA-DQ8. In some Asian countries, including Indonesia, The Philippines, South Korea, and in the rest of the South Eastern Asian region, CD is a rare disease, thanks both to the population's eating habits and its genetic characteristics which feature a low frequency of allele HLA-DQB1*02. In India, Pakistan, and the other parts of the Asian continent, the prevalence of CD is similar to that in Europe [40–43]. In China, the frequency of the HLA-DQ alleles associated with CD, and the disease itself, are not rare in the Jiangsu and Zhejiang regions [44]. Middle-Eastern populations are among the highest consumers of wheat in the world, and genetic studies demonstrate a high frequency of CD-associated alleles. In Iran, Israel, Turkey, and Saudi Arabia, the frequency of HLA-DQB1*02 and the prevalence of CD range from 1:166 reported in Iran to 1:32 found in some regions in Saudi Arabia [45–56]. In the latter, the frequency of CD is among the highest reported in risk groups [57,58]. The elevated prevalence of the...