or celiac sprue, also known as gluten intolerance
edited by Elisa Magnanelli M.D.
Celiac disease is an autoimmune disorder of the small intestine (enteron), due to ingestion of gluten in genetically predisposed people. The onset of symptoms is usually gradual and may be experienced several months or years after gluten ingestion. Nevertheless, even patients adhering to a gluten free diet for a long time, could experience an immediate outbreak of symptoms, including vomit and abdominal colic, if they accidentally ate gluten.
Celiac disease affects 1% of general population; it is one of the most common disorders in countries whose inhabitants are mainly of European origin (Europe, North and South America, Australia). According to recent studies, the frequency of celiac disease is increasing during the last decades, for still unknown reasons. As showed by epidemiological investigations celiac disease is a common disorder even in other world areas including Northern Africa, Middle East countries and part of Asia.
Celiac disease is likely to increase also in underdeveloped countries due to a progressive diffusion of westernized diet. For example many Asiatic countries are witnessing a rapid decrease in traditional rice consumption and a parallel growth of wheat product consumption, caused by urbanization and increasing incomes.
Genetic predisposition is a celiac disease determinant factor; recently important headways have been made in identifying genes involved in celiac disease. We know that celiac disease is strongly related to specific class II genes of human leukocyte antigen (HLA), known as HLA-DQ2 and HLA-DQ8, located in 6p21 chromosome.
The main part of celiac patients(nearly 95%) express genes coding class II protein of Major Histocompatibility Complex (MHC) HLA-DQ2; The remaining patients are generally HLA-DQ8 positive. Haplotype HLA-DQ2 is ordinary and can be found in nearly 30% of individuals, which entails that the presence of HLA-DQ2 and/or HLA-DQ8 is necessary to develop celiac disease, but not sufficient by itself: the presence of these genes actually increase the risk of developing celiac disease only from 36% to 52%. On the other hand, non -HLA genes contribute together to celiac disease more than HLA; it is clear then that predisposition to celiac disease depends on several genes, and each one of them takes just a small part in the development of actual celiac disease.
It has been shown that the action of intestinal transglutaminase (tTG) increases gliadin-specific T lymphocyte response. It has been suggested that once gliadine is "activated” by tissue transglutaminase, it binds to HLA DQ2/8 molecules of the antigen-presenting cells and activates T lymphocytes CD4+ in the lamina propria of intestinal mucosa. Afterwards activated gliadin T lymphocytes migrate from lamina propria into subepithelial location and start cytokines production, i.e. interferon gamma, interleukin 2, interleukin 4, TNF alpha. These cytokines cause apoptosis and cellular hyperproliferation leading to flattened intestinal mucosa.
In addition to T lymphocytes, also B lymphocytes acting in untreated celiac patients lead to anti-gliadin, antiendomysial and anti tissue transglutaminase antibodies production. Even though these antibodies are really useful for diagnosis, it remains still unclear if they are responsible for mucosal damage too or if they are somehow a consequence. All these antibodies are gluten sensitive, i.e. they disappear from serum of patients on gluten-free diet..
Despite the existence of at least 50 epitopes in gluten protein stimulating T lymphocytes, the most immunogenic among gliadin peptides is fragment 33. Moreover, it resists to all enzymatic degradation of gastric, pancreatic and enterocytes microvilli juices. The activation of an immune response is supposed to be preceded by alterations of intraluminal enzymatic digestion and of the normal intestinal permeability.
Figure 3: Alpha gliadin genes mapping. Sequences having citotoxic activity are shown in red, those with immunomodulating activity in yellow, those having function of zonulin release and intestinal permeability regulation in blue and those with function of CXCR3-dependent release of IL-8 in celiac patients are dark grey. (Sapone et al. BMC Medicine 2012 10:13 doi:10.1186/1741-7015-10-13)
Celiac disease presents itself in different ways, varying from the classic form (with chronic diarrhoea and loss of weight) to extra-abdominal symptoms (anaemia, osteoporosis, neurological disorders) and silent forms, which actually get discovered accidentally thanks to clinical tests. Cases of serum auto-antibody positivity without histological intestinal damage have also been identified (potential celiac disease) (Figure 1 ).
Diarrhoea, a typical chronic celiac disease symptom, is pale, voluminous and malodorous. Abdominal pain or distension (due to fermentative intestinal gas production), cramps and mouth ulcers can also be detected.
Celiac disease entails an increased risk of small bowel adenocarcinoma and lymphoma (more frequently T cells lymphoma). Thanks to appropriate diet, this risk can be reduced to the normal values that can be spotted in general population. Celiac disease, if not treated, may lead to further complications, such as jejunal ulcer.
Celiac disease involves also remarkable intestinal mucosa change, up to a complete villous flattening, causing malabsorption symptoms. Fat and carbohydrates absorption disorders can cause loss of weight (or failure to thrive as far as children are concerned) and fatigue; iron malabsorption can cause iron deficiency anaemia, whereas folic acid and vitamin B12 malabsorption can be responsible for megaloblastic anaemia; calcium and vitamin D malabsorption (balanced through the development of secondary hyperparathyroidism) can cause osteopenia or osteoporosis. A small part of patients experienced an abnormal coagulation capacity due to via vitamin K deficiency, with a moderate risk of abnormal bleeding. Celiac disease can also be associated with small intestine bacterial proliferation, which can worsen or cause malabsorption in spite of an adequate diet .In many cases it is difficult to state whether intestinal symptoms are caused by the disease or may be considered as a common predisposition to it.
Celiac disease can also be related to many other medical conditions:
Due to frequent atypical manifestation, celiac disease is often underdiagnosed, exposing patients to chronicity risk and complications (intestinal lymphoma, (infertility), but now the incidence of such phenomena has decreased compared to a few years ago.
The first step in the diagnosis of celiac disease is a set of blood tests to measure levels of certain antibodies, in particular anti transglutamiase antibodies(IgA), whereas anti EMA IgA test is considered a confirmation test. Recently, IgG anti deaminated gliadin peptide antibodies (DPG) have been introduced, which are as sensible and specific as anti Tg and anti EMa, but could be detected even in subjects affected by congenital IgA deficiency and children aged less than three years. High levels of IgA anti Tpa (and, possibly, of IgG anti DPG) together with an elevation 10x IgA anti EMA or more, are almost always associated with a classic celiac enteropathy evidenced in jejunal biopsy histology. For patients affected by IgA deficiency we use IgG testing
Intestinal biopsy is a very important test; every patient should undergo it if celiac disease is suspected. Histological alterations are characterized by: increase in lymphocitary infiltrate (>25 lymphocytes for 100 enterocytes), crypt elongation, intestinal villous atrophy and a lower villi/crypt ratio.
Currently could be used also oligonucleotide typing methods specific for gliadin sequences based on PCR, method for the determination of HLA-DQ2 and HLA-DQ8 allele sequence. In spite of the fact that HLA genotype is a predisposing factor essential for developing celiac disease, the negative predictive value of hystotipe HLA is very high, being ascertained that HLA-DQ2 and HLA-DQ8 negative subjects will never develop celiac disease.
The considerable variability of evidence as far as celiac disease is concerned let us understand that it is impossible to individuate rigid diagnostic algorithms including all the possible forms of this disease. For this reason a quantitative diagnostic approach have recently been suggested (following the model "at least 4 in 5 factors").
According to the above mentioned model, celiac disease can be diagnosed when at least 4 in the following 5 symptoms and signs can be observed:
- typical symptoms of celiac disease
- high specific IgA positivity for celiac disease
- positivity for genotypes HLA-DQ2 and/or HLA-DQ8
- celiac enteropathy at jejunal biopsy