Celica disease

موضوع: Celica disease الأربعاء أكتوبر 31, 2012 6:45 pm

Celica disease

Celica disease spelled celiac disease in North America and often celiac sprue) is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward. Symptoms include chronic diarrhoea, failure to thrive (in children), and fatigue, but these may be absent, and symptoms in other organ systems have been described. Increasingly, diagnoses are being made in asymptomatic persons as a result of increased screening;the condition is thought to affect between 1 in 1,750 and 1 in 105 people in the United States. Celiac disease is caused by a reaction to gliadin, a prolamin (gluten protein) found in wheat, and similar proteins found in the crops of the tribe Triticeae (which includes other common grains such as barley and rye).

Upon exposure to gliadin, and specifically to three peptides found in prolamins, the enzyme tissue transglutaminase modifies the protein, and the immune system cross-reacts with the small-bowel tissue, causing an inflammatory reaction. That leads to a truncating of the villi lining the small intestine (called villous atrophy). This interferes with the absorption of nutrients, because the intestinal villi are responsible for absorption. The only known effective treatment is a lifelong gluten-free diet. While the disease is caused by a reaction to wheat proteins, it is not the same as wheat allergy.

This condition has several other names, including: cœliac disease (with œ ligature), c (o) eliac sprue, non-tropical sprue, endemic sprue, gluten enteropathy or gluten-sensitive enteropathy, and gluten intolerance. The term coeliac derived from the Greek κοιλιακός (koiliakós, "abdominal"), and was introduced in the 19th century in a translation of what is generally regarded as an ancient Greek description of the disease by Aretaeus of Cappadocia

Signs and symptoms

Severe coeliac disease leads to the characteristic symptoms of pale, loose and greasy stool (steatorrhoea), and weight loss or failure to gain weight (in young children). People with milder coeliac disease may have symptoms that are much more subtle and occur in other organs rather than the bowel itself. It is also possible to have coeliac disease without any symptoms whatsoever. Many adults with subtle disease only have fatigue or anaemia.

Gastrointestinal

The diarrhoea that is characteristic of coeliac disease is (chronic) pale, voluminous and malodorous. Abdominal pain and cramping, bloatedness with abdominal distension (thought to be due to fermentative production of bowel gas) and mouth ulcers may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop. Frequently, the symptoms are ascribed to irritable bowel syndrome (IBS), only later to be recognised as coeliac disease; a small proportion of patients with symptoms of IBS have underlying coeliac disease, and screening for coeliac disease is recommended for those with IBS symptoms. Coeliac disease leads to an increased risk of both adenocarcinoma (small intestine cancer) and lymphoma of the small bowel (enteropathy-associated T-cell lymphoma or EATL). This risk returns to baseline with diet. Longstanding and untreated disease may lead to other complications, such as ulcerative jejunitis (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring with obstruction of the bowel).

Malabsorption-related

The changes in the bowel make it less able to absorb nutrients, minerals and the fat-soluble vitamins A, D, E, and K.

The inability to absorb carbohydrates and fats may cause weight loss (or failure to thrive/stunted growth in children) and fatigue or lack of energy.
Anaemia may develop in several ways: iron malabsorption may cause iron deficiency anaemia, and folic acid and vitamin B₁₂ malabsorption may give rise to megaloblastic anaemia.
Calcium and vitamin D malabsorption (and compensatory secondary hyperparathyroidism) may cause osteopenia (decreased mineral content of the bone) or osteoporosis (bone weakening and risk of fragility fractures).
A small proportion have abnormal coagulation due to vitamin K deficiency and are slightly at risk for abnormal bleeding.
Coeliac disease is also associated with bacterial overgrowth of the small intestine, which can worsen malabsorption or cause malabsorption despite adherence to treatment.

Miscellaneous

Celica disease has been linked with a number of conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.

I g A deficiency is present in 2.3% of patients with coeliac disease, and in turn, this condition features a tenfold increased risk of coeliac disease. Other features of this condition are an increased risk of infections and autoimmune disease
Dermatitis herpetiformis; this itchy cutaneous condition has been linked to a transglutaminase enzyme in the skin, features small-bowel changes identical to those in coeliac disease, and may respond to gluten withdrawal even if there are no gastrointestinal symptoms. Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition. Evaluation of growth failure often includes coeliac screening^. Recurrent miscarriage and unexplained infertility^.
Hyposplenism (a small and underactive spleen); this occurs in about a third of cases and may predispose to infection given the role of the spleen in protecting against bacteria.
Abnormal liver function tests (randomly detected on blood tests).

Celiac disease is associated with a number of other medical conditions, many of which are autoimmune disorders: diabetes mellitus type 1, autoimmune thyroiditis, primary biliary cirrhosis, and microscopic colitis.

A more controversial area is a group of diseases in which anti-gliadin antibodies (an older and non-specific test for coeliac disease) are sometimes detected, but no small bowel disease can be demonstrated. Sometimes, these conditions improve by removing gluten from the diet. This includes cerebellar ataxia, peripheral neuropathy, schizophrenia and autism.

Other grains

Wheat subspecies (such as spelt, semolina and durum) and related species such as barley, rye, triticale and Kamut also induce symptoms of celiac disease. A small minority of celiac patients also react to oats. It is most probable that oats produce symptoms due to cross contamination with other grains in the fields or in the distribution channels. Generally, oats are therefore not recommended. However, many companies assure the 'purity' of oats, and are therefore still able to be consumed through these sources.

Other cereals such as maize (corn), millet, sorghum, teff, rice, and wild rice are safe for patients to consume, as well as non cereals such as amaranth, quinoa or buckwheat. Non-cereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.

Pathophysiology

Celica disease appears to be polyfactorial, both in that more than one genetic factor can cause the disease and that more than one factor is necessary for the disease to manifest in a patient.

Almost all people with celiac disease have either the variant HLA-DQ2 allele or (less commonly) the HLA-DQ8 allele. However, about 20–30% of people without celiac disease have also inherited either of these alleles. This suggests additional factors are needed for celiac disease to develop – that is, the predisposing HLA risk allele is necessary but not sufficient to develop celiac disease. Furthermore, around 5% of those people who do develop celiac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles (see below).

Genetics

DQ α⁵-β² -binding cleft with a deamidated gliadin peptide (yellow), modified from PDB 1S9V

The vast majority of celiac patients have one of two types of the HLA-DQ protein. HLA-DQ is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. The two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of the sixth chromosome.

There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of celiac patients have the is form of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in risk of celiac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.

Most celiac patients bear a two-gene HLA-DQ2 heliotype referred to as DQ2.5 haplotype. This haplotype is composed of two adjacent gene alleles, DQA1*0501 and DQB1*0201, which encode the two subunits, DQ α⁵ and DQ β². In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents (DQ2.5cis). Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk for coeliac disease, as well as being more susceptible to severe complications. Some individuals inherit DQ2.5 from one parent and an additional portion of the haplotype (either DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent (DQ2.5trans), called a trans-haplotype association, and these individuals are at similar risk for celiac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, disease tends not to be familial. Among the 6% of European celiac that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 4% have the DQ2.2 is form, and the remaining 2% lack DQ2 or DQ8.

The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country and Irelandwith highest frequencies) and portions of Africa and is associated with disease in India, but is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ2.5, and is particularly common in South and Central America; up to 90% of individuals in certain Amerindian populations carry DQ8 and thus may display the celiac phenotype. Other genetic factors have been repeatedly reported in CD; however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population. Many of the loci detected have been found in association with other autoimmune diseases. One locus, the LPP or lipoma-preferred partner gene is involved in the adhesion of extracellular matrix to the cell surface and a minor variant (SNP = rs1464510) increases the risk of disease by approximately 30%. This gene strongly associates with celiac disease (p < 10⁻³⁹) in samples taken from a broad area of Europe and the US. The prevalence of CD genotypes in the modern population is not completely understood. Given the characteristics of the disease and its apparent strong heritability, it would normally be expected that the genotypes would undergo negative selection and to be absent in societies where agriculture has been practised the longest (compare with a similar condition, Lactose intolerance, which has been negatively selected so strongly that its prevalence went from ~100% in ancestral populations to less than 5% in some European countries.) This expectation was first proposed by Simoons (1981). By now, however, it is apparent that is not the case; on the contrary, there is evidence of positive selection in CD genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections.

Prolamins

The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine (-amin) that dissolve in alcohols and are resistant to proteases and peptidases of the gut. Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley (hordein), rye (secalin), corn (zein) and as a minor protein, avenin in oats. One region of α-gliadin stimulates membrane cells, enterocytes, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than three amino acids to enter circulation.

Illustration of deamidated α-2 gliadin's 33mer, amino acids 56–88, showing the overlapping of three varieties of T-cell epitope

Membrane leaking permits peptides of gliadin that stimulate two levels of immune response, the innate response and the adaptive (T-helper cell mediated) response. One protease-resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. This innate response to gliadin results in immune-system signalling that attracts inflammatory cells and increases the release of inflammatory chemicals. The strongest and most common adaptive response to gliadin is directed toward an α2-gliadin fragment of 33 amino acids in length.

The response to the 33mer occurs in most coeliacs who have a DQ2 isoform. This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 isoform will bind and stay bound to peptide when recognised by T-cells. Gliadin in wheat is the best-understood member of this family, but other prolamins exist, and hordein (from barley) and secalin (from rye) may contribute to coeliac disease. However, not all prolamins will cause this immune reaction, and there is ongoing controversy on the ability of avenin (the prolamin found in oats) to induce this response in celiac disease.

Tissue transglutaminase

Tissue transglutaminase, drawn from PDB 1FAU

Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in an overwhelming majority of cases. Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively. These peptides are modified by tTG in two ways, deamidation or transamidation.

Deamidation is the reaction by which a glutamate residue is formed by cleavage of the epsilon-amino group of a glutamine side chain. Transamidation, which occurs three times more often than deamidation, is the cross-linking of a glutamine residue from the gliadin peptide to a lysine residue of tTg in a reaction which is catalysed by the transglutaminase. Crosslinking may occur either within or outside the active site of the enzyme. The latter case yields a permanently, covalently linked complex between the gliadin and the tTg. This results in the formation of new epitopes which are believed to trigger the primary immune response by which the autoantibodies against tTg develop.

Stored biopsies from suspected coeliac patients have revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anaemia or malabsorption phenomena at a much-increased rate over the normal population. Endomysial components of antibodies (EMA) to tTG are believed to be directed toward cell-surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative coeliac patients tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms including autoimmune disease. In this study, the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with recent work showing that gliadin has an innate response component, suggests that gliadin may be more responsible for the primary manifestations of coeliac disease, whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of coeliac patients, the anti-tTG antibodies also recognise a rotavirus protein called VP7. These antibodies stimulate monocyte proliferation, and rotavirus infection might explain some early steps in the cascade of immune cell proliferation.
Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy. This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a second source of crossreactive antibodies