Celiac Sprue

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Contents 1 Etiology 2 Diagnosis 3 Signs/Symptoms 4 Biochemical Nature of Disease 5 Protein Structure 6 Treatment 7 Epidemiology 8 Primary Sources 9 References

Etiology

Coeliac or Celiac Disease and often referred to as "gluten sensitive enteropahty" or "non-tropical sprue" is a T-cell mediated disease occuring in genetically susceptible individuals induced by the ingestion of one of several proteins such as gliadin, hordein, and secalinin. This disease is also a chronic inflammatory bowel condition affecting the mucosa of the small intestine and is offset by a reaction in the bowel wall to gluten. This disease has a number of distressing symptoms, but also the potential of many long term compliactions. Since the disease is still relatively unknown, it is thought to be heavily under-diagnosed.

Diagnosis

Celiac Sprue Disease was first diagnosed in the late 19th century as being an illness that caused constant diarrhea and malabsorption that was prevalent among children. It was just in the 1950s that the rule of the gluten or the protein gliadin was associated with the disease(Davis, 2001). In today’s society, the most common age of displaying symptoms is around middle age and women are affected three times ad frequently as men. Also, the definitive diagnosis of Celiac Disease is made by fulfilling the triad of (1) a positive serologic test, (2) histologic finidngs of small-bowell biopsy specimens and (3)favorable clinical serological response follwoing a gluten free diet. Serologic markers are used to screen patients with suspected Celiac Disease and to monitor their response to treatment with of a gluten-free diet. Serological studies currently in clinical use inlcude IgA endomysial antibody and IgA tissue transglutaminase anitbody. "A diagnostic dilemma arises when either a serological test or histologic specimen is positive, but not both. If the seologic test is positive and histologic specimen is negative for Celiac Disease then the biopsy specimen should be reviewed and if necessary, repeated. If the serology is negative but the histology is positive or with inconclusive results, then consider IgA deficiency. If this study is still negative, consider other causes of enteritis. If no cause is found depsite a thorough evaluation, then HLA genotyping should be considred. Though HLA-DQ2 and DQ8 are not specific for CD, if they are not present, this essentially rules out the disease. All of these antibodies can be used to monitory dietary compliance, with values becoming undetectable withing three to six months after a gluten-free diet is instituted.Furthermore, what is interesting is the fact that the disease in children is highly uncommon for reasons that cannot be understood. In addition, there is evidence that proves that Celiac like BSE has a preference in the UK of 1 in 300, “although the number of patients who have a confirmed diagnosis is more like 1 in 1,000.” Earlier it was discussed that Celiac is highly under-diagnosed. It is believed that the condition is significantly under-diagnosed, because the similarity between many of the symptoms of Celiac disease and other bowel conditions such as irritable bowel syndrome (IBS). “Another reason is the variability in severity of symptoms of the disease between one patient and another. This has been referred to as the ‘iceberg model’ with a small number of severely affected individuals at the tip of the iceberg and a large number of people with the potential for the disease, but as yet without symptoms, at the bottom.” Moreover, it is thought that there are certain groups who are at a higher risk of having the disease due to the supposed underlying genetic basis. These groups are the following:

• Those with a relative who has celiac disease. There is a 1 in 10 chance of developing the condition if a first degree relative already has it.

• Patients with type II diabetes-probably because there seems to be a preponderance of similar genotypes in patients with these conditions

• People with Down’s syndrome

• Dermatitis herpetiformis, an itchy skin condition characterized by small blisters on the extensor surfaces of the arms, legs, and buttocks, has a strong association with the existence of Celiac disease and responds to the same treatment

• Patients with autoimmune thyroid disease

Signs/Symptoms

The symptoms of Celiac disease vary from individual to individual, but the most common are the following in adults:

• Persistent fatigue

• Persistent diarrhea

• Anaemia-usually iron deficient-due to malabsorption

• Other deficiencies such as folate, vitamin D and vitamin K

• Recurrent mouth ulcers

“These are often associated with recurrent abdominal pains similar to those normally associated with IBS. In rare instances, Celiac disease may present as infertility or neurological problems, resulting in ataxia or even as osteoporosis.”

The most common symptoms in children are as follows:

• Failure to thrive/short stature

• Persistent diarrhea or sometimes constipation

• Iron deficient anaemia not responsive to oral iron

• Symptoms normally associated with IBS

• Recurrent mouth ulcers

“In babies or younger children, the classical presentation is an onset of the following symptoms in a previously well infant following weaning and the introduction of cereals into the diet, together with:”

• Failure to thrive

• Soft, pale, offensive stools

• Abdominal distension

• Sometimes muscle wasting and hypotonia

Biochemical Nature of Disease

Celiac Sprue or Celiac disease is an autoimmune disease of the small bowel that takes place in genetically predisposed people since birth. Since Celiac disease is an autoimmune disease, the small bowel fails to recognize its own constituent parts (down to the sub-molecular levels) as self, which results in an immune response against its own cells and tissues and in this case the lining of the small intestine. After much research, it has been demonstrated that the biochemical nature of the disease lies in the infected hosts’ reaction to gliadin, which is a gluten protein found in wheat, barley, and rye. It is upon exposure to this protein that the enzyme tTG or tissue transglutaminase changes the protein structure, thus causing the immune system to fail to recognize itself and cross-reacting with the bowel tissue causing an inflammatory reaction. This inflammatory reaction leads to immune response in the body or the flattening of the lining of the small intestine, which prohibits the hosts’ ability to absorb nutrients.

Gliadin the main protein involved is a glycoprotein present in wheat and several other cereals within the grass genus Triticum. Gliadins are prolamins and are separated on the basis of electrophoretic mobility and isoelectric focusing. There are three distinct types of gliadin. The first being α-/β-gliadins, which are soluble in low percentage alcohols. The second being γ-gliadins, which are derived forms of cysteine-abundant gliadin with disulfide bridges, and the third type being ω-gliadins, which are soluble in higher percentage alcohols. The different types of gliadin serve a pivotal role in food/ cooking in terms of their ability to form gluten. Gluten and Gliadin both are two of the reasons for autoimmune nature of Celiac disease. These proteins are essentially known for their ability to give the bread the capability to rise properly and maintain its structure. This demonstrates the ability of food to be a way pathogenesis, because people with gluten-sensitive enteropathy or Celiac disease are prone to an autoimmune reaction to the three different types of gliadin. In addition to gliadin, it is also important to analyze the role of prolamins in Celiac Sprue. The proteins in food responsible for the immune reaction of celiac disease are prolamins. Prolamins are storage proteins abundant in the amino acid praline and glutamine, which dissolve in alcohol. Gliadin connects to prolamins, because it is the best understood or researched member of the prolamin family. Furthermore, many scientists have conducted research as to of why those with Celiac disease are so sensitive to the gluten that most people can consume free of response. Most scientists believe that it has a small part to do with the deamidated form of gliadin, which is produced by enzymatic treatment of gluten. In simpler terms, most scientist believe the problem lies in the way that the protein is being broken down. The enzyme tTG or tissue transglutaminase converts the glutamines in gluten to glutamic acid. As discussed before, the conversion of the gliadin protein structure occurs due the soluble nature of gliadins in alcohol.

Continuing with the biochemical analysis of Celiac Sprue disease, the primary immune reaction occurs in response to the way of that tissue transglutaminase is breaking down the gliadin. Tissue transglutaminase or tTG is an enzyme of the transglutaminase family, that cross links proteins between the ε-amino group of any lysine residue and a γ-carboxyamide group of glutamine residue, thus creating an intramolecular bond that is resistant to proteolysis or protein degradation. Moreover, in relation to Celiac Sprue, many scientists have discovered that in a plethora of cases one can find anti-transglutaminase antibodies to the enzyme tTG. The tTG or tissue transglutaminase changes the gliadin protein structure or modifies the gluten peptides into a form that provokes the immune system. Furthermore, it has also been proven that the endomysial component of antibodies to tissue transglutaminase causes cell surface transglutaminase, which scientists use to confirm Celiac Sprue. “However, a 2006 study showed that [endomysial antibodies]-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 allegic responses and secondary autoimmune diseases. In a large percentage of coeliac patients the anti-tTG antibodies also recognize a rotavirus, [a genus of double-stranded RNA virus in the family reoviridae known for causing severe diarrhea,] protein called VP7.These antibodies stimulate monocytes proliferation and rotavirus infection might explain some early steps in the cascade of immune cell proliferation.” This quotation or research demonstrates the multidimensional nature of Celiac disease and that viral proteins may also be the reason for the initial flattening of the intestine.

After understanding the role of tTG and Gliadin, it is essential to actually analyze the inflammatory process, which is mediated by T cells. T cells are a type of white blood cell that is of key importance to the immune system and is at the core of adaptive immunity, the system that tailors the body's immune response to specific pathogens. The T cells are like soldiers who search out and destroy the targeted invaders. In terms of Celiac Disease the inflammatory process, mediated by T cells, leads to the change of structure and function of the small bowell’s mucosal lining, which causes malabsorption-thus impairing the body’s ability to absorb minerals, nutrients, and fat-soluble vitamins A, E, D, and K from food leading to in some cases anemia or an iron deficiency.

The final role of understanding the biochemical nature of Celiac Disease is a simple one. How do we contract the disease? The majority of patients have one of two types of HLA DQ, which is a cell surface type protein found on antigen presenting cells. This gene is derived from the Major Histocompatiability Complex class II antigen-presenting receptor system, which distinguishes cells between self and non-self for the purpose of the immune system. Celiac disease is sustained by abnormal intestinal mucosal T-cell responses to gluten and it is strongly associated with the MHC class II molecules encoded by a two-gene haplotype that most patients bear. This information serves an integral role in Celiac Disease, because Celiac is an autoimmune disease, which means that the small bowel fails to recognize itself and creates an immune reaction or the flattening of the intestine.

Protein Structure

The crystal protein structure of gliadin contains 21 beta sheets and 2 alpha helices!

Treatment

The best method of treatment is a gluten-free diet. This means avoiding all foods containing wheat, rye, barley and possibly oats so that you may avoid ingesting their proteins.Once diagnosed with Celiac Disease, patients should be referred to a dietician. They should also contact the Celiac Society, which can provide information and advice on how to maintain a long-term gluten-free "k" diet with the capability of leading a normal life. Although many gluten-free products are available on prescription, it is difficult for anyone to change their dietary habits forever even if they have no specific dietary restriction other than to eat less of the gluten. However, most patients with Celiac disease have two motivating forces.One being that after adopting a gluten-free diet their symptoms will soon improve and subside. Second being that it is worth also mentioning t the patient that the effect of the long-term conditions associated with Celiac Disease are mitigated by sticking to a gluten-free diet. "Progress and adherence to a gluten-free diet can be monitored by intermittent testing of antiendomysial antibody or antigliadin anitbodies. If in doubt, referral to a gastroenterologist for consideration of a repeat intestinal biopsy should be considered."

Epidemiology

"The prevalence of clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the prevalence may be between 0.33 and 1.06% in children (5.66% in one study of Saharawi children) and 0.18–1.2% in adults. People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors. Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due to many clinicians being unfamiliar with the condition.

A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic patients, 2.6% in second-degree relatives of a patient with coeliac disease and 4.5% in first-degree relatives. This profile is similar to the prevalence in Europe."

Primary Sources

(Bell, 2004) (Gheller-Rigoni, 2004) (, 2004) (Lasher, 2004) (Moustakas, 2000) (Medical Dictionary) (Salmi, 2006)

References

References