Study And About Coeliac Disease Anthropology Essay

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A 3 year old child has been regularly attending a paediatric clinic for review of her frequent upper respiratory tract infections. The child also had a history of reflux as a baby. However, the paediatrician also noted how thin her 24 year old mother was and enquired of her general health. She replied that she had difficulty in maintaining her weight, despite needing to eat every few hours and in fact she had slowly lost 25 lb during the past year.She also admitted to suffering from bouts of diarrhoea but infrequently.

Both mother and child were tested for food allergies and were found to be strongly positive for gluten allergy, suggestive of coeliac disease, a major auto-immune disorder of the small intestine that causes malabsorption."

Gross Pathological Changes to the Small Intestine in Coeliac Disease

Coeliac disease is caused by an abnormal reaction between gluten (a part that makes up wheat flour) and the jejuna mucosa of the small intestine. 1 It damages the surface enterocytes of the small intestine, which consequently causes a severe reduction in their absorptive capacity. 1 The reduction in absorption is done in several ways. Normally, the enterocytes are constantly shed from the ends of the villi and replaced with new cells originating from the crypts. However, with a person suffering from coeliac disease the rate of cell loss is far greater than the rate of gain, leading to villous atrophy, where the surface epithelium shows cuboidal transformation. 1 2 3 Villous atrophy is the flattening of villi and a reduction in epithelial surface area. 1 2 Hyperplasia of the crypts of Lieberkuhn also occur, 2 which is due to the elongation, hypercellularity and high mitotic activity of the crypts.1 The amount of chronic inflammatory cells in the lamina propria would also be raised in a person who has the disease. 3 This is due to the increased number of plasma cells and lymphocytes that are infiltrating the lamina propria of the villi. 2 3 The level of destruction to the mucosa can be categorised by using the "Marsh Classification". 18 The stages range from 0-4 with 0 being a normal mucosa and 4 being severe atrophy and hypoplasia of the bowels. Sufferers of coeliac disease normally having Marsh type II or III due to partial villous atrophy. 18 Figure 1 shows the degrading process of the mucosa according to the Marsh classification. 4

Immunological Mechanisms Involved with Gluten Allergy and how they correlate with the Underlying Genetic Basis of the Disease

Coeliac disease is a common gastrointestinal disorder that occurs in genetically susceptible individuals when gluten in ingested. 5 Ideas have been put forward of the disease actually being an autoimmune one, however what actually causes the disease is still idiopathic.

When the gluten reaches the small intestine, the disease has certain autoimmune features such as the autoimmune antibodies to the enzyme, tissue transglutaminase (tTG) in which it breaks down.5 The tissue transglutaminase is an enzyme that catalyses the cross-linking of peptides (transamidation) which cross-links a glutamine residue from the gliadin peptide to a lysine residue of tTG. 6 7 8 The tissue transglutaminase also deaminades gliadin (a gluten protein) peptides, where a glutamate residue is produced by cleaving an epsilon-amino group of a glutamate side chain. 6 7 8 It has been shown, that the up-regulation of zonulin, an intestinal peptide involved in tight junction regulation is partly accountable for the increased epithelial cell permeability to gliadin peptides. 9 When transamidating, the cross-linking could either occur from inside the active site of the enzyme, or outside it. 7 8 If it is outside of the active site, then this produces a permanent, covalently linked complex between the tTG and gliadin, which consequently produces new epitopes. 9 10 This, all starting from the ingestion of gluten, is believed to be the trigger for the primary immune response in which the development of autoantibodies to tTG therefore occur. 10

The human leukocyte antigen genes (HLA) are a group of genes that are located in the major histocompatabilty complex (MHC. After the tTg has catalysed reactions, it develops a strong affinity to HLA molecules that are located on the membrane of antigen presenting cells such as macrophages. 8 These HLA molecules then create a groove where the short peptides, from digestive products of gliadin, can be specifically linked to. 8 An idea is that the intestinal T cells are activated due to the interaction between the gliadin peptides and HLA molecules. 8 Therefore the release of pro-inflammatory cytokines produced by the activated T cells could damage the enterocytes, consequently causing hyperplasia in the intestinal crypts, and hence resulting in severe damage to the intestinal mucosa structure. 8

Conversely, another study found that the antibodies formed due to the tTG did not correlate to villous destruction of the intestines.11 This shows that that peptide derived from gluten, gliadin, may be more accountable for the primary destructive effects of coeliac disease, whereas the tTG may be responsible for mainly the secondary effects of the disease such as allergic responses. 11

Looking at a systematic review that analysed 55 articles, 12 it summarised in a discussion that rather than it being an autoimmune disease, it can be a disease of immunological intolerance. This is due to the IL-15 response to the toxic gliadin peptides found in gluten for people who are genetically susceptible. 12 The study had also established a link that IgA antibodies specific against tTG are a consequence of activated, gliadin specific, T helper cells (leukocytes). 12 These T cells provide assistance for B lymphocytes (which differentiate into plasma cells) which have antibodies specific for tTG, that take up complexes of tTG rather than being an actual causative factor towards coeliac disease. 12

How immunology Correlates with the Underlying Genetic Basis of Coeliac Disease

"A recently published analysis of a large cohort of 73 Italian twins with at least one affected with coeliac disease found around an 87% genetic component to this condition". 12 The rate of the disease is approximated to be 1 in 250 (0.4%), which is about the same rate as the European population mainly thanks to the large samples of people who were carefully studied. 12 13 Although it occurs throughout the world, it is especially rare to see it in the black African population. 20 It has been shown that there is an increased incidence of the disease within families, but similar to the immunological mechanisms, the exact cause due to inheritance is unknown; 20 however 10-15% of cases is due to first degree inheritance, although it may be asymptomatic. 20

Most patients suffering from coeliac disease either have one of the two types of HLA-DQ; 13 14 this is either DQ2 or DQ8 which is found in approximately 95% of people with coeliac disease. 13 As mentioned previously above, the HLA genes which are responsible for differentiating between self and non-self for the immune system is found on the short arm of the sixth chromosome. 15 The first genome-wide associated scan (GWAS) in 2007 found that patients who have coeliac disease have at least one copy of the multi histocompatability complex (MHC) type 2 HLA-DQ2 gene, 16 however only a handful of people who possess this genotype develop the disease. The HLA genes have two component proteins which have a separate gene to encode them. 17 The two haplotype alleles, DQA1*0501 and DQB1*0201, encode the subunits DQ a5 (alpha) and DQ ß2 (beta). 17 People who are susceptible to the disease has to have HLA-DQ proteins made up of a certain combination of alpha and beta proteins. The proteins with these combinations consequently are called HLA-DQ2 and HLA-DQ8. 17

Most people who have the disease usually inherit only one copy of the haplotype allele, although some can inherit this from both of their parents resulting in a substantially higher risk to the disease as well as being more susceptible to other complications. 18 Even though it is less commonly seen, some people might inherit the DQA1*0501 allele from one of their parents, and a DQB1*0201 from their other parent. The risk of obtaining the disease is similar to one being susceptible from only having one allele. 18

Over 90% of people suffering from coeliac disease will have DQ2, compared to 20-30% of the general population who do not suffer from it. 20 There are some non-HLA regions that may also be linked to coeliac disease on the chromosome such as 5q31-33, and perhaps 11q. 20 There could be others that are yet to be identified.

The fact that not all people who possess these haplotypes, and also that the chances of the disease occurring in only one of identical twins is 30%, may possibly show that genetic factors are not the sole cause of the disease, but maybe additional factors, such as the environment may play a part in this. 20

Screening for Coeliac Disease using Immunology and Genetics

There are a few methods that can be used to screen for the disease. One method involves investigating endomysial (EMA) and tTG antibodies (IgA) in the body. 20 As these antibodies have a high specificity and sensitivity for the disease, it will be quite useful to use it as a method of screening. Another method is that a duodenal or jejunal biopsy can be performed on the patient. 20 Errors can occur with this method although it is regarded as "gold standard".  When an endoscopy is performed, the duodenal folds look worn away and a dye is sprayed on the mucosa of the duodenum to show the smoothness of it before a biopsy is taken. 20

Treatments Available for Coeliac Disease

The only truly effective method of treatment is a strict gluten-free diet, 21 which usually produces a quick clinical and morphological improvement. 22 This includes avoiding foods that contain grains such as wheat, rye and barley. 23 Replacement haematinics such as calcium, folic acid and iron can be given initially to replace body stores. 21 Once sufferers stick to this diet, healing of the tissue of the small intestine begins to get better, and their general health also begins to improve, and in the majority of cases the symptoms disappear completely. 23 Patients should also have pneumococcal vaccinations, due to splenic atrophy, once every 5 years. 21 A few patients still do not recover after a strict diet (unresponsive coeliac disease). 21 There are mostly no causes for this, however intestinal lymphoma, ulcerative jejunitis or carcinoma are sometimes responsible. 21 Steroids and immunosuppressive agents such as azathioprine are used. 21

The treatment for coeliac disease may be problematic in children as the strict restrictions of a gluten free diet may affect the psychosocial well-being of the child mentioned in the case above. 24 However sources show that the highest rates of compliance are from those who are diagnosed at a young age, whereas patients who are diagnosed when they are teenagers or adults have a higher chance of transgression. 24 If the child is given a gluten free diet that is well planned, although the nutrition it will provide may be sufficient it will still be quite restrictive. 24 Restriction of the diet may get in the way of the child's social activities such as school and extracurricular activities. Family activities such as dining out at restaurants, holidays and shopping may also be problematic. 24 Studies show that most children adjusted well to the diet, especially from a young age, however roughly 25% felt angry all or most of the time having to follow it, 25% of children felt secluded and embarrassed about their condition, while 13% felt left out of activities at a friend's home or school. 24 Social activities such as birthday parties, sleepovers and summer camp would provide a challenge to a child with coeliac disease. 24

Although the child is only 3 years old, these problems may arise later in life when the child becomes an adolescent, where having a normal social life may be challenging.

Studies have shown that 40% of young patients that have coeliac disease were not complying with the diet that they were supposed to adhere to. 23 The poor compliance to diet was linked with poor parental knowledge about the disease and how it can be managed. 23 In the case above, if the mother is educated well enough from an early stage this may improve the compliance towards the diet and motivation in general for both mother and child.

The complications that will affect the child will also certainly affect the mother as well, possibly to a larger extent. In terms of diet, it will be much harder for the mother to adjust to a new diet compared to her daughter. The daughter should not really struggle with the diet as it will be her mother who controls it. However for the mother who has lived with a diet based on gluten-containing cereals for most of her life, it will be more hassling. This may consist of shopping at specialist stores or shops that are less convenient to access. It would also hamper her social life too such as eating out at restaurants, going on holiday, and going out in general would be troublesome.

The mother would also have a problem when it comes to looking after the health of her daughter. She would have to constantly control her daughter's diet whenever the daughter was away from home until she is old enough to do it herself. This could especially be difficult for her when her child is at nursery or a friend's house where food given to her could contain gluten. She would therefore need to inform the school and parents about the girl's condition. The mother would probably also need to be aware that her daughter may be subject to bullying from other children at school due to her disease, so she should be prepared to emotionally support her daughter as she is growing up.

Conclusion

The fact that the mother is struggling to maintain her weight, suffering from diarrhoea, and was tested positive for a gluten allergy makes me believe that the mother has a high chance of having coeliac disease. This is strengthened by the fact that her daughter is suffering from symptoms linked to the disease, as the disease has a chance of being inherited, being tenfold in first degree relatives. The upper respiratory problems and reflux could be due to the lack of absorption in the small intestines. Although destructive to the intestines if gluten is ingested, the disease can be easily reversed by sticking to a gluten free diet even though this method of treatment can be greatly restricting to the sufferers' lifestyle.

Psychosocially, the mother and child may find it difficult to "fit in" due to their highly selective diet, and this may especially cause problems for the child when she is in school which could make her feel isolated and different to the rest of the children. Consequently it may lead to bullying which is why it is imperative for the mother and the rest of the family to be well educated about the disease and its management, physically and socially.

References

1. Underwood J.C.E, General and Systematic Pathology 4th Edition p. 379-381, Elselvier, Philadelphia U.S.A 2004

2. http://www.celiac.com/articles/54/1/Pathology-of-Celiac-Disease/Page1.html (found on 20th October 2009)

3. Chandrasoma P, Gastrointestinal Pathology p. 174-177 ,Hong Kong 1999

4. http://www.theglutensyndrome.net/Marsh_Classification.png (found on 23rd November 2009)

5. Sollid LM, Jabri B, Is celiac disease an autoimmune disorder? Current opinion in Immunology Volume 17 Issue 6, December 2005, Pg 595-600

6. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO,Schuppan D, Identifying Tissue Transglutaminase as the auto antigen of Celiac Disease, Nature Medicine 3, 797 - 801 (1997) doi:10.1038/nm0797-797

7. Sollid LM, Molecular Basis of Celiac Disease, Annu Rev Immunol. 2000 ;18 :53-81 10837052

8. Catassi C, Fornaroli F, Fasano A, Celiac Disease: From basic Immunology to Bedside Practice, Clinical and Applied Immunology Reviews Volume 3 Issue 1-2, November 2002 pages 61-71

9. A. Fasano, T. Not, W. Wang, S. Uzzau, I. Berti, A. Tommasini et al., Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 358 (2000), pp. 1518-1519

10. Koning, F.; Schuppan, D.; Cerf-Bensussan, N.; Sollid, M. (Jun 2005)."Pathomechanisms in celiac disease". Best practice & research. Clinical gastroenterology 19 (3): 373-387.

11. Londei M, Ciacci C, Ricciardelli I, Vacca L, Quaratino S, and Maiuri L. (2005). "Gliadin as a stimulator of innate responses in celiac disease". Mol Immunol 42 (8): 913-918.

12. C.S. Hourigan, The molecular basis of coeliac disease, Clin Exp Med (2006) 6:53-59DOI 10.1007/s10238-006-0095-6

13. http://www.enabling.org/ia/celiac/cel-hla.html (found on 18th October 2009)

14. W. Martin Howell, Shu Tong Leung, David B. Jones, Imad Nakshabendi, Margaret A. Hall, Jerry S. Lanchbury, Paul J. Ciclitira, Dennis H. Wrigh, HLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma : Common features and additional risk factors for malignancy, Human Immunology Volume 43 Issue 1, May 1995 pg 29-37

15. http://www.celiac.com/articles/21628/1/Celiac-Disease-Genetics/Page1.html (found on 19th November 2009)

16. http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-99-015.html (found on 19th November 2009)

17. https://www.23andme.com/health/Celiac-Disease/ (found on 19th November 2009)

18. Kati Karell, Andrew S. Louka, Simon J. Moodie, Henry Ascher, Fabienne Clot, Luigi Greco, Paul J. Ciclitira, Ludvig M. Sollid, Jukka Partanen and Members of the European Genetics Cluster on Celiac Disease, Hla types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the european genetics cluster on celiac disease, Human Immunology Volume 64 Issue 4, April 2003 pages 469-477

19. http://www.ei-resource.org/illness-information/related-conditions/celiac-disease/ (found on 25th October 2009)

20. Kumar P, Clark M, Clinical Medicine 6th Edition p. 301-303, Philadelphia 2008

21. http://www.webmd.com/digestive-disorders/celiac-disease/celiac-disease-treatment (found on 25th October 2009)

22. Rashid M, Cranney A, Zarkadas M, Graham ID, Switzer C,Case S, Molloy M, Warren R, Burrows V, Decker Butzner J, Celiac Disease: Evaluation of the Diagnosis and Dietary Complience in Canadian Children, Official Journal of the American Academy of Pediatrics

23. Pietzak MM ,Follow-up of patients with celiac disease: Achieving compliance with treatment, Gastroenterology Volume 128 Issue 4 Supplement 1 Pages 135-141, April 2005

24. Jackson PT, Glasgow JF, Thom R, Parents' Understanding of Coeliac Disease and Diet, Arch. Dis. Child. 1985;60;672-674 doi:10.1136/adc.60.7.672

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