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3. Никитина В. В., Жлоба А. А., Баранцевич Е. Р., Белякова Л. А., Порхун Ф. Н. Способ диагностики тяжести дисциркуляторной энцефалопатии у мужчин. Патент на изобретение - № 2561288 от - 05.11.2014.
4. Никитина В. В., Жлоба А. А., Баранцевич Е. Р., Белякова Л. А. Способ диагностики тяжести дисциркуляторной энцефалопатии у больных с гипергомоцистеинемией. Патент на изобретение № 2546519 от 27.03.2014.
5. Рожинская Л. Я. Соли кальция в профилактике и лечении остеопороза. Остеопороз и остеопатии. - 1998; 1:43-45.
6. Рубин М. П., Чечурин Р. Е., Зубова О. М. Остеопороз: диагностика, соавременные подходы к лечению, профилактика. Терапевтический архив. - 2002; 74 (1): 32-37.
7. Cavalca V., Cighetti G., Bamonti F. et al, Oxidative Stress and Homocysteine in Coronary Artery Disease. Clinical chemistry. - 2001; 47: 887-892.
8. Cighetti G, Debiasi S, Paroni R. et al. Free and total malondialdehyde assessment in biological matrices by gas chromatography-mass spectrometry: what is needed for an accurate detection. Anal Biochem. - 1999; 266: 222-229.
9. DAngelo A., Mazzola G., Crippa L. et al. Hyperhomocysteinemia and venous thromboembolic disease. Heama-tologica. - 1997; 82 (2): 211-219.
10. De J., Stehouwer C. D., van-den-Berg M. еt al. Endothelial marker proteins in hyperhomocysteinemia. Thromb. Haemost. - 1997; 78 (5): 1332-1337.
11. Farkas M., Keskitalo S., Smith D. E., Bain N., Semmler A., Ineichen B., Smulders Y., Blom H., Kulic L., Linnebank M. Hyperhomocysteinemia in Alzheimer's Disease: The Hen and the Egg? J Alzheimers Dis. - 2013; 33 (4):1097-1104.
12. Graham I. M., Daly L. E., Refsum H. M. et al Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. - 1997; 277: 1775-1781.
13. Harpel P. C., Zhang X., Borth W. Homocysteine and hemostasis: pathogenetic mechanisms predisposisng to thrombosis. J. Nutr. 1996; 126 (4): 1285-1289.
14. Karaca M., Hismi B., Ozqul R. K., Karaca S., Yimaz D. Y., Coskun T., Sivri H. S., Tokatli A., Dursun A. High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: molecular and clinical findings of Turkish probands. Gene. - 2014; 25 (534 (2)): 197-203.
15. Pal A., Siotto M., Prasad R., Squitti R. Towards a Unified Vision of Copper Involvement in Alzheimer's Disease: A Review Connecting Basic, Experimental, and Clinical Research. J Alzheimers Dis. - 2015; 44 (2): 343-54. -doi: 10.3233/JAD-141194.
16. Piolot A., Nadler F., Pazer N., Jacolot B. L homocysteine: ses liens avec les maladies cardiovasculaires ischemiques. Rev.Med.Interne. - 1996; 17: 34-45.
17. Sarov M., Not A., de Baulny H. O., Masnou P., Vahedi K., Bousser M. G., Denier C. A case of homocystinuria due to CBS gene mutations revealed by cerebral venous thrombosis. J Neurol Sci. - 2014; 336 (1-2): 257-9.
18. Sen U., Mishra P. K., Tyagi N., Tyagi S. C. Homocysteine to hydrogen sulfide or hypertension. Cell Biochem Biophys. - 2010; 57 (2-3): 49-58.
DOI: http://dx.doi.org/10.20534/ELBLS-17-2-9-12
Seydaliyeva Aytan Ilham, Azerbaijan Medical University, Student, Treatment-Prophylaxis faculty E-mail: ayten.seydaliyeva@gmail.com
Analysis of risk factors and diagnosis of celiac disease
Abstract: The risk factors of celiac disease were researched and age, gender, heredity and absent breastfeeding were identified. The diagnostic methods of celiac disease were analysed and HLA typing, antibody level
and endoscopy were reviewed. The general principles of treatment methods of celiac disease were estimated.
Keywords: celiac disease, gluten, infant diet, enteropathy, HLA typing, Marsh stages.
Celiac disease was first described in 100 AD by the Greek doctor Aretaeus, who used the term abdominal diathesis. His extant works were first published in Latin in 1552 [2]. Although celiac disease was formally described late in the 19th century, treatment remained empiric until the middle of the 20th century when patients were noted to improve dramatically after wheat was removed from their diet. With the development of small-bowel biopsy techniques, the small intestine was identified as the target organ. Disease causality was established when the characteristic features of villous flattening, crypt hyperplasia, and increased intraepithelial lymphocytes were shown to normalize after the institution of a gluten-free diet.
Celiac disease is characterized by small bowel enteropathy, precipitated in genetically susceptible individuals by the ingestion of "gluten," a term used to encompass the storage proteins of wheat, rye, and barley [3]. It is estimated to affect 1 in 100 people worldwide. Celiac disease affects 0.5% to 1% of the people in the western hemisphere and Europe.
When people with celiac disease eat gluten (a protein found in wheat, rye and barley), their body mounts an immune response that attacks the small intestine. These attacks lead to damage on the villi, small fingerlike projections that line the small intestine, that promote nutrient absorption. When the villi get damaged, nutrients cannot be absorbed properly into the body.
Celiac disease is hereditary, meaning that it runs in families. People with a first-degree relative with celiac disease (parent, child, sibling) have a 1 in 10 risk of developing celiac disease.
Causes and risk factors
• Gliadins and glutenins in the presence of CD4+ T cells with HLA-DQ2 and HLA-DQ8 activate cytokine production and clonal expansion of antibody-producing B cells, which lead to lymphocyte-mediated destruction of the epithelium and mucosa. This is termed the adaptive response. The resulting injury impairs villous function and absorption of nutrients, producing the clinical signs and symptoms of celiac disease. In addition, there is an innate response, which involves interleukin-15 expressed by enterocytes;
• Celiac disease affects predominantly the mucosa of the proximal small intestine, which receives the majority of dietary gluten. Distal parts of the small intestine are less affected because gluten has generally been absorbed by the time the enteric bolus reaches these areas.
Risk factors:
Geographic: The highest incidence of celiac disease is found in western Europe and the U. S.
Age: Peaks in diagnosis occur in childhood (when approximately 6% of the cases are diagnosed) and between the fifth and seventh decades of life.
Female gender: The female-to-male ratio in celiac disease is about 2:1.
Heredity:
• Celiac disease is an inherited condition with a concordance rate of70% to 100% between monozygotic twins;
• The concordance rate among siblings is 7% to 30%. The rate increases up to 40% if the sibling has the same HLA risk haplotype as the index case;
• Risk is higher among first- degree relatives of those with the condition, with a 1:22 ratio, compared with the risk among second-degree relatives (1:29);
• At lease 11% of first-degree relatives of index cases have celiac disease.
Infant diet:
• If gluten-containing foods are brought into the diet within the first 3 months or after 7 months of life, the risk of developing celiac disease increases five-fold;
• The risk is higher in the first 3 months because of the infant's underdeveloped intestinal mucosal barrier, which allows immunogenic peptides to cross the epithelium.
Absent breastfeeding:
Breastfeeding protects against the development of celiac disease in childhood. Gradual introduction of gluten-containing foods while breastfeeding decreases the risk by 48%.
Breastfeeding may have the following protective effects:
• Breast milk protects against gastrointestinal infections that increase the permeability of the intestinal mucosa to gluten;
• IgA in breast milk agglutinates with antigen, preventing the antigen's uptake to the mucosa;
• Breast milk has T-cell-specific suppressive effects.
Inflammatory bowel disease: A few studies have
shown an increased prevalence of celiac disease in patients with Crohn disease and, to a lesser extent, ulcer-ative colitis.
Comorbid risk factors:
• Lymphocytic colitis (increases risk of celiac disease 15%-27%);
• Down syndrome (increases risk 12%);
• Type 1 diabetes mellitus (increases risk 5%-6%);
• Autoimmune thyroid disease (increases risk 5%);
• Chronic fatigue syndrome (increases risk 2%).
Diagnosis
Approach to initial CD diagnosis
In 1970, the European Society of Paediatric Gastroenterology laid down criteria for the diagnosis of CD in children, entailing three biopsies ofan initial flat mucosa in the upper small intestine, restoration of the mucosa to normal on a GFD, and a deterioration of the mucosa after gluten challenge. Given the current availability of serological tests being highly sensitive and specific, the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition has proposed a revised CD diagnostic protocol. Based on this protocol, if the symptoms (either "classical" or "atypical") and serological tests are suggestive of CD, small bowel biopsy followed by a favourable clinical and serological response to the GFD is now considered sufficient to definitely confirm the diagnosis. In asymptomatic patients improvement in mucosal appearance may be required to confirm the diagnosis, but in majority symptomatic patients, continual abnormality of mucosa at the second biopsy is more likely to indicate slow/partial mucosal recovery. This may also reflect that the site of re-biopsy (proximal small intestine) is often the last site to improve.
The current approach to evaluating CD has been modified by the advent of highly sensitive and specific serological tests. An algorithm for diagnosing CD is given in. Assays for IgA anti-tissue transglutaminase (TGA) and IgA anti-endomysial (EMA) have both the highest specificities and sensitivities, and are therefore regarded as being superior serological screening tools for diagnosis of CD. Initial CD evaluation is based on a combination of positive CD-specific serological tests, histological findings in the intestinal biopsy, CD-predisposing gene encoding HLA DQ2 or DQ8, family and medical history of CD, and clinical or histological response to GFD. However, CD diagnosis can be challenging in some non-responsive patients to GFD. Practically all patients with CD carry HLA-DQ2 or HLA-DQ8. Thus the absence of these gene pairs reflects a very high negative predictive value for CD and should prompt consideration of other causes of small bowel-related symptoms and pathological changes. Positive TGA or EMA at initial diagnosis of CD or at any time in the clinical course of the disease helps to confirm the diagnosis of CD because of their excellent specificities of over 99% when small bowel villous atrophy is present on biopsy.
Serological tests
HLA typing: The contribution of HLA type to the genetic risk for CD has been variously estimated at 30%-
50%. Many of the polymorphic genes are involved in susceptibility to CD encode products that influence the immune response upon gluten ingestion, as shown for the HLA-linked genes. Although Non-HLA genes contribute more than HLA genes to the genetic background of CD, each of them adds only a minor contribution to the disease development.
There is strong association between CD and the presence of HLA DQA1*0501-DQB1*02 (DQ2) and DQA1*0301-DQB1 [0302 (DQ8) haplotypes. Approximately 90% to 95% of patients with CD carry DQ2 and those patients that are negative for HLA-D Q2 are usually positive for HLA-DQ8, indicating a strong genetic risk for the disease. Several studies also have confirmed that the absence of HLA-DQ2, HLA-DQ8, or both virtually excludes the diagnosis of CD]. However, the modest sensitivity (HLA-DQ2, 70%-99.8%; HLA-DQ8, 1.6%-38%) and specificity (HLA-DQ2, 69%-77%; HLA-DQ8, 77%-85%) of the test means that a positive result is not sufficient to diagnose the disease [having a low positive predictive values (HLA-DQ2, 6.3-18; HLA-DQ8, 0.28-8.1) and likelihood ratios (HLA-DQ2, 2.25-4.33; HLA-DQ8, 0.07-2.53)]. Even the presence of HLA-DQ2 or HLADQ8 in patients with positive serologic test results is strongly suggestive but not pathognomonic for CD. Antibody screening to identify participants with preclinical CD may be reduced by preselecting HLA risk group from the large populations with long-term follow-up for CD. Hence HLA-DQ genotyping could be included in the algorithm of selecting large populations prospectively screened for CD.
Antibody level: Several serum antibodies have been used to initially evaluate patients with suspected CD, monitor adherence and response to GFD, and screen asymptomatic individuals. Anti-gliadin antibodies (AGA) detection has low sensitivity and specificity, leading to high false-positive rate in patients. Recent reports of de-amidated gliadin peptide AGA (DGP-AGA) have suggested a much improved accuracy. The sensitivity and specificity for IgA DGP-AGA is 84.3% and 79.8%, whereas for IgG DGP-AGA the sensitivity and specificity are 82.3% and 98.9%, respectively. As shown in Table, EMA and TGA have been found to be superior to AGA and gives highest sensitivity and specificity of greater than 95% when used in combination. EMA testing, however, produces a subjective and highly observer-dependent result, whereas TGA testing is quantitative [4].
Endoscopy: The only way to confirm a celiac disease diagnosis is by having an endoscopic biopsy. During the biopsy, the gastroenterologist will insert a small
tube with a camera through the digestive tract to the small intestine. Once there, the physician will examine the duodenum and take multiple tissue samples due to the "patchy" nature of villous atrophy. The tissue samples will then be examined by a pathologist under a microscope and assigned a Marsh classification [5].
Marsh Stages
Marsh 0: The mucosa (intestinal lining) is normal, so celiac disease is unlikely. Stage 0 is known as the "pre-infiltrative stage."
Marsh I: The cells on the surface of the intestinal lining (the epithelial cells) are being infiltrated by white blood cells known as lymphocytes. This is also seen in tropical sprue, giardiasis, acute infective enteropathy, H. pylori gastritis, Crohn's disease, during NSAID usage,
and in various autoimmune disorders. Therefore, it is not specific for celiac disease.
Marsh II: The changes of Marsh I are present (increased lymphocytes), and the crypts (tube-like depressions in the intestinal lining around the villi) are "hyperplastic" (larger than normal).
Marsh III: The changes of Marsh II are present (increased lymphocytes and hyperplastic crypts), and the villi are shrinking and flattening (atrophy). Most patients with celiac disease are Marsh III. There are three subsets of Marsh III: partial villous atrophy, subtotal villous atrophy and total villous atrophy.
Marsh IV: The villi are totally atrophied (completely flattened) and the crypts are now shrunken, too.
References:
1. David A., Nelsen, JR., M. D., M. S., University of Arkansas for Medical Sciences, Little Rock, Arkansas. Am Fam Physician. - 2002 Dec 15;66 (12):2259-2266.
2. Lancet Neurology, The, - 2010-03-01, - Volume 9, - Issue 3, - P. 318-330, Copyright © 2010 Elsevier Ltd.
3. Gastroenterology Clinics of North America, - 2007-03-01, - Volume 36, - Issue 1, - P. 93-108, Copyright © 2007 Elsevier Inc.
4. World J. Gastroenterol. - 2012. - Nov 14; - 18 (42): 6036-6059.
5. URL: http://celiac.org/wp-content/uploads/2013/07/Capsule_Endoscopy.jpg
