DISKUSNÉ FÓRUM

CELIAKIA, ODBORNY CLANOK V AJ

Chapter 140 - [b] Celiac disease[/b]
Michael T. Murray ND
Joseph E. Pizzorno Jr ND

[b] DIAGNOSTIC SUMMARY[/b]
• A chronic intestinal malabsorption disorder caused by an intolerance to gluten
• Bulky, pale, frothy, foul-smelling, greasy stools with increased fecal fat
• Weight loss and signs of multiple vitamin and mineral deficiencies
• Increased levels of serum gliadin antibodies
• Diagnosis confirmed by jejunal biopsy.

[b] GENERAL CONSIDERATIONS[/b]
Celiac disease, also known as non-tropical sprue, gluten-sensitive enteropathy, or celiac sprue, is characterized by malabsorption and an abnormal small intestine structure which reverts to normal on removal of dietary gluten. The protein gluten and its polypeptide derivative, gliadin, are found primarily in wheat, barley, and rye grains. Symptoms most commonly appear during the first [b] 3 years of life[/b], [b] after cereals are introduced into the diet[/b]. A second peak incidence occurs during the third decade. Breast feeding appears to have prophylactic effect, and breast-fed babies have a decreased risk of developing celiac disease. [1] [2] [3] The [b] early introduction of cow’s milk is also believed to be a major etiological factor[/b] [u] [/u]. [1] [2] [3] [4] Research in the past few years has clearly indicated that breast feeding, along with delayed administration of cow’s milk and cereal grains, are primary preventive steps that can greatly reduce the risk of developing celiac disease.

[b] Epidemiology and genetics[/b]
Precise epidemiological data on celiac disease is unavailable, due in part to the fact that asymptomatic disease makes ascertainment of true prevalence rates difficult.

Celiac disease appears to have a genetic etiology, as evidenced by an increased frequency of serum histocompatibility antigens, particularly HLA-B 8 and DRw3
types.[3] [5] The HLA-B8 antigen has been found in 85–90% of these celiac patients, as compared with 20–25% in normal subjects. The HLA-B 8 gene locus is believed to be linked to the immunologic recognition of antigens and specific T-cell-regulated immune responses.

There is a low prevalence of HLA-B8 within long-standing agrarian populations, while the frequency in northern and central Europe and the north-west Indian
subcontinent is much higher.[3] [6] Wheat cultivation in these high HLA-B 8 areas is a relatively recent development (1000 BC). The prevalence of celiac disease is much higher in these areas compared with other parts of the world (e.g. 1:300 in south-west Ireland compared with 1:2,500 in the United States [estimated]).


[b] Chemistry of grain proteins[/b]
Gluten, a major component of the wheat endosperm, is composed of gliadins and glutenins. Only the [b] gliadin[/b] portion has been demonstrated to activate celiac disease.

In rye, barley, and oats, the proteins that appear to activate the disease are termed secalins, hordeins, and avenins, respectively, and [b] prolamines [/b]collectively. Cereal grains belong to the family Gramineae. The closer a grain’s taxonomic relationship to wheat, the greater is its ability to activate celiac disease. [b] [b] Rice and corn, two grains that do not appear to activate celiac disease (Ryza a kukurica, zdasa, neaktivuju celiakiu[/b]), are further removed taxonomically from wheat. [3] [7]

Gliadins are single polypeptide chains that range in molecular weight from 30,000 to 75,000, with a very high glutamine and proline content. Gliadins have been divided into four major electrophoretic fractions: alpha-, beta-, gamma-, and omega-gliadin. Alpha-gliadin is believed to be the fraction most capable of activating celiac disease, although beta- and gamma-gliadin are also capable. Omega-gliadin does not appear to activate the disease, although it has the highest content of glutamine and proline. Gliadin that has been subjected to complete hydrolysis does not activate celiac disease in susceptible individuals, suggesting a possible relation to deficient brush border peptidase or similar defect in some other factor involved with protein digestion. [3]

Opioid activity
Pepsin hydrosylates of wheat gluten have demonstrated opioid activity. [8] [9] This activity is believed to be the factor responsible for the association between wheat
consumption and schizophrenia.[10] [11] [12] The hypothesis that gluten is a pathogenic factor in the development of schizophrenia is substantiated by epidemiological, clinical, and experimental studies. [10] [11] [12]

Pathogenesis
Various hypotheses have been proposed to explain the pathogenesis of celiac disease. Currently, the most likely relates to abnormalities in the immune response rather than some “toxic” property of gliadin.[13] Sensitization to gliadin occurs both in humoral and cell-mediated immunity and it appears that T-cell dysfunction is the main factor responsible for the enteropathy. [14] Cell-mediated mechanisms can produce in animals the characteristic lesions seen in celiac disease, i.e. crypt hyperplasia, villous atrophy, and intraepithelial lymphocyte infiltration and mitosis. Although patients with celiac disease have high titers of serum antibodies to [b] gliadin and other food proteins[/b] [u] [/u], it appears that these titers are probably secondary to the [b] increased intestinal permeability [/b] [u] [/u] [u] (prilisna crevna priepustnost[/u])which is the result of the enteropathy produced by the T-cell defect.[14] Of course, these immune complexes (e.g. antibody + gliadin) also contribute to the enteropathy through antibody-dependent cell-mediated cytotoxicity and activation of complement.[3]
The histologic lesions of celiac disease are often indistinguishable from those changes caused by tropical sprue, food allergy, diffuse intestinal lymphoma, and viral gastroenteritis. Furthermore, celiac disease will often lead to a disaccharidase deficiency, causing lactose intolerance, and the increased intestinal permeability usually results in multiple food allergies. [u] As stated earlier, cow’s milk intolerance may precede celiac disease. [/u][1] [2] [3] [4]

[b] Associated conditions[/b]
Conditions such as thyroid abnormalities, insulin-dependent diabetes mellitus, psychiatric disturbances (including schizophrenia), dermatitis herpetiformis, and
urticaria have also been linked to gluten intolerance. [3] A more ominous association is the increased risk for malignant neoplasms seen in celiac patients. [3] [15] [16] This may be a result of decreased vitamin and mineral absorption, particularly vitamin A and carotenoids (see Chs 67 and 121 ). However, it may also be a result of gliadin-activated suppressor cell activity. [17] Alpha-gliadin has demonstrated suppressor cell activation on the cells of celiac patients but has no effect on those of healthy controls or patients with Crohn’s disease. Two other dietary antigens, casein and beta-lactoglobulin, have failed to produce suppressor cell activation in similar experimental settings. This depression in the immune response makes these patients more susceptible to infection and neoplasm.

Diagnosis
Jejunal biopsy is the definitive diagnostic procedure. However, the presence of the characteristic symptoms along with a positive titer for antibodies against gliadin (anti-alpha-gliadin antibodies) spares the patient the rigor of a small intestine biopsy. The ELISA test for alpha-gliadin antibodies has a diagnostic sensitivity of 100% and a diagnostic specificity of 97%.[18] The fluorescent immunosorbent test has yielded similar impres-sive results (100% sensitivity and 84% specificity). [19] It appears that both IgA and IgG gliadin antibody levels should be taken into consideration rather than relying on just one antibody assay.
Anti-endomysium antibodies are now also reliable markers for celiac disease. [20]

[b] THERAPEUTIC CONSIDERATIONS[/b] [u] [/u]

[b] Diet[/b]
Once the diagnosis has been established, a gluten-free diet is indicated. [b] This diet does not contain any wheat, rye, barley, triticale, or oats.[/b] [u] [/u] [b] Buckwheat (pohanka) and millet (ovos) are often excluded as well.[/b] [i] [/i] [u] [/u] Although buckwheat is not in the grass family, and millet appears to be more closely related to rice and corn, [b] they do contain prolamines with similar antigenic activity to the alpha-gliadin of wheat. [/b] [u] [/u]A recent study of 52 adults with celiac disease suggests that modest amounts of oats may be tolerated without
adverse side-effects.[21]

[b] In addition, other foods should be rotated, and milk and milk products should be eliminated until the patient redevelops an intestinal structure and function returns to normal.[/b] [i] [/i] [u] [/u]

[b] Patient response[/b]
Usually clinical improvement will be apparent within a few days or weeks (30% respond within 3 days, another 50% within 1 month, and 10% within another month). However, 10% of patients only respond after 24–36 months of gluten avoidance. [22]

If the patient does not appear to be responding, the following should be considered: [3] [23]

• incorrect diagnosis
• the patient is not adhering to the diet or is being exposed to hidden sources of gliadin
• [b] the presence of an associated disease or complication, such as zinc deficiency.[/b]

[b] The latter highlights the importance of multivitamin and mineral supplementation in these patients[/b]. In addition to treating any underlying deficiency, supplementation provides the necessary cofactors for growth and repair. Celiac disease will be refractive to dietary therapy if an underlying zinc deficiency is present. [3] [23]

[b] Pancreatic enzymes[/b] [u] [/u]
The effect of pancreatic enzyme substitution therapy in the 2 months following the initial diagnosis of celiac disease (gluten enteropathy) was investigated in a recent double-blind study. The study sought to clarify the benefit of pancreatic enzyme therapy because previous studies had shown pancreatic insufficiency in 8–30% of celiac patients. The standard treatment of celiac disease is a gluten-free diet. In the study, patients followed a gluten-free diet and received either [b] two capsules of pancreatic enzymes with each meal (six to 10 capsules a day with each capsule containing lipase 5,000 IU, amylase 2,900 IU, and protease 330 IU) or two placebo capsules with meals.[/b] [u] [/u] Complete nutritional and anthropomorphic evaluations were conducted at days 0, 30, and 60. Results indicated that pancreatic enzyme supplementation enhanced the clinical benefit of a gluten-free diet during the first 30 days.

These results support the use of pancreatic enzyme preparations in the first 30 days after diagnosis of celiac disease (see Ch. 101 for a complete discussion).[24]

THERAPEUTIC APPROACH
The therapeutic approach is quite straightforward: eliminate all sources of gliadin (see Appendix 5 ), eliminate dairy products initially, correct underlying nutritional deficiencies, treat any associated conditions, and determine and eliminate all food allergens. If the patient does not begin to respond within 1 month, reconsider the diagnosis and search for hidden sources of gliadin.

Maintenance of a [b] strict gluten-free diet [/b]is quite difficult in the United States, due to the ubiquitous distribution of gliadin and other activators of celiac disease in
processed foods. Patients must be encouraged to read labels carefully in order to avoid hidden sources of gliadin, such as is found in some brands of soy sauce,
modified food starch, ice cream, soup, beer, wine, vodka, whisky, malt, etc. Patients should also be encouraged to consult resources for patient education and information on gluten-free recipes (see below for a list of patient education resources).

Patient resources
American Celiac Society
45 Gifford Avenue
Jersey City, NJ 07304
American Digestive Disease Society
7720 Wisconsin Avenue
Bethesda, MD 20014
Gluten Tolerance Group of North America
PO Box 23053
Seattle, WA 98102
National Digestive Disease Education and Information Clearing House
1555 Wilson Boulevard, Suite 600
Rosslyn, VA 22209

REFERENCES
1. Auricchio S. Gluten-sensitive enteropathy and infant nutrition. J Ped Gastroenterol Nutr 1983; 2: S304–309
2. Auricchio S, Follo D, deRitis G et al. Does breast feeding protect against the development of clinical symptoms of celiac disease in children? J Ped Gastroenterol Nutr 1983; 2: 428–433
3. Cole SG, Kagnoff MF. Celiac disease. Ann Rev Nutr 1985; 5: 241–266
4. Fallstrom SP, Winberg J, Anderson HJ. Cow’s milk malabsorption as a precursor of gluten intolerance. Acta Paediatrica Scand 1965; 54: 101–115
5. McNicholl B, Egan-Mitchell B, Stevens FM et al. History, genetics, and natural history of celiac disease – gluten enteropathy. In: Walker DN, Kretchmer N, eds. Food, nutrition and evolution. New
York, NY: Masson. 1981: p 169–178
6. Simoons FJ. Celiac disease as a geographic problem. In: Walker DN, Kretchmer N, eds. Food, nutrition and evolution. New York, NY: Masson. 1981: p 179–200
7. Kasarda DD. Toxic proteins and peptides in celiac disease: relations to cereal genetics. In: Walker DN, Kretchmer N, eds. Food, nutrition and evolution. New York, NY: Masson. 1981: p 201–216
8. Morley JE, Levine A, Yamada T et al. Effect of exorphins on gastrointestinal function, hormonal release, and appetite. Gastroenterol 1983; 84: 1517–1523
9. Morley JE. Food peptides – a new class of hormones. JAMA 1982; 247: 2379–2380
10. Singh MM, Kay SR. Wheat gluten as a pathogenic factor in schizophrenia. Science 1976; 191: 401–402
11. Dohan FC, Gasberger JC. Relapsed schizophrenics. Earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatry 1973; 130: 685–688
12. Dohan FC, Harper EH, Clark MH et al. Is schizophrenia rare if grain is rare? Biol Psychiatry 1984; 19: 385–399
13. Robbins SL, Cotran RS, Kumar V. Pathologic basis of disease. Philadelphia, PA: WB Saunders. 1984: p 847–848
14. Ferguson A, Ziegler K, Strobel S. Gluten intolerance (coeliac disease). Annals Allergy 1984; 53: 637–642
15. Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac disease and malignancy. Lancet 1983; i: 111–115
16. Cooper BT, Holmes KY, Ferguson R et al. Celiac disease and malignancy. Medicine 1980; 59: 249–261
17. O’Farrelly C, Whelan CA, Feighery CF, Weir DG. Suppressor-cell activity in coeliac disease induced by alpha-gliadin, a dietary antigen. Lancet 1984; ii: 1305–1306
18. Stenhammar L, Kilander AF, Nilsson LA et al. Serum gliadin antibodies for detection and control of childhood coeliac disease. Acta Paediatr Scand 1984; 73: 657–663
19. Burgin-Wolff A, Bertele RM, Berger R et al. A reliable screening test for childhood celiac disease. Fluorescent immunosorbent test for gliadin antibodies. J Pediatr 1983; 102: 655–660
20. Ferfoglia G et al. Do dietary antibodies still play a role in the diagnosis and follow-up of coeliac disease? A comparison among different serological tests. Panminerva Med 1995; 37: 55–59
21. Janatuinen ER, Pikkarainen P, Kemppainen TA. A comparison of diets with and without oats in adults with celiac disease. New Engl J Med 1995; 333: 1033–1038
22. Krause MV, Mahan KL. Food, nutrition and diet therapy. 7th edn. Philadelphia, PA: WB Saunders. 1984: p 452–457
23. Love AHG, Elmes M, Golden M et al. Zinc deficiency and celiac disease. In: McNicholl B, McCarthy CF, Fotrell PF, eds. Perspectives in celiac disease. Baltimore, MD: University Press. 1978: p
335–342
24. Carroccio A, Iacono G, Montalto G. Pancreatic enzyme therapy in childhood celiac disease. A double-blind prospective randomized study. Dig Dis Sci 1995; 40: 2555–2560

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