Unusual manifestations of celiac disease
http://www.100md.com
《美国医学杂志》
Paediatric Research Centre, University of Tampere, Finland
Abstract
Celiac disease is multifaced autoimmune disorder with several extraintestinal manifestations and connections to other autoimmune diseases and other conditions. The recognition of the complex clinical picture of the disease helps doctors to search and diagnose celiac disease even if the gastrointestinal symptoms are lacking. Individuals at risk for celiac disease should be thoroughly investigated and individuals with unusual manifestations of the disease should be screened actively.
Keywords: Celiac disease; Extraintestinal manifestations; Autoimmune diseases
Defining celiac disease
Celiac disease is defined as an autoimmune disorder causing a permanent intolerance to gluten; a cereal protein present in grain from wheat, barley and rye. The susceptibility for the disease is in all populations strongly associated with certain genetic risk factors, i.e. HLA-DQ2 and -DQ8.[1] According to the current criteria the diagnosis is based on a typical finding of villous atrophy and crypt hyperplasia in small-bowel mucosal specimen.[2] For the case finding there are highly sensitive and specific autoantibody tests available: endomysial and tissue transglutaminase autoantibody tests correlate well with the small bowel mucosal findings.[3] The population based screening studies have shown that the overall prevalence of celiac disease is among most European populations at least 1%.[4],[5] However, in clinical practise the disease often remains underdiagnosed. The major problem in diagnosing celiac disease is the multifaceted clinical picture of the condition. The disease is generally considered to affect mainly the gastrointestinal tract even though the severity of symptoms may vary from mild to severe irrespective of the occurrence of a manifest gluten-dependent small-bowel mucosal lesion. Further, recent evidence shows that the gastrointestinal symptoms may be even absent despite of the mucosal lesion and the condition may involve a number of extra-intestinal manifestations as only sign of the disease.[4] Sometimes all the symptoms are lacking and the only way of diagnosing this symptomless form of the disease is active serological screening. The only treatment of celiac disease known so far is life-long gluten-free diet.
Typical symptoms
Classically celiac disease has been a disease of infancy. The symptoms and signs of malabsorption may become obvious within some months after starting a gluten-containing diet. The most striking symptoms in the classical form of the disease are diarrhea, vomiting, distended abdomen and failure to thrive.[6] Hypotonic and dehydrated infants may be suffering from a variety of subclinical isolated nutrient deficiencies: hypoporteinemia, hypokalemia, hypoprothrombinemia or hypocalcemia. In some communities, the delay in diagnosis may be due to the presence of other diseases clinically resembling celiac disease.
Nowadays, celiac disease presenting with a severe malabsorption syndrome is an exception. Instead, the disease seems to express itself with milder and non-typical symptoms and the age at diagnosis seems to increase.[7] Abdominal discomfort, loose stools, flatulence problems and recurrent abdominal pain are symptoms which should remind us of the possibility of celiac disease in schoolchildren and adults. Weight loss and fatigue may occur, but also constipation may be a sign of the disease. Anemia due to iron malabsorption[8],[9] and lactose intolerance due to impaired absorption of lactose[10] are common findings in celiac disease as well as diffuse arthritis and arthralgy.[11] Short stature is one of the most common sign of celiac disease in schoolchildren.[12] Gastrointestinal symptoms usually disappear on a gluten-free diet within a couple of weeks, whereas the recovery of the small bowel mucosa may take over a year. It is to be noted that a gluten-free diet often alleviates abdominal symptoms also in non-celiac individuals.[13] Dietary interventions are not hence recommended for diagnostic purposes.
Extraintestinal Manifestations
The best known extraintestinal manifestation of celiac disease is dermatitis herpetiformis .[14] This skin disorder is characterized by itchy, blistering rash appearing predominantly at the knees, elbows and buttock. The diagnosis is based on immunoglobulin IgA deposits in the papillary dermis in skin biopsies. Less than 10% of dermatitis herpetiformis patients present gastrointestinal symptoms, although 70% of them have gluten-sensitive enteropathy. Rash responds to gluten withdrawal but dermatitis herpetiformis patients are usually very sensitive for even small amounts of gluten.
Decreased bone mineral density is available in 30-40% of untreated celiac disease cases, both in adults[15],[16],[17],[18],[19], and in children[20],[21],[22],[23],[24],[25],[26], even when no signs of malabsorption are detectable. The mechanisms of disturbances in bone mineral metabolism are poorly understood. During normal bone remodelling the rate of supply of new osteoblasts and osteoclasts and the timing of the death of osteoclasts, osteoblasts and osteocytes by apoptosis are critical determinants in bone turnover. In celiac disease the fine balance among these components may be disrupted, leading to impaired bone mineral density.[27] Disturbed calcium metabolism and primary or secondary hyperparathyreoidism may also play a role in the development of osteopenia.[18] Further, in women celiac disease can lead to amenorrhea and early menopause which are associated with osteoporosis.[28] Some data confirms that celiac disease is more common among patients with osteoporosis than among non-osteoporotic individuals; 2.4 to 3.9% of patients suffering from osteoporosis are positive for coeliac disease related autoantibodies.[29],[30],[31] Thus, decreased bone mineral density may be the first and only sign of untreated celiac disease. Targeted case-finding of celiac disease is recommended among patients with osteoporosis even though there are controversial opinions in different studies about bone fracture risk in patients with celiac disease.[32],[33],[34],[35] In any case, evidence shows that osteoporosis and osteopoenia are alleviated on a gluten-free diet, although not always completely.[15],[16],[17],[18],[19] Only in children osteopenia seems to be cured completely with appropriate diet.[20]-[23],[25],[26]
Oral mucosal lesions or dental enamel defects may be the only presenting features of celiac disease.[36],[37],[38],[39] Even 66% of celiac disease patients have oral symptoms.[38] Dental enamel defects of the permanent teeth develop if a child has untreated celiac disease during the calcification of the permanent teeth. The calcification process normalizes in response to gluten-free diet treatment.[36]
Recently, a growing body of distinct neurologic conditions has been connected to untreated celiac disease, mainly in middle-aged adults. These manifestations are usually chronic, such as occipital lobe epilepsy with cerebral calcifications, cerebellar ataxia, chronic neuropathies, myoclonic ataxia, progressive leukoencephalopathy and dementia.[40] Seven per cent of all untreated celiac disease patients are diagnosed on the basis of various neurological symptoms.[41] Although earlier studies reported neurologic disorders in patients with classical gluten enteropathy, some recent studies report neurologic symptoms in otherwise asymptomatic celiac disease patients.[42],[43] The pathogenic mechanisms underlying neurological disorders remain obscure, but immunological mechanisms are implicated. In few cases neurological symptoms seem to be alleviated by gluten-free diet but mostly the disorders are permanent.[42]
An increased incidence of reproductive problems exists in women with celiac disease.[28],[44] Women with untreated celiac disease tend to have a shorter reproductive period, are relatively infertile, and have a higher incidence of spontaneous abortions than women of control population.[44] Problems are mainly caused by subclinical celiac disease.[45],[46] The prevalence of undetected celiac disease among infertile women seems to be 3%.[46] Offspring of mothers with untreated celiac disease carry an increased risk for intrauterine growth retardation.[47] Infertility and the outcome of offspring react successfully to gluten-free diet.[44],[47] Male hypogonadism, infertility and sexual dysfunction are less studied but untreated celiac disease seems to affect also gonadal function of males.[48] Also father's celiac disease seems to lower the birth weight of offsprings.[49]
Mild liver abnormalities are common in patients with celiac disease: even 30% of celiac disease patients evince a transient elevation of liver enzymes at the time of diagnosis.[50],[51] The prevalence of silent celiac disease in patients with chronically abnormal liver tests of unexplained etiology is 4%.[52] Further, silent celiac disease is present in 3.5% of patients with autoimmune cholestasis,[53] in 6.3% of patients with autoimmune hepatitis[54] and in 3.4% of patients with non-alcoholic fatty liver.[55] Even in the population with end-stage liver failure and liver transplantation celiac disease seems to be overrepresented.[56] The mechanisms behind the liver disorders associated with celiac disease are still unknown, but it has been suggested that the immunological process ongoing in the gut may equally affect the liver. There is evidence that hepatic failure may be reversed on a gluten-free diet.[56] High prevalence of celiac disease in autoimmune cholestasis suggests that serological screening for celiac disease should be routinely performed in such patients.
Idiopathic dilated cardiomyopathy and autoimmune myocarditis are connected to celiac disease. According to different studies 2.1 to 5.7% of patients suffering from idiopathic dilated cardiomyopathy[57],[58] and 4.4% of patients with autoimmune myocarditis[59] are positive for autoantibodies connected to celiac disease. These studies suggest that immune-mediated mechanisms underlying behind these autoimmune disorders are of similar origin. There is no data about the effect of gluten-free diet on autoimmune heart diseases.
Few reports exist about an association between celiac disease and alopecia areata.[60],[61],[62] Results of these studies show that alopecia areata may constitute the only clinical manifestation of celiac disease. In children the gluten-free diet showed to be successful for hair growth[62] but in adults no effect was established.[61]
One recent study has suggested that there is a connection between celiac disease and antiphospholipid syndrome.[63] Especially cutaneous manifestations seemed to be associated with endomysial antibodies. Further studies are warranted on this issue.
Depressive symptoms are a feature of celiac disease.[64],[65],[66],[67] They are present to a similar extent in patients with childhood- and adulthood-diagnosed celiac disease. Possible mechanism underlying depressive and behavioral symptoms in celiac disease patients may be serotonergic dysfunction due to impaired availability of tryptophan.[67] Gluten-free diet treatment has shown diverse results in alleviating psychiatric symptoms in celiac disease.
In context with celiac disease malignancies are usually connected to poor compliance or delayed diagnosis of the disease. According to a recent population based cohort study, 2.8% of all celiac disease patients had at least one malignancy.[68] The most common malignancy among celiac disease patients is small-bowel T-cell lymphoma which is diagnosed in 0.5% of the patients.[69] Especially patients with refractory sprue - gluten sensitive disorder reacting poorly to strict gluten-free diet treatment - are at risk for small-bowel lymphoma and other malignancies.[70] The overall mortality of celiac disease patients is 2.0-fold compared to non-celiac individuals.[71]
Disease Associations
Celiac disease is associated with many other autoimmune disorders.[72] table1 summarizes the prevalence of celiac disease in the most common autoimmune disorders. The best known connection is that between coeliac disease and insulin-dependent diabetes mellitus which is most probably due to the common genetic background of the two diseases. Gluten-free diet treatment does not seem to improve the metabolic control of diabetes.[72] Celiac disease should also be kept in mind when other autoimmune disorders, such as autoimmune thyroiditis and rheumatoid arthritis are considered. There is vast over-representation of celiac disease also among these patients table1. Less known is the connection between celiac disease and Sj φgren's syndrome - an autoimmune exocrinopathy with systemic manifestations including arthritis, fever, fatigue and mucosal dryness. Celiac disease seems to exist in 12 to 15 % of these patients. table1
Certain genetic disorders are also connected to celiac disease. Case-finding of celiac disease by autoantibody screening among individuals with Down's syndrome, Turner's syndrome and Williams' syndrome seems to be justified: 4.6% to 16% of patients with Down's syndrome,[85],[86] 5.0% of Turner's syndrome patients[87] and 9.5% of Williams' syndrome patients[88] are suffering from coeliac disease.
Selective immunoglobulin A (IgA) deficiency is a relatively rare condition which is connected to celiac disease: about 5% of endomysial antibody-positive individuals[89] and 2.6% of biopsy-proven celiac disease patients[90] suffer from selective IgA deficiency. This minority of celiac disease patients with selective IgA deficiency constitutes a marked problem in diagnosing celiac disease. Celiac disease patients suffering from this condition remain often undiagnosed because in IgA deficient patients IgA-class autoantibody tests remain negative and IgG-class antibodies should be tested instead.
New Diagnostic Approach
The current criteria for celiac disease may give the false impression that coeliac disease is purely a gastrointestinal disorder with manifest small-bowel mucosal lesion. The reality known today is much more complex. In the course of the disease the small intestin mucosal damage develops gradually, from normal morphology through inflammation to the so-called flat lesion (subtotal villous atrophy with crypt hyperplasia). This process or mucosal deterioration may take years or even decades. This means that when a child, an adult, or an elderly person on a gluten-containing diet has been shown to have a normal small intestinal mucosal morphology, even with no cellular inflammation, the disease is not excluded for ever. The mucosa may deteriorate later. Oral tolerance to gluten in celiac disease may be broken in some individuals after decades. This may be due to decreased amount of gluten in the diet but it may also depend on other environmental factors. However, these individuals are exposed to the harmful effect of the gluten and may develop a manifest disease outside the intestine without any gastrointestinal symptoms or signs. According to the current criteria celiac disease is excluded if the small bowel mucosa is normal but the disease is still there. It may manifest itself in liver or in brain and cause even death before the diagnosis is settled. Therefore it is important to identify those patients who are at risk of developing the disease: first-degree relatives of celiac disease patients who carry an increased risk for the disease, patients suffering from typical and especially untypical symptoms related to celiac disease and patients who have diseases that are associated with the disease. These individuals should be thoroughly investigated and the threshold of diagnosing the disease should be low. Small bowel biopsy is still the official diagnostic criteria but in the near future the criteria should be reconsidered and widened towards "genetic gluten intolerance" - i.e. criteria including correct HLA-DQ-type and positive celiac disease specific autoantibodies. Meanwhile the wide knowledge of the multifaceted clinical picture of the disease helps us to recognize the disease and follow up the patients at high risk.
References
1. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F and Thorsby E. Evidence for a primary association of celiac disease to a particular HLA-DQ a/b heterodimer. J Exp Med 1989; 169 : 345-350.
2. Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH and Visakorpi JK. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65 : 909-911.
3. Carroccio A, Vitale G, Di Prima L et al. Comparison of anti-transglutaminase ELISAs and an anti-endomysial antibody assay in the diagnosis of celiac disease: a prospective study. Clin Chem 2002; 48 : 1546-1550.
4. Mδki M, Mustalahti K, Kokkonen J, Kulmala P et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003; 348 : 2517-2524.
5. Volta U, Bellentani S, Bianchi FB, De Franceschi L, Miglioli L, Granito A, Balli F and Tiribelli C. High prevalence of celiac disease in Italian general population. Dig Dis Sci 2001; 46 : 1500-1505.
6. Visakorpi JK, Immonen P, Kuitunen P. Malabsorption syndrome in childhood. The occurence of absorption defects and their clinical significance. Acta Paediatr Scand 1967; 56 : 1-9.
7. Collin P, Reunala T, Rasmussen M et al. High incidence and prevalence of adult coeliac disease. Augmented diagnostic approach. Scand J Gastroenterol 1997; 32 : 1129-1133.
8. Ransford RA, Hayes M, Palmer M and Hall MJ. A controlled, prospective screening study of celiac disease presenting as iron deficiency anemia. J Clin Gastroenterol 2002; 35 : 228-233.
9. Kalayci AG, Kanber Y, Birinci A, Yildiz L, Albayrak D. The prevalence of celiac disease as detected by screening in children with iron deficiency anaemia. Acta Paediatr 2005; 94 : 678-681.
10. Ojetti V, Nucera G, Migneco A et al. High prevalence of coeliac disease in patients with lactose intolerance. Digestion 2005; 71 : 106-110.
11. Slot o, Locht H. Arthritis as presenting symptom in silten adult celiac disease. Two cases and review of the literature. Scand J Rheumatol 2000; 29 : 260-263.
12. Stenhammar L, Fallstr φm SP, Jansson G, Jansson U and Lindberg T. Coeliac disease in children of short stature without gastrointestinal symptoms. Eur J Pediatr 1986; 145 : 185-186.
13. Kaukinen K, Turjanmaa K, Mδki M et al. Intolerance to cereals is not specific for coeliac disease. Scand J Gastroenterol 2000; 35 : 942-946.
14. Reunala TL. Dermatitis herpetiformis. Clin Dermatol 2001; 19 : 728-736.
15. Corazza GR, Di Sario A, Cecchetti L et al. Influence of pattern of clinical presentation and of gluten-free diet on bone mass and metabolism in adult celiac disease. Bone 1996; 18 : 525-530.
16. Kemppainen T, Kroger H, Janatuinen E et al . Bone recovery after a gluten-free diet: a 5-year follow-up study. Bone 1999; 25 : 355-360.
17. Mustalahti K, Collin P, Sievδnen H, Salmi J, Mδki M. Osteopenia in patients with clinically silent celiac disease warrants screening. Lancet 1999; 28 : 744-745.
18. Valdimarsson T, Toss G, L φfman O and Str φm M. Three years' follow-up of bone density in adult celiac disease: significance of secondary hyperparathyroidism. Scand J Gastroenterol 2000; 35 : 274-280.
19. Meyer D, Stavropolous S, Diamond B, Hane E, Green PH. Osteoporosis in a North American adult population with coeliac disease. Am J Gastroenterol 2001; 96 : 112-119.
20. Scotta MS, Salvatore S, Salvatoni A, De Amici M, Ghiringhelli D, Broggini M and Nespoli L. Bone mineralization and body composition in young patients with celiac disease. Am J Gastroenterol 1997; 92 : 1331-1334.
21. Mora S, Barera G, Ricotti A, Weber G, Bianchi C and Chiumello G. Reversal of low bone density with a gluten-free diet in children and adolescents with celiac disease. Am J Clin Nutr 1998; 67 : 477-481.
22. Szathmari M, Tulassay T, Arato A, Bodanszky H, Szabo A, Tulassay Z. Bone mineral content and density in asymptomatic children with celiac disease on a gluten-free diet. Eur J Gastroenterol Hepatol 2001; 13 : 419-424.
23. Kavak US, Yuce A, Kocak N, Demir H, Saltik IN, Gurakan F, Ozen H. Bone mineral density in children with untreated and treated coeliac disease. J Pediatr Gastroenterol Nutr 2003; 37 : 434-436.
24. Puri AS, Garg S, Monga R, Tyagi P, Saraswat MK. Spectrum of atypical celiac disease in North Indian children. Indian Pediatr 2004; 41 : 822-827.
25. Barera G, Beccio S, Proverbio MC, Mora S. Longitudinal changes in bone metabolism and bone mineral content in children with coeliac disease during consumption of gluten-free diet. Am J Clin Nutr 2004; 79 : 148-154.
26. Tau C, Mautalen C, De Rosa S, Roca A, Valenzuela X. Bone mineral density in children with celiac disease. Effect of a Gluten-free diet. Eur J Clin Nutr 2006; 60 : 358-363.
27. Weinstein RS and Manolagas SC. Apoptosis and osteoporosis. Am J Med 2000; 108 : 153-164.
28. Sher KS, Mayberry JF. Female fertility, obstetric and gynaecological history in celiac disease: a case control study. Acta Paediatr Suppl 1996; 412 : 76-77.
29. Nuti R, Martini G, Valenti R, Giovani S, Salvadori S and Avanzati A. Prevalence of undiagnosed coeliac syndrome in osteoporotic women. J Intern Med 2001; 250 : 361-366.
30. Stenson WF, Newberry R, Lorenz R, Baldus C, Civitelli R. Increased prevalence of coeliac disease and need for routine screening among patients with osteoporosis. Arch Intern Med 2005; 28 : 393-399.
31. Armagan O, Uz T, Tascioglu F, Colak O, Oner C, Akgun Y. Serological screening for coeliac disease in premenopausal women with idiopathic osteoporosis. Clin Rheumatol 2005; 24 : 239-243.
32. Vasquez H, Mazure R, Gonzales D, Flores D, Pedreire S, Niveloni S, Smecuol E, Maurino E and Bai JC. Risk of fractures in celiac disease patients: a cross-sectional, case-control study. Am J Gastroenterol 2000; 95 : 183-189.
33. Thomason K, West J, Logan RF, Coupland C, Holmes GK. Fracture experience of patients with celiac disease: a population based survey. Gut 2003; 52 : 518-522.
34. West J, Logan RF, Card TR, Smith C, Hubbard R. Fracture risk in people with celiac disease: a population based cohort study. Gastroenterology 2003; 125 : 429-436.
35. Moreno ML, Vazquez H, Mazure R et al. Stratification of bone fracture risk in patients with coeliac disease. Clin Gastroenterol Hepatol 2004; 2 : 127-134.
36. Aine L. Coeliac-type permanent-tooth enamel defects. Ann Med 1996; 28 : 9-12.
37. Martelossi S, Zanatta E, Del Santo E, Clarich P, Radovich P, Ventura A. Dental enamel defects and screening for celiac disease. Acta Paediatr Suppl 1996; 412 : 47-48.
38. Lδhteenoja H, Toivanen A, Viander M et al. Oral mucosal changes in coeliac patients on a gluten-free diet. Eur J Oral Sci 1998; 106 : 899-906.
39. Bucci P, Carile F, Sngianantoni A, D'Angio F, Satarelli A, Lo Muzio L. Oral aphthous ulcers and dental enamel defects in children with celiac disease. Acta Paediatr 2006; 95 : 203-207.
40. Zelnik N, Pacht A, Obeid R, Lerner A. Range of neurologic disorders in patients with coeliac disease. Pediatrics 2004; 113 : 1672-1676. Rewiev.
41. Luostarinen L, Pirttilδ T and Collin P. Coeliac disease presenting with neurological disorders. Eur Neurol 1999; 42 : 132-135.
42. Pellecchia MT, Scala R, Perreti A et al. Cerebellar ataxia associated with subclinical coeliac disease responding to gluten-free diet. Neurology 1999; 53 : 1606-1608.
43. Burk K, Bosch S, Muller CA et al. Sporadic cerebellar taxia associated with gluten sensitivity. Brain 2001; 124 : 1013-1019.
44. Rostami K, Steegers EA, Wong WY, Braat DD, Steegers-Theunissen RP. Coeliac disease and reproductive disorders: a neglected association. Eur J Obstet Gynecol Reprod Biol 2001; 96 : 146-149.
45. Kolho KL, Tiitinen A, Tulppala M, Unkila-Kallio L and Savilahti E. Screening for coeliac disease in women with a history of miscarriage or infertility. Br J Obstet Gynaecol 1999; 106 : 171-173.
46. Meloni GF, Dessole S, Vargiu N, Tomasi PA and Musumeci S.The prevalence of coeliac disease in infertility. Hum Reprod 1999; 14 : 2759-2761.
47. Norgard B, Fonager K, Sorensen HT, Olsen J. Birth outcomes of women with coeliac disease: a nationwide historical cohort study. Am J Gastroenterol 1999; 94 : 2435-2440.
48. Farthing MJ, Edwards CR, Rees LH and Dawson AM. Male gonadal function in coeliac disease:1: Sexual dysfunction, infertility and semen quality. Gut 1982; 23 : 608-614.
49. Ludvigsson JF, Ludvigsson J. Coeliac disease in the father affects the newborn. Gut 2001; 49 : 169-175.
50. Volta U, De Franceschi L, Lari F, Molinaro N, Zoli M and Bianchi FB. Coeliac disease hidden by cryptogenic hypertransaminasemia. Lancet 1998; 352 : 26-29.
51. Farre C, Esteve M, Curcoy A, Cabre E, Arranz E, Amat LLand Garcia-Tornel S. Hypertransaminasemia in pediatric celiac disease patients and its prevalence as a diagnostic clue. Am J Gastroenterol 2002; 97 : 3176-3181.
52. Lo Iacono O, Petta S, Venezia G et al. Anti-tissue transglutaminase antibodies in patients with abnormal liver tests: is it always celiac disease. Am J Gastroenterol 2005; 100 : 2472-2477.
53. Volta U, Rodrigo L, Granito A et al. Coeliac disease in autoimmune cholestatic liver disorders. Am J Gastroenterol 2002; 97 : 2609-2613.
54. Villalta D, Girolami D, Bidoli E et al. High prevalence of celiac disease in autoimmune hepatitis detected by anti-tissue transglutaminase autoantibodies. J Clin Lab Anal 2005; 19 : 6-10.
55. Bardella MT, Valenti L, Pagliari C et al. Searching for coeliac disease in patients with non-alcoholic fatty liver disease. Dig Liver Dis 2004; 36 : 333-336.
56. Kaukinen K, Halme L, Collin P et al. Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology 2002; 123 : 2158-2159.
57. Not T, Faleschini E, Tommasini A et al. Coeliac disease in patients with sporadic and inherited cardiomyopathies and in their relatives. Eur Heart J 2003; 24 : 1455-1461.
58. Curione M, Barbato M, De Biase L, Viola F, Lo Russo L, Vardi E. Prevalence of celiac disease in idiopathic dilated cardiomyopathy. Lancet 1999; 354 : 222-223.
59. Fustaci A, Cuoco L, Chimenti C et al. Coeliac disease associated with autoimmune myocarditis. Circulation 2002; 105 : 2611-2618.
60. Corazza GR, Andreani ML, Venturo N, Bernardi M, Tosti A, Gasbarrini G. Coeliac disease and alopecia areata: report of a new association. Gastroenterology 1995; 109 : 1333-1337.
61. Bardella MT, Marino R, Barbareschi M, Bianchi F, Faglia G, Bianchi P. Alopecia areata and celiac disease: no effect of a gluten-free diet on hair growth. Dermatology 2000; 200 : 108-110.
62. Fessatou S, Kostaki M, Karpathios T. Coeliac disease and alopecia areata in childhood. J Paediatr Child Health 2003; 39 : 152-154.
63. Shamir F, Shoenfeld Y, Blank M et al. The prevalence of celiac disease antibodies in patients with the antiphospholipid syndrome. Lupus 2003; 12 : 394-399.
64. Ciacci C, Iavarone A, Mazzacca G, De Rosa A. Depressive symptoms in adult celiac disease. Scand J Gastroenterol 1998; 33 : 247-250.
65. Addolorato G, Capristo E, Ghittoni G et al. Anxiety but not depression decreases in celiac patients after one-year gluten-free diet: a longitudinal study. Scand J Gastroenterol 2001; 36: 502-506.
66. Fera T, Cascio B, Angelini G, Martini S, Guidetti CS. Affective disorders and quality of life in adult celiac disease patiens on a gluten-free diet. Eur J Gastroenterol Hepatol 2003; 15 : 1287-1292.
67. Pynn φnen PA, Isometsδ ET, Verkasalo MA et al. Gluten-free diet may alleviate depressive and behavioural symptoms in adolescents with celiac disease: a prospective follow-up case-series study. BMC Psychiatry 2005; 17 : 14
68. West J, Logan R, Smith C, Hubbard R, Card T. Malignancy and mortality in people with celiac disease: population based cohort study. BMJ 2004; 329 : 716-719.
69. Catassi C, Fabiani E, Corrao G, Barbato M, De Renzo A, Carella AM, Gabrielli A, Leoni P, Carroccio A, Baldassarre M, Bertolani P, Caramaschi P, Sozzi M, Guariso G, Volta U and Corrazza GR. Risk of non-Hodgkin lymphoma in celiac disease. JAMA 2002; 287; 1413-1419.
70. Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, Macintyre E, Cerf-Bensussan N and Brousse N. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet 2000; 35 6 : 178-179.
71. Peters U, Askling J, Gridley G, Ekbom A, Linet M. Causes of death in patients with coeliac disease in a population-based Swedish cohort. Arch Intern Med 2003; 163 : 1566-1572.
72. Collin P, Kaukinen K, Vδlimδki M and Salmi J. Endocrinological disorders and celiac disease. Endocr Rev 2002; 464-483.
73. Collin P, Salmi J, Hδllstr φm O, Oksa H, Oksala H, Jδki M, Reunala T. High frequency of coeliac disease in adult patients with type-I diabetes. Scand J Gastroenterol 1989; 24 : 81-84.
74. Talal AH, Murray JA, Goeken JA, Sivitz WI. Celiac disease in an adult population with insulin-dependent diabetes mellitys; use of endomysial antibody testing. Am J Gastroenterol 1997; 92 : 1280-1284.
75. Not T, Tommasini A, Tonini G et al. Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with type I diabetes mellitys. Diabetologia 2001; 44 : 151-155.
76. Holmes GK. Screening for coeliac disease in type 1 diabetes. Arch Dis Child 2002; 87 : 495-498.
77. Valentino R, Savastano S, Tommaselli AP, Dorato M, Scarpitta MT, Gigante M, Micillo M, Paparo F, Petrone E, Lombardi G and Troncone R. Prevalence of coeliac disease in patients with thyroid autoimmunity. Horm Res 1999; 51 : 124-127.
78. Berti I, Trevisiol C, Tommasini A et al. Usefulness of screening program for coeliac disease in autoimmune thyroiditis. Dig Dis Sci 2000; 45 : 678-685
79. Volta U, Ravaglia G, Granito A, et al. Coeliac disease in patients with autoimmune thyroiditis. Digestion 2001; 64 : 61-65.
80. Larizza D, Calcaterra V, De Giacomo C, De Silvestri A, Asti M, Badulli C, Autelli M, Coslovich E and Martinetti M. Celiac disease in children with autoimmune thyroid disease. J Pediatr 2001; 139 : 738-740.
81. Lepore L, Martelossi S, Pennesi M et al. Prevalence of celiac disease in patients with juvenile chronic arthritis. J Pediatr 1996; 129 : 311-313.
82. Francis J, Carty JE and Scott BB. The prevalence of coeliac disease in rheumatoid arthritis. Eur J Gastroenterol Hepatol 2002; 14 : 1355-1356.
83. Luft LM, Barr SG, Martin LO, Chan EK, Frizler MJ. Autoantibodies to tissue transglutaminase in Sj φgren's syndrome and related rheumatic diseases. J Rhematol 2003; 30: 2613-2619.
84. Iltanen S, Collin P, Korpela M et al. Celiac disease and markers of celiac disease latency in patients with primary Sj φgren's syndrome. Am J Gastroenterol 1999; 94 : 1042-1046.
85. Bonamico M, Mariani P, Danesi HM et al. Prevalence and clinical picture of celiac disease in Italian Down syndrome patients: a multicenter study. J Pediatr Gastroenterol Nutr 2001; 33 : 139-143.
86. Carlsson A, Axelsson I, Borulf S et al. Prevalence of IgA-antigliadin antibodies and IgA-antiendomysium antibodies related to celiac disease in children with Down syndrome. Pediatrics 1998; 101 : 272-275.
87. Ivarsson SA, Carlsson A, Bradberg A et al. Prevalence of coeliac disease in Turner syndrome. Acta Paediatr 1999; 88 : 933-936.
88. Giannotti A, Tiberio G, Castro M et al. Coeliac disease in Williams syndrome. J Med Genet 2001; 38 : 767-768.
89. Prince HE, Norman GL and Binder WL. Immunoglobulin A (IgA) deficiency and alternative celiac disease-associated antibodies in sera submitted to a reference laboratory for endomysial IgA testing. Clin Diagn Lab Immunol 2000; 7 : 192-196.
90. Cataldo F, Marino V, Bottaro G, Greco P and Ventura A. Celiac disease and selective immunoglobulin A deficiency. J Pediatr 1997; 131 : 306-308.(Mustalahti K)
Abstract
Celiac disease is multifaced autoimmune disorder with several extraintestinal manifestations and connections to other autoimmune diseases and other conditions. The recognition of the complex clinical picture of the disease helps doctors to search and diagnose celiac disease even if the gastrointestinal symptoms are lacking. Individuals at risk for celiac disease should be thoroughly investigated and individuals with unusual manifestations of the disease should be screened actively.
Keywords: Celiac disease; Extraintestinal manifestations; Autoimmune diseases
Defining celiac disease
Celiac disease is defined as an autoimmune disorder causing a permanent intolerance to gluten; a cereal protein present in grain from wheat, barley and rye. The susceptibility for the disease is in all populations strongly associated with certain genetic risk factors, i.e. HLA-DQ2 and -DQ8.[1] According to the current criteria the diagnosis is based on a typical finding of villous atrophy and crypt hyperplasia in small-bowel mucosal specimen.[2] For the case finding there are highly sensitive and specific autoantibody tests available: endomysial and tissue transglutaminase autoantibody tests correlate well with the small bowel mucosal findings.[3] The population based screening studies have shown that the overall prevalence of celiac disease is among most European populations at least 1%.[4],[5] However, in clinical practise the disease often remains underdiagnosed. The major problem in diagnosing celiac disease is the multifaceted clinical picture of the condition. The disease is generally considered to affect mainly the gastrointestinal tract even though the severity of symptoms may vary from mild to severe irrespective of the occurrence of a manifest gluten-dependent small-bowel mucosal lesion. Further, recent evidence shows that the gastrointestinal symptoms may be even absent despite of the mucosal lesion and the condition may involve a number of extra-intestinal manifestations as only sign of the disease.[4] Sometimes all the symptoms are lacking and the only way of diagnosing this symptomless form of the disease is active serological screening. The only treatment of celiac disease known so far is life-long gluten-free diet.
Typical symptoms
Classically celiac disease has been a disease of infancy. The symptoms and signs of malabsorption may become obvious within some months after starting a gluten-containing diet. The most striking symptoms in the classical form of the disease are diarrhea, vomiting, distended abdomen and failure to thrive.[6] Hypotonic and dehydrated infants may be suffering from a variety of subclinical isolated nutrient deficiencies: hypoporteinemia, hypokalemia, hypoprothrombinemia or hypocalcemia. In some communities, the delay in diagnosis may be due to the presence of other diseases clinically resembling celiac disease.
Nowadays, celiac disease presenting with a severe malabsorption syndrome is an exception. Instead, the disease seems to express itself with milder and non-typical symptoms and the age at diagnosis seems to increase.[7] Abdominal discomfort, loose stools, flatulence problems and recurrent abdominal pain are symptoms which should remind us of the possibility of celiac disease in schoolchildren and adults. Weight loss and fatigue may occur, but also constipation may be a sign of the disease. Anemia due to iron malabsorption[8],[9] and lactose intolerance due to impaired absorption of lactose[10] are common findings in celiac disease as well as diffuse arthritis and arthralgy.[11] Short stature is one of the most common sign of celiac disease in schoolchildren.[12] Gastrointestinal symptoms usually disappear on a gluten-free diet within a couple of weeks, whereas the recovery of the small bowel mucosa may take over a year. It is to be noted that a gluten-free diet often alleviates abdominal symptoms also in non-celiac individuals.[13] Dietary interventions are not hence recommended for diagnostic purposes.
Extraintestinal Manifestations
The best known extraintestinal manifestation of celiac disease is dermatitis herpetiformis .[14] This skin disorder is characterized by itchy, blistering rash appearing predominantly at the knees, elbows and buttock. The diagnosis is based on immunoglobulin IgA deposits in the papillary dermis in skin biopsies. Less than 10% of dermatitis herpetiformis patients present gastrointestinal symptoms, although 70% of them have gluten-sensitive enteropathy. Rash responds to gluten withdrawal but dermatitis herpetiformis patients are usually very sensitive for even small amounts of gluten.
Decreased bone mineral density is available in 30-40% of untreated celiac disease cases, both in adults[15],[16],[17],[18],[19], and in children[20],[21],[22],[23],[24],[25],[26], even when no signs of malabsorption are detectable. The mechanisms of disturbances in bone mineral metabolism are poorly understood. During normal bone remodelling the rate of supply of new osteoblasts and osteoclasts and the timing of the death of osteoclasts, osteoblasts and osteocytes by apoptosis are critical determinants in bone turnover. In celiac disease the fine balance among these components may be disrupted, leading to impaired bone mineral density.[27] Disturbed calcium metabolism and primary or secondary hyperparathyreoidism may also play a role in the development of osteopenia.[18] Further, in women celiac disease can lead to amenorrhea and early menopause which are associated with osteoporosis.[28] Some data confirms that celiac disease is more common among patients with osteoporosis than among non-osteoporotic individuals; 2.4 to 3.9% of patients suffering from osteoporosis are positive for coeliac disease related autoantibodies.[29],[30],[31] Thus, decreased bone mineral density may be the first and only sign of untreated celiac disease. Targeted case-finding of celiac disease is recommended among patients with osteoporosis even though there are controversial opinions in different studies about bone fracture risk in patients with celiac disease.[32],[33],[34],[35] In any case, evidence shows that osteoporosis and osteopoenia are alleviated on a gluten-free diet, although not always completely.[15],[16],[17],[18],[19] Only in children osteopenia seems to be cured completely with appropriate diet.[20]-[23],[25],[26]
Oral mucosal lesions or dental enamel defects may be the only presenting features of celiac disease.[36],[37],[38],[39] Even 66% of celiac disease patients have oral symptoms.[38] Dental enamel defects of the permanent teeth develop if a child has untreated celiac disease during the calcification of the permanent teeth. The calcification process normalizes in response to gluten-free diet treatment.[36]
Recently, a growing body of distinct neurologic conditions has been connected to untreated celiac disease, mainly in middle-aged adults. These manifestations are usually chronic, such as occipital lobe epilepsy with cerebral calcifications, cerebellar ataxia, chronic neuropathies, myoclonic ataxia, progressive leukoencephalopathy and dementia.[40] Seven per cent of all untreated celiac disease patients are diagnosed on the basis of various neurological symptoms.[41] Although earlier studies reported neurologic disorders in patients with classical gluten enteropathy, some recent studies report neurologic symptoms in otherwise asymptomatic celiac disease patients.[42],[43] The pathogenic mechanisms underlying neurological disorders remain obscure, but immunological mechanisms are implicated. In few cases neurological symptoms seem to be alleviated by gluten-free diet but mostly the disorders are permanent.[42]
An increased incidence of reproductive problems exists in women with celiac disease.[28],[44] Women with untreated celiac disease tend to have a shorter reproductive period, are relatively infertile, and have a higher incidence of spontaneous abortions than women of control population.[44] Problems are mainly caused by subclinical celiac disease.[45],[46] The prevalence of undetected celiac disease among infertile women seems to be 3%.[46] Offspring of mothers with untreated celiac disease carry an increased risk for intrauterine growth retardation.[47] Infertility and the outcome of offspring react successfully to gluten-free diet.[44],[47] Male hypogonadism, infertility and sexual dysfunction are less studied but untreated celiac disease seems to affect also gonadal function of males.[48] Also father's celiac disease seems to lower the birth weight of offsprings.[49]
Mild liver abnormalities are common in patients with celiac disease: even 30% of celiac disease patients evince a transient elevation of liver enzymes at the time of diagnosis.[50],[51] The prevalence of silent celiac disease in patients with chronically abnormal liver tests of unexplained etiology is 4%.[52] Further, silent celiac disease is present in 3.5% of patients with autoimmune cholestasis,[53] in 6.3% of patients with autoimmune hepatitis[54] and in 3.4% of patients with non-alcoholic fatty liver.[55] Even in the population with end-stage liver failure and liver transplantation celiac disease seems to be overrepresented.[56] The mechanisms behind the liver disorders associated with celiac disease are still unknown, but it has been suggested that the immunological process ongoing in the gut may equally affect the liver. There is evidence that hepatic failure may be reversed on a gluten-free diet.[56] High prevalence of celiac disease in autoimmune cholestasis suggests that serological screening for celiac disease should be routinely performed in such patients.
Idiopathic dilated cardiomyopathy and autoimmune myocarditis are connected to celiac disease. According to different studies 2.1 to 5.7% of patients suffering from idiopathic dilated cardiomyopathy[57],[58] and 4.4% of patients with autoimmune myocarditis[59] are positive for autoantibodies connected to celiac disease. These studies suggest that immune-mediated mechanisms underlying behind these autoimmune disorders are of similar origin. There is no data about the effect of gluten-free diet on autoimmune heart diseases.
Few reports exist about an association between celiac disease and alopecia areata.[60],[61],[62] Results of these studies show that alopecia areata may constitute the only clinical manifestation of celiac disease. In children the gluten-free diet showed to be successful for hair growth[62] but in adults no effect was established.[61]
One recent study has suggested that there is a connection between celiac disease and antiphospholipid syndrome.[63] Especially cutaneous manifestations seemed to be associated with endomysial antibodies. Further studies are warranted on this issue.
Depressive symptoms are a feature of celiac disease.[64],[65],[66],[67] They are present to a similar extent in patients with childhood- and adulthood-diagnosed celiac disease. Possible mechanism underlying depressive and behavioral symptoms in celiac disease patients may be serotonergic dysfunction due to impaired availability of tryptophan.[67] Gluten-free diet treatment has shown diverse results in alleviating psychiatric symptoms in celiac disease.
In context with celiac disease malignancies are usually connected to poor compliance or delayed diagnosis of the disease. According to a recent population based cohort study, 2.8% of all celiac disease patients had at least one malignancy.[68] The most common malignancy among celiac disease patients is small-bowel T-cell lymphoma which is diagnosed in 0.5% of the patients.[69] Especially patients with refractory sprue - gluten sensitive disorder reacting poorly to strict gluten-free diet treatment - are at risk for small-bowel lymphoma and other malignancies.[70] The overall mortality of celiac disease patients is 2.0-fold compared to non-celiac individuals.[71]
Disease Associations
Celiac disease is associated with many other autoimmune disorders.[72] table1 summarizes the prevalence of celiac disease in the most common autoimmune disorders. The best known connection is that between coeliac disease and insulin-dependent diabetes mellitus which is most probably due to the common genetic background of the two diseases. Gluten-free diet treatment does not seem to improve the metabolic control of diabetes.[72] Celiac disease should also be kept in mind when other autoimmune disorders, such as autoimmune thyroiditis and rheumatoid arthritis are considered. There is vast over-representation of celiac disease also among these patients table1. Less known is the connection between celiac disease and Sj φgren's syndrome - an autoimmune exocrinopathy with systemic manifestations including arthritis, fever, fatigue and mucosal dryness. Celiac disease seems to exist in 12 to 15 % of these patients. table1
Certain genetic disorders are also connected to celiac disease. Case-finding of celiac disease by autoantibody screening among individuals with Down's syndrome, Turner's syndrome and Williams' syndrome seems to be justified: 4.6% to 16% of patients with Down's syndrome,[85],[86] 5.0% of Turner's syndrome patients[87] and 9.5% of Williams' syndrome patients[88] are suffering from coeliac disease.
Selective immunoglobulin A (IgA) deficiency is a relatively rare condition which is connected to celiac disease: about 5% of endomysial antibody-positive individuals[89] and 2.6% of biopsy-proven celiac disease patients[90] suffer from selective IgA deficiency. This minority of celiac disease patients with selective IgA deficiency constitutes a marked problem in diagnosing celiac disease. Celiac disease patients suffering from this condition remain often undiagnosed because in IgA deficient patients IgA-class autoantibody tests remain negative and IgG-class antibodies should be tested instead.
New Diagnostic Approach
The current criteria for celiac disease may give the false impression that coeliac disease is purely a gastrointestinal disorder with manifest small-bowel mucosal lesion. The reality known today is much more complex. In the course of the disease the small intestin mucosal damage develops gradually, from normal morphology through inflammation to the so-called flat lesion (subtotal villous atrophy with crypt hyperplasia). This process or mucosal deterioration may take years or even decades. This means that when a child, an adult, or an elderly person on a gluten-containing diet has been shown to have a normal small intestinal mucosal morphology, even with no cellular inflammation, the disease is not excluded for ever. The mucosa may deteriorate later. Oral tolerance to gluten in celiac disease may be broken in some individuals after decades. This may be due to decreased amount of gluten in the diet but it may also depend on other environmental factors. However, these individuals are exposed to the harmful effect of the gluten and may develop a manifest disease outside the intestine without any gastrointestinal symptoms or signs. According to the current criteria celiac disease is excluded if the small bowel mucosa is normal but the disease is still there. It may manifest itself in liver or in brain and cause even death before the diagnosis is settled. Therefore it is important to identify those patients who are at risk of developing the disease: first-degree relatives of celiac disease patients who carry an increased risk for the disease, patients suffering from typical and especially untypical symptoms related to celiac disease and patients who have diseases that are associated with the disease. These individuals should be thoroughly investigated and the threshold of diagnosing the disease should be low. Small bowel biopsy is still the official diagnostic criteria but in the near future the criteria should be reconsidered and widened towards "genetic gluten intolerance" - i.e. criteria including correct HLA-DQ-type and positive celiac disease specific autoantibodies. Meanwhile the wide knowledge of the multifaceted clinical picture of the disease helps us to recognize the disease and follow up the patients at high risk.
References
1. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F and Thorsby E. Evidence for a primary association of celiac disease to a particular HLA-DQ a/b heterodimer. J Exp Med 1989; 169 : 345-350.
2. Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH and Visakorpi JK. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65 : 909-911.
3. Carroccio A, Vitale G, Di Prima L et al. Comparison of anti-transglutaminase ELISAs and an anti-endomysial antibody assay in the diagnosis of celiac disease: a prospective study. Clin Chem 2002; 48 : 1546-1550.
4. Mδki M, Mustalahti K, Kokkonen J, Kulmala P et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003; 348 : 2517-2524.
5. Volta U, Bellentani S, Bianchi FB, De Franceschi L, Miglioli L, Granito A, Balli F and Tiribelli C. High prevalence of celiac disease in Italian general population. Dig Dis Sci 2001; 46 : 1500-1505.
6. Visakorpi JK, Immonen P, Kuitunen P. Malabsorption syndrome in childhood. The occurence of absorption defects and their clinical significance. Acta Paediatr Scand 1967; 56 : 1-9.
7. Collin P, Reunala T, Rasmussen M et al. High incidence and prevalence of adult coeliac disease. Augmented diagnostic approach. Scand J Gastroenterol 1997; 32 : 1129-1133.
8. Ransford RA, Hayes M, Palmer M and Hall MJ. A controlled, prospective screening study of celiac disease presenting as iron deficiency anemia. J Clin Gastroenterol 2002; 35 : 228-233.
9. Kalayci AG, Kanber Y, Birinci A, Yildiz L, Albayrak D. The prevalence of celiac disease as detected by screening in children with iron deficiency anaemia. Acta Paediatr 2005; 94 : 678-681.
10. Ojetti V, Nucera G, Migneco A et al. High prevalence of coeliac disease in patients with lactose intolerance. Digestion 2005; 71 : 106-110.
11. Slot o, Locht H. Arthritis as presenting symptom in silten adult celiac disease. Two cases and review of the literature. Scand J Rheumatol 2000; 29 : 260-263.
12. Stenhammar L, Fallstr φm SP, Jansson G, Jansson U and Lindberg T. Coeliac disease in children of short stature without gastrointestinal symptoms. Eur J Pediatr 1986; 145 : 185-186.
13. Kaukinen K, Turjanmaa K, Mδki M et al. Intolerance to cereals is not specific for coeliac disease. Scand J Gastroenterol 2000; 35 : 942-946.
14. Reunala TL. Dermatitis herpetiformis. Clin Dermatol 2001; 19 : 728-736.
15. Corazza GR, Di Sario A, Cecchetti L et al. Influence of pattern of clinical presentation and of gluten-free diet on bone mass and metabolism in adult celiac disease. Bone 1996; 18 : 525-530.
16. Kemppainen T, Kroger H, Janatuinen E et al . Bone recovery after a gluten-free diet: a 5-year follow-up study. Bone 1999; 25 : 355-360.
17. Mustalahti K, Collin P, Sievδnen H, Salmi J, Mδki M. Osteopenia in patients with clinically silent celiac disease warrants screening. Lancet 1999; 28 : 744-745.
18. Valdimarsson T, Toss G, L φfman O and Str φm M. Three years' follow-up of bone density in adult celiac disease: significance of secondary hyperparathyroidism. Scand J Gastroenterol 2000; 35 : 274-280.
19. Meyer D, Stavropolous S, Diamond B, Hane E, Green PH. Osteoporosis in a North American adult population with coeliac disease. Am J Gastroenterol 2001; 96 : 112-119.
20. Scotta MS, Salvatore S, Salvatoni A, De Amici M, Ghiringhelli D, Broggini M and Nespoli L. Bone mineralization and body composition in young patients with celiac disease. Am J Gastroenterol 1997; 92 : 1331-1334.
21. Mora S, Barera G, Ricotti A, Weber G, Bianchi C and Chiumello G. Reversal of low bone density with a gluten-free diet in children and adolescents with celiac disease. Am J Clin Nutr 1998; 67 : 477-481.
22. Szathmari M, Tulassay T, Arato A, Bodanszky H, Szabo A, Tulassay Z. Bone mineral content and density in asymptomatic children with celiac disease on a gluten-free diet. Eur J Gastroenterol Hepatol 2001; 13 : 419-424.
23. Kavak US, Yuce A, Kocak N, Demir H, Saltik IN, Gurakan F, Ozen H. Bone mineral density in children with untreated and treated coeliac disease. J Pediatr Gastroenterol Nutr 2003; 37 : 434-436.
24. Puri AS, Garg S, Monga R, Tyagi P, Saraswat MK. Spectrum of atypical celiac disease in North Indian children. Indian Pediatr 2004; 41 : 822-827.
25. Barera G, Beccio S, Proverbio MC, Mora S. Longitudinal changes in bone metabolism and bone mineral content in children with coeliac disease during consumption of gluten-free diet. Am J Clin Nutr 2004; 79 : 148-154.
26. Tau C, Mautalen C, De Rosa S, Roca A, Valenzuela X. Bone mineral density in children with celiac disease. Effect of a Gluten-free diet. Eur J Clin Nutr 2006; 60 : 358-363.
27. Weinstein RS and Manolagas SC. Apoptosis and osteoporosis. Am J Med 2000; 108 : 153-164.
28. Sher KS, Mayberry JF. Female fertility, obstetric and gynaecological history in celiac disease: a case control study. Acta Paediatr Suppl 1996; 412 : 76-77.
29. Nuti R, Martini G, Valenti R, Giovani S, Salvadori S and Avanzati A. Prevalence of undiagnosed coeliac syndrome in osteoporotic women. J Intern Med 2001; 250 : 361-366.
30. Stenson WF, Newberry R, Lorenz R, Baldus C, Civitelli R. Increased prevalence of coeliac disease and need for routine screening among patients with osteoporosis. Arch Intern Med 2005; 28 : 393-399.
31. Armagan O, Uz T, Tascioglu F, Colak O, Oner C, Akgun Y. Serological screening for coeliac disease in premenopausal women with idiopathic osteoporosis. Clin Rheumatol 2005; 24 : 239-243.
32. Vasquez H, Mazure R, Gonzales D, Flores D, Pedreire S, Niveloni S, Smecuol E, Maurino E and Bai JC. Risk of fractures in celiac disease patients: a cross-sectional, case-control study. Am J Gastroenterol 2000; 95 : 183-189.
33. Thomason K, West J, Logan RF, Coupland C, Holmes GK. Fracture experience of patients with celiac disease: a population based survey. Gut 2003; 52 : 518-522.
34. West J, Logan RF, Card TR, Smith C, Hubbard R. Fracture risk in people with celiac disease: a population based cohort study. Gastroenterology 2003; 125 : 429-436.
35. Moreno ML, Vazquez H, Mazure R et al. Stratification of bone fracture risk in patients with coeliac disease. Clin Gastroenterol Hepatol 2004; 2 : 127-134.
36. Aine L. Coeliac-type permanent-tooth enamel defects. Ann Med 1996; 28 : 9-12.
37. Martelossi S, Zanatta E, Del Santo E, Clarich P, Radovich P, Ventura A. Dental enamel defects and screening for celiac disease. Acta Paediatr Suppl 1996; 412 : 47-48.
38. Lδhteenoja H, Toivanen A, Viander M et al. Oral mucosal changes in coeliac patients on a gluten-free diet. Eur J Oral Sci 1998; 106 : 899-906.
39. Bucci P, Carile F, Sngianantoni A, D'Angio F, Satarelli A, Lo Muzio L. Oral aphthous ulcers and dental enamel defects in children with celiac disease. Acta Paediatr 2006; 95 : 203-207.
40. Zelnik N, Pacht A, Obeid R, Lerner A. Range of neurologic disorders in patients with coeliac disease. Pediatrics 2004; 113 : 1672-1676. Rewiev.
41. Luostarinen L, Pirttilδ T and Collin P. Coeliac disease presenting with neurological disorders. Eur Neurol 1999; 42 : 132-135.
42. Pellecchia MT, Scala R, Perreti A et al. Cerebellar ataxia associated with subclinical coeliac disease responding to gluten-free diet. Neurology 1999; 53 : 1606-1608.
43. Burk K, Bosch S, Muller CA et al. Sporadic cerebellar taxia associated with gluten sensitivity. Brain 2001; 124 : 1013-1019.
44. Rostami K, Steegers EA, Wong WY, Braat DD, Steegers-Theunissen RP. Coeliac disease and reproductive disorders: a neglected association. Eur J Obstet Gynecol Reprod Biol 2001; 96 : 146-149.
45. Kolho KL, Tiitinen A, Tulppala M, Unkila-Kallio L and Savilahti E. Screening for coeliac disease in women with a history of miscarriage or infertility. Br J Obstet Gynaecol 1999; 106 : 171-173.
46. Meloni GF, Dessole S, Vargiu N, Tomasi PA and Musumeci S.The prevalence of coeliac disease in infertility. Hum Reprod 1999; 14 : 2759-2761.
47. Norgard B, Fonager K, Sorensen HT, Olsen J. Birth outcomes of women with coeliac disease: a nationwide historical cohort study. Am J Gastroenterol 1999; 94 : 2435-2440.
48. Farthing MJ, Edwards CR, Rees LH and Dawson AM. Male gonadal function in coeliac disease:1: Sexual dysfunction, infertility and semen quality. Gut 1982; 23 : 608-614.
49. Ludvigsson JF, Ludvigsson J. Coeliac disease in the father affects the newborn. Gut 2001; 49 : 169-175.
50. Volta U, De Franceschi L, Lari F, Molinaro N, Zoli M and Bianchi FB. Coeliac disease hidden by cryptogenic hypertransaminasemia. Lancet 1998; 352 : 26-29.
51. Farre C, Esteve M, Curcoy A, Cabre E, Arranz E, Amat LLand Garcia-Tornel S. Hypertransaminasemia in pediatric celiac disease patients and its prevalence as a diagnostic clue. Am J Gastroenterol 2002; 97 : 3176-3181.
52. Lo Iacono O, Petta S, Venezia G et al. Anti-tissue transglutaminase antibodies in patients with abnormal liver tests: is it always celiac disease. Am J Gastroenterol 2005; 100 : 2472-2477.
53. Volta U, Rodrigo L, Granito A et al. Coeliac disease in autoimmune cholestatic liver disorders. Am J Gastroenterol 2002; 97 : 2609-2613.
54. Villalta D, Girolami D, Bidoli E et al. High prevalence of celiac disease in autoimmune hepatitis detected by anti-tissue transglutaminase autoantibodies. J Clin Lab Anal 2005; 19 : 6-10.
55. Bardella MT, Valenti L, Pagliari C et al. Searching for coeliac disease in patients with non-alcoholic fatty liver disease. Dig Liver Dis 2004; 36 : 333-336.
56. Kaukinen K, Halme L, Collin P et al. Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology 2002; 123 : 2158-2159.
57. Not T, Faleschini E, Tommasini A et al. Coeliac disease in patients with sporadic and inherited cardiomyopathies and in their relatives. Eur Heart J 2003; 24 : 1455-1461.
58. Curione M, Barbato M, De Biase L, Viola F, Lo Russo L, Vardi E. Prevalence of celiac disease in idiopathic dilated cardiomyopathy. Lancet 1999; 354 : 222-223.
59. Fustaci A, Cuoco L, Chimenti C et al. Coeliac disease associated with autoimmune myocarditis. Circulation 2002; 105 : 2611-2618.
60. Corazza GR, Andreani ML, Venturo N, Bernardi M, Tosti A, Gasbarrini G. Coeliac disease and alopecia areata: report of a new association. Gastroenterology 1995; 109 : 1333-1337.
61. Bardella MT, Marino R, Barbareschi M, Bianchi F, Faglia G, Bianchi P. Alopecia areata and celiac disease: no effect of a gluten-free diet on hair growth. Dermatology 2000; 200 : 108-110.
62. Fessatou S, Kostaki M, Karpathios T. Coeliac disease and alopecia areata in childhood. J Paediatr Child Health 2003; 39 : 152-154.
63. Shamir F, Shoenfeld Y, Blank M et al. The prevalence of celiac disease antibodies in patients with the antiphospholipid syndrome. Lupus 2003; 12 : 394-399.
64. Ciacci C, Iavarone A, Mazzacca G, De Rosa A. Depressive symptoms in adult celiac disease. Scand J Gastroenterol 1998; 33 : 247-250.
65. Addolorato G, Capristo E, Ghittoni G et al. Anxiety but not depression decreases in celiac patients after one-year gluten-free diet: a longitudinal study. Scand J Gastroenterol 2001; 36: 502-506.
66. Fera T, Cascio B, Angelini G, Martini S, Guidetti CS. Affective disorders and quality of life in adult celiac disease patiens on a gluten-free diet. Eur J Gastroenterol Hepatol 2003; 15 : 1287-1292.
67. Pynn φnen PA, Isometsδ ET, Verkasalo MA et al. Gluten-free diet may alleviate depressive and behavioural symptoms in adolescents with celiac disease: a prospective follow-up case-series study. BMC Psychiatry 2005; 17 : 14
68. West J, Logan R, Smith C, Hubbard R, Card T. Malignancy and mortality in people with celiac disease: population based cohort study. BMJ 2004; 329 : 716-719.
69. Catassi C, Fabiani E, Corrao G, Barbato M, De Renzo A, Carella AM, Gabrielli A, Leoni P, Carroccio A, Baldassarre M, Bertolani P, Caramaschi P, Sozzi M, Guariso G, Volta U and Corrazza GR. Risk of non-Hodgkin lymphoma in celiac disease. JAMA 2002; 287; 1413-1419.
70. Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, Macintyre E, Cerf-Bensussan N and Brousse N. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet 2000; 35 6 : 178-179.
71. Peters U, Askling J, Gridley G, Ekbom A, Linet M. Causes of death in patients with coeliac disease in a population-based Swedish cohort. Arch Intern Med 2003; 163 : 1566-1572.
72. Collin P, Kaukinen K, Vδlimδki M and Salmi J. Endocrinological disorders and celiac disease. Endocr Rev 2002; 464-483.
73. Collin P, Salmi J, Hδllstr φm O, Oksa H, Oksala H, Jδki M, Reunala T. High frequency of coeliac disease in adult patients with type-I diabetes. Scand J Gastroenterol 1989; 24 : 81-84.
74. Talal AH, Murray JA, Goeken JA, Sivitz WI. Celiac disease in an adult population with insulin-dependent diabetes mellitys; use of endomysial antibody testing. Am J Gastroenterol 1997; 92 : 1280-1284.
75. Not T, Tommasini A, Tonini G et al. Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with type I diabetes mellitys. Diabetologia 2001; 44 : 151-155.
76. Holmes GK. Screening for coeliac disease in type 1 diabetes. Arch Dis Child 2002; 87 : 495-498.
77. Valentino R, Savastano S, Tommaselli AP, Dorato M, Scarpitta MT, Gigante M, Micillo M, Paparo F, Petrone E, Lombardi G and Troncone R. Prevalence of coeliac disease in patients with thyroid autoimmunity. Horm Res 1999; 51 : 124-127.
78. Berti I, Trevisiol C, Tommasini A et al. Usefulness of screening program for coeliac disease in autoimmune thyroiditis. Dig Dis Sci 2000; 45 : 678-685
79. Volta U, Ravaglia G, Granito A, et al. Coeliac disease in patients with autoimmune thyroiditis. Digestion 2001; 64 : 61-65.
80. Larizza D, Calcaterra V, De Giacomo C, De Silvestri A, Asti M, Badulli C, Autelli M, Coslovich E and Martinetti M. Celiac disease in children with autoimmune thyroid disease. J Pediatr 2001; 139 : 738-740.
81. Lepore L, Martelossi S, Pennesi M et al. Prevalence of celiac disease in patients with juvenile chronic arthritis. J Pediatr 1996; 129 : 311-313.
82. Francis J, Carty JE and Scott BB. The prevalence of coeliac disease in rheumatoid arthritis. Eur J Gastroenterol Hepatol 2002; 14 : 1355-1356.
83. Luft LM, Barr SG, Martin LO, Chan EK, Frizler MJ. Autoantibodies to tissue transglutaminase in Sj φgren's syndrome and related rheumatic diseases. J Rhematol 2003; 30: 2613-2619.
84. Iltanen S, Collin P, Korpela M et al. Celiac disease and markers of celiac disease latency in patients with primary Sj φgren's syndrome. Am J Gastroenterol 1999; 94 : 1042-1046.
85. Bonamico M, Mariani P, Danesi HM et al. Prevalence and clinical picture of celiac disease in Italian Down syndrome patients: a multicenter study. J Pediatr Gastroenterol Nutr 2001; 33 : 139-143.
86. Carlsson A, Axelsson I, Borulf S et al. Prevalence of IgA-antigliadin antibodies and IgA-antiendomysium antibodies related to celiac disease in children with Down syndrome. Pediatrics 1998; 101 : 272-275.
87. Ivarsson SA, Carlsson A, Bradberg A et al. Prevalence of coeliac disease in Turner syndrome. Acta Paediatr 1999; 88 : 933-936.
88. Giannotti A, Tiberio G, Castro M et al. Coeliac disease in Williams syndrome. J Med Genet 2001; 38 : 767-768.
89. Prince HE, Norman GL and Binder WL. Immunoglobulin A (IgA) deficiency and alternative celiac disease-associated antibodies in sera submitted to a reference laboratory for endomysial IgA testing. Clin Diagn Lab Immunol 2000; 7 : 192-196.
90. Cataldo F, Marino V, Bottaro G, Greco P and Ventura A. Celiac disease and selective immunoglobulin A deficiency. J Pediatr 1997; 131 : 306-308.(Mustalahti K)