Celiac Disease SUMMARY A national survey of 1937 members of the Canadian Celiac and Dermatitis Association was conducted by mail questionnaire in June 1989 to study problems in diagnosing and managing celiac disease Herpetiformis (CD) and dermatitis herpetiformis. Although 82% of the 1294 respondents were National survey indicates delays in diagnosis biopsied, 14% were diagnosed by their dramatic response to A. GEORGE F. DAVIDSON, MD, FRCPC the gluten-free diet. Fifteen J. ALEXANDER CAMPBELL, PHD percent of biopsy-proven respondents saw five or more doctors before CD was diagnosed. Mean delays in diagnosis ranged from 5.8 (±10.9) years for those with * HE CLINICAL EFFECTS OF CELI- symptoms.7 A more recent study suggest- nausea or vomiting to 13.9 ac disease (CD) vary widely ed8 that the delay has been markedly (±14.5) years for those with but typically include diar- reduced, but other researchers9 found a headache or migraine. rhea, weight loss, and mal- mean delay of 10.6 ± 11 years before absorption of nutrients. diagnosis. Thus, although the problem of RESUME Some persons with the disease also have delay in diagnosis has been identified, lit- En juin 1989, un questionnaire other seemingly unrelated conditions, tle progress has been made toward its postal a permis de mener une such as edema, tetany, fatigue, and irri- solution. enquete nationale aupres de tability." 2 Other conditions, such as der- To determine the problems facing its 1937 membres de l'Association matitis herpetiformis, lactose intolerance, members, the Canadian Celiac ceeliaque canadienne afin and aphthous ulcerations, often accompa- Association decided to conduct a national d'etudier les problemes ny CD.3 Thus, celiac patients may present diagnostiques et therapeutiques survey by mail questionnaire. The main relies a la maladie celiaque et a to almost any hospital department, and objectives were to determine: la dermatite herpetiforme. diagnosis may be delayed or missed unless * the length and nature of the diagnostic Malgre la biopsie effectuee chez clinicians are aware of CD's many mani- process; 82% des 1294 repondants, festations. * the occurrence of CD, or symptoms 14% ont vu leur diagnostic Changes in the clinical features of the suggesting CD, in family members; confirme par leur reponse disease over time have been noted,4 and * the response of celiac patients to diet; remarquable suite a une diete some have suggested that CD is under- * the nature of advice received; and sans gluten. Quinze pourcent diagnosed. Even after diagnosis, the * the problems of dietary compliance. des repondants dont le treatment of CD and dermatitis herpeti- This report presents the results of the diagnostic avait ete prouve par formis (DH), requiring lifelong adher- diagnostic aspects of the first objective. biopsie avaient vu au moins cinq ence to the gluten-free diet- although Data on the dietary aspects have been medecins avant d'en arriver au seemingly simple - is a source of concern reported elsewhere.'0 diagnostic. Les delais to many.6 In 1960, a study found that diagnostiques moyens ont varie 81% of patients remained undiagnosed de 5.8 a 10.9 ans pour les for 5 years after the onset of their METHOD patients qui presentaient des A comprehensive questionnaire was nausees et des vomissements et Dr Davidson is a Professor in the Department of developed by a survey committee de 13.9 a com- 14.5 ans pour les Pediatrics at the British Columbia Children's Hospital prised of representatives from the patients presentant des in Vancouver. Dr cephalees ou des migraines. Campbell, afood and nutrition Medical and Nutrition Advisory Boards consultant in Ottawa, is Chairman ofthe Canadian and members of the Canadian Celiac Ghn km 1992,38:2604-2608. Celiac Association's Survey Committee. Association. The questionnaire consisted

2604 Canadian Family Physician VOL 38: November 1992 Table 1. Duration of symptoms experienced by biopsy-proven respondents before diagnosis of celiac disease

| ~~~~~~~DELAWYSINDIAGNOSIS RANGE MEDIAN MINIMUM MAXIMUM NO. OF SYMPTOM (YEARS) MEAN (YEARS) SD (YEARS) (MONTHS) (YEARS) RESPONDENTS Diarrhea 1.9 6.6 11.7 1 75 774 ...... I...... Abdominal pain 2.0 8.0 12.4 1 65 583 ...... Gas or belching 2.5 8.4 13.0 1 74 629 ...... I...... Fatigue or lethargy 2.0 7.9 12.6 1 79 688 ...... I...... Bloating 2.0 7.9 12.4 1 79 770 ...... Nausea or vomiting 1.0 5.8 10.9 1 65 334 ...... I...... I...... Lack of appetite 1.0 6.2 12.7 1 70 330 ...... Skin rash (DH) 4.0 10.3 13.0 1 57 155 ...... Headache or migraine 10.0 13.9 14.5 1 62 204 of 43 questions, about half of which were self-diagnosis (3%), CD "confirmed" by medical. It was pre-tested on subjects of doctor (11%), and DH (2%). varying age and background for readabil- Respondents were asked whether they ity and ease of completion. Most ques- had experienced any of nine separate tions required specific answers rather symptoms before they were "officially" than being open-ended. diagnosed as having CD, and for how The questionnaire was mailed in June long they believed they had had these 1989 to 1937 members of the Association symptoms. Mean delays for biopsy- across Canada who had CD or DH. For proven respondents varied from persons younger than 18 years, we 5.8 ± 10.9 years for those reporting requested that the questionnaire be filled nausea or vomiting to 13.9 ± 14.5 years out by a parent or guardian. Strict confi- for those reporting headache or migraine. dentiality was maintained. Most median delays were 1 to 3 years Cross-tabulations for biopsy-proven (Table 1). The proportion ofbiopsy-proven and non-biopsy-proven respondents were respondents experiencing symptoms was examined for all variables. Most data are generally similar for male and female given for biopsy-proven respondents. patients, but the number experiencing more than 5 years' delay was somewhat RESULTS higher for female respondents for some symptoms (Table 2). Of 1937 questionnaires distributed, 1294 When asked how many doctors they (67%) were returned and analyzed. Of had consulted about their problem, 25% the respondents, 93% reported that they of 960 biopsy-proven respondents said had CD and 7% DH. Of those claiming one doctor, 29% two doctors, 17% three to have CD, 82% were biopsy-proven. doctors, 12% four doctors, 6% five doc- Female respondents comprised 74% of tors, 6% six to 10 doctors, and 3% more the total, and the female to male ratio than 10 doctors. was 2.82:1. When respondents were asked what The reasons for diagnosis of CD given other diagnoses were given for their con- by those respondents who had no biopsy dition before they were diagnosed with proof of CD were diagnosis before biopsy CD, they identified a variety of conditions procedure was available (6%), dramatic (Table 3). Virus, influenza, and bacterial response to the gluten-free diet (14%), infection were most often reported.

Canadian Family Physician VOL 38: November 1992 2605 Table 2. Proportion of male and female biopsy-proven respondents experiencing delays in diagnosis of celiac disease

-1 ALL BIOPSY-PROVEN RESPONDENTS MORE THAN 5 YEARS' DELAY

MALE FEMALE

SYMPTOMS N (%) N (%)

Diarrhea 207 (83) 567 (72) 58 (23) 184 (23) ...... A.....p...... Abdominal pain 133 (82) 450 (82) 45 (28) 178 (33)

Gas or belching 151 (84) 478 (85) 57 (32) 189 (34)

Fatigue or lethargy 158 (83) 530 (85) 45 (24) 208 (33)

...... Bloating 142 (83) 500 (84) 50 (29) 190 (32)

Nausea or vomiting 57 (72) 275 (86) 15 (19) 76 (24)

Lack of appetite 65 (76) 265 (83) 9 (I11) 67 (21)

Skin rash (DH) 57 (75) 98 (81) 21 (28) 54 (45)

Headache or migraine 31 (79) 173 (78) 14 (36) 115 (52) individuals had had the symptoms all their DISCUSSION lives. With lack of appetite, skin rash, and The response to this survey compares headache and migraine symptoms, the favourably with that reported elsewhere."l proportion of female respondents report- The female to male ratio of 2.82:1 reflects ing delays of more than 5 years tended to the membership of the Canadian Celiac be greater than that of male respondents. Association rather than the true ratio for The reason for this is unclear but may be CD in the Canadian population. A pre- related to menstrual and related disorders. ponderance of female patients has also The fact that 21% to 52% of biopsy- been reported in other surveys.'2 proven female respondents and 110% to Although 82% of respondents had 360% of biopsy-proven male respondents biopsies, it is a matter of concern that with these conditions have had diagnosis 140% of respondents' diagnoses were delayed for more than 5 years is a matter based on a dramatic response to the of real concern. It seems that, in spite of gluten-free diet and 11 % were "con- advances in modern diagnostic tech- firmed" by doctors by some other means. niques, little progress has been made in As has been recently reemphasized,'3 no hastening the diagnosis of CD. sure diagnosis of celiac disease can be When asked to indicate which condi- made without identifying the characteris- tions were diagnosed before CD diagno- tic histological picture of the duodenal- sis, respondents rated anemia, stress, jejunal mucosa. This point needs to be nervous condition, and irritable bowel more widely recognized. most frequently. Much more attention Less delay in diagnosis was encoun- must be given, particularly to the finding tered with nausea or vomiting and lack of of anemia, to a possible early indicator of appetite than with the other symptoms. CD. Considerable confusion of CD with Particularly long delays were reported irritable bowel syndrome appeared to with headache and migraine symptoms, have occurred in both the biopsy-proven suggesting that it was difficult to relate and non-biopsy-proven groups. headache or migraine symptoms to CD. Because so many doctors were con- The ranges in delays indicated that some sulted before CD was diagnosed, it was

2606 Canadian Family Physician VOL 38: November 1992 obvious that many doctors did not under- Mlississauga, Ont, with significantfinancial contribu- stand the disease. In this regard, many tionsfrom the Ottawa Chapter ofthe Canadian Celiac respondents expressed deep concerns Association, was presented in part at the meeting ofthe about the problems they had encoun- Royal College of Physicians and Surgeons in Quebec tered in being properly and promptly Ciy in September 1991. diagnosed. They considered it quite unacceptable to have to see so many doc- Table 3. Diagnoses of diseases made before celiac disease tors to be diagnosed properly and to be was diagnosed given such a variety of diagnoses. There was a feeling among respondents that RESPONDENTS (%) many doctors were not informed about BIOPSY-PROVEN NOT BIOPSY-PROVEN the disease or were unaware of the need DIAGNOSIS (N = 686) (N = 145) for a biopsy; that they did not know that adults were subject to CD as well as chil- Anemia 47 30 ...... I...... dren; and that they were unaware that Stress 45 39 treatment of CD and DH requires strict ...... adherence to the gluten-free diet. Nervous condition 41 39 Delay in diagnosing CD has resulted in Irritable bowel 34 43 long periods of ill health for many respon- ...... I...... dents. Little emphasis seems to have been Stomach ulcer 23 14 placed on this aspect of the disease. Food allergy 19 32 Numerous screening methods have been ...... I...... I...... proposed."4- As Guandalini et al'3 have Colitis 1 3 23 suggested, it may be time for a change in ...... I...... I...... I...... diagnosis. The diagnostic accuracy of esti- Menstrual problems 13 17 ...... mating antigliadin antibodies is quite Edema 9 8 high. New patients with CD lack IgG ...... I...... I...... antigliadin antibodies, and few patients Gallstones 9 10 ...... I...... who have IgA antigliadin antibodies do Diverticulitis 6 9 not have CD. The absence of IgG antigliadin antibodies and the presence of Dermatitis herpetiformis 4 5 ...... IgA antigliadin antibodies together are a Other 36 39 reliable indication of CD. Much greater emphasis must be placed on developing Requests for reprints to: Dr JA. Campbell, appropriate screening methods. c/o Canadian Celiac Association, 6519B Mioissauga Rd, Mississauga, OJ\A L5N A6

CONCLUSION References Serious delays still exist in the diagnosis 1. Mann JG, Brown WVR, Kern FJr. The suLbtle aind of CD. There is an urgent need to make variable clinical expressions of gluten-induced physicians more aware of the symptoms enteropathy (adult celiac disease, nontropical of CD and to investigate and apply pro- sprue). An analysis of twenty-one consecutive cedures that will hasten and simplify cases.,4mMMed 1970;48:357-66. diagnosis. U 2. Cooke WNT, Homes GKT. Coeliac disease. Newv York: Churchill Livingstone, 1984. Acknowledgments 3. Ferguson A. Coeliac disease (gluten We acknowledge the assistance of Dr Atlurray hypersensitivity). J Hum .,Vutr 1976;30: 193-201. MacKinnon of Jiincouver and the advice ofother mem- 4. Logan RFA, TIucker G, Rifkin EA, Heading RC, Ferguson A. Changes in clinical features of bers of the survey committee: Dr Al. C. Champion, coeliac disease in adults in Edinburgh and the University Ottawa; Mls Universiy of Mlavis Aivolloy, Lothians, 1960-79. BAII7 1983;286:95-7. of British Columbia; AVls Lynne Alortimer-Bankier, 5. Swinson CNI, Levi AJ. Is coeliac disease U'niversity of Ottawa; AIs Alary Smith, Canadian underdiagnosed? B.AJ7 1980;281:1258-60. Celiac Association, Ottawa; and Als Rosie Wirtecker, 6. CampbellJA. Diet therapy ofceliac disease and Canadian Celiac Association, Toronto. This study, dermatitis herpetiformis. 11'orld Rev ,utr Diet sponsored by the Canadian CGeliac As.sociation of 1987;51:189-233.

Canadian Family Physici'an VOL 38: ,November 1992 2607 NaprosynSR 7. Green PA, Wollaeger EE. The clinical Naprosyn (naproxen) behavior of sprue in the United States. Prescribing Information: Gastroenterology 1960;38:399-418. Therapeutic Classification: Anti-inflamma- signs of infections. Periodic liver function 8. Campbell CB, Roberts RK, Cowen AE. The tory, analgesic and antipyretic agent. Indi- tests and ophthalmic studies are recom- changing clinical presentation of coeliac cation: The treatment of osteoarthritis, mended for patients on chronic therapy. rheumatoid arthritis, ankylosing spondylitis Caution should be exercised by patients disease in adults. Medj7Aust 1977;1:89-93. and juvenile rheumatoid arthritis. Contrain- whose activities require alertness if they 9. Gregory C, Ashworth M, Eade OE, dications: Naprosyn should not be given to experience drowsiness, dizziness, vertigo or Holdstock G, Smith CL, Wright R. Delay in patients with active peptic ulcer or active depression during naproxen therapy. inflammatory disease of the gastrointestinal Naprosyn may displace other albumin- diagnosis of adult coeliac disease. Digestion tract. It is also contraindicated for those bound drugs from their binding sites and 1983;28:201-4. who have shown a sensitivity to it and for may lead to drug interactions or interfere patients in whom ASA or other NSAIDs with certain laboratory tests. See Product 10. CampbellJA, Molloy MK, Davidson AGF, induce the syndrome of asthma, rhinitis or Monograph for specific examples. Mortimer-Bankier L. Dietary aspects from uticaria. Sometimes severe and occasion- ADVERSE REACTIONS - (1) Denotes inci- ally fatal anaphylactoid reactions have dence of reported reaction between 3% and National Survey of Persons with Celiac occurred in such individuals. Suppositories 9%/o. (2) Denotes incidence of reported reac- Disease and Dermatitis Herpetiformis. 7 Can should not be given to patients under 12 tions between 1% and 3%. See Product years of age or those with inflammatory Monograph for reactions occurring in less DietAssoc 1991;52:161-5. lesions of the rectum or anus. Wamings: than 1% of patients. Gastrointestinal: 11. Biemond I, Pena AS, Groenland F, Mulder Peptic ulceration, perforation and gastroin- Heartbum (1), constipation (1), abdominal testinal bleeding, sometimes severe and pain (1), nausea (1), diarrhea (2), dyspep- CJJ, Tytgat GNJ. Coeliac disease in the occasionally fatal have been reported sia (2), stomatitis (2), diverticulitis (2). Rectal Netherlands: demographic data of a patient during therapy with NSAIDs, including burning (1) has been reported occasionally Naprosyn. with the use of naproxen suppositories. survey among the members of the Dutch Naprosyn should be given underclose super- Central Nervous System: Headache(1), Coeliac Society. .AethJ Med 1987;31:263-8. vision to patients prone to gastrointestinal dizziness(1), drowsiness(1), lightheaded- tract irritation particularlythose with a history ness (2), vertigo (2), depression (2), and 12. CarringtonJM. Coeliac disease: an analysis of peptic ulcer, diverticulosis or other inflam- fatigue (2). Skin: Pruritus (1), ecchymo- of Coeliac Society membership records. NZ matory disease of the gastrointestinal tract. ses (1), skin eruptions (1), sweating (2), and Patients taking any NSAID should be instruc- purpura (2). Cardiovascular: Dyspnea (1), Med] 1986;99:279-81. ted to contact a physician immediately if they peripheral edema (1), and palpitations (2). 13. Guandalini S, Ventura A, Ansaldi N, experience symptoms or signs suggestive Special senses: Tinnitus (1), and hearing of peptic ulceration or gastrointestinal bleed- disturbances (2). Others: Thirst (2). Giunta AM, Greco L, Lazzari R, et al. ing. These reactions can occur without DOSAGE AND ADMINISTRATION - Diagnosis ofcoeliac disease: time for a waming at any time during the treatment. Adult: Oral: The usual total daily dosage for Elderly, frail and debilitated patients appear osteoarthritis, rheumatoid arthritis and change? Arch Dis Child 1989;64: 1320-5. to be at higher risk from a variety of adverse ankylosing spondylitis is 500 mg (20 mL, 14. Garst PM. Results ofthe 1983 Celiac-Sprue reactions from NSAIDs. For such patients, 4 teaspoons) a day in divided doses. It may consideration should be given to a starting be increased gradually to 750 or 1000 mg Adult Survgy. Proceedings ofthe Midwest Celiac Sprue dose lowerthan usual. or decreased depending on the patient's Association Conference. Mimeo report. Des The safety of Naprosyn in pregnancy and response. Patients with rheumatoid arthritis Moines: Midwest Celiac Sprue Association, lactation has not been established and its or osteoarthritis maintained on a dose of use is therefore not recommended. 750 mg/day in divided doses can be 1984:9. Precautions: Naprosyn (naproxen) switched to a once daily dose of Naprosyn 15.Juby LD, RothwellJ, Axon ATR. should not be used concomitantly with SR 750 mg. The single daily dose of the related drug Anaprox (naproxen Naprosyn SR should not be exceeded and Cellobiose/mannitol sugar test - a sensitive sodium) since they both circulate in can be administered in the morning or eve- tubeless test for coeliac disease: results on plasma as the naproxen anion. GI system: ning. Naprosyn SR tablets should be swal- If peptic ulceration is suspected or con- lowed whole. Rectal: Naprosyn Supposito- 1010 unselected patients. Gut 1989;30:476-80. firmed, or if gastrointestinal bleeding or ries (500 mg) can replace one of the oral 16. Burgin-WolffA, Berger R, Gaze H, Hubes perforation occurs Naprosyn should be doses in patients receiving 1000 mg of discontinued, and appropriate treatment Naprosyn daily. Juvenile Rheumatoid H, Lentze MJ, Mussle D. IgG, IgA and IgE instituted. Renal effects: Patients with Arthrifis: The recommended daily dose is gliadin antibody determinations as screening impaired renal function, extracellular approximately 10 mg/kg in two divided doses. volume depletion, sodium restrictions, heart AVAILABILITY - Naprosyn is available as: test for untreated coeliac disease in children, a failure, liver dysfunction, those taking diure- 125 mg, 250 mg, 375 mg, and 500 mg multicentre study. Eurjr Pediatr tics, and the elderly are at greatest risk of Tablets, as 750 mg Sustained-Release developing overt renal decompensation. Tablets and 500 mg Suppositories. 1989; 148:496-502. Assessment of renal function in these Suspension: Each 5 mL contains 125 mg of 17. Calabuig M, Torregosa R, Polo P, Tuset L, patients before and during therapy is naproxen. Shake bottle gently before use. recommended. Naprosyn and its metaboli- Pharmacists are to provide the Naprosyn Tomas C, Alvarez V, et al. Serological tes are eliminated primarily by the kidneys, Patient Information leaflet when dispensing markers and celiac disease: a new diagnostic and therefore, a reduction in daily dosage this drug. Product Monograph available to should be anticipated to avoid the possibi- health professionals upon request. approach. 7 Pediatr Gastroenterol Nutr lity of drug accumulation in patients with 1990; 10:435-42. significantly impaired renal function. References: 1. Allen, B. et al., New Peripheral edema has been observed, Zealand Medical Journal (1 989)102(870): consequently, patients with compromised 310-312. 2. Ling, T.L. et al., Journal of cardiac function should be kept under Clinical Pharmacology (1987)27:325-329. observation when taking Naprosyn. Naprosyn Suspension contains sodium ___ ~~~~~~~~~~~~~~~~~~~~~FP-AB]_ chloride (20 mg/mL). This should be considered in patients whose overall intake Syntex Inc.* Mississauga (Ontario) Montr6al (Quebec) of sodium must be restricted. As with other drugs used with the elderly or those with impaired liver function it is pru- ONCE-A-DAY R dent to use the lowest effective dose. Severe hepatic reactions including jaun- dice, and cases of fatal hepatitis have been reported with NSAIDs. The prescriber should be alert to the fact that the anti- inflammatory, analgesic and antipyretic effects of Naprosyn may mask the usual