Should adults be screened for celiac disease? What are the benefits and harms of screening?

Should adults be screened for celiac disease? What are the benefits and harms of screening?

GASTROENTEROLOGY 2005;128:S104 –S108 Should Adults Be Screened for Celiac Disease? What Are the Benefits and Harms of Screening? PEKKA COLLIN Departme...

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GASTROENTEROLOGY 2005;128:S104 –S108

Should Adults Be Screened for Celiac Disease? What Are the Benefits and Harms of Screening? PEKKA COLLIN Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland

The symptoms of celiac disease are diverse, and the disease is often asymptomatic. Without active serologic screening, most cases probably remain undiagnosed. Recent serologic screening assays allow mass screening for the disease. However, there is no evidence as yet to suggest that symptom-free celiac disease patients run an increased risk of small intestinal lymphoma or other complications. The prevention of osteoporosis seems to be the strongest indicator for widespread screening today. Screening asymptomatic individuals for celiac disease may be even harmful. A lifelong gluten-free diet is not easy to maintain, and the subject’s quality of life may deteriorate. It is also debatable whether patients found by active screening adhere to a gluten-free diet similarly to symptomatic ones. The cost-effectiveness of population screening is dubious. Serologic screening should be applied in individuals with even subtle symptoms indicative of celiac disease, such as subclinicalisolated iron deficiency. In various autoimmune conditions, the risk of celiac disease is approximately 5% and, in individuals with affected first-degree relatives, 15%. Infertility, neurologic symptoms such as polyneuropathy, ataxia, epilepsy with posterior cerebral calcification, and osteoporosis are conditions in which celiac disease should be kept in mind. Elevated aminotransferases and liver failure can lead to a diagnosis of celiac disease. Evidence today does not support mass screening of celiac disease. Instead, increased alertness should be observed in patients at risk of the condition.

eliac disease is an immune-mediated condition in which ingestion of dietary gluten results in small intestinal mucosal inflammation, crypt hyperplasia, and villous atrophy in genetically susceptible individuals. Typical symptoms in adults are diarrhea, loss of weight, abdominal discomfort, bloating, and various types of malabsorption. The classic symptoms as described in textbooks at this time constitute only a minor subgroup of patients with gluten sensitivity, and many patients present with only subtle or no symptoms. The symptoms may also be atypical and appear outside the gastrointestinal tract. The search for celiac disease in subjects having unequivocal symptoms and signs of the disease is

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challenging. The widespread use of serologic screening methods could potentially help to reduce the “celiac iceberg” effect. Screening programs could include unselected populations, patients with a clinical suspicion of celiac disease, or patients known to be at risk of the condition.

Screening for Celiac Disease In large population-based screening programs, useful tests must be easy to perform on large numbers of individuals. The disease to be screened must be a common disorder that causes an important health problem. Finally, an effective treatment of the disease must be available; the treatment should result in symptomatic relief and also prevent the complications of the disease. Thus, theoretically, there are many points favoring mass screening in celiac disease. Antireticulin and antigliadin antibodies were the first tests to be used in screening. The benefits of the IgAclass antiendomysial and the more recent antitissue transglutaminase tests are obvious. They offer a sensitivity of 85%–100% and 95%–100%, and a specificity of 95%–100% and 94%–100%, respectively.1–3 The antitissue transglutaminase test, based on enzyme-linked immunosorbent assay test, is easier to perform and less observer dependent and is therefore more suitable for large screening programs than the antiendomysial test. Screening studies in different populations have shown that the prevalence of the disease is much higher than previously thought, 1% or more in both the United States and Europe.4,5 The prevalence of detected cases is much lower, from 0.27% to 0.02%.6,7 This means that, for every patient with the diagnosis of celiac disease, 3–10 remain undetected. The symptoms are diverse, and the disease may be symptom free4,5; it is therefore apparent that, without active serologic screening, the ma© 2005 by the American Gastroenterological Association

0016-5085/05/$30.00 doi:10.1053/j.gastro.2005.02.021

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jority of celiac cases will remain undiagnosed in the future. Untreated celiac disease predisposes individuals to several complications. Abdominal symptoms, anemia, osteopenia, and severe malabsorption can obviously be prevented by early diagnosis and gluten-free dietary treatment.8 The risk of small intestinal lymphoma is increased in celiac disease,9 and dietary treatment has been shown to prevent the development of malignancy.10 Similarly, the mortality in untreated celiac disease exceeds that in the population in general, which seems not to be the case in adequately treated individuals.11,12 The obvious reason for the increased mortality is the occurrence of small intestinal lymphoma.12 It has been hypothesized that gluten would be directly involved in the pathogenesis of autoimmune conditions in genetically susceptible individuals, and autoimmune development might be prevented with an early commencement of gluten-free diet. Ventura et al13 showed that, when adolescents with celiac disease had adopted a gluten-free diet in early childhood, the number of autoimmune conditions was lower than in patients in whom the treatment had been introduced later in life. The hypothesis is still debatable: On the contrary, it has been suggested that it is the age of the patients and not the duration of gluten exposure that predicts the occurrence of autoimmune conditions.14

Screening for Symptom-Free Celiac Disease The crucial questions in considering population screening are whether we are doing more harm than benefit, and what are the costs of the approach? The benefits of early diagnosis of celiac disease seem to be obvious. However, most studies have been carried out in symptomatic and clinically detected celiac disease patients. The natural history of symptom-free or screendetected disease is less well understood.

Quality of Life and Dietary Compliance To answer the question of whether mass screening is justified, its impact on quality of life must be considered. Health-related quality of life takes into account, apart from the physical, also the social and emotional aspects of well-being. It appears that adults with newly detected celiac disease gain substantial improvement in health-related quality of life within the first year of treatment with a gluten-free diet.15 However, evidence suggests that the long-term effects are less satisfactory. Hallert et al16 showed that the burden of disease was

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worse in female celiac disease patients who had been on a gluten-free diet for 10 years than in age-matched female controls. Similarly, long-term-treated adults with celiac disease, again especially female patients, experienced significantly more gastrointestinal symptoms than controls.17 Male and female celiac disease patients may cope differently with the everyday dietary restrictions, which might explain the sex difference in perceived well-being.15 In the study of Mustalahti et al,18 quality of life was significantly better in 19 screen-detected than in 21 symptom-detected celiac patients before the treatment. After 1 year on a gluten-free diet, quality of life improved in screen-detected subjects and seemed to be actually better than that in controls without celiac disease. It is possible, however, that the observed improvement would be only temporary; the long-term impact of diet on quality of life in apparently symptom-free patients is subject to further studies. An additional concern is the poor long-term adherence to the gluten-free diet, even in symptom detected patients: According to some studies, only 45%– 65% were following a strict glutenfree diet.19 –21 The compliance might be even worse in screen-detected patients. In the study of Fabiani et al,22 only 5 of 22 patients with celiac disease, diagnosed by means of serologic screening, were maintaining a strict gluten-free diet after 5 years of treatment. The poor compliance in screen-detected individuals may jeopardize many conceivable advantageous effects of the mass screening. When asymptomatic patients are encouraged to withdraw gluten from their diet lifelong, this may increase the burden of disease and impair quality of life.15

Complications in Symptom-Free Celiac Disease Most screen-detected patients with celiac disease do not have apparent symptoms. What is their lifetime risk of serious or significant complications of celiac disease, provided that they remain undetected? The risk of small intestinal lymphoma has earlier been reported to be 50 –100-fold compared with the population in general.23 This notwithstanding, it is not known whether active population screening would reduce the development of malignancy or mortality. In earlier studies, only a minority of celiac patients had been detected and treated, and the overall risk of malignancy is thus lower than previously thought.9,11,24 It is debatable whether patients with silent celiac disease have any increased risk of lymphoma. Provided that celiac disease would be a major etiologic factor in

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the development of lymphoma, one would also expect to detect many silent cases in patients suffering from lymphoma. Some recent screening studies have addressed this issue. Catassi et al25 found celiac disease in 6 (0.92%) of 653 patients with non-Hodgkin lymphoma. Another study from Italy reported 1 (1.25%) of 80 patients with non-Hodgkin lymphoma to suffer from celiac disease.26 Similarly, in Spain, the overall risk of celiac disease in patients suffering from non-Hodgkin lymphoma was low, only 0.67% (2 of 298).27 These results indicate that untreated symptom-free celiac disease is not a major factor in the development of non-Hodgkin lymphoma. It has been found in many studies that low bone mineral density is a common complication of celiac disease. Evidence shows that osteopenia and osteoporosis are alleviated on a gluten-free diet, although not completely in adults.28,29 Small studies from Finland30 and France31 indicate that the bone mineral density would be reduced also in adults with symptom-free untreated celiac disease. The clinical importance of the reduction of bone mineral density is the increased risk of fractures. Vazquez et al32 observed that patients with celiac disease seem to have experienced more fractures than nonceliac disease controls. By contrast, Thomason et al33 demonstrated only a small and nonsignificant increase in fracture risk in celiac disease patients. A large populationbased cohort study in the United Kingdom, comprising 4732 subjects with celiac disease and 23,620 matched controls, showed that the overall hazard ratio in celiac disease patients for any fracture was 1.30 and for hip fracture, 1.90.34 These excess risks were statistically significant but, as the authors stated, were at most modest from the clinical point of view. The results of this important study, therefore, indicate that mass screening for celiac disease is not warranted.

Costs of the Screening Cost-effectiveness and cost-utility studies are necessary before introducing mass screening for celiac disease outside of clinical trials. Such studies are lacking so far. For comparison, testing for celiac disease in patients with irritable bowel syndrome suggested that screening costs would be acceptable when the prevalence of celiac disease is 1.0%–3.4%, and the testing would be the dominant strategy when the prevalence exceeds 8%.35 These recommendations cannot of course be applied in symptomless patients or in the general population. A similar decision analysis model showed that testing with antitissue transglutaminase antibody test alone achieved most of the clinical benefits with a reasonable cost when comparisons were made with different test panels.36 In irritable bowel syndrome, the testing proved to be effective, even at relatively low prevalence rates of celiac disease, namely 0.5%–1.0%. The authors emphasized that these results do not advocate mass screening: They measured gains in quality-adjusted life years, and such symptomatic improvement would be unlikely in asymptomatic subjects with celiac disease. In the absence of evidence to the contrary, it is reasonable to assume that celiac screening would be acceptable even when subtle or nonspecific symptoms are present, provided that the estimated prevalence of celiac disease is approximately 4%.

Alternative Approach: Screening in Risk Groups Celiac disease is a common disorder with a specific dietary treatment, and patients with a high suspicion of celiac disease should undergo a thorough diagnostic approach, including small intestinal biopsy, and serologic

Table 1. Proposal for Serologic Screening for Celiac Disease in Adults

Screening recommended Malabsorption, isolated iron deficiencya Infertility Osteoporosis Ataxia and polyneuropathy Arthritis of unknown etiology Chronic liver disease of unknown etiology Suspicion of dermatitis herpetiformis (consider skin biopsy) Irritable bowel syndromea Lactose intolerance aConsider

Screening recommended, when subtle symptoms consistent with celiac disease are present Family history of celiac disease Autoimmune thyroid disease Sjögren’s syndrome Type I diabetesb Addison’s disease Autoimmune endocrinologic diseases in general Any chronic gastrointestinal symptomsa

small intestinal biopsy when screening test is negative. symptoms indicative of celiac disease. cWithout any symptoms indicative of celiac disease. bWith

Screening not necessary General population Acute or short-term gastrointestinal symptoms Atopic symptoms Type I diabetesc

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Table 2. Assumed Beneficial and Harmful Effects of Screening for Celiac Disease Population screening Early detection of celiac disease Specific treatment available Dietary compliance adequate after diagnosis Prevention of complications Improvement in quality of life

Screening at risk groups

Beneficial

Beneficial

Beneficial Questionable

Beneficial Probable

Questionable May be harmful

Probable Probable

testing in these people in a way confirms the diagnosis. A number of groups run an increased risk of celiac disease. Increased alertness should be observed in patients at risk of the condition. Serologic screening should be applied in individuals with even subtle indicative symptoms such as subclinical isolated iron deficiency. In various autoimmune conditions, the risk of celiac disease is approximately 5%.29 Type 1 diabetes mellitus has been studied most thoroughly, but the value of screening in symptom-free patients with diabetes is to some extent doubtful: The impact of a gluten-free diet on metabolic control is not unanimously positive.29 Individuals with affected first-degree relatives have an approximately 15% risk of celiac disease or dermatitis herpetiformis. Infertility,37 neurologic symptoms,38,39 and osteoporosis28 are conditions in which celiac disease should be borne in mind. Elevated aminotransferases40 and even liver failure41 can lead to a diagnosis of celiac disease. A proposal for screening strategy is depicted in Table 1. In population-screening programs, false-positive antiendomysial or antitissue transglutaminase antibodies may give cause for uncertainty. Some, if not most, of the false-positive test results may indicate so-called latent celiac disease, which means that the subjects will develop overt celiac disease later in life.42 In screening at-risk groups, the likelihood of genetic gluten intolerance is higher, and the probability of “true false positive” antibodies is thus low.

Conclusions In conclusion, evidence today does not support mass screening of celiac disease. Potential benefits and harms of population-based celiac disease screening are listed in Table 2. More research is needed to assess the cost-effectiveness benefits of mass screening. The occurrence of osteoporosis and fractures and the possible beneficial effect of a gluten-free diet should be investigated in a large group of symptom-free patients. Dietary compliance and quality of life before and after a gluten-free diet should likewise be evaluated thoroughly. Currently,

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the best approach is to focus on case finding by screening in individuals known to have an increased risk of celiac disease.

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32. Vazquez H, Mazure R, Gonzalez D, Flores D, Pedreira S, Niveloni S, Smecuol E, Maurino E, 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 GKT. Fracture experience of patients with coeliac 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. Spiegel BM, Derosa VP, Gralnek 1M, Wang V, Dulai GS. Testing for celiac sprue in irritable bowel syndrome with predominant diarrhea: a cost-effectiveness analysis. Gastroenterology 2004; 126:1721–1732. 36. Mein SM, Ladabaum U. Serological testing for coeliac disease in patients with symptoms of irritable bowel syndrome: a costeffectiveness analysis. Aliment Pharmacol Ther 2004;19:1199 – 1210. 37. Sher KS, Jayanthi V, Probert CS, Stewart CR, Mayberry JF. Infertility, obstetric and gynaecological problems in coeliac sprue. Dig Dis 1994;12:186 –190. 38. Hadjivassiliou MJ, Chattopadhyay AK, Davies-Jones GAB, Gibson A, Grunevald RA, Lobo AJ. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 1997;63:770 –775. 39. Gobbi G, Bouquet F, Greco L, Lambertini A, Tassari A, Ventura A, Zaniboni M. Coeliac disease, epilepsy and cerebral calcifications. Lancet 1990:340:439 – 442. 40. Bardella MT, Vecchi M, Conte D, Del Ninno E, Fraquelli M, Pacchetti S, Minola E, Landoni M, Cesana BM, De Franchis R. Chronic unexplained hypertransaminasemia may be caused by occult celiac disease. Hepatology 1999;29:654 – 657. 41. Kaukinen K, Halme L, Collin P. Farkkila M, Maki M, Vehmanen P, Partanen J, Hockerstedt K. Celiac disease in patients with severe liver diseases: gluten-free diet may reverse hepatic failure. Gastroenterology 2002;122:881– 888. 42. Kaukinen K, Maki M, Partanen J, Sievanen H, Collin P. Celiac disease without villous atrophy. Revision of criteria called for. Dig Dis Sci 2001;46:879 – 887.

Address requests for reprints to: Pekka Collin, MD, PhD, Medical School FIN-33014, University of Tampere, Tampere, Finland. e-mail: [email protected]fi; fax: (358) 3 2158402. Supported by a grant from the Medical Research Fund of Tampere University Hospital.