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Celiac disease in patients with an affected member, type 1 diabetes, iron-deficiency, or osteoporosis?

2005; Elsevier BV; Volume: 128; Issue: 4 Linguagem: Inglês

10.1053/j.gastro.2005.02.029

1528-0012

Joseph A. Murray,

Microscopic Colitis

Celiac disease (CD) may be a much under recognized condition, in part because it is not considered in those patients at high risk or in clinical conditions that may be a manifestation of CD. Screening high-risk groups may reveal a higher prevalence than seen in the general population. Several diseases have been described to have an association with CD that may be greater than by chance alone. The presence of autoimmune conditions such as insulin-dependent diabetes mellitus (T1DM) or a family history of CD or dermatitis herpetiformis may increase the risk of coexisting CD. The prevalence of CD may be increased in certain patient groups, including the following: osteoporosis or low bone mass or iron-deficiency anemia. Many studies, including population-based work, suggest a prevalence of CD of 3%–7% of T1DM and 4%–10% of first-degree family members. Anemia and osteoporosis are common in patients with newly diagnosed CD. Conversely, CD is common in referral populations with those conditions but makes a relatively small contribution to the overall community prevalence of anemia or postmenopausal osteoporosis. Most screen-found patients tend to have little or no gastrointestinal symptoms. In conclusion, significant reservoirs of CD can be found in some at-risk groups, such as those with T1DM, family members, and referred patients with osteoporosis and anemia. It is not clear what impact CD has on the quality of life of these individuals. Celiac disease (CD) may be a much under recognized condition, in part because it is not considered in those patients at high risk or in clinical conditions that may be a manifestation of CD. Screening high-risk groups may reveal a higher prevalence than seen in the general population. Several diseases have been described to have an association with CD that may be greater than by chance alone. The presence of autoimmune conditions such as insulin-dependent diabetes mellitus (T1DM) or a family history of CD or dermatitis herpetiformis may increase the risk of coexisting CD. The prevalence of CD may be increased in certain patient groups, including the following: osteoporosis or low bone mass or iron-deficiency anemia. Many studies, including population-based work, suggest a prevalence of CD of 3%–7% of T1DM and 4%–10% of first-degree family members. Anemia and osteoporosis are common in patients with newly diagnosed CD. Conversely, CD is common in referral populations with those conditions but makes a relatively small contribution to the overall community prevalence of anemia or postmenopausal osteoporosis. Most screen-found patients tend to have little or no gastrointestinal symptoms. In conclusion, significant reservoirs of CD can be found in some at-risk groups, such as those with T1DM, family members, and referred patients with osteoporosis and anemia. It is not clear what impact CD has on the quality of life of these individuals. Many early case reports documented the occurrence of celiac disease (CD) in siblings, identical twins, parent and child pairs, as well as more extended kindreds.1Stokes P.L. Ferguson R. Holmes G.K. Cooke W.T. Familial aspects of coeliac disease.QJM. 1976; 45: 567PubMed Google Scholar, 2Mallas E.G. Williamson N. Cooper N.T. Cooke W.T. IgA class reticulin antibodies in relatives of patients with coeliac disease.Gut. 1997; 18: 647Crossref Scopus (19) Google Scholar, 3Stenhammar L. Brandt A. Wagermark J. A family study of coeliac disease.Acta Paediatrica Scandinavica. 1982; 71: 625Crossref PubMed Scopus (48) Google Scholar, 4Korponay-Szabo I. Kovacs J. Lorincz M. Torok E. Goracz G. Families with multiple cases of gluten-sensitive enteropathy.Zeitschrift fur Gastroenterologie. 1998; 36: 553PubMed Google Scholar At least 20% of index cases will have an affected family member if screening is done.1Stokes P.L. Ferguson R. Holmes G.K. Cooke W.T. Familial aspects of coeliac disease.QJM. 1976; 45: 567PubMed Google Scholar, 2Mallas E.G. Williamson N. Cooper N.T. Cooke W.T. IgA class reticulin antibodies in relatives of patients with coeliac disease.Gut. 1997; 18: 647Crossref Scopus (19) Google Scholar, 5Corazza G. Valentini R.A. Frisoni M. Volta U. Corrao G. Bianchi F.B. Gasbarrini G. Gliadin immune reactivity is associated with overt and latent enteropathy in relatives of celiac patients.Gastroenterology. 1992; 103 (1992): 1517PubMed Google Scholar, 6Vogelsang H. Wyatt J. Penner E. Lochs H. Screening for celiac disease in first-degree relatives of patients with celiac disease by lactulose/mannitol test.Am J Gastroenterol. 1995; 90: 1838PubMed Google Scholar The exact degree of increased risk for specific family members has not been reliably ascertained, but estimates have been made based on screening studies undertaken at one point in time.7Houlston R.S. Ford D. Genetics of coeliac disease.QJM. 1996; 89: 737Crossref PubMed Scopus (91) Google Scholar Identical twins have a 75% to 100% concordance rate for the disease. Siblings are at the next highest risk at 7% to 20% concordance rate. It has been suggested that, if siblings share the same HLA disease risk haplotype, their risk approaches 40%.8Bevan S. Popat S. Braegger C.P. Busch A. O'Donoghue D. Falth-Magnusson K. Ferguson A. Godkin A. Hogberg L. Holmes G. Hosie K.B. Howdle P.D. Jenkins H. Jewell D. Johnston S. Kennedy N.P. Kerr G. Kumar P. Logan R.F. Love A.H. Marsh M. Mulder C.J. Sjoberg K. Stenhammer L. Houlston R.S. Contribution of the MHC region to the familial risk of coeliac disease.J Med Genet. 1999; 36: 687PubMed Google Scholar It is less so for parents or children of the proband. Most of these studies were in homogenous populations in which the background risk for CD was high. A recent multicenter study in the United States identified a rate of 4%–5% of first-degree relatives with CD based on endomysial antibody testing, a rate significantly greater than the rate in the not-at-risk individuals.9Fasano A. Berti I. Gerarduzzi T. Not T. Colletti R.B. Drago S. Elitsur Y. Green P.H.R. Guandalini S. Hill I. Pietzak M. Ventura A. Thorpe M. Kryszak D. Fornaroli F. Wasserman S.S. Murray J.A. Horvath K. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States a large multicenter study.Arch Intern Med. 2003; 163: 286Crossref PubMed Scopus (1495) Google Scholar Furthermore, these studies have based their risk estimations on the numbers of relatives that were screened, not necessarily the number of first-degree relatives. Many of these studies are subject to the selection bias of family members coming forward or agreeing to screening. Additionally, there often is incomplete follow-up of family members to determine whether the screening at one point in time is an adequate estimation of the risk over time. Not all studies were so positive. In one study, of 100 first-degree family members who underwent biopsy, only 2 had CD.3Stenhammar L. Brandt A. Wagermark J. A family study of coeliac disease.Acta Paediatrica Scandinavica. 1982; 71: 625Crossref PubMed Scopus (48) Google Scholar Five others appeared to have transient changes. Occasional cases of progression to CD have been reported in a few cases initially negative for CD.10Pittschieler K. Gentili L. Niederhofer H. Onset of coeliac disease a prospective longitudinal study.Acta Paediatrica. 2003; 92: 1149Crossref PubMed Google Scholar, 11Niveloni S. Pedreira S. Sugai E. Vazquez H. Smecuol E. Fiorini A. Cabanne A. Dezi R. Valero J. Kogan Z. Maurino E. Bai J.C. The natural history of gluten sensitivity report of two new celiac disease patients resulting from a long-term follow-up of nonatrophic, first-degree relatives.Am J Gastroenterol. 2000; 95: 463Crossref PubMed Google Scholar In our ongoing community study, 10% of tested first-degree relatives are found to have undiagnosed CD. A further 2% had possible CD with subtle histopathologic changes on intestinal biopsies. Almost as many family members had CD diagnosed clinically as found by screening, usually because of heightened awareness of the risk in a symptomatic relative. Serologic testing detected most but not all screened-found CD patients; however 5 of 49 symptomatic family members were found to have CD based by biopsy alone despite negative serology. Although most screen-found patients had little or no symptoms, compliance with a gluten-free diet was good. It is worth testing family members for CD at least once, and, in symptomatic patients, consider biopsy even in those who are seronegative.12Rostami K. Mulder C.J. van Overbeek F.M. Kerckhaert J. Meijer J.W. von Blomberg M.B. Heymans H.S. Should relatives of coeliacs with mild clinical complaints undergo a small-bowel biopsy despite negative serology?.Eur J Gastroenterol Hepatol. 2000; 12: 51Crossref PubMed Scopus (42) Google Scholar An association between CD and type 1 diabetes mellitus (T1DM) has been recognized for more than 40 years.13Harnden A.R. Brown R.S. Insulin dependent diabetes mellitus and coeliac disease.J Royal Soc Med. 1991; 84: 436PubMed Google Scholar, 14Maki M. Hallstrom O. Huupponen T. Vesikari T. Visakorpi J.K. Increased prevalence of coeliac disease in diabetes.Arch Dis Child. 1884; 59: 739Crossref Scopus (124) Google Scholar Several studies, both in children and adults, have shown that there is a 1.5% to 7% prevalence of CD in type 1 diabetes.15Rossi T.M. Albini C.H. Kumar V. incidence of celiac-disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent diabetes-mellitus.J Pediatr. 1983; 123: 262Google Scholar, 16Talal A.H. Murray J.A. Goeken J.A. Sivitz W.I. Celiac disease in an adult population with insulin-dependent diabetes mellitus use of endomysial antibody testing.Am J Gastroenterol. 1997; 92: 1280PubMed Google Scholar, 17Fraser-Reynolds K.A. Butzner J.D. Stephure D.K. Trussell R.A. Scott R.B. Use of immunoglobulin A-antiendomysial antibody to screen for celiac disease in North American children with type 1 diabetes.Diabetes Care. 1985; 1009: 21Google Scholar, 18Koletzko S. Burgin-Wolff A. Koletzko B. Knapp M. Burger W. Gruneklee D. Herz G. Ruch W. Thon A. Wendel U. Prevalence of coeliac disease in diabetic children and adolescents a multicentre study.Eur J Pediatr. 1998; 148: 113Crossref Scopus (89) Google Scholar, 19Sigurs N. Johansson C. Elfstrand P.O. Viander M. Lanner A. Prevalence of coeliac disease in diabetic children and adolescents in Sweden.Acta Paediatrica. 1993; 82: 748Crossref PubMed Scopus (93) Google Scholar, 20Collin P. Salmi J. Hallstrom O. Oksa H. Oksala H. Maki M. Reunala T. High frequency of coeliac disease in adult patients with type-I diabetes.Scand J Gastroenterol. 1989; 24: 81Crossref PubMed Scopus (128) Google Scholar There is some evidence that undiagnosed CD may not only coexist with diabetes but may precede it; it has been suggested that delayed diagnosis of CD is associated with an increased risk for subsequently developing T1DM. Patients in whom CD was identified and treated in early childhood had a lower rate of developing diabetes than children in whom CD was diagnosed later in childhood or as adults.21Ventura A.M.G. Greco L. SIGEP Study Group for Autoimmune Disorders in Celiac DiseaseDuration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease.Gastroenterology. 1999; 117: 297Abstract Full Text Full Text PDF PubMed Scopus (829) Google Scholar Autoantibodies directed against islet cells are frequently present in untreated CD but disappear with the gluten-free diet.22Ventura A. Neri E. Ughi C. Leopaldi A. Citta A. Not T. Gluten-dependent diabetes-related and thyroid-related autoantibodies in patients with celiac disease.J Pediatr. 2000; 137: 263Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Studies of American children with insulin-dependent diabetes mellitus (IDDM) revealed a prevalence of CD of 4%–6%,23Bao F. Yu L. Babu S. Wang T. Hoffenberg E.J. Rewers M. Eisenbarth G.S. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies.J Autoimmun. 1999; 13: 143Crossref PubMed Scopus (204) Google Scholar and studies of adult American patients with IDDM reported a prevalence of CD of 4%–6.4%.24Rensch M.J. Merenich J.A. Lieberman M. Long B.D. Davis D.R. McNally P.R. Gluten-sensitive enteropathy in patients with insulin-dependent diabetes mellitus.Ann Intern Med. 1996; 124: 564Crossref PubMed Scopus (82) Google Scholar These studies were largely based in tertiary referral centers or specialized diabetic clinics and hence may not be representative of the prevalence of CD in the IDDM community. Studying the occurrence of CD in a pediatric group alone may underestimate the lifetime risk of CD, which requires extended follow-up. Our community-based study was of CD in residents of Olmsted County, MN, who have T1DM encompassing all ages. T1DM was defined by a strict application of clinical criteria. The prior incidence of CD in this cohort was just 1%. Unlike many prior studies that focused on just adults or children, we studied a sample of all ages and found CD in 6.5% of this sample. By extrapolating from this sample to the whole diabetic population, we expect as many as 30 cases of CD within the type 1 diabetic cohort within the community. The prevalence of CD in the type 1 diabetic population is substantially higher than expected in the general population. One half of subjects did not have any gastrointestinal (GI) symptoms. The rest had only mild symptoms. It would seem that DM is a rich source for discovering CD. Indeed, many diabetic patients undergo endoscopy to investigate the frequent GI symptoms that afflict those with T1DM. It would require little extra effort or cost to obtain duodenal biopsies at least once to identify CD, and the biopsy result may explain the GI symptoms for which the procedure has been done. It is not clear what impact that discovery has, if any, on diabetic control or complications, although GI symptoms seem to improve on a gluten-free diet.25Acerini C.L. Ahmed M.L. Ross K.M. Sullivan P.M. Bird G. Dunger D.B. Coeliac disease in children and adolescents with IDDM clinical characteristics and response to gluten-free diet.Diabetic Med. 1998; 15: 38Crossref PubMed Scopus (128) Google Scholar Certainly, our data, which suggest that only 6% of T1DM patients have CD, do not support the hypothesis that CD is a significant risk factor in the subsequent development of DM. Iron is absorbed by the proximal small intestine, the site of the greatest damage in CD. Active CD is also associated with heme-positive stools.26Fine K.D. The prevalence of occult gastrointestinal bleeding in celiac sprue.N Engl J Med. 1996; 334: 1163Crossref PubMed Scopus (116) Google Scholar It is not surprising therefore that iron-deficiency anemia is a common finding in newly diagnosed CD.27Bode S. Gudmand-Hoyer E. Symptoms and haematologic features in consecutive adult coeliac patients.Scand J Gastroenterol. 1996; 31: 54Crossref PubMed Scopus (113) Google Scholar It also usually resolves with the institution of a gluten-free diet.28Bonamico M. Vania A. Monti S. Ballati G. Mariani P. Pitzalis G. Benedetti C. Falconieri P. Signoretti A. Iron deficiency in children with celiac disease.J Pediatr Gastroenterol Nutr. 1987; 6: 702Crossref PubMed Scopus (23) Google Scholar, 29Casanova C. Fogue L. Sueiro A. Stahlberg M.R. Iron deficiency in coeliac disease is mild and it is detected and corrected by gluten-free diet.Chest. 1991; 99: 1525Crossref PubMed Scopus (42) Google Scholar, 30Ogunji F. Saloum Y. Beharry S. Crippin J. Weinstein J. Annibale B. Efficacy of gluten-free diet alone on recovery from iron deficiency anemia in adult celiac patients.Am J Gastroenterol. 2001; 96: 138Crossref PubMed Google Scholar Several studies from Europe and North America have suggested that iron-deficiency anemia may be the sole manifestation of CD in the absence of diarrhea.31Corazza G.R. Valentini R.A. Andreani M.L. D'Anchino M. Leva M.T. Ginaldi L. De Feudis L. Quaglino D. Gasbarrini G. Subclinical coeliac disease is a frequent cause of iron-deficiency anaemia.Scand J Gastroenterol. 1995; 30: 153Crossref PubMed Scopus (199) Google Scholar, 32Garrido C. Gaya J. Liompart A. Vaquer P. Sanso A. Riera J. Ginard D. Bonet L. Obrador A. Prevalencia de enfermedad celiaca monosintomatica en pacientes con anemia ferropenica.Gastroenterologia y Hepatologia. 1997; 20: 172PubMed Google Scholar The association of CD may be especially high in those unresponsive to oral iron therapy.33Takei N. Mukai Y. Hasegawa Y. Suzukawa K. Nagata M. Noguchi M. Mori N. Nagasawa T. Mody R.J. Refractory iron deficiency anemia as the primary clinical manifestation of celiac disease.Ann Hematol. 2003; 82: 53PubMed Google Scholar Another Italian study of 200 consecutive adult patients presenting with iron deficiency revealed a 5% prevalence of CD. The prevalence of CD in patients referred to GI endoscopy for investigation of iron deficiency varies from 3% to 12%.34Ackerman Z. Eliakim R. Stalnikowicz R. Rachmilewitz D. Role of small bowel biopsy in the endoscopic evaluation of adults with iron deficiency anemia.Am J Gastroenterol. 1996; 91: 2099PubMed Google Scholar, 35Grisolano S.W. Murray J.A. Burgart L.J. Dierkhising R.A. Alexander J.A. The usefulness of routine small bowel biopsies in evaluation of iron deficiency anemia.J Clin Gastroenterol. 2004; 38: 756Crossref PubMed Scopus (61) Google Scholar These studies may be subject to selection bias because of referral patterns. It is interesting to note that as many as one half of patients undergoing upper endoscopy for anemia do not undergo duodenal biopsy in academic endoscopy units, whereas private practice gastroenterologists are more likely to biopsy in this circumstance. Iron deficiency is common in the general population. If it occurs in young women, it is often ascribed to excess menstrual loss, and empiric therapy with iron supplementation is instituted. However, older patients or those with anemia that is refractory anemia are often further investigated. Similarly, the persistence of anemia after menopause was a frequent precipitant for investigation that leads to the detection of CD.36Ransford R.A. Hayes M. Palmer M. Hall M.J. A controlled, prospective screening study of celiac disease presenting as iron deficiency anemia.J Clin Gastroenterol. 2002; 35: 228Crossref PubMed Scopus (63) Google Scholar Indeed, patients have undergone hysterectomies to treat the iron deficiency that persisted until the correct diagnosis was made. If the majority of subjects with CD have iron malabsorption, then it is reasonable to surmise that many of the undiagnosed CD patients should present and be detectable in a population of anemic individuals. We have identified a total of 529 prevalent cases of diagnosed iron-deficiency anemia resident in Olmsted County in 2001, of whom 142 community residents had otherwise unexplained anemia. These were tested for CD, and 6 were found to have CD. Two additional patients had possible CD based on subtle pathologic changes. Anemia was rarely sought or diagnosed in children. However, iron-deficiency anemia is a very common illness in primary care and often does not spur investigation in the younger patient. In fact, hemoglobin is not measured routinely in children. What is incompletely explained is why all patients with CD are not anemic. One potential confounder is the association between the genes that cause hemochromatosis (iron overload genes) and CD. The hemachromatosis-associated gene 282Y was more common in CD and was associated with higher Hgb and iron stores.37Butterworth J.R. Cooper B.T. Rosenberg W.M. Purkiss M. Jobson S. Hathaway M. Briggs D. Howell W.M. Wood G.M. Adams D.H. Iqbal T.H. The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease.Gastroenterology. 2002; 123: 444Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar It is also clear that there is a substantial variation in the extent of involvement of the proximal small intestine in CD, which may allow for compensation. Clinicians should consider CD as a possible, although not common, cause of unexplained anemia, and gastroenterologists should biopsy the duodenum when endoscoping patients with iron-deficiency anemia, even if biopsies are not specifically requested. Low bone mass is common in patients with newly diagnosed CD.38Delco F. El-Serag H.B. Sonnenberg A. Celiac sprue among US military veterans associated disorders and clinical manifestations.Dig Dis Sci. 1999; 44: 966Crossref PubMed Scopus (49) Google Scholar The mechanism for this effect may be due to malabsorption of vitamin D and calcium and decreased intake of calcium because of lactose intolerance.39Bernstein C.N. Leslie W.D. The pathophysiology of bone disease in gastrointestinal disease.Eur J Gastroenterol Hepatol. 2003; 15: 857Crossref PubMed Scopus (118) Google Scholar, 40Burrows R. Leiva L. Burgueno M. Lillo R. Pumarino H. Rios G. Chavez E. Bergenfield C. Muzzo S. Bone mineral density (BMD) in children with celiac disease (CD) its relation to puberty and calcium intake.Nutr Res. 1999; 19: 493Abstract Full Text PDF Scopus (6) Google Scholar Other cofactors such as sex, malnutrition, and physical activity also contribute to the risk of low bone density in CD.41Di Stefano M. Veneto G. Corrao G. Corazza G.R. Role of lifestyle factors in the pathogenesis of osteopenia in adult coeliac disease a multivariate analysis.Eur J Gastroenterol Hepatol. 2002; 12: 1195Crossref Scopus (19) Google Scholar However, low bone mass may be due not only to osteoporosis but also to osteomalacia. Although osteomalacia would therefore be expected to be the bone consequence of malabsorption, osteoporosis has been described in CD on bone biopsy. A raised alkaline phosphatase and other stigmata of osteomalacia may not always be present.42Bai J.C. Gonzalez D. Mautalen C. Mazure R. Pedreira S. Vazquez H. Smecuol E. Siccardi A. Cataldi M. Niveloni S. Boerr L.A. Maurino E. Long-term effect of gluten restriction on bone mineral density of patients with coeliac disease.Aliment Pharmacol Ther. 1997; 11: 157Crossref PubMed Scopus (104) Google Scholar Low bone density associated with CD responds to a gluten-free diet with a gradual restoration of bone over 2 years.43Mora S. Barera G. Ricotti A. Weber G. Bianchi C. 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: 477PubMed Scopus (124) Google Scholar, 44McFarlane X.A. Bhalla A.K. Reeves D.E. Morgan L.M. Robertson D.A.F. Osteoporosis in treated adult celiac-disease.Gut. 1995; 36: 710Crossref PubMed Scopus (171) Google Scholar The earlier in life that treatment is begun the better the response.42Bai J.C. Gonzalez D. Mautalen C. Mazure R. Pedreira S. Vazquez H. Smecuol E. Siccardi A. Cataldi M. Niveloni S. Boerr L.A. Maurino E. Long-term effect of gluten restriction on bone mineral density of patients with coeliac disease.Aliment Pharmacol Ther. 1997; 11: 157Crossref PubMed Scopus (104) Google Scholar, 45Gonzalez D. Mazure R. Mautalen C. Vazquez H. Bai J. Body composition and bone mineral density in untreated and treated patients with celiac disease.Bone. 1995; 16: 231Abstract Full Text PDF PubMed Scopus (104) Google Scholar Conversely, those young adults who were diagnosed early in life but were not compliant with the gluten-free diet were more likely to have low bone density. Although this is so for clinically apparent CD, there is some evidence that otherwise silent CD results in substantial bone problems.46Mazure R. Vazquez H. Gonzalez D. Mautalen C. Pedreira S. Boerr L. Bai J.C. Bone mineral affection in asymptomatic adult patients with celiac disease.Am J Gastroenterol. 1994; 89: 2130PubMed Google Scholar It is possible that low bone mass is the only manifestation of CD in a significant proportion of patients with this disorder, and, consequently, CD may be an under-diagnosed cause of low bone mass in the general population. A limited number of screening studies for CD among patients with low bone mass have been performed in Europe. CD was found in 3.4% in adults with low bone mass.47Lindh E. Ljunghall S. Larsson K. Lavo B. Screening for antibodies against gliadin in patients with osteoporosis.J Intern Med. 1992; 231: 403Crossref PubMed Scopus (113) Google Scholar, 48Meddings J.B. Beck P.L. Scott R.B. Hanley D.A. Meyer D. Osteoporosis in a North American adult population with celiac disease.Am J Gastroenterol. 2001; 96: 120Crossref PubMed Google Scholar, 49Nuti R. Martini G. Valenti R. Giovani S. Salvadori S. Avanzati A. Prevalence of undiagnosed coeliac syndrome in osteoporotic women.J Intern Med. 2001; 250: 361Crossref PubMed Scopus (88) Google Scholar However, a carefully performed Canadian study in predominantly postmenopausal women with osteoporosis has not identified an increased prevalence of CD.50Mather K.J. Beck P.L. Scott R.B. Hanley D.A. Prevalence of IgA-antiendomysial antibody in asymptomatic low bone mineral density.Am J Gastroenterol. 2001; 96: 120Crossref PubMed Google Scholar Why the difference? The early studies were predominantly based in serology alone without biopsy confirmation. Referral bias may have been a factor because our studies in a community-based sample with low bone density have not identified an increased rate of CD in patients with osteoporosis. Although initial serologic tests had a high rate of low-level positivity to tissue transglutaminase antibodies, follow-up serologic tests and biopsies have confirmed CD in just 2 of 25 initially seropositive persons, yielding an overall rate close to the expected general population prevalence by screening but greater than that of the diagnosed rate. The other way the association has been examined is by screening a large population for CD and relating it to measured bone density. The single best study is the Cambridge health study, which suggested a 3-fold increased risk of osteoporosis in seropositive individuals. However, the attributable risk to CD was low. One likely explanation for the differences in these studies is the way the low bone density is defined. Individuals with bone mineral density more than 2.5 standard deviations below the sex-specific peak bone mass are presumed to have osteoporosis.45Gonzalez D. Mazure R. Mautalen C. Vazquez H. Bai J. Body composition and bone mineral density in untreated and treated patients with celiac disease.Bone. 1995; 16: 231Abstract Full Text PDF PubMed Scopus (104) Google Scholar This means that many women by virtue of their age attained have a bone density that reaches the osteoporotic level but are at no greater risk of CD than others of their age. However, in patients who have low bone density and subtle markers for osteomalacia (who were excluded from one negative association study), CD may be a real possibility. Therefore, it seems that screening those patients with simple postmenopausal osteoporosis as defined by WHO criteria is unhelpful. By contrast, when patients with CD are screened for bone disorders, many have elevated parathyroid hormone and low calcium levels, and it would be in these patients, whose z-scores are low, that CD should be considered. However, it remains to be determined whether using the z-score as a guide would be a better guide to determining risk of CD in this population. One Scandinavian study screened a pediatric population with low bone density and demonstrated a 5% prevalence of CD. The finding of low bone density in a young person may well be a risk factor for CD, but bone densitometry is not a routine test at this age, so the point is moot. It is not known what, if any, consequences of low bone mass occur in CD. Ultimately, it is the risk of fractures posed by osteoporosis that is the major outcome of interest. CD has been associated with an increase in fracture risk, although not all studies agree on this point.51Moreno M.L. Vazquez H. Mazure R. Smecuol E. Niveloni S. Pedreira S. Sugai E. Maurino E. Gomez J.C. Bai J.C. Stratification of bone fracture risk in patients with celiac disease.Clin Gastroenterol Hepatol. 2004; 2: 127Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 52West J. Logan R.F. Card T.R. Smith C. Hubbard R. Fracture risk in people with celiac disease a population-based cohort study.Gastroenterology. 2003; 125: 429Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar What effect silent, undiagnosed CD has on lifelong fracture risk is not known. One study did not discover an increased prevalence of CD in patients with osteoporotic fractures; however, these were, in the main, elderly adults at the time of fractures.53Fisher A.A. Davis M.W. Budge M.M. Should we screen adults with osteoporotic fractures for coeliac disease?.Gut. 2004; 53: 154Crossref PubMed Google Scholar Case finding of CD is feasible in some high-risk situations. Family members are often the most accessible and most likely of these groups to have the disease. Subjects with symptoms suggesting CD should not only have serologic testing done but also should be considered for intestinal biopsy because some family members may have intestinal damage without serologic evidence of the disease. Those with T1DM and those with iron-deficiency anemia have a small but significant risk of CD. The impact of screening these at-risk groups on the overall detection of CD is unknown but probably represents only a small proportion of the prevalent cases overall.