Hypocalcemia and Skeletal Disease as PresentingFeatures of Celiac DiseaseJoseph L. Shaker, MD; Robert C. Brickner, MD; James W. Findling, MD; Thomas M. Kelly, MD;Richard Rapp, MD; Ghyass Rizk, MD; John G. Haddad, MD; Don S. Schalch, MD; Yoram Shenker, MD

Objective: To describe 15 patients examined for hypo-calcemia, skeletal disease, or both in whom the diagno-sis of celiac disease was subsequently made.

Design: Observational case series.Patients: Fifteen patients (7 women and 8 men) wereexamined for hypocalcemia (n=11), skeletal disease(n=3), or both (n=1). The diagnosis of celiac diseasewas subsequently made. The mean age of the patientswas 62 years, and 11 patients were 60 years of age orolder.

Results: Four patients had no gastrointestinal symp-toms, 7 patients had mild or intermittent gastrointesti-nal symptoms, and 4 patients had persistent diarrhea. Ten

patients had experienced weight loss. The serum total al-kaline phosphatase level was elevated in 10 of 15 pa-tients, the parathyroid hormone level was elevated in allpatients, and the urinary calcium level was low in all 6of the patients tested. The level of 25-hydroxyvitamin Dwas frankly low in 4 patients, marginal in 8 patients, andnormal in 3 patients. Bone mineral density was reducedin all 8 patients in whom it was measured.

Conclusions: Celiac disease should be considered in pa-tients with unexplained metabolic bone disease or hy-pocalcemia, especially because gastrointestinal symp-toms may be absent or mild. Advanced age does notexclude the diagnosis of celiac disease.Arch Intern Med. 1997;157:1013-1016

_I_

Metabolic bone diseaseand hypocalcemia areknown complicationsofgastrointestinal (GI)disorders that causemal-

absorption ofcalcium, vitamin D, or both.1Celiac disease (CD), or gluten-sensitive en-teropathy, is a disorder resulting from ex¬

posure ofpredisposed individuals to somecereal grain proteins and is associated his-tologicallywith villous atrophy of the mu¬cosa of the small intestine.2,3 The diagno¬sis of CD is made most frequently duringchildhood, with another peak during thefourth and fifth decades of life.2 Celiac dis¬ease is diagnosed less often in the UnitedStates than in Europe.3 This may be re¬

lated to a truly lower incidence of CD inthe United States, although a low index ofsuspicion among physicians heremay con¬tribute to this difference.3 The diagnosisof CD is usually considered in young pa¬tients with typical symptoms of malab¬sorption. Occasionally, isolated iron or fo-late deficiency (witbout GI symptoms)may be the presenting feature in patientswhose disease involves only the duode¬num and the proximal jejunum.2 There

have also been a few reports of osteoma¬lacia or tetany as presenting features ofCD.410We describe 15 patients in whomhypocalcemia or skeletal disease was theclinical presentation leading to the diag¬nosis of CD.

RESULTS

The clinical and laboratory data are sum¬marized in the Table. Seven women and8 men were examined. Three patientswere referred for evaluation of skeletaldisease. Patient 1 had bilateral hip painand was found to have bilateral femoralpseudofractures. Patient 2 was found tohave a low spinal BMD when he volun¬teered for a BMD study. Patient 3 had os¬teoporosis and spinal compression frac¬tures. Twelve patients had hypocalcemia,1 of whom also had established osteopo¬rosis (patient 15). In the patientswith hy¬pocalcemia, the corrected calcium levelwas 1.80±0.32 mmol/L (7.2±1.3 mg/dL). The mean age of the patients was 62years, and 11 patients were 60 years of ageor older. Four patients had no GI symp¬toms, 7 patients reported mild or inter-

From the Departmentof Medicine, St Luke's MedicalCenter, Milwaukee, Wis(Drs Shaker, Brickner,Findling, and Rizk); theDepartment of Medicine, StJoseph's Hospital, Milwaukee(Dr Kelly); the Department ofMedicine, St Mary's Hospital,Racine, Wis (Dr Rapp); theDepartment of Medicine,University of PennsylvaniaSchool of Medicine,Philadelphia (Dr Haddad);the Department of Medicine,University of Wisconsin Schoolof Medicine, Madison(Drs Schalch and Shenker);and the Department ofMedicine, William S.Middleton Memorial VeteransHospital, Madison(Dr Shenker).

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METHODS

Calcium, albumin, phosphorus, creatinine, and al¬kaline phosphatase levels were measured by auto-analyzer. The corrected calcium level was calcu¬lated by adding 0.20 mmol/L (0.8 mg/dL) to thecalcium for every 10 g/L decrement in albumin be¬low 40 g/L. Because the normal ranges for the alka¬line phosphatase varied, the results are reported asthe percentage of the upper limit of the normal range.The level of parathyroid hormone (PTH) was mea¬sured using a carboxyl-terminal assay in patient 1 andby a sensitive 2-site immunoradiometric assay (in¬tact molecule) in patients 2 through 15. These re¬sults were also expressed as the percentage of the up¬per limit of normal. The levels of vitamin Dmetabolites weremeasured by different reference labo¬ratories with slight differences in normal ranges. Lev¬els of 25-hydroxyvitamin D (250HD) less than 22nmol/L (<9 ng/mL) were considered low, 22 to 35nmol/L (9-14 ng/mL), marginal, and greater than 35nmol/L (>14 ng/mL), normal. We considered 1,25dihydroxyvitamin D (l,25-[OH]2D) levels of 36 to144 pmol/L (15-60 pg/mL) to be normal. When morethan 1 value for biochemical tests was available, themean is presented. Bone mineral density (BMD) ofthe lumbar spine and femoral neck was obtained bydual photon absorptiometry or dual energy x-ray ab-sorptiometry. The results of testing for BMD are ex¬

pressed as the percentage of the predicted value (age-matched). In patient 1, a transiliac bone biopsy wasperformed after standard double tetracycline label¬ing. Data are given as mean±SD.

mittent GI symptoms, and 4 patients had persistent di¬arrhea. Weight loss was reported by 10 patients. The al¬kaline phosphatase level was elevated in 10 of 15 pa¬tients, and the level of PTFf was elevated in all patients.The serum inorganic phosphate level was low in 3 pa¬tients and mildly elevated in 2 patients, both of whomhad mildly elevated creatinine levels. The urinary cal¬cium level was low, at 0.22±0.28 mmol/d (9±11 mg/24 h) in 6 patients in whom it was measured beforecalcium and vitamin D therapy. The 250HD level for the15 patients was 26±14 nmol/L (10.4±5.6 ng/mL). The250HD level was frankly low in 4 patients, marginal in8 patients (22.5-32.5 nmol/L; 9-13 ng/mL), and normalin 3 patients (37.5-55 nmol/L; 15-22 ng/mL). The 1,25-(OH)2D level was 101 ±49 pmol/L (42.1 ±20.4 pg/mL)in 13 patients. The l,25-(OH)2D level was low in pa¬tient 9, who had an undetectable 250HD level, but it wasnormal or elevated in the remaining patients, presum¬ably because of stimulation of renal 250HD-l-a-hydroxylase by PTH. The presence of antigliadin anti¬bodies, endomysial antibodies, or both was assessed in10 patients. The IgA antigliadin antibodies were presentin 9 of 10 patients, and IgA endomysial antibodies werepresent in 6 of 7 patients tested. The BMD of the lumbarspine was 68%±8% of the predicted value (n=8), and ofthe femoral neck, 77%± 8% of the predicted value (n=7).In addition to CD, the surgical menopause was presum¬ably an important factor in the osteoporosis present inpatient 15. The evaluation of the bone biopsy specimenfrom patient 1 revealed excessive osteoid and absent tet-racycline uptake consistentwith osteomalacia. A biopsyof the small intestine was performed in 11 patients, andfindings consistent with CD were present in all. Endo¬mysial and antigliadin antibodies were present in 3 of the

Clinical and Laboratory Data*

Patient No./Sex/Age, y Presentation GI Symptoms

WeightLoss, kg

CorrectedCalcium,mmol/L

InorganicPhosphate,mmol/L

Creatinine,fimol/L

AlkalinePhosphatasef

1/M/78 Pseudofractures Intermittent diarrhea 8.2 2.24 1.58 1242/M/48 Osteopenia Occasional soft stool None 2.30 1.10 883/F/70 Osteoporosis None None 2.24 1.23 714/F/64 Hypocalcemia None Yes§ 1.47 1.58 1685/M/26 Hypocalcemia Diarrhea 15.9 1.75 0.52 626/F/72 Hypocalcemia Diarrhea 9.1 1.65 1.16 1947/M/66 Hypocalcemia Diarrhea 11.4 1.62 0.64 718/M/72 Hypocalcemia Mild abdominal bloating 5.9 1.82 1.10 809/F/21 Hypocalcemia None None 1.05 0.74 3510/F/60 Hypocalcemia Some loose stools None 2.04 1.23 7111/M/51 Hypocalcemia Intermittent diarrhea 4.5 2.04 1.10 7112/M/76 Hypocalcemia Intolerance of lettuce 21.4 2.14 1.00 8013/IW83 Hypocalcemia Diarrhea 22.7 2.14 1.23 8814/F/77 Hypocalcemia Intermittent diarrhea 17.9 1.77 0.94 6215/F/62 Hypocalcemia None None 2.18 1.19 97

and osteoporosis!)Normal range NA NA NA 2.20-2.54 0.81-1.45 <106

1083021013331471411874516110414363549185

NA

*GI indicates gastrointestinal; PTH, parathyroid hormone; 250HD, 25-hydroxyvitamin D; 1,25 (0H)2D, 1,25 dihydroxyvitamin D; Ab, antibody:BMD, bone mineral density; ellipses, not tested; plus sign, positive results; minus sign, negative results; and NA, not applicable.tReported as the percentage of the upper limit of the normal range.^.Reported as the percentage of the age-matched predicted value.^Unknown amount.\\Possibly related to surgically Induced menopause while in her 20s.isee the "Methods" section of the text.

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4 patients who did not undergo biopsy of the small in¬testine; only antigliadin antibodies were tested in the otherpatient, and the results were positive. Two patients hadcoexistent hypothyroidism, and 1 of them also had typeI diabetes mellitus.

Celiac disease is usually diagnosed in young patientswith clinically evident malabsorption. There have beenreports of isolated vitamin deficiencies in CD2 and ofCD presenting with hypocalcemia4,3 or osteomala¬cia.4,6"10 We describe 11 patients with hypocalcemia, 3patientswith skeletal disease, and 1 patientwith both inwhom the diagnosis of CD was made. Gastrointestinalsymptoms were absent or mild in several patients and,when present, were often not considered by patients orphysicians to be clinically significant. Two patientswere previously believed to have PTH resistance, and 1patient was previously believed to have Paget's diseaseof the bone.

In 1956, Juergens et al6 described 5 patients withosteomalacia due to CD. Mild GI symptoms and weightloss were present in 4 patients, and hypocalcemia waspresent in all 5. Moss et al7 described a patient with os¬

teomalacia and mild hypocalcemia secondary to CD whodid not have steatorrhea. Ross et al4 reviewed the find¬ings in 42 patients with CD. Bone pain was reported by19% of patients and tetany in 10%. Osteomalacia wasfound in 12 patients. Bone mineral density is lower inuntreated patientswith CD, and treatmentwith a gluten-free diet probably improves the BMD.11"13 Patients withpersistent villous atrophy because of inadequate adher¬ence to a gluten-free diet have lower BMD than patients

in whom the results of biopsy of the small intestine nor¬malize after treatment with a gluten-free diet.14

Subclinical CD may be more common than previ¬ously believed. Catassi et al15 screened 5280 students aged11 to 15 years using antigliadin and endomysial anti¬bodies to select patients for biopsy of the small intes¬tine. They found undiagnosed CD in 23 subjects (4.36per 1000). Lindh et al15 reported findings in 92 consecu¬tive patientswith idiopathic osteoporosis screened for CDby testing for the presence of IgA antigliadin antibodies.Resultswere positive in 11 patients (12%). None of thesepatients had GI symptoms. Six of these patients under¬went biopsy of the small intestine, and, in 3, findings wereconsistent with CD. Thus, in their series, at least 3% ofpatients referred for osteoporosis had CD. There is an as¬sociation of CDwith autoimmune thyroid disease,17,18 andunexplained increases in the dose requirements for le-vothyroxine sodium in patientswith hypothyroidism mayindicate subclinical CD.19

Insulin-dependent diabetes mellitus (IDDM) is alsoassociated with CD.20,21 Sategna-Guidetti et al20 screened383 consecutive adults with IDDM. Endomysial anti¬bodies were present in 12 patients. Ten of the patientswith positive results of the antibody screening (2.6% ofthe total group) underwent biopsy of the small intes¬tine, and the findings for all were compatible with CD.Only 1 of these patients had GI symptoms. Page et al21found CD in 2% of adults with IDDM.

Although vitamin D deficiency contributes to cal¬cium malabsorption in some patients with CD, im¬paired calcium absorption occurs even in the presenceof adequate vitamin D stores. In our series, the levels of250HD were often normal or marginal. Low or mar¬ginal 250HD levels may be present because of fat mal-

25QHD, 1.25 (OH)2D, Urinary Calcium, Antigliadin Endomysial Spine Femoral Results of SmallPTHt nmol/L pmol/L mmol/d Ab (IgA) Ab (IgA) BMD* Neck BMD* Intestine Biopsy1361311821026185545241213406118172178474348511

NA

27.525.020.040.037.555.027.527.5<2.522.532.525.032.515.0

<12.5

14977130914853108110<24137190

110108

36-144

0.750.20

0.10

0.30

<0.90

1.25-7.50 NA

+

NA

7368

65717963

74

53

NA

89

65747979

83

69

NA NA

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absorption and because the increased l,25-(OH)2Dlevels due to secondary hyperparathyroidism acceler¬ate the plasma clearance of 250HD.22"24 Low serum

inorganic phosphate levels were present in a few ofour patients, presumably because of the phosphaturiceffect of PTH.

Celiac disease should be considered in patientswithunexplained hypocalcemia or skeletal disease. Patientsmay have minimal or no gastrointestinal symptoms. Thepresence of hypocalciuria or hyperparathyroidism in pa¬tients with normal calcium levels and metabolic bone dis¬ease should prompt examination for malabsorption andCD. Patients with unexplained hypocalcemia and sec¬

ondary hyperparathyroidism should also be examined formalabsorption and CD even in the absence of GI symp¬toms. Testing for IgA antigliadin and endomysial anti¬bodies may be useful for screening patients. Advancedage does not exclude CD, and the diagnosis of CD maybe delayed for many years in elderly patients.25 Physi¬cians should be particularly aware of CD in patientswithautoimmune thyroid disease and IDDM who are at in¬creased risk of CD. This is especially important in pa¬tients with IDDM in whom diarrhea may be attributedto diabetic enteropathy and weight loss attributed to poorglycémie control. Prompt diagnosis and treatment witha gluten-free diet, calcium, and vitamin D may preventlong-term skeletal complications.Accepted for publication October 14, 1996.

Presented in part as a poster at the 77th annual meet¬ing of the Endocrine Society, Washington, DC, June 15,1995.

Reprints: Joseph L. Shaker, MD, Department ofMedi¬cine, St Luke's Medical Center, 2901 W Kinnickinnic RiverPkwy, Suite 503, Milwaukee, WI 53215.

1. Bikle DD. Bone disease due to nutritional, gastrointestinal, and hepatic disor-ders. In: Coe FL, Favus MJ, eds. Disorders of Bone and Mineral Metabolism.New York, NY: Raven Press; 1992:951-976.

2. Trier JS. Diagnosis and treatment of celiac sprue. Hosp Pract. April 30,1993:41-54.

3. Michalski JP, McCombs CC. Celiac disease: clinical features and pathogen-esis. Am J Med Sci. 1994;307:204-211.

4. Ross JR, Gibb SP, Hoffman DE, Clerkin EP, Dotter WE, Hurxthal LM. Glutenenteropathy and skeletal disease. JAMA. 1966;196:180-184.

5. Rakover Y, Hager H, Nussinson E, Luboshitzky R. Celiac disease as a cause oftransient hypocalcemia and hypovitaminosis D in a 13 year-old girl. J PediatrEndocrinol. 1994;7:53-55.

6. Juergens JL, Scholz DA, Wollaeger EE. Severe osteomalacia associated withoccult steatorrhea due to nontropical sprue. Arch Intern Med. 1956;98:774\x=req-\782.

7. Moss AJ, Waterhouse C, Terry R. Gluten-sensitive enteropathy with osteoma-lacia but without steatorrhea. N Engl J Med. 1965;272:825-830.

8. Hajjar ET, Vincenti F, Salti IS. Gluten-sensitive enteropathy: osteomalacia asits principal manifestation. Arch Intern Med. 1974;134:565-566.

9. Jawad ASM, Squire SB, Perry JD. Osteomalacia and coeliac disease present-ing as isolated dactylitis. Ann Rheum Dis. 1988;47:692-694.

10. De Boer WA, Tytgat GNJ. A patient with osteomalacia as single presentingsymptom of gluten-sensitive enteropathy. J Intern Med. 1992;232:81-85.

11. Molteni N, Caraceni MP, Bardella MT, Ortolani S, Gandolini GG, Bianchi P.Bone mineral density in adult celiac patients and the effect of gluten-free dietfrom childhood. Am J Gastroenterol. 1990;85:51-53.

12. Mora S, Weber G, Barera G, et al. Effect of gluten-free diet on bone mineralcontent in growing patients with celiac disease. Am J Clin Nutr. 1993;57:224\x=req-\228.

13. Gonz\l=a'\lezD, Mazure R, Mautalen C, Vazquez H, Bai J. Body composition andbone mineral density in untreated and treated patients with celiac disease. Bone.1995;16:231-234.

14. Valdimarsson T, Toss G, Ross I, L\l=o"\fmanO, Str\l=o"\mM. Bone mineral densityand coeliac disease. J Gastroenterol. 1994;29:457-461.

15. Catassi C, R\l=a"\tschIM, Fabiani E, et al. High prevalence of undiagnosed coeliacdisease in 5280 Italian students screened by antigliadin antibodies. Acta Pae-diatr. 1995;84:672-676.

16. Lindh E, Ljunghall S, Larsson K, Lav\l=o"\B. Screening for antibodies against glia-din in patients with osteoporosis. J Intern Med. 1992;231:403-406.

17. Collin P, Salmi J, H\l=a"\llstr\l=o"\mO, Reunala T, Pasternack A. Autoimmune thyroiddisease and coeliac disease. Eur J Endocrinol. 1994;130:137-140.

18. Counsell CE, Taha A, Ruddell WSJ. Coeliac disease and autoimmune thyroiddisease. Gut. 1994;35:844-846.

19. Grinspoon SK, Daniels GH. Case report: increased levothyroxine require-ment in a patient with cryptic celiac-sprue disease. Endocr Pract. 1995;1:88-90.

20. Sategna-Guidetti C, Grosso S, Pulitan\l=o'\R, Benaduce E, Dani F, Carta Q. Celiacdisease and insulin-dependent diabetes mellitus: screening in an adult popu-lation. Dig Dis Sci. 1994;39:1633-1637.

21. Page SR, LLoyd CA, Hill PG, Peacock I, Holmes GKT. The prevalence of coe-liac disease in adult diabetes mellitus. QJM. 1994;87:631-637.

22. Halloran BP, Bikle DD, Levens MJ, Castro ME, Globus RK, Holton E. Chronic1,25-dihydroxyvitamin D3 administration in the rat reduces the serum concen-tration of 25-hydroxyvitamin D by increasing metabolic clearance rate. J ClinInvest. 1986;78:622-628.

23. Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitaminD deficiency in calcium deprivation. Nature. 1987;325:62-65.

24. Clements MR, Davies M, Hayes ME, et al. The role of 1,25-dihydroxyvitamin Din the mechanism of acquired vitamin D deficiency. Clin Endocrinol (Oxf). 1992;37:17-27.

25. Hankey GL, Holmes GKT. Coeliac disease in the elderly. Gut. 1994;35:65-67.

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