Celiac disease occurring in a patient with hypoparathyroidism and autoimmune thyroid disease.

Abstract: Patients with an underlying autoimmune endocrine disorder are at an increased risk of developing other autoimmune diseases. We describe a patient with idiopathic autoimmune hypoparathyroidism who developed hyperthyroidism due to Graves disease and subsequently was diagnosed with celiac disease. Malabsorption of L-thyroxine was the only clue regarding the presence of celiac disease. This particular association of these three autoimmune disorders occurring in the same patient has not, to our knowledge, been previously reported. The presentation, investigations performed, and treatment provided are discussed and the literature pertaining to similar cases is reviewed.

Key Words: autoimmune thyroid disease, Graves disease, celiac disease, hypoparathyroidism, autoimmune polyglandular syndromes

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Graves disease, celiac disease and idiopathic hypoparathyroidism are all thought be autoimmune in pathogenesis. Although patients with one autoimmune endocrinopathy are at an increased risk of developing another, the occurrence of all three of the above disorders in one patient has not, to our knowledge, been previously reported. We present the history, results of investigations, and response to treatment in one such patient and provide a review of the literature for similar cases.

Case Report

A 24-year-old Chinese female was referred for ongoing management of hypothyroidism and hypoparathyroidism. She was diagnosed with hypocalcemia at the age of 14, at which time she had recurrent episodes of perioral numbness, muscle cramps and tetany and was started on calcium and vitamin D therapy. The cause of hypocalcemia was not investigated at that time. At age 21, she was found to have an enlarged thyroid gland on examination. Although she denied any symptoms of hyper- or hypothyroidism, laboratory investigations revealed hyperthyroidism and subsequent investigations, including radioactive iodine uptake and scan, suggested Graves disease. She was treated with radioactive iodine therapy and became hypothyroid. At the time of our assessment, the patient was euthyroid, and asymptomatic in regards to her hypocalcemia. She had no complaints suggestive of other underlying autoimmune disorders or endocrinopathies, specifically, adrenal insufficiency, pernicious anemia or diabetes. Her weight had remained stable and she had no gastrointestinal complaints and had noticed no skin rashes. There was no history of recurrent fungal skin or nail infections. She did not have a history of neck surgery or radiation and the family history was significant for the absence of any endocrine problems. At the time of referral, she was on 150 [micro]g of L-thyroxine, 2.0 [micro]g of calcitriol and 3 g of calcium carbonate/day. The patient weighed 50 kg. Her physical examination was unremarkable, and there were no abnormalities to suggest pseudohyperparathyroidism. Chvostek and Trousseau signs were absent and there was no dermatitis herpetiformis, vitiligo or cataracts. Laboratory investigations revealed a TSH of 25.38 mu/mL (0.3-5.50), calcium of 9.52 mg/dL (8.40-10.2), phosphate of 4.28 mg/dL (2.43-4.78) and PTH of <9.5 pg/mL (12.5-72.0). Electrolytes, creatinine, albumin and CBC were normal. The antithyroid peroxidase, antithyroglobulin and thyroid stimulating antibodies were elevated and antiadrenal, antiglutamic acid decarboxylase (GAD) and anti-islet cell antibodies were negative. Given the laboratory findings, the negative surgical or radiation history to the neck, and the absence of any symptoms suggestive of infiltrative disorders of the parathyroid glands, the diagnosis of idiopathic autoimmune hypoparathyroidism as a cause of her hypocalcemia was made. As the patient was not biochemically euthyroid on the appropriate weight-adjusted L-thyroxine dosage, malabsorption of L-thyroxine was considered in the differential diagnosis. Due to the presence of two autoimmune disorders, the diagnosis of celiac disease was entertained, despite the absence of gasterointestinal symptoms. The tissue transglutaminase antibody was 6.0 Keu/L (<20.0), antigliadin IgG antibody was 24.0 Keu/L (0-20) and antigliadin IgA antibody was 2.0 Keu/L (0-20). The patient was referred for a duodenal biopsy which revealed partial villous atrophy consistent with celiac disease (Fig. 1).

Discussion

Graves disease, celiac disease and hypoparathyroidism are all autoimmune disorders. Patients with one autoimmune endocrinopathy have an increased risk of developing other autoimmune disorders. The association of chronic mucocutaneous candidiasis, adrenal insufficiency and hypoparathyroidism as components of the autoimmune polyglandular syndrome type 1 (APS-I) or autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED) is well recognized. (1) Other associated manifestations of APS-I include vitiligo, alopecia, pernicious anemia, and autoimmune hepatitis. APS-I is an autosomal recessive condition due to mutations in the autoimmune regulator gene (AIRE) on chromosome 21q 22.3. The most common initial manifestation of APS-I is oral candidiasis followed by hypoparathyroidism, the peak incidence of which is between ages 2 to 11. In contrast to APS-I, in autoimmune polyglandular syndrome type II (APS-II), primary adrenal insufficiency is most often associated with autoimmune type 1 diabetes and autoimmune thyroid disorders. Other conditions associated with APS-II include pernicious anemia, celiac disease, vitiligo hypophysitis, and premature ovarian failure. The diagnosis of APS-II is based on clinical and laboratory evidence of two or more components of this syndrome. Thus, although there is some overlap in the endocrinopathies seen in the two syndromes, in general the occurrence of thyroid or celiac disease is thought to be very rare in APS-I. Similarly, hypoparathyroidism as part of APS-II is extremely unusual.

[FIGURE 1 OMITTED]

Celiac disease and autoimmune thyroid disease have similarities in pathogenesis. (2,3) Celiac disease is associated with HLA-DR3, and such an association has been demonstrated in Graves disease and Hashimoto thyroiditis as well. The activation of T-cells, which results in expression of major histocompatibility type 2 antigens have been described in both celiac disease and autoimmune thyroid diseases. There is some hypothesis that gluten may be the primary antigen which initiates the formation of antithyroid antibodies as well as antibodies directed against other endocrine glands. The prevalence of celiac disease in the general population is approximately 1:300 (0.3%). (4) The frequency of celiac disease in patients with autoimmune thyroid disease has been reported to be between 3 to 5%, which is much higher than the prevalence of celiac disease in the general population. Similarly, the prevalence of autoimmune thyroid disease, thyroid antibody positivity and thyroid ultrasonographic abnormalities in patients with celiac disease is reported to be as high as 30%. Although the association of celiac disease and autoimmune thyroid disorders is well appreciated, the coexistence of autoimmune hypoparathyroidism and autoimmune thyroid disorders is rare and only a few cases have been described in the literature. (5-9) Although hypercalcemia, due to increased bone resorption, has been described in patients with severe hyperthyroidism, hypocalcemia, particularly due to coexisting hypoparathyroidism, is extremely rare and only a few cases have been reported in the literature. The association of celiac disease and idiopathic hypoparathyroidism is also very rare. Although hypocalcemia due to calcium and vitamin D malabsorption may be the presenting feature of celiac disease, it would be associated with an elevated PTH level. Persistent hypocalcemia due to underlying hypoparathyroidism has been reported very rarely in celiac disease. (10-13) Finally, the association of Graves disease, hypoparathyroidism and celiac disease occurring in one patient, as we report, has not been previously described.

This case highlights the importance of considering the presence of, and screening for, multiple endocrinopathies in patients with autoimmune endocrine disorders. It also emphasizes the need to appreciate the occult presentation of celiac disease. In our patient, there were no gastrointestinal symptoms to suggest celiac disease and the diagnosis was entertained primarily due to the fact that more L-thyroxine was required to achieve euthyroidism. Although malabsorption of L-thyroxine occurs commonly in celiac disease, it has rarely been reported as the presenting feature of the disease. (14)

Conclusion

Patients with one autoimmune endocrine disorder are at an increased risk of developing other autoimmune diseases, which highlights the need for increased awareness and life-long monitoring of such patients. The association of hypoparathyroidism, Graves disease and celiac disease occurring in one patient has not, to our knowledge, been previously reported.

References

1. Eisenbarth GS, Gottlieb PA. Autoimmune polyendrocrine syndromes. N Engl J Med 2004;350:2068-2079.

2. Collin P, Salmi J, Hallstrom O, et al. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol 1994;130:137-140.

3. Valentino R, Savastano S, Tommaselli AP, et al. Prevalence of coeliac disease in patients with thyroid autoimmunity. Horm Res 1999;51:124-127.

4. Maki M, Collin P. Coeliac disease. Lancet 1997;349:1755-1759.

5. Yamaji Y, Hayashi M, Suzuki Y, et al. Thyroid crisis associated with severe hypocalcemia. Jpn J Med 1991;30:179-181.

6. Yoshioka K, Ohsawa A, Yoshida D, et al. Insulin-dependent diabetes mellitus associated with Graves' disease and idiopathic hypoparathyroidism. J Endocrinol Invest 1993;16:643-646.

7. Cakir M, Karayalcin U. Graves' disease co-existing with probable autoimmune hypoparathyroidism. Exp Clin Endocrinol Diabetes 2003;111:374-376.

8. Ycaza MM, Stinebaugh BJ. Idiopathic hypoparathyroidism with hyperthyroidism. South Med J 1972;65:246.

9. Farup PG. Idiopathic hypoparathyroidism and hyperthyroidism. Acta Med Scand 1977;202:261-264.

10. Wortman J, Kumar V. Case report: idiopathic hypoparathyroidism coexisting with celiac disease: immunologic studies. Am J Med Sci 1994;307:420-427.

11. Sari R, Yildirim B, Sevinnc A, et al. Idiopathic hypoparathyroidism and celiac disease in two patients with previous history of cataract. Indian J Gastroenterol 2000;19:31-32.

12. Matsueda K, Rosenberg IH. Malabsorption with idiopathic hypoparathyroidism responding to treatment with coincident celiac sprue. Dig Dis Sci 1982;27:269-273.

13. Isaia GC, Casalis S, Grosso I, et al. Hypoparathyroidism and co-existing celiac disease. J Endocrinol Invest 2004;27:778-781.

14. Khandwala HM, Chibbar R, Worobetz LJ. A case of celiac disease presenting with malabsorption of thyroxine. Endocrinologist 2005;15:14-17.</p> <pre> Feeling gratitude and not expressing it is like wrapping a present and not giving it. --William Arthur Ward </pre> <p>Hasnain M. Khandwala, MD, FRCPC, Rajni Chibbar, MD, FRCPC, and Anil Bedi, MD, FRCPC

From the Divisions of Endocrinology, Gastroenterology and Pathology, University of Saskatchewan, Saskatoon, Canada.

Reprint requests to Hasnain M. Khandwala, Royal University Hospital, Division of Endocrinology-Room 3654, 103 Hospital Drive, Saskatoon, SK, S7K 7A9, Canada. Email: [e-mail]

Accepted November 23, 2005.

RELATED ARTICLE: Key Points

* Patients with one autoimmune endocrine disorder have an increased risk of developing other autoimmune diseases.

* The association between autoimmune thyroid disease and celiac disease is common.

* Celiac disease may present only as malabsorption of L-thyroxine.

* The association of Graves disease, hypoparathyroidism and celiac disease in one patient has not, to our knowledge, been reported previously.