Abstract
Introduction
Hypoparathyroidism and co-existing coeliac disease can lead to dramatic fluctuations in plasma calcium levels, a therapeutic challenge doctors should be aware of. Acquired hypoparathyroidism is usually the result of surgery and is estimated to occur in 0.5–6.6% of patients following total thyroidectomy, with an even higher rate in some case series, but a lower rate in endocrine surgical centres, where it ranges from 0.9% to 1.6%. 1, 2, 3, 4 The occurrence of hypoparathyroidism depends on the surgeon's experience, the extent of thyroid resection and the underlying thyroid disease, with the presence of substernal goitre, cancer or Graves' disease increasing the risk. 5 Hypoparathyroidism may also occur secondary to autoimmune invasion and destruction of the parathyroid gland, as in polyglandular syndrome type 1.
In comparison, coeliac disease has a high prevalence of 1:300 in white Caucasians of northern European ancestry. 6 Both these conditions lead to hypocalcaemia. When calcium levels in a previously stable treated patient with hypoparathyroidism decrease or begin to fluctuate significantly, the differential diagnosis includes prolonged use of laxatives or anticonvulsant therapy, chronic renal failure, decreased dietary intake of calcium and Vitamin D or malabsorption such as occurs with coeliac disease. On the other hand, the institution of and adherence to a gluten-free diet in a newly-diagnosed patient with coeliac disease on Vitamin D may lead to rapid improvement of intestinal absorption with prompt increases in plasma calcium levels. Here we present two patients diagnosed with hypoparathyroidism, both of whom went on to develop coeliac disease at a later stage. Profound alterations in calcium balance occurred before and after the diagnosis of coeliac disease, which serves to illustrate the changes in calcium levels that may result from the combination of hypoparathyroidism and coeliac disease, and to alert us to the potential complications of this combination of pathologies.
Subjects
Patient 1
A 59-year-old woman underwent a total thyroidectomy for papillary thyroid cancer in 1977 and developed postoperative hypocalcaemia. She was treated with alpha-calcidol 1 μg four times daily and remained well until the beginning of August 2001, when she noticed progressively worsening tingling of her hands, feet and around her mouth. Having previously been stable with normal plasma calcium levels over several years, her plasma calcium was now found to be 1.8 mmol/L, and she was urgently admitted to hospital for intravenous calcium in 2001. After the infusion, despite a transient increase, her calcium levels remained low at 1.7 mmol/L. She received further intravenous calcium and subsequently her medication was changed to calcitriol 1 μg once daily, which was gradually increased to 3 μg once daily. Antiendomysial antibodies were checked in February 2002 and found to be positive. The patient underwent gastroscopy with duodenal biopsies, which showed crypt hyperplasia and villous atrophy. After starting a gluten-free diet, she could gradually reduce her calcitriol dose to 2 μg once daily and remains stable with a calcium of 2.1 mmol/L.
Patient 2
A 40-year-old woman underwent total thyroidectomy for uncontrolled hyperthyroidism in
2004 in a hospital outside Oxford Plasma calcium levels in patient 1 before and after initiation of
gluten-free diet Plasma calcium levels in patient 2 after initiation of gluten-free diet
Discussion
This paper demonstrates the potentially serious aberrations that can occur in calcium levels in patients on Vitamin D for hypoparathyroidism in whom coeliac disease is diagnosed and treated. Cases of idiopathic hypoparathyroidism co-existing with coeliac disease are described in a handful of cases in the literature, 7, 8, 9, 10, 11 although this situation occurs very rarely and mainly in patients with longstanding disease and therefore lengthy exposure to antibodies. 12 Studies have found that parathyroid antibodies can be of two types: one specific for the parathyroid gland, the other non-specific and able to mimic the anti-endomysial antibodies associated with coeliac disease. On the other hand, tissue transglutaminase antibodies produced in coeliac disease have been shown to cross-react with other antigens and endomysial antibody reactions on parathyroid tissue have been shown to lead to parathyroid atrophy. 12, 13 Postoperative hypoparathyroidism may also co-exist with coeliac disease, as described in the two patients mentioned above.
When a gluten-free diet is adhered to, approximately 70% of patients notice symptomatic improvement within two weeks 14 and antiendomysial antibodies generally disappear in 6–12 months. The speed and degree of histologic improvement is unpredictable but invariably lags behind the clinical response and may not be evident on repeated biopsy for 2–3 months. 15 Given that the response to a gluten-free diet is so rapid, this must be considered when a patient taking calcium and Vitamin D supplements starts the diet. Calcium levels need to be monitored carefully, as dangerously high plasma calcium levels and acute renal failure can develop, as illustrated in patient 2. On the other hand, sudden falls in plasma calcium levels that cannot be explained by interfering drugs, worsening chronic renal failure or decreased dietary intake of calcium warrant investigation for coeliac disease. When the index of suspicion is moderate to high, antiendomysial antibodies should be checked. 6 Once coeliac disease is confirmed and a gluten-free diet is commenced, plasma calcium levels normalize quickly, as illustrated in patient 1.
Hypoparathyroidism causes hypocalcaemia through a fall in PTH levels, leading to reductions in bone reabsorption and intestinal calcium absorption and, in patients without end-stage renal disease, increased calcium excretion. In coeliac disease, the mechanism leading to hypocalcaemia is chronic inflammation of the intestinal mucosa leading to malabsorption of vitamin D and calcium. 16 Hypocalcaemia is often exacerbated by a decreased intake of dairy products because of lactose intolerance, as lactase cannot be produced by degenerated intestinal epithelial cells and is not available to cleave the lactose in dairy products. 17 Enteric bacteria switch to lactose metabolism, and the resultant fermentation produces large amounts of gas, which can cause painful abdominal bloating. In both conditions oral or intravenous calcium (if calcium levels fall rapidly and severe symptoms occur) as well as vitamin D supplements are given. In hypoparathyroidism, the aim of treatment is to achieve near normalization of plasma calcium levels and to avoid symptoms of neuromuscular excitability by aiming for a plasma calcium at, or just below, the normal lower limit. As the renal retention of calcium brought about by PTH has been lost, any attempt to raise plasma calcium into the normal range will result in hypercalciuria with the risk of nephrocalcinosis and kidney stones. 18 Acceptable plasma calcium concentrations can rarely be achieved using calcium supplements alone in hypoparathyroidism, and vitamin D supplements are necessary. The more potent analogues of vitamin D such as calcitriol or alpha-calcidol are preferred over calciferol or ergocalciferol because of their potency and rapid onset and offset of action. 5 The dose of vitamin D is determined by the clinical response and lies between 0.5–2 μg of the potent analogues once daily. In coeliac disease on the other hand, the aim is to achieve normal plasma calcium levels. As coeliac disease can remain undiagnosed for some time, it may lead to metabolic bone disorders, 19, 20, 21 although a decrease in bone mineral density associated with coeliac disease responds to a gluten-free diet, with a gradual restoration to normal over two years.
Conclusion
Coeliac disease has a high prevalence in the general population and approximately 19,000 thyroid operations are performed in the UK each year. 22 Although postoperative hypoparathyroidism develops in only a small percentage of patients, a number of patients are affected due to the large number of thyroid surgeries undertaken each year, making the combination of coeliac disease and postoperative hypoparathyroidism in a single patient possible. In addition, further autoimmune diseases can develop in patients suffering from either coeliac disease or hypoparathyroidism, for which physicians must remain vigilant. When a gluten-free diet for coeliac disease is started, plasma calcium levels should be monitored on a weekly basis during the first weeks of treatment as intestinal inflammation settles. Monitoring can then be prolonged to once monthly, with twice yearly measurements once the regimen has been stabilized. 5 Equally, blood for anti-endomysial antibodies should be taken in previously stable patients in whom plasma calcium levels acutely begin to fluctuate.
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Acknowledgements
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