1Department of Metabolic Medicine and 2Department of Pathology, Division of Investigative Sciences, 3Department of Surgery, Division of Surgery and 4Molecular Endocrinology Group, Division of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK
Correspondence and offprint requests to: Dr Graham R. Williams, Molecular Endocrinology Group, MRC Clinical Sciences Centre, 5th Floor, Clinical Research Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Email: graham.williams{at}imperial.ac.uk
Keywords: hyperparathyroidism; hypomagnesaemia; magnesium deficiency; parathyroid adenoma; thyroid disease
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Introduction |
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Case |
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On examination, the patient's blood pressure was 120/70 mmHg and there were signs of psoriasis with arthropathy. Investigations at the admitting hospital revealed total plasma Mg 0.35 mmol/l (normal range 0.71.0), total plasma Ca 2.66 mmol/l (normal range 2.22.6), Na+ 143 mmol/l, K+ 3.2 mmol/l, urea 3.5 mmol/l and creatinine 64 µmol/l. She was treated with i.v. MgSO4 (64 mmol over 24 h). The following day, Mg was 1.43 mmol/l, Ca 2.60 mmol/l, K+ 3.1 mmol/l, and she was discharged. Two days later, she was readmitted and investigations revealed Mg 0.44 mmol/l, Ca 3.25 mmol/l, K+ 3.2 mmol/l, bicarbonate 35.7 mmol/l and PO43 0.44 mmol/l. Treatment consisted of i.v. 0.9% NaCl (4 l), oral KCl (27 mmol) and 40 mg furosemide on the first day. She received KCl 40 mmol i.v. 12 hourly on the second day when the plasma K+ was 2.7 mmol/l, but no K+ supplementation was required thereafter. The patient was then transferred to our care.
Rehydration had resulted in further Mg depletion (lowest value 0.17 mmol/l) associated with persistent sinus tachycardia and an episode of Torsade de Pointes (QTc 427 ms). The patient was treated with i.v. MgSO4 (16 mmol over 24 h) and the plasma Mg corrected over 4 days. Serum PTH at presentation, before the Mg infusion, was 4.84 pmol/l (0.364.95) and rose to 164 pmol/l 1 day following i.v. MgSO4. The urinary molar Ca to creatinine ratio was 0.61, excluding familial hypocalciuric hypercalcaemia [1]. Several indices of renal Mg wasting are available [2], but measurement of 24-h urinary Mg excretion is most widely used. A 24-h urinary Mg excretion of >1 mmol with co-existent hypomagnesaemia is considered diagnostic of renal Mg loss. The patient's 24-h urinary Mg was 3.6 mmol/24 h in the presence of hypomagnesaemia (concurrent plasma Mg 0.27 mmol/l, tests performed when the patient was not receiving Mg replacement). The urinary molar Mg to creatinine ratio was 0.58.
Arterial blood gas measurement revealed a pH of 7.459 and plasma bicarbonate of 29.5 mmol/l. Renal tubular investigations were normal and included a random urinary osmolality of 509 mOsm/kg (concurrent plasma Na+ 138 mmol/l, K+ 3.9 mmol/l, urea 2.1 mmol/l), 24 h urinary Na+ of 157 mmol and 24 h urinary K+ of 37 mmol. No aminoaciduria or ß2-microglobulinuria was detected, and urinary TB culture was negative. Plasma uric acid was 0.3 mmol/l (0.140.37), 25-OH vitamin D was 4.8 µg/l (750) and thyroid function was normal. A 99mTc-Sestamibi scintigraphic examination suggested the presence of a parathyroid adenoma inferior to the right lobe of the thyroid. A renal ultrasound scan was normal and excluded nephrocalcinosis or renal calculi. At parathyroid surgery, the right and left lower parathyroid glands were localized and removed. The thyroid gland was considered to be abnormal during surgical examination and a total thyroidectomy was performed. The two identified parathyroids were enlarged and hyperplastic with areas of adenomatous change in both on histological examination. Histological analysis of the thyroid revealed multifocal microscopic papillary thyroid carcinoma with no evidence of local, vascular or capsular invasion. A diagnosis of chronic renal Mg wasting with autonomous hyperparathyroidism, in association with multifocal papillary thyroid cancer, was made.
Post-operatively, the hypercalcaemia normalized within 1 day and the patient required treatment with 1-(OH)vitamin D3 (1 µg/day), tri-iodothyronine (20 µg tds) and ablative 131I (3.7 GBq). The PTH concentration fell rapidly to just around the level of detection at 0.4 pmol/l (concurrent Ca 2.23 mmol/l) and plasma Mg stabilized to 0.40.6 mmol/l following prolonged treatment with oral Mg glyceropyrophosphate (64 mmol/day) (Figure 1). Plasma PTH concentrations have remained undetectable. The patient's Mg-losing nephropathy persisted for 18 months following parathyroidectomy although she has remained normocalcaemic. In the presence of a plasma Mg of 0.49 mmol/l, Ca 2.25 mmol/l and K+ 3.5 mmol/l, the urinary Mg was 6.3 mmol/24 h, the urinary molar Mg to creatinine ratio was 0.53, and the urinary molar Ca to creatinine ratio was 0.18. A value below 0.10.12 would have been highly suggestive of Gitelman's syndrome [3,4]. Nevertheless, hypocalciuria is actually an inconsistent finding in this condition [4], indicating that the biochemical features in this patient may still be consistent with a diagnosis of Gitelman's syndrome. Ambulatory plasma renin activity was 5.2 pmol/ml/h (normal range 0.53.1) with an aldosterone of 170 pmol/l (normal range 100450). The patient underwent whole body 125I scanning following her initial ablative radioiodine treatment, and at 6 months a recurrence of thyroid tissue was evident in the neck. This was treated with further 131I (5.5 GBq) and no recurrence has been observed.
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Discussion |
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What are the mechanisms by which hypomagnesaemia may influence PTH secretion? The predominant mechanism causing an increase in PTH secretion is likely to be via inhibition of the Ca/Mg sensing receptor (Ca/Mg-SR) by longstanding hypomagnesaemia. However, when Mg depletion is very severe, as occurred initially in our patient, there may be increased activity of the Ca/Mg-SR-coupled G subunit protein that is independent of Mg or Ca binding to the Ca/Mg-SR [5]. This increased G
activity results in blunted PTH secretion. Thus, our patient presented with a mildly elevated Ca and a PTH of 4.84 pmol/l. However, correction of her severe Mg depletion precipitated a marked elevation of PTH to 164 pmol/l with subsequent gross hypercalcaemia, suggesting that both mechanisms described above were in operation. Furthermore, histological examination of the parathyroid glands revealed the presence of adenomatous change in a background of hyperplasia, indicating the additional presence of autonomous PTH secretion.
The finding of multifocal papillary thyroid cancer is not readily explained and may be coincidental. There was no family history of thyroid cancer and there is no reported association between thyroid cancer and hypomagnesaemia. Furthermore, although there are several reports of an association between non-medullary thyroid cancer and primary hyperparathyroidism, a causal relationship has not been defined [6] and our patient probably did not have primary hyperparathyroidism. The occurrence of late onset and chronic renal Mg wasting associated with autonomous hyperparathyroidism has not been reported before and may represent a new syndrome of renal hypermagnesiuric hypomagnesaemia. The condition appears to be sporadic, but the possibility of familial disease cannot be excluded in this case because of the lack of samples from inaccessible siblings in Pakistan.
Nevertheless, our patient does not display typical features of known inherited causes of hypomagnesaemia. In Barrter's syndrome, there is early presentation, hypercalciuria, more severe hypokalaemia and only mild hypomagnesaemia in a minority of cases, whereas in Gitelman's syndrome there is hypocalciuria and more severe hypokalaemia. There has been a recent case of a patient with Gitelman's syndrome whose hypomagnesaemia resulted in secondary hypocalcaemia that corrected with Mg supplementation [7]. However, the urinary Ca excretion was never low enough in our patient, even 18 months after parathyroidectomy, to clearly suggest this diagnosis, although the possibility has not been excluded. Furthermore, the plasma potassium has only once fallen below 3.4 mmol/l and the patient has not required potassium supplementation. The newly described mutations in the long transient receptor potential channel gene TRPM6 cause abnormal intestinal Mg transport and reduced renal resorption resulting in severe hypomagnesaemia in infancy [8], also dissimilar from the patient presented, whose symptoms presented later in life and were not associated with malabsorption or gastrointestinal disease. Mutations in the paracellin-1 gene (PCN-1) cause reduced Mg resorption via the tight junction protein paracellin in the loop of Henle and are associated with high plasma uric acid concentrations, calciuria, nephrocalcinosis and ocular abnormalities [9]; none of these was seen in our patient. A Dutch family with autosomal dominant isolated Mg wasting was found to have mutations in the gene encoding the Na+K+-ATPase -subunit (FXYD2) [10]. Other similar forms of isolated Mg wasting not linked to chromosomes 3 (PCLN1) or 11q23 (FXYD2) have been reported [11]. Comparisons indicate no resemblance of any of these to the case reported here, indicating that the biochemical features in our patient are unique.
In conclusion, autonomous hyperparathyroidism in a patient with hypomagnesaemia and hypermagnesiuria was unmasked following i.v. Mg therapy. Despite the known heterogeneity of Mg wasting disorders, the described condition of renal hypermagnesiuric hypomagnesaemia appears to be an isolated case and a novel cause of hyperparathyroidism.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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