An unusual cause of hypercalcemia.

Abstract: We describe a case of pronounced symptomatic hypercalcemia as a consequence of thyrotoxicosis alone. Primary hyperparathyroidism and other secondary causes of hypercalcemia were excluded. Hypercalcemia completely abated after treatment of thyrotoxicosis. Notwithstanding that hypercalcemia is an unusual manifestation of hyperthyroidism, asymptomatic elevation of serum calcium concentration had been documented in up to one-fourth of patients with proved hyperthyroidism. The current case is unusual in that the patient demonstrated a significant degree of hypercalcemia secondary to hyperthyroidism alone, with a serum calcium level as high as 3.14 mmol/L. We further discuss the putative pathophysiology of this "thyroid bone disease," highlighting the repercussion on calcium and bone metabolism in hyperthyroidism.

Key Words: bone metabolism, hypercalcemia, thyrotoxicosis

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Hypercalcemia might be associated with hyperthyroidism alone or may occur as a manifestation of associated primary hyperparathyroidism, although neither disorder has been hitherto adequately understood. In the former scenario, an accelerated bone turnover state is speculated to increase bone resorption sufficiently to cause hypercalcemia.

Case Report

A 27-year-old woman presented with weight loss of more than 10 lb within 1 month. For the past month, she had been troubled by intermittent bouts of vomiting, thirst symptoms, and constipation. On examination, she was tachycardic but not obviously dehydrated. There was diffuse, smooth goiter accompanied by fine hand tremor. Her pregnancy test was negative. Initial investigation at admission revealed pronounced hypercalcemia. The patient's serum adjusted calcium was 3.14 mmol/L, her albumin was 32 g/L, her phosphate was 1.41 mmol/L (normal range, 0.82-1.40 mmol/L), her creatinine was 59 [micro]mol/L, and her alkaline phosphatase was 167 IU/L (normal range, 30-80 IU/L). Further investigations confirmed the presence of thyrotoxicosis with serum sensitive thyroid-stimulating hormone less than 0.03 mIU/L (normal range, 0.3-4.0 mIU/L) and free thyroxine more than 155 pmol/L (normal range, 10.2-19.6 pmol/L). Her chest radiograph showed clear lung field. Plasma intact parathyroid hormone was 0.1 pmol/L (normal range, 1.3-7.6 pmol/L). Her ratio of maximum tubular phosphate reabsorption-to-glomerular filtration rate was 0.95 mmol/L (normal range, 0.80-1.35 mmol/L). Serum protein electrophoresis and a search for underlying malignancy were unrevealing. On close questioning, she indicated no symptoms of peptic ulcer, and there was neither exogenous vitamin D intake nor family history of endocrinopathy. No recent history of immobilization was noted. A diagnosis of hypercalcemia secondary to hyperthyroidism (toxic multinodular goiter) was suggested. She was treated with saline hydration, carbimazole, propranolol, and a single dose of pamidronate (30 mg). The patient's serum adjusted calcium was 2.79 mmol/L 5 days afterward. Her hypercalcemia resolved completely after being rendered euthyroid. Her serum calcium and alkaline phosphatase concentrations were 2.38 mmol/L (normal range, 2.20-2.62 mmol/L) and 69 IU/L, respectively, 18 months afterward.

Discussion

Von Recklinghausen (1) first noted disturbed bone and mineral metabolism secondary to hyperthyroidism when he reported the anatomic finding of decalcification of thyrotoxic origin in a 23-year-old woman in 1891. More recently, alterations in calcium metabolism have been demonstrated in thyrotoxicosis, as evident from increased excretion of calcium and phosphorus in urine and stool. Because intestinal calcium absorption is usually low or normal in thyrotoxicosis, excess calcium is presumed to originate from bone. (2,3) The direct effect of thyroid hormones in stimulating bone resorption, as indicated by densitometry, gives rise to bone demineralization and thus hypercalcemia. An elevated serum calcium concentration was found in one-fourth of patients with proven hyperthyroidism, which was not associated with increased parathyroid hormone levels. (4) Prospective screening in another population-based cohort further showed that serum calcium concentration was significantly higher in patients with hyperthyroidism (2.36 [+ or -] 0.11 mmol/L) than in healthy people. (5) For those with prolonged hypercalcemia, significant renal impairment might ensue, (6,7) thus leading to diagnostic confusion with hyperparathyroidism.

The most common cause of hypercalcemia in the setting of hyperthyroidism is concomitant primary hyperparathyroidism. (5,7) Our case is unusual in that the patient demonstrated a significant degree of hypercalcemia secondary to hyperthyroidism alone, with a serum calcium level as high as 3.14 mmol/L (compared with reported mean values ranging from 2.53-2.70 mmol/L in other series (4,5,8)). This explains the occurrence of thirst, constipation, and hyperemesis symptoms, which are usually minimal or absent in hypercalcemia of hyperthyroidism. It would therefore be important to exclude concomitant hyperparathyroidism, inasmuch as the hypercalcemia of uncomplicated thyrotoxicosis is usually mild. (2,3,9)

It is intriguing that decreased tubular reabsorption of phosphate might not be an infallible distinguishing feature of primary hyperparathyroidism. (8) In particular, the current case had displayed a normal phosphate reabsorption index, in contradiction to an expected increase of proximal tubular phosphate reabsorption in thyrotoxicosis. Furthermore, increased serum phosphate concentrations and normal or low normal values have all been reported in hyperthyroidism. (3) Apart from the biochemical evidence from radioimmunoassay for parathyroid hormone level, one of the most useful clinical clues to the presence of coexisting hyperparathyroidism is the persistence of hypercalcemia after control of the thyrotoxic state. Conversely, resolution of hypercalcemia is almost the rule after treatment of hyperthyroidism in cases of calcium disturbance mediated by thyrotoxicosis alone, (8,10) as exemplified by our case.

Conclusion

Symptomatic hypercalcemia is an uncommon manifestation of thyrotoxicosis and should be distinguished from concomitant hyperparathyroidism. Complete resolution with antithyroid treatment should occur in the former situation, as illustrated by our case.

Accepted February 7, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0588

References

1. Von Recklinghausen FC. Die fibrose oder deformierende ostitis, die osteomalazie, und die osteoplastische karzinose in ihren gegenseitigen beziehungen, in Festschrift Rudolph Virchow. Berlin, G. Reimer, 1891, pp 20-89.

2. Alikhan Z, Singh A. Hyperthyroidism manifested as hypercalcemia. South Med J 1996;89:997-998.

3. Auwerx J, Bouillon R. Mineral and bone metabolism in thyroid disease: A review. Q J Med 1986;60:737-752.

4. Burman KD, Monchik JM, Earll JM, et al. Ionized and total serum calcium and parathyroid hormone in hyperthyroidism. Ann Intern Med 1976;84:668-671.

5. Wagner B, Begic-Karup S, Raber W, et al. Prevalence of primary hyperparathyroidism in 13,387 patients with thyroid diseases, newly diagnosed by screening of serum calcium. Exp Clin Endocrinol Diabetes 1999;107:457-461.

6. Epstein FH, Freedman LR, Levitin H. Hypercalcemia, nephrocalcinosis and reversible renal insufficiency associated with hyperthyroidism. N Engl J Med 1958;258:782.

7. Parfitt AM, Dent CE. Hyperthyroidism and hypercalcaemia. Q J Med 1970;39:171-187.

8. Farnsworth AE, Dobyns BM. Hypercalcaemia and thyrotoxicosis. Med J Aust 1974;2:782-784.

9. Richards AJ. Hypercalcaemia in thyrotoxicosis with and without hyperparathyroidism. Postgrad Med J 1970;46:440-446.

10. Baxter JD, Bondy PK. Hypercalcemia of thyrotoxicosis. Ann Intern Med 1966;65:429-442.

RELATED ARTICLE: Key Points

* Hypercalcemia is becoming increasingly recognized in the setting of thyrotoxicosis, with cases mediated by thyroid hormone alone or occurring secondary to concomitant hyperparathyroidism.

* Parathyroid hormone level assay and persistence of hypercalcemia after control of the thyrotoxic state offer clues to the presence of coexisting hyperparathyroidism.

* Conversely, resolution of hypercalcemia is almost the rule after control of hyperthyroidism in cases of calcium disturbance mediated by thyrotoxicosis alone.

Kai Ming Chow, MD, and Cheuk Chun Szeto, MD

From the Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China.

Reprint requests to Cheuk Chun Szeto, MD, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China. Email: [e-mail]