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An interesting case of thirst and polyuria

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Q1: What are the possible causes of thirst and polyuria in this woman?

The two likely causes of thirst and polyuria in this patient are central diabetes insipidus secondary to previous pituitary surgery and hypercalcaemia. In our patient, a normal water deprivation test excluded central diabetes insipidus.

Cranial surgery accounts for 20% cases of central diabetes insipidus in adults. After pituitary surgery, persistent polyuria develops only when the injury is sufficiently high in the supraopticohypophyseal tract to cause degeneration of the supraoptic and paraventricular nucleus. Thus although transient diabetes insipidus may follow any injury to the neurohypophysis, permanent cranial diabetes insipidus is uncommon after pituitary surgery.1

Hypercalcaemia causes transient nephrogenic diabetes insipidus manifested primarily as a defect in maximum renal concentrating ability accompanied by a reduction in glomerular filtration rate. Other factors may include reduction in medullary solute content and inhibition by calcium of adenylate cyclase activation by arginine vasopressin in hormone sensitive epithelia.1

Q2: What are the possible causes of hypercalcaemia?

The possible causes of hypercalcaemia include thyrotoxicosis, relative glucocorticoid insufficiency during illness and stress, dehydration, acromegaly, and hyperparathyroidism as part of multiple endocrine neoplasia syndromes.

Total serum calcium is raised in 27% and ionised calcium raised in up to 47% hyperthyroid patients.2 Patients have low PTH and 1,25-dihydroxycholecalciferol concentrations, and hypercalciuria.1 Serum calcium concentrations are generally less than 2.7 mmol/l, but life threatening hypercalcaemia has been described. Thyroid hormones absorb bone directly, although indirect resorption may also occur by activation of local factors such as interleukin-1 or by increasing sensitivity to circulating PTH.3 β-Adrenergic blocking agents can reverse the hypercalcaemia1 as can definitive therapy with carbimazole.3

Hypercalcaemia is detected in 6% cases of primary adrenal insufficiency but it is less common in secondary hypoadrenalism. Raised calcium binding proteins caused by haemoconcentration are a factor, but volume repletion with saline does not restore calcium concentrations to normal, for which glucocorticoid replacement is required.1

Growth hormone stimulation of renal 1α-hydroxylase activity increases serum 1,25-dihydroxycholecalciferol concentrations resulting in increased intestinal calcium absorption and hypercalciuria. Hypercalcaemia is uncommon in the absence of associated hyperparathyroidism1 and has been reported in none4 to 10%5 of cases in various series of patients with acromegaly.

In this patient the hypercalcaemia was due to thyrotoxicosis and glucocorticoid deficiency. It responded partially to rehydration with isotonic saline and intravenous hydrocortisone and normalised completely after hyperthyroidism was treated with propranolol and carbimazole.

Q3: What is the cause of her thyrotoxicosis?

Her thyrotoxicosis is due to Graves' disease as proved by homogenously increased tracer uptake on 99mTc thyroid uptake scan (fig 1; see p 248) and positive TSHRAb.

Figure 1

(A) Haematoxylin and eosin stain showing Merkel cells. Arrow shows a typical cell with a central nucleolus. (B) Merkel cells showing positive staining with neuron specific enolase.

TSHRAb binds to the thyroid stimulating hormone receptor, activates adenylate cyclase, and increases thyroid hormone production and secretion. The TSHRAb in Graves' disease is referred to as stimulating or agonist type TSHRAb, while other varieties including a blocking TSHRAb may also be present. The blocking antibody may be coincident with the stimulating antibody. TSHRAb are not detectable in the normal population. A total of 80% to 100% of untreated hyperthyroid patients with Graves' disease have detectable TSHRAb with thyroid stimulating activity.1

99mTechnetium pertechnate, like iodine, is actively concentrated by the thyroid gland, undergoes negligible organic binding, and diffuses out of the thyroid as the plasma concentration decreases. The short half life (six hours) and consequent low radiation makes it suitable for thyroid imaging. Thyroid scintigraphy is used in the evaluation of nodular thyroid disease, thyroid cancer, ectopic thyroid tissue, and thyroiditis. It is not recommended in the evaluation of straightforward Graves' disease. In our patient, a diffusely increased uptake (even though thyroxine replacement was stopped only seven days earlier) confirmed the diagnosis of autoimmune hyperthyroidism.

Q4: Is there an association between acromegaly and thyrotoxicosis?

Acromegaly is well known to be associated with goitre as part of generalised organomegaly. In a series of 80 patients with acromegaly from an iodine deficient region, 71% had goitre compared with 35% in patients with prolactinomas. Goitres were more common in female acromegalic patients compared with males. Hyperthyroidism was noted in 5% cases and none were due to Graves' disease.6 Graves' disease in patients with active or previous acromegaly has been reported very rarely in the literature and presented an unusual diagnostic challenge in this case, specially as she was on thyroxine replacement therapy after hypopituitarism.

Final diagnosis

Thyrotoxicosis due to Graves' disease causing hypercalcaemia in a patient with hypopituitarism after treatment of acromegaly.


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