Dihydrotachysterol therapy for hypoparathyroidism: consequences of inadequate monitoring. Five cases and a review.

BACKGROUND: The half synthetic Vitamin D analogue dihydrotachysterol (DHT) is widely used for hypocalcaemic hypoparathyroidism following surgical removal of parathyroids. Such treatment generally initiated by surgeons right after surgery has to be continued in clinical practice. Unfortunately, the required careful monitoring of calcium metabolism is often lacking and as demonstrated may lead to life-threatening conditions. PATIENTS AND METHODS: Here we report on five patients referred to our nephrology unit because of unknown impairment of renal function during therapy with DHT. All patients had clinical signs of hypercalcaemia. Since most symptoms are nonspecific they were not perceived by primary care physicians. In fact DHT treatment was continued for 4 - 50 years. In all cases calcium levels were determined after inadequate long intervals ranging from 3.08 to 4.97 mmol/l. Creatinine levels ranged from 277 to 365 micromol/l. All patients suffered from symptoms of severe hypercalcaemia, three of them needing intensive care unit treatment. RESULTS: All patients were treated effectively with a regimen consisting of intravenous saline, a loop diuretic, and application of bisphosphonates. As confirmed by renal biopsy persisting alleviation of renal function was due to calcifications. After discontinuation of DHT therapy patients were safely switched to shorter acting vitamin D derivates maintaining a normal calcium level. CONCLUSIONS: In comparison to short acting vitamin-D derivates hypercalcaemic episodes with DHT appear to last longer and may therefore occur with higher incidence. A future option could be the use of synthetic parathyroid hormone (s-PTH) recently shown to be safe and effective. Nevertheless a customized therapy and careful monitoring is indispensable in any case to prevent irreversible organ damage.

Hypercalcemia-induced renal insufficiency during therapy with dihydrotachysterol.

During vitamin-D therapy drug accumulation and intoxication should be considered. In the present study we report on five patients with renal insufficiency during therapy with dihydrotachysterol or calcitriol. Four patients received dihydrotachysterol for 29 (7-44) years and one patient received calcitriol for 4 years to treat hypoparathyroidism after thyroid surgery. As confirmed by renal biopsy impairment of renal function was due to calcifications as a consequence of prolonged hypercalcemia. The effective duration of dihydrotachysterol is ten days as compared with five days for calcitriol. Severe hypercalcemic episodes with dihydrotachysterol are longer-lasting than those with the shorter acting vitamin-D derivatives. Further, they occur with higher incidence as was shown by our own observations and previously published data by other workers. Hence, impairment of renal function during therapy with dihydrotachysterol should be considered as being due to hypercalcemia and hypercalciuria.

Unaccountable severe hypercalcemia in a patient treated for hypoparathyroidism with dihydrotachysterol.

This report describes a forty-seven-year-old female patient with a complex medical history. She was suffering from an unspecified interstitial lung disease, papillary thyroid carcinoma which had been treated, hypoparathyroidism after thyroidectomy for which she was receiving dihydrotachysterol and calcium, and atrial fibrillation and congestive heart failure as a result of mitral stenosis. Shortly after mitral valve replacement she developed a severe hypercalcemia (serum calcium 5.95 mmol/l) during a febrile illness. At that time anti-tuberculous agents were also being administered for presumed tuberculosis. The possible mechanisms for this severe elevation of the calcium level are discussed. Immobilization, while Paget's bone disease was present, and perhaps enhanced activation of dihydrotachysterol by rifampicin, could have led to increased calcium-release into the circulation. Continuous supplecation of calcium and vitamin D, provoked dehydration and the mechanism of the milk-alkali syndrome also contributed to this extremely high calcium level. It is concluded that hypoparathyroid patients being treated with vitamin D and calcium should be carefully monitored in the case of an intercurrent illness or a change in medication.

Hypercalcemia in a calcitriol-treated hypoparathyroid woman during lactation.

We treated a hypoparathyroid woman with calcitriol during pregnancy and did not reduce the dosage after delivery. Despite lactation, the serum calcium level increased to 15.4 mg/dL 11 days postpartum. We treated two other hypoparathyroid women during four pregnancies with either calcitriol or dihydrotachysterol. In all five pregnancies, requirements for the vitamin D preparations increased beginning at the 20-28th week of gestation. Hypercalcemia did not occur in the two women who did not breast-feed and in whom we reduced the dose of calcitriol or dihydrotachysterol after delivery. We conclude the following: 1) Calcitriol is effective for treating hypoparathyroidism during pregnancy; 2) the dose usually needs to be increased during the latter half of gestation; 3) the calcitriol dose should be reduced during lactation; and 4) both mother and infant should be monitored to detect hypercalcemia during breast-feeding. We speculate that low serum estrogen levels associated with breast-feeding promote bone resorption and diminish calcitriol needs in lactating hypoparathyroid women.

[Pseudohypoparathyroidism, calcifying arteriopathy and ischemic skin necrosis]. / Pseudohypoparathyreoidismus, verkalkende Arteriopathie und ischämische Hautnekrosen.

A patient with longstanding pseudohypoparathyroidism undergoing substitution with dihydrotachysterin, with normal to low serum calcium and phosphorus levels, developed extensive calcification of the subcutaneous tissue and an obliterative and calcified arteriopathy of the small subcutaneous arteries with ischemic skin signs (livedo reticularis, skin infarction and ulcerative necrosis). After stimulation with exogenous parathyroid hormone there was no increase in urinary cyclic AMP and the G-unit was significantly decreased. It was concluded that the patient is suffering from pseudohypoparathyroidism type 1a. The likely pathophysiological mechanisms and the therapeutic implications are discussed.

Vitamin D replacement therapy and renal function. Calcitriol v dihydrotachysterol.

We treated 24 patients who had chronic renal insufficiency and renal osteodystrophy with either calcitriol (1,25-dihydroxyvitamin D3) or dihydrotachysterol. Renal function was evaluated before and during treatment to determine if these vitamin D analogues caused an accelerated rate of renal function deterioration. An accelerated rate of increase in the serum creatinine level was found in three of 12 patients in each treatment group after therapy was started, but the mean rate of increase during treatment did not differ significantly from the rate during the pretreatment control period in either group. The occurrence of hypercalcemia or an excessive serum calcium x phosphorus-product did not correlate with the rate of change in renal function during treatment with either drug. We concluded that children receiving calcitriol are not at greater risk for an accelerated rate of renal function deterioration than are children treated with dihydrotachysterol. Furthermore, neither vitamin D analogue could be directly implicated as a cause of an accelerated rate of renal function deterioration when episodes of hypercalcemia were transient and occurred infrequently.

Hypercalcaemia induced by increased thyroxine substitution in a patient treated with dihydrotachysterol.

The metabolism of vitamin D is essential in the control of bone and mineral metabolism. Hyperthyroidism as well as hypothyroidism effect the metabolism of bone tissue and vitamin D. We present a dihydrotachysterol-calcium treated patient with post-operative hypothyroidism, who developed hypercalcaemia, when the thyroxine dosage was increased.

Effect of treatment with dihydrotachysterol on renal function in patients with chronic renal failure.

16 patients with advanced renal failure and histologic evidence of renal osteodystrophy were treated with dihydrotachysterol (DHT) in a dose of 0.125-0.375 mg/day. All patients had creatinine clearances of less than 22 ml/min, but none were undergoing dialysis. The rate of deterioration in renal function was determined by serial measurements of the serum creatinine and by plotting the reciprocal of the serum creatinine against time. The duration of follow-up was 17.0 +/- 8.6 months. There was no significant deterioration in renal function in 12 patients. The remaining 4 patients showed acceleration in the rate of deterioration, but the relationship to DHT therapy was unclear.

Autosomal dominant idiopathic hypoparathyroidism and nervous system dysfunction: report of three cases and review of the literature.

The neurological manifestations of idiopathic hypoparathyroidism in a father, his son, and his daughter are reported. In all three epilepsy was the first manifestation of the disease. Father and son also showed mental deterioration and striocerebellar symptoms; their CT scans revealed symmetrical calcification in the basal ganglia and dentate nuclei. The extent of this calcification increased during normocalcemia, which was produced by dihydrotachysterol therapy. This indicates that other factors than merely hypocalcemia influence the intracerebral calcifying process. Somatosensory evoked potentials (SSEP) showed an abnormal nonspecific complex, indicating dysfunction of the cortical gray matter. It is suggested that in the evaluation of idiopathic hypoparathyroidism one also must be beware of the possibility of epilepsy, mental deterioration, striocerebellar symptoms, intracerebral calcification and SSEP disturbances.

Hypercalcaemia due to dihydrotachysterol treatment in patients with hypothyroidism after thyroidectomy.

Hypercalcaemia is a recognised complication of hypothyroidism. We describe three patients who developed hypercalcaemia after thyroidectomy when thyroid supplements were discontinued. They were treated with thyroxine, dihydrotachysterol, and calcium after operation, and in all three cases serum calcium concentrations remained constant during combined treatment. Thyroxine treatment was discontinued several weeks before a radioiodine scan was performed; dihydrotachysterol and calcium were continued throughout. Serum calcium concentrations rose to hypercalcaemic levels in all cases. Elimination of dihydrotachysterol from plasma may be delayed in hypothyroidism, resulting in hypervitaminosis D. It is advisable to reduce the dose of dihydrotachysterol and to check serum calcium concentrations regularly in patients whose thyroid treatment is interrupted.

Hypercalcaemia in pregnancy: a case report.

A case of hypercalcaemia in a pregnant patient on substitution therapy for hypoparathyroidism is reported. The clinical picture included transient cerebral disturbances, acute pancreatitis and persistent partial blindness. Calcium metabolism in pregnancy is discussed, and a possible mechanism for the sequence of events is postulated. The relevant literature is reviewed.

The effects of various diphosphonates on a rat model of cardiac calciphylaxis.

Seven diphosphonate analogs were treated for their effects on myocardial and cardiovascular degeneration and calcification in an experimental model of cardiac calciphylaxis. A single oral dose of dihydrotachysterol (DHT) administered to rats induced myocardial and vascular degeneration, focal myocarditis and vasculitis, and myocardial and vascular mineralization. The results demonstrated a considerable variation among the various diphosphonates in their ability to block the pathological changes observed in this model. Ethane-1-hydroxy-1,1-diphosphonate (EHDP) was the most effective diphosphonate in reducing myocardial and vascular degeneration and calcification, whereas diphosphonates such as ethane-1-amino-1,1-diphosphonate (EADP) and hydroxymethylene diphosphonate (HMDP) had little or no effect compared to saline controls. For those diphosphonates which were effective, e.g., EHDP, the tissue-protective effects were observed whether the rats were treated with drug prior to the administration of DHT, or whether drug treatment commenced after DHT administration. The results are discussed in terms of the known biological properties of the diphosphonate drugs.

Rate of reversal of hypercalcaemia and hypercalciuria induced by vitamin D and its 1alpha-hydroxylated derivatives.

The rate of reversal of hypercalcaemia or hypercalciuria induced by calciferol, dihydrotachysterol, 1-alpha-hydroxycholecalciferol (1-alpha-OHD3), or 1-alpha, 25-dihydroxycholecalciferol (1-alpha, 25-(OH)2D3) was measured in three normal subjects, two patients with osteoporosis, and 14 patients with disorders resistant to vitamin D. The half time for reversal after stopping 1-alpha, 25 (OH)2D3 was less than that after stopping 1-alpha-OHD3, calciferol, or dihydrotachysterol. The differences observed were independent of the dose given or length of treatment. When 1-alpha-OHD3 or 1-alpha-25-(OH)2D3 was stopped patients with vitamin D resistant states (hypoparathyroidism, renal tubular hypophosphataemia, or chronic renal failure) showed less rapid reversal of hypercalcaemia and hypercalciuria than did normal subjects. These studies show one potential advantage of 1-alpha-25-(OH)2D3 over vitamin D, and possibly over 1-alpha-OHD3, in the management of vitamin D resistant states.