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Abstract

Hypercalcemia is a relatively common problem. Primary hyperparathyroidism and malignancy, taken together, explain 90% of cases of hypercalcemia. Among the other rarest causes, vitamin D intoxication occurs mainly during supplementation with active vitamin D metabolites, frequently used in the setting of renal insufficiency or as a treatment of hypoparathyroidism. Dihydrotachysterol, a synthetic derivative of vitamin D_2, has the same biologic activity as 1-25(OH) vitamin D, but with a longer half-life than calcitriol. Its use is infrequent nowadays, mainly indicated to treat hypocalcemia in hypoparathyroidism. We report the case of an 84-year-old female with symptomatic hypercalcemia (serum calcium 3.60 mmol/l) caused by dihydrotachysterol intoxication. Initially, the etiology had been unrecognized because of inaccurate information on home medication and the inability of conventional vitamin D assays to detect dihydrotachysterol. With treatment including hydration and zoledronic acid, serum calcium slowly normalized although her renal function was still altered at hospital discharge.

Key words

hypercalcemia, dihydrotachysterol, vitamin D intoxication

Introduction

Symptoms of hypercalcemia are mostly non-specific, and they usually appear at concentration above 3.00 mmol/l [1]. They include polyuria, polydipsia, dehydration, anorexia, nausea, muscle weakness and neuropsychiatric disturbances. Values above 3.25 mmol/l are unusual in primary hyperparathyroidism and should evoke the possibility of malignancy. Differential diagnosis also includes vitamin D intoxication, granulomatosis, thyrotoxicosis, adrenal insufficiency, vitamin A intoxication, therapy with thiazide or lithium and familial hypocalciuric hypercalcemia. Suppressed levels of parathyroid hormone (PTH) and lack of high levels of 25(OH)vitamin D or 1-25(OH)vitamin D usually suggest a neoplastic etiology. When malignancy is excluded, uncommon etiologies must be evoked [2].

Dihydrotachysterol is a structural analogue of vitamin D2 but its configuration mimics the active 1-25(OH) vitamin D [3]. It promotes mobilization of calcium from bone and stimulates active calcium and phosphate intestinal absorption. It was introduced in the 1930s, but the use of this compound declined when 1-25(OH) vitamin D and 1 (OH) vitamin D became available [4]. Dihydrotachysterol is nowadays used as a second line treatment of hypoparathyroidism, because of its longer half-life than calcitriol. It is not detected by the 25(OH) vitamin D and 1-25(OH) vitamin D current assays. It can only be measured by high performance liquid chromatography, which is not commonly available in routine [5-7].

We report here a case of a patient with Dihydrotachysterol-induced hypercalcemia and low serum 25(OH) vitamin D and 1-25(OH) vitamin D.

Case report

An 84-year-old female, living independently, presented to the hospital with generalized weakness which increased for the last three days. Medical history was relevant for low back pain caused by degenerative disorders and vertebral fracture, for which the dose of her fentanyl patch was increased one week before and then reduced by her husband, due to the altered general health, without improvement. She was also known for arterial hypertension, dyslipidemia and hyperuricemia. Her medication was aspirin, perindopril, indapamide and diltiazem. She was also taking a vitamin D supplementation 40 drops/day, but the exact content at hospital admission was unknown. She had no complaint except her back pain and her weight was stable.

On examination, she had psychomotor retardation and disorientation. Her blood pressure was 149/96. Neurological examination was within normal, except an inability to walk due to diffuse weakness. The palpation of lower back was slightly painful. QT interval on electrocardiogram was within reference range.

Initial laboratory investigations demonstrated: a severe hypercalcemia (total serum calcium 3.60 mmol/l (normal range 2.20-2.52)) with an acute renal failure (Table 1). Serum creatinine was measured at 85 µmol/l one year earlier. She was first treated with hydration, and furosemide. The next morning, laboratory tests demonstrated a serum calcium level that remained high with an adapted low PTH. Serum phosphates and 25(OH) vitamin D were within normal range. 1-25(OH) vitamin D and serum magnesium were low. The complete blood count was normal as were serum protein electrophoresis and immunofixation, TSH (0.546 mUI/l, normal range 0.4-4.0), angiotensin converting enzyme (31 U/l, normal range 8-52), and PTHrp (8.5 pg/ml, normal < 13). ACTH stimulation test was normal.

Table 1. Laboratory findings upon admission.

Serum	Units	Normal range	2.2	3.16	3.17	3.18	3.19	3.22	3.27	4.07	4.23
				Hospital Admission		Zoledronic acid #1			Zoledronic acid #2
Calcium corrected for albumin	mmol/l	2.2-2.52	2.71	3.64	3.82	3.23	2.96	2.66	2.81	2.5	2.15
Phosphates	mmol/l	0.8-1.5			1.28	1.03			0.99	1.01	1.01
Magnésium	mmol/l	0.59-0.83			0.48			0.56	0.72	0.76
Creatinine	µmmol/l	62-106		162	150	148	118	140	121	106	127
eGFR*	ml/min			25	27	28	36	30	36	42	34
Albumine	g/l	35-48	38	38	39	37	38	34	40	36	46
PTH**	pmol/l	1.06-6.9			1.3
25 OH D	nmol/l	28-107	29		61						51
1,25 OH D	pmol/l	40-140	10			6					43

*eGFR: Estimated Glomerular filtration rate, **PTH: Parathyroid hormone.

Radiological exams were performed to exclude a neoplastic condition. Low dose chest CT scan only showed a non-specific lung micro-nodule and bone scan was normal.

After 36 hours of hydration, serum calcium was still elevated at 3.17 mmol/l. She received a perfusion of zoledronic acid 3 mg, the dose being adapted to her altered glomerular filtration rate. Serum calcium improved but failed to normalize and started to rise 9 days later so she received a second perfusion of zoledronic acid 3 mg. Serum calcium then normalized, 17 days after admission.

Because of the persistence of the renal insufficiency, kidney ultrasound was performed. There was no calcification and their sizes were normal. Her renal function didn’t recover, and she was discharged from hospital with an estimated glomerular function rate at around 30 ml/min.

Her general practitioner was reached only 10 days after the beginning of her hospitalization. He revealed that he introduced Dihydrotachysterol (a vitamin D derivative), 1 year before. The dose was progressively increased because of the lack of elevation of the 25(OH) vitamin D level. About 1 month before her admission, calcemia was already elevated at 2.67 mmol/l, serum PTH 0.5 pmol/l, 25(OH)vitamin D 29 nmol/l and 1-25(OH)vitamin D 10 pmol/l. She was taking 40 drops (1.5 mg) daily for ten days before hospital admission. There has been a misunderstanding of the indication of dihydrotachysterol since there was no evidence of hypoparathyroïdism.

Discussion

Vitamin D intoxication is a rare cause of hypercalcemia. In this case, hypercalcemia was attributed to Dihydrotachysterol. Indapamide treatment, a thiazide-like diuretic, could have contributed but to a lesser extent.

Vitamin D supplementation is recommended for all adults who do not have regular effective sun exposure year-round and they should consume at least 600 to 800 UI of vitamin D3 or D2 supplement [8]. Treatment with vitamin D actives metabolites is indicated when there is an abnormal vitamin D metabolism, as in renal or liver disease. The most common indications are secondary hyperparathyroidism due to chronic renal failure and to treat hypocalcemia caused by hypoparathyroidism. The usual form of vitamin D active metabolite prescribed is calcitriol. Dihydrotachysterol has the same biological action than calcitriol. It promotes mobilization of calcium from bone and stimulates calcium and phosphate intestinal absorption. It was initially thought, that because of its configuration, it doesn’t need to be hydroxylated in position 1 to exert its biologic action [3]. Then, it was demonstrated that 1,25 derivatives are formed extra renally during the ingestion of Dihydrotachysterol and may be the active forms [4]. Calcitriol is preferred to Dihydrotachysterol because of its shorter onset of action (1-2 days for calcitriol and 4-7 days for Dihydrotachysterol), half-life (3-6 hours for calcitriol and 10-13 hours for Dihydrotachysterol) and the time to offset of action being much shorter (2-3 days and 7-21 days, respectively) [9] In this case of Dihydrotachysterol intoxication, there was no indication for treatment with a vitamin D active metabolite. She was given high dose of Dihydrotachysterol despite hypercalcemia. There was a misunderstanding of the nature of the drug since the dose was increased in reason of vitamin D insufficiency. Because the molecule can’t be measured by available assays, her general practitioner believed erroneously that she had hypovitaminosis D. Since Dihydrotachysterol is rarely used, is not detected by standard assays and drops of vitamine D3 are frequently prescribed, it is not surprising that it was not part of the initial diagnostic work-up.

Persistent renal failure is probably secondary to the prolonged hypercalcemia and hypercalciuria, even if there was no evidence of nephrocalcinosis on ultrasound examination. Renal insufficiency has been described in patients treated taking Dihydrotachysterol, with kidney biopsies that showed the presence of calcifications [10]. The low serum PTH level is explained by hypercalcemia although with the severity of calcium elevation we could have expected an even lower value. The unsuppressed serum PTH level may be explained by renal failure interfering with the laboratory test. Indeed, the proportion of circulating PTH fragments detected by second-generation immunometric PTH assays increases with reduction of renal function. This diminution of serum PTH results in inhibition of the renal 1α-hydroxylase and then a reduction of the level of 1-25(OH) vitamin D. The 25(OH) vitamin D level increased between the dosage by her general practitioner and the admission, 1 month later, without known supplementation. This increase cannot be explained by Dihydrotachysterol itself or its interaction with vitamin D metabolism. Serum magnesium level was low the day after admission, which can be due to the increased renal loss caused by hypercalcemia, but hydration received and indapamide treatment may also have contributed.

Conclusion

Dihydrotachysterol intoxication is a rare cause of hypercalcemia which bring additional diagnostic difficulties because it is not measurable by standard assays. Practitioners must be aware of the different forms of vitamin D and their metabolic actions. Frequent monitoring of serum calcium concentrations is critical when using such medications.

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