Confusion and hypercalcemia in an 80-year-old man
Hyperthyroidism
As many as half of all patients with hyperthyroidism have elevated levels of ionized serum calcium.9 Increased osteoclastic activity is the likely mechanism. Hyperthyroid patients have increased levels of serum interleukin 6 and increased sensitivity of bone to this factor. This cytokine induces differentiation of monocytic cells into osteoclast precursors.10 These patients also have normal or low PTH levels.9
Our patient was receiving levothyroxine for hypothyroidism, but there was no evidence that the dosage was too high, as his thyroid-stimulating hormone level was within an acceptable range.
Hypervitaminosis D
Vitamin D precursors arise from the skin and from the diet. These precursors are hydroxylated in the liver and then the kidneys to biologically active 1,25-dihydroxyvitamin D (Figure 1).11 Vitamin D’s primary actions are in the intestines to increase absorption of calcium and in bone to induce osteoclast action. These actions raise the serum calcium level, which in turn lowers the PTH level through negative feedback on the parathyroid gland.
,Most vitamin D supplements consist of the inactive precursor cholecalciferol (vitamin D3). To assess the degree of supplementation, 25-hydroxyvitamin D levels, which indicate the size of the body’s vitamin D reservoir, are measured.11,12
Our patient’s 25-hydroxyvitamin D level is extremely elevated, well beyond the 250-ng/mL upper limit that is considered safe.13 His low PTH level, lack of other likely causes, and history of supplement use point toward the diagnosis of hypervitaminosis D.
Sarcoidosis
Up to 10% of patients with sarcoidosis have hypercalcemia that is not mediated by PTH. Hypercalcemia in sarcoidosis has several potential mechanisms, including increased activity of the enzyme 1-alpha hydroxylase with a subsequent increase in physiologically active 1,25-dihydroxyvitamin D3 production.14
Our patient had elevated levels of 25-hydroxyvitamin D, but his biologically active 1,25-dihydroxyvitamin D level remained within the laboratory’s reference range.
LESS LIKELY CAUSES OF HYPERCALCEMIA
2. Which of the following would be least likely to cause hypercalcemia?
- Thiazide diuretics
- Over-the-counter antacid tablets
- Lithium
- Vitamin A supplementation
- Proton pump inhibitors
Thiazide diuretics
This class of drugs is well known to cause hypercalcemia. The most familiar of the mechanisms is a reduction in urinary calcium excretion. There is also an increase in intestinal absorption of dietary calcium. Evidence is increasing that most patients (as many as two-thirds) who develop hypercalcemia while using a thiazide diuretic have subclinical primary hyperparathyroidism that is uncovered with use of the diuretic.
Of importance, the hypercalcemia that thiazide diuretics cause is mild. In a series of 72 patients with thiazide-induced hypercalcemia, the average serum calcium level was 10.7 mg/dL.15
Our patient was receiving a thiazide diuretic but presented with severe hypercalcemia, which is inconsistent with thiazide-induced hypercalcemia.
Over-the-counter antacid tablets
Calcium carbonate, a popular over-the-counter antacid, can cause a milk-alkali syndrome that is defined by ingestion of excessive calcium and alkalotic substances, leading to metabolic alkalosis, hypercalcemia, and renal insufficiency. To induce this syndrome generally requires up to 4 g of calcium intake daily, but even lower levels (1.0 to 1.5 g) are known to cause it.16
Lithium
Lithium is known to cause hypercalcemia. Multiple mechanisms have been proposed, including direct action on renal tubules and the intestines leading to calcium reabsorption and stimulation of PTH release. Interestingly, parathyroid gland hyperplasia has been noted in long-term users of lithium. An often-proposed mechanism is that lithium increases the threshold at which the parathyroid glands slow their production of PTH, making them less sensitive to serum calcium levels.17
Vitamin A supplementation
Multiple case reports have linked hypercalcemia to ingestion of large doses of vitamin A. The mechanism is thought to be increased bone resorption.18.19
Although our patient reported supplement use, he denied taking vitamin A in any form.
Proton pump inhibitors
Proton pump inhibitors are not known to cause hypercalcemia. On the contrary, case reports suggest that prolonged use of proton pump inhibitors is associated with hypocalcemia and hypomagnesemia, although the mechanism is still not fully understood. A low magnesium level is known to reduce PTH secretion and also skeletal responsiveness to PTH, which can lead to profound hypocalcemia.20
CASE CONTINUED
On further questioning, the patient revealed that the supplement prescribed by his naturopathic practitioner contained vitamin D. Although he had been instructed to take 1 tablet weekly, he had begun taking it daily with his other routine medications, resulting in a daily dose in excess of 60,000 IU of cholecalciferol (vitamin D3). The recommended dose is no more than 4,000 IU/day.
The supplement was immediately discontinued. His hydrochlorothiazide was also held due to its known effect of reducing urinary calcium excretion.
INITIAL TREATMENT OF HYPERCALCEMIA
3. Which of the following treatments is not recommended as part of this patient’s initial treatment?
- Bisphosphonates
- Calcitonin
- Intravenous fluids
- Furosemide
Our patient met the criteria for the diagnosis of hypercalcemic crisis, usually defined as an albumin-corrected serum calcium level higher than 14 mg/dL associated with multiorgan dysfunction resulting from the hypercalcemia.21 The mnemonic “stones, bones, abdominal moans, and psychic groans” captures the renal, skeletal, gastrointestinal, and neurologic manifestations.1
Bisphosphonates
Bisphosphonates are analogues of pyrophosphonates, which are normally incorporated into bone. Unlike pyrophosphonates, bisphosphonates inhibit osteoclast function. They are often used to treat hypercalcemia of any cause, although they are currently approved by the US Food and Drug Administration for treating hypercalcemia of malignancy only. As intravenous monotherapy, they are superior to other forms of treatment and are among the first-line agents in management.
Two bisphosphonates shown to be effective in hypercalcemia are zoledronate and pamidronate. Pamidronate begins to lower serum calcium levels within 2 days, with a peak effect at around 6 days.22 However, in studies comparing the 2 drugs, zoledronate has been shown to be more effective in normalizing serum calcium, with the additional benefit of having a much more rapid infusion time.23 Zoledronate is contraindicated in patients with creatinine clearance less than 30 mL/min; however, pamidronate may continue to be used.24
Calcitonin
This hormone inhibits bone resorption and increases excretion of calcium in the kidneys. It is not recommended for use alone because of its short duration of action and tachyphylaxis, but it can be used in combination with other agents, particularly in hypercalcemic crisis.22 It has the most rapid onset (within 2 hours) of the available medications, and when used in combination with bisphosphonates it produces a more substantial and rapid reduction in serum calcium.25,26
In a patient such as ours, with severe hypercalcemia and evidence of neurologic consequences, calcitonin should be used for its rapid and effective action in lowering serum calcium as other interventions take effect.
Intravenous fluids
Like our patient, many patients with significant hypercalcemia have volume depletion as a result of calciuresis-induced polyuria. Many also have nephrogenic diabetes insipidus from the cytotoxic effect of calcium on renal cells, leading to further volume depletion.27
All management approaches call for fluid repletion as an initial step in hypercalcemia. However, for severe hypercalcemia, volume resuscitation alone is unlikely to completely correct the imbalance. In addition to correcting dehydration, giving fluids increases glomerular filtration, allowing for increased secretion of calcium at the distal tubule.28 The recommendation is 2.5 to 4 L of normal saline over the first 24 hours, with continued aggressive hydration until good urine output is established.21
Our patient, in addition to having acute kidney injury thought to be due to prerenal azotemia, appeared to be volume-depleted and was given aggressive intravenous hydration.
Furosemide
Furosemide inhibits calcium reabsorption at the thick ascending loop of Henle, but this effect depends on the glomerular filtration rate. While our patient would likely eventually benefit from furosemide, it should not be considered the first-line therapy, as diuretic use in the setting of volume depletion can cause circulatory collapse.29 A relative contraindication was his presentation with acute kidney injury.
