Vitamin D toxicity – a very rare cause of increased plasma calcium

In health total plasma calcium concentration is maintained within the approximate reference range of 8.8-10.5 mg/dL (2.20-2.62 mmol/L) so that raised plasma calcium (hypercalcemia) is usually diagnosed if plasma calcium is >10.5 mg/dL (>2.62 mmol/L) and severe, potentially life-threatening hypercalcemia is roughly defined as plasma calcium >14.4 mg/dL (>3.60 mmol/L). 

The two most common causes of hypercalcemia are primary hyperparathyroidism and malignant disease (cancer), together accounting for close to 80 % of all cases. The long list of other, rarer causes of hypercalcemia includes excessive intake of vitamin D (vitamin D toxicity). This reflects the central role that the vitamin D-derived hormone calcitriol plays in regulation of plasma calcium concentration. Calcitriol promotes increased absorption of dietary calcium and resorption of calcium from bone to blood – the net effect of calcitriol action and by extension, vitamin D toxicity – is increase in plasma calcium concentration. 

But just how common is vitamin D toxicity and resulting hypercalcemia? That is the question addressed by a recently published retrospective study conducted by researchers at University of Iowa Hospitals and Clinics, a 734-bed tertiary care teaching facility in the US. 

Vitamin D status is determined by the serum/plasma concentration of the vitamin D metabolite, 25-hydroxyvitamin D [25(OH)D]. Researchers interrogated laboratory records to identify all serum/plasma 25(OH)D estimations at their institution during a 16-year study period (2000-2016). From this huge data base, they extracted results that indicated possible vitamin D toxicity according to two cut-off values for elevated 25(OH)D: >80 ng/mL (>200 nmol/L)  and >120 ng/mL (>300 nmol/L).

[Two cut-off values were chosen because there is currently no definitive cut-off value for vitamin D toxicity. The study authors report that the literature suggests toxicity is ”unlikely” unless plasma/serum 25(OH)D exceeds the higher cut-off value, 120 ng/mL; there is apparently just one report of toxicity occurring in a patient with 25(OH)D value of 80 ng/mL.]  

During the 16-year study period, 127,932 measurements of 25(OH)D were made on 73,779 patients (age range 0.3-90 yrs). Of these, 1068 results from 780 patients were >80 ng/mL and of these, just 89 patients had a result >120 ng/mL. So, during a 16-year study period just 89 (0.1 %) of all patients tested had a 25(OH)D value (>120ng/mL) consistent with possible vitamin D toxicity. 

The second part of the study focused on these 89 patients (age range 0.3-90 yrs). The medical record of each was retrieved for review to identify those with recorded symptoms of vitamin D toxicity (defined as one or more of the following, without identifiable alternative cause): polydipsia, polyuria, decreased appetite, vomiting, constipation, abdominal pain, renal failure, nephrocalcinosis, and/or failure to thrive). Each patient record was also interrogated for results of plasma calcium estimations and record of any vitamin D supplementation.

The records of just four of the 89 patients (4.5 %) revealed symptomatic evidence of vitamin D toxicity. Hypercalcemia was evident in three of these four cases; one was particularly severe: plasma calcium 19.8 mg/dL (4.94 mmol/L). But despite symptoms of vitamin toxicity and a markedly raised 25(OH)D concentration (247 ng/mL, 616 nmol/L), one of these four patients with vitamin D toxicity had a normal total calcium (9.6 mg/dL, 2.40 mmol/L). No patient with 25(OH)D <194 ng/mL (<484 nmol/L) had symptoms of vitamin D toxicity. 

Of all 89 patients, whose 25(OH)D was >120 ng/mL, 53 had a plasma calcium result recorded. Just seven (13 %) of these had hypercalcemia; this includes the three patients already mentioned who had symptoms of vitamin D toxicity. Linear regression analysis revealed, perhaps surprisingly, weak correlation (r2 0.10) between plasma 25(OH)D concentration and total calcium concentration. Remarkably, one study patient without apparent symptoms of vitamin D toxicity had 25(OH)D level of 850 ng/mL (2122 nmol/L) and normal plasma calcium (9.0 mg/dL, 2.25 mmol/L). 

Results of this study confirms the considerable rarity of vitamin D toxicity despite increased use of vitamin D supplementation in recent years, and suggests counterintuitively that hypercalcemia is not necessarily always a feature of vitamin D toxicity anyway, so hypercalcemia due to vitamin D toxicity must be rare indeed.