Student Discussion
Student Discussion Document (pdf)
Umair Sajid, Dennis Orton, Martin Kaufmann, Glenville Jones, and Gregory A. Kline
Case Description
A 69-year-old man presented to a tertiary care center with several weeks of polyuria, polydipsia, blurred vision, and confusion. His initial investigations showed an elevated serum calcium 15.4 (reference interval: 8.4 to 10.4) mg/dL (3.86 [2.10 to 2.60] mmol/L), ionized calcium 7.9 (4.6 to 5.4) mg/dL (1.97 [1.15 to 1.35] mmol/L), and phosphate 5.26 (2.17 to 4.65) mg/dL (1.70 [0.70 to 1.50] mmol/L) with a concurrent acute kidney injury, the creatinine rising from a baseline of 1.13 to 5.73 (0.57 to 1.36) mg/dL (100 to 507 [50 to 120] μmol/L). The patient had known hypertension, treated with an angiotensin receptor blocker, heterozygous hereditary hemochromatosis (C282Y/H63D) managed with phlebotomy, and had previously recovered from hepatitis virus C with therapy. He had also been using an unknown amount of 4 unregulated health supplements, with package labeling for one suggesting a vitamin D content of 1000 IU/drop (labeling was not available for the other 3).
The patient was hospitalized for 20 days, during which he was medically managed for hypercalcemia, first with intravenous fluids and empiric pamidronate, then diuretics. The initial parathyroid hormone (PTH) level was suppressed at 6 (7 to 37) pg/mL, confirming this to be non-PTH mediated hypercalcemia. Other causes such as PTH-related peptide (<2.0 [<4.2)] pmol/L), hyperthyroidism (thyroid stimulating hormone [TSH], 1.63 [0.20 to 4.00] mIU/L), myeloma (unremarkable skeletal survey and serum protein electrophoresis), and overt solid organ malignancy (based on computed tomography [CT] of the chest, abdomen, and pelvis) were excluded.
After some initial mild improvement in hypercalcemia during the first week, the serum calcium rose to >14 mg/dL (>3.5 mmol/L). The working diagnosis of vitamin D toxicity was determined based on total 25-hydroxyvitamin D (25(OH)D) of 599 (32 to 80) ng/mL (1495 [80 to 200] nmol/L) by immunoassay (DIASORIN® Liaison XL). Concomitant 1,25-dihydroxyvitamin D (1,25(OH)2D) by immunoassay (DIASORIN Liaison XL) was extremely high at 1000 (25 to 87) pg/mL (2400 [60 to 208] pmol/L) with an angiotensin-converting enzyme level of 27 (13 to 57) U/L. In the absence of imaging evidence for sarcoidosis or other granulomatous disease, the working diagnosis continued to be vitamin D intoxication. The patient’s supplements were discontinued at admission, and empiric glucocorticoid treatment was administered until hospital discharge, with minimal effect upon calcium levels. Over serial observations, serum calcium slowly decreased, along with 25(OH)D and 1,25(OH)2D levels.
During outpatient follow-up, 3 months later, a marked elevation in calcium and 25(OH)D once again was noted, the patient sharing that he had resumed use of his supplements. Hypervitaminosis D as the cause of hypercalcemia was queried, based on a persistently elevated 1,25(OH)2D of 510.4 (25 to 86.7) pg/mL (1225 [60 to 208] pmol/L), in addition to 25(OH)D of 351 (32 to 80) ng/mL (876 [80 to 200] nmol/L). Along with supplement discontinuation, treatment with ketoconazole was utilized for nearly 3 months during which time the calcium level normalized.
A hypothesis of possible overactivation of cytochrome P450 family 27 subfamily B member 1 (CYP27B1, encoding for 1-α-hydroxylase) was considered, alongside disorders of vitamin D metabolism, such as a defect in the catabolic enzyme cytochrome P450 family 24 subfamily A member 1 (CYP24A1, encoding for 24-hydroxylase), which principally makes 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). By measuring 24,25(OH)2D using liquid chromatography–tandem mass spectrometry (LC-MS/MS) (Mayo Clinic Laboratories), we were able to rule out a defect in catabolism based on a normal, 25(OH)D:24,25(OH)2D, vitamin D metabolite ratio (VMR) of 19.1 (<25). Simultaneously, testing via LC-MS/MS confirmed that the 25(OH)D3 was truly elevated at 359.6 ng/mL (897.5 nmol/L) (>80.1 ng/mL [>200 nmol/L], indicating toxicity possible). Repeat chest CT to follow up incidental pulmonary nodules showed a possible small granuloma; however, this was not hypermetabolic on subsequent positron emission tomography (PET). Overall, no hypermetabolic activity to suggest sarcoid was found on a full body PET/CT.