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There are many reasons why the diagnosis of vitamin D toxicity of the recent case report by Auguste et al (1) was probably wrong, and was the result of a red herring. The patient had been taking 8,000-10,000 IU/day of vitamin D for 2.5 yrs while serum creatinine was not an issue. When the serum 25-hydroxyvitamin D ( 25(OH)D ) was first measured, and it was 241 nmol/L, consistent with long-term intake of the patient’s reported vitamin D intake but almost double the top of the reference range for people not taking a supplement. However, the serum 1,25-dihydroxyvitamin D ( 1,25(OH)2D ) was exceptionally high along with serum calcium and creatinine.
The Institutes of Medicine specifies 10,000 IU/day as the “No Observed Adverse Effect Level” – an intake that is not advisable, but which is not considered objectively harmful either (2). Doses of vitamin D higher than 10,000 IU/day have been used in clinical trials that achieved higher 25(OH)D values and for longer duration, yet there was not one case of hypercalcemia, and certainly no kidney damage reported from among those hundreds of those study subjects (3–9). The case report described by Auguste et al is not consistent with any previous clinical experience with vitamin D intake. What is unusual is the high serum 1,25(OH)2D level, because even in the most extreme cases of vitamin D toxicity, with 25(OH)D exceeding 2,000 nmol/L, the total serum 1,25(OH)2D was only modestly increased (10). The primary cause of the renal impairment in the case report of Auguste et al was something beyond the vitamin D intake: either a tumor, or sarcoidosis.
Auguste et al speculate that their patient might have been unusually susceptible to vitamin D because of a mutation in the CYP24A1 gene that encodes for the breakdown enzyme of 25(OH)D and 1,25(OH)2D (1). But if that were the case, the condition would not have required 2.5 years of vitamin D supplementation to manifest itself, and it could not have been resolved within a few months. Since several genetic defects can impair the CYP24A1 enzyme, the diagnosis is suitably screened for with a biochemistry-lab test, the ratio of 25(OH)D to 24,25(OH)2D concentrations (11). That test was conducted for my research group at the same hospital laboratory that Auguste et al used for their own 25(OH)D results (12). It is not likely that a rare CYP24A1 defect is pertinent to this case report, because of the duration of vitamin D intake, and by the elevated 1,25(OH)2D, as well as by the recent onset of symptoms.
The high serum 1,25(OH)2D levels, hypercalcemia renal impairment and recent onset are entirely consistent with published case reports on sarcoidosis (13,14). The only difference was that in those, serum 25(OH)D was normal. The high 1,25(OH)2D in the case report of Auguste et al (1) is not a sign of vitamin D toxicity, and likely, a consequence of sarcoidosis (13–15). The renal biopsy used by Auguste et al does not rule out sarcoidosis (16). Hydroxychloroquine is not a conventional treatment for vitamin D toxicity, but it is a first-line treatment for sarcoidosis (13–15). While the case reported by Auguste et al was probably not a primary disease of vitamin D toxicity, it is important to limit sources of vitamin D in patients with sarcoidosis.
The lesson here, is that it is common for patients to take dietary supplements in amounts that may raise test values beyond the laboratory’s reference range. But an abnormally high lab value does not in itself justify a diagnosis of toxicity. The consequence of accepting the false clue of a high vitamin D level was that no serious effort was made at establishing the true cause of the problem.
Literature Cited.
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