Abstract
Introduction
Vitamin D is present in free and bound forms; the bound form is complexed mainly to vitamin D binding protein (DBP). Vitamin D levels are affected by age, pregnancy, liver disease, obesity, and DBP mutations. We report a patient with treatment-resistant vitamin D deficiency suggestive of a DBP with abnormal vitamin D binding.
Clinical Case
A 58-year-old Pakistani male with a history of hypertension, sleep apnea and hypogonadism presented to endocrine clinic with symptoms including fatigue, generalized muscle cramps, and joint pain. Evaluation of common causes of fatigue, such as anemia, thyroid dysfunction and adrenal insufficiency were ruled out with CBC, thyroid hormone levels and ACTH stimulation test results all within normal ranges. A 25-OH vitamin D level was profoundly low (4.2 ng/ml; normal 30-100), and a 1,25-OH vitamin D level was undetectable (<8 pg/ml; normal 18-72), leading to a presumptive diagnosis of severe vitamin D deficiency. However, his calcium, phosphorus, alkaline phosphatase and kidney function were in the normal range. Furthermore, the absence of osteoporosis, fracture history, or kidney stones suggested adequate vitamin D action at target tissues; PTH levels were high-normal to minimally elevated, ranging 70-94 pg/ml (12-88pg/mL). Aggressive supplementation with vitamin D3 at 50,000 IU 3 times a week and 5,000 IU daily failed to normalize 25-OH vitamin D (ranged 4.6-10ng/ml; normal 30-100) and 1,25-OH vitamin D levels remained undetectable. Addition of calcitriol resulted in mild hypercalcemia and was discontinued. Malabsorption did not appear to be a contributing factor, as a negative tTG antibody (with normal IgA) excluded celiac disease. Vitamin D metabolites levels measured with mass spectrometry showed undetectable 25-OH vitamin D levels (D2 <4 ng/ml, D3 <2 ng/ml; total <6ng/ml; normal 20-50) and 1,25-OH vitamin D levels (<8 pg/ml). Urine N-telopeptide, 24-hour urine calcium (177mg; 100-240) and bone-specific alkaline phosphatase were all normal. Repeat testing over more than five years showed similar results. DBP levels of 269 ug/ml [104-477] excluded DBP deficiency.
Clinical Lesson
Vitamin D deficiency is increasingly part of routine testing in internal medicine and endocrinology clinics, as is repletion with high-dose vitamin D. However, in rare cases such as this, relying on 25-OH vitamin D levels can be misleading, and supplementation unnecessary or potentially harmful. Thus, treatment decisions should consider the full clinical context and further evaluation performed when warranted. This patient’s labs are suggestive of an abnormality in the DBP, supporting future examination using molecular testing.
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