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The toxicity of vitamin D is rare, but clinicians need to be aware of the risks of using vitamin D to limit the complications of hypercalcemia.
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Calcium levels may worsen before improving in patients, even after the cessation of supplements, because vitamin D is fat soluble.
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The observation data and expert opinion suggest that glucocorticoids, ketoconazole and hydroxychloroquine are reasonable options for treating hypercalcemia related to vitamin D toxicity by decreasing the "active" value 1, 25 of dihydroxyvitamin D3 levels.
A 54-year-old man was referred urgently to the nephrology clinic by his family doctor in case of suspicion of acute kidney injury, with a creatinine level of 376 μmol / L. He had just returned from a trip to Southeast Asia, where he had spent long periods of tanning (6 to 8 h / d) for two weeks. His medical history included hypertension, dyslipidemia and gout, for which he was taking perindopril 8 mg daily, rosuvastatin 10 mg daily, amlodipine 10 mg daily, indapamide at 2.5 mg daily and febuxostat at 80 mg daily.
On his return to Canada, the patient's creatinine level was initially reduced from 100 μmol / L to 132 μmol / L. His family doctor ordered him to temporarily stop his antihypertensive and diuretic agents because he was suffering from a possible depletion of the extracellular fluid following exposure to heat. Despite this measure, a new measurement performed 4 weeks later, the creatinine level of the patient had increased to 376 μmol / L. During this period of 4 weeks, he had not used anti-inflammatory drugs not steroids nor new drugs, had not been exposed to an intravenous contrast medium and had no acute illness. As his creatinine level continued to increase rapidly without clear etiology, the patient was referred to nephrology.
The patient's family history included autosomal dominant polycystic kidney disease, with two first-degree relatives requiring dialysis before 60 years of age. However, he had undergone radiographic screening by abdominal ultrasound, which was negative for the polycystic kidneys.
At the nephrology clinic, the patient's blood pressure was 149/98 mmHg, with no urgent clinical indication of dialysis. Renal ultrasound showed normal sized kidneys without hydronephrosis or echogenicity. An accidental bladder mass of 1.2 cm was observed on ultrasound and was subsequently diagnosed as a non invasive urothelial carcinoma. (This has been treated with local excision with interval monitoring, requiring no chemotherapy.)
Urine studies performed during the patient's first nephrology visit did not show leucocytes, erythrocytes or proteins. Under the urinary microscope, there was no formation of cell crystals or cell crystals. The results of serum and urinary protein electrophoresis studies were negative. The blood count was normal. However, serum calcium and parathyroid hormone (PTH) levels in the patient showed non-PTH mediated hypercalcemia (Box 1). Test of 25-hydroxyvitamin D3 and 1,25 dihydroxyvitamin D3 levels has been ordered. The imaging studies of the chest and abdomen were unremarkable.
Serum laboratory values relevant to the patient's initial and most recent clinic visits over a 10-month period, with hydroxychloroquine starting after his or her second visit to the clinic *
The differential diagnosis at this stage included malignant hypercalcemia, multiple myeloma, and granulomatous diseases, such as sarcoidosis. Renal biopsy showed features of nephrosclerosis and microcalcifications, but no sarcoidosis or light chain deposition (Figure 1).
Photomicrograph of the tubulointerstitium of a 54-year-old man with vitamin D toxicity and microcalcifications (arrow). Arterioles exhibit hyalinosis (hematoxylin-eosin × 40 staining).
During a more detailed interview, the patient indicated that he was consulting a naturopath who had prescribed him high doses of vitamin D, advising him to take 8 drops of a specific brand a day. He had no history of fragility fracture or documented vitamin D deficiency. The recommended mark contained 500 IU per drop. Without knowing it, the patient obtained another vitamin D preparation containing 1000 IU per drop. The patient was not informed of the risks of toxicity and, over a period of 2.5 years, took 8 to 12 drops of vitamin D per day, for a total daily dose of 8,000 to 12,000 IU.
At the nephrology clinic, patient-measured 1,25 dihydroxyvitamin D3 level was 274 pmol / L and its 25-hydroxyvitamin D3 level was 241 nmol / L (Box 1). He was asked to stop taking all vitamin D supplements and calcium-rich foods. His diuretics remained on hold, but one of his antihypertensives (amlodipine) was resumed after his second visit to the clinic. His 1,25 dihydroxyvitamin D3 and ionized calcium levels continued to increase (Figure 2). His only new symptom related to hypercalcemia was pruritus.
Hydroxyvitamin D in series3 (25-OH D), 1,25 dihydroxyvitamin D3 (1,25 OH D) and ionized calcium over a period of 10 months. Ionized calcium and 1,25 dihydroxyvitamin D3 Levels continued to increase 4 weeks after the end of the supplements. Hydroxychloroquine started during the visit to the clinic in June and 1,25 dihydroxyvitamin D3 levels gradually decreased after initiation.
Given its worsening of hypercalcemia and increased levels of active vitamin D, we advised the patient to begin treatment with glucocorticoids. He was reluctant to take glucocorticoids, fearing potential weight gain. As an alternative, we offered oral hydroxychloroquine at a rate of 400 mg per day and advised the patient about adverse effects, including retinal toxicity.
The patient's calcium and vitamin D levels decreased after the initiation of hydroxychloroquine. Near one year after diagnosis, his calcium and vitamin D levels returned to normal, but he remains at stage 3B (glomerular filtration rate estimated at 34 mL / min / 1.73 m3) chronic kidney disease.
Discussion
Historically, reports have described the benefits of vitamin D in relation to bone health.1 Other presumed benefits of vitamin D included non-skeletal effects, such as cardiovascular benefits, prevention of falls, and reduced infections and malignancies.2 Reviews and meta-analyzes have not shown that vitamin D reduces the risk of primary fracture nor convincingly improves other non-skeletal health effects.3 In addition, a recent review by the US Preventive Services Task Force (Preventive Services Task Force) has shown no benefit for the prevention of primary fracture in unidentified persons with deficiency, osteoporosis or anterior fracture.4
In its 2010 guideline, Osteoporosis Canada recommended vitamin D supplementation of 10-25 μg (400-1000 IU) to most low-risk adults under 50 years of age to achieve serum 25-hydroxyvitamin D3 above 75 nmol / L (Level 3 evidence) 1, stating that the potential benefits outweigh the risks. Daily vitamin D intake of 20 to 50 μg (800 to 2,000 IU) is recommended for high-risk adults and the elderly (level 2 evidence) .1
Mechanism of toxicity of vitamin D
Although the toxicity of vitamin D is rare due to a wide therapeutic range, its widespread availability in various over-the-counter formulations may pose a significant risk to uninformed patients. After consumption, vitamin D is transported to the liver where it undergoes hydroxylation and is activated either by microsomal CYP2R1 or by mitochondrial CYP27A1 in 25-hydroxyvitamin D.3.5,6 The resulting 25-hydroxyvitamin D3 binds to the vitamin D binding protein and is transported in the kidneys for 1α-hydroxylation to be performed by CYP27B1 to produce 1,25 dihydroxyvitamin D3.6 This 1,25 dihydroxyvitamin D3 is transported to the target cells and enters the vitamin D receptor nucleus, leading to a positive regulation of gene expression. Although transported by the vitamin D binding protein, 1,25 dihydroxyvitamin D3 has a lower binding affinity to 25-hydroxyvitamin D3 and its metabolites.5 A major hypothesis suggests that a supersaturation of the vitamin D binding protein results in an increase in free active vitamin D (1,25 dihydroxyvitamin D3), leading to hypercalcemia.
CYP24A1 plays an important role in the deactivation of 1,25 dihydroxyvitamin D3 Calcitroic acid.6 CYP24A1 also breaks down the 25-hydroxyvitamin D precursor3 at 24,25-dihydroxyvitamin D3. Mutations by loss of function at CYP24A1 have been associated with hypercalcemia due to increased sensitivity to vitamin D.6 Although we have not performed genetic testing on our patient, it is plausible that he CYP24A1 mutation, increasing its susceptibility to the toxicity of vitamin D.
Toxicity manifestations
The toxicity may occur over a short period of time in patients intentionally or inadvertently ingesting large doses of vitamin D.7 The literature maintains that doses greater than 10,000 IU per day for several months may result in toxicity (> 200 nmol / L on 25-hydroxyvitamin D3However, differences in patient characteristics such as malabsorption and CYP24A1 may result in substantial variation in the doses required for toxicity to occur.
Patients may have symptoms involving the central nervous system and the gastrointestinal, genitourinary and cardiovascular systems. The manifestations of the central nervous system include lethargy, hypotonia, hyporeflexia, confusion and coma. Gastrointestinal symptoms include nausea, vomiting, pancreatitis and constipation; Symptoms of cardiovascular toxicity, such as hypertension, arrhythmias and shortening of the QT segment, may also appear.9 Genitourinary symptoms include polyuria, nephrocalcinosis, and renal failure. The symptomatology associated with the toxicity of vitamin D highlights the hypothesis that hypercalcemia could be responsible for most of the observed symptoms7. Prolonged hypercalcemia can also lead to dysregulation of calcium phosphate homeostasis, leading to suppression of PTH and impaired bone remodeling3.,5
It is important to note that patients may be asymptomatic, which delays the diagnosis and that abnormalities related to the toxicity of vitamin D can only be detected by chance.
In terms of renal impairment, hypercalcemia can cause acute or chronic kidney damage. Hypercalcemia can cause acute kidney injury mainly through 2 mechanisms: Afferent arteriolar constriction and intravascular volume depletion due to a diuretic effect by activation of the calcium-sensitive receptor in the sodium chloride cotransporter in Henle's loop.10 The acute renal injury of our patient was probably aggravated by volume depletion due to the use of diuretics, prolonged exposure to heat, and pre-existing hypercalcemia due to toxicity. Vitamin D has been shown to improve kidney function as calcium levels decline, stop vitamin D supplements and temporarily maintain diuretics and antihypertensives. However, we believe that our patient has developed a chronic disease, as shown by kidney biopsy nephrosclerosis (Figure 1).
Toxicity management
In cases where there is suspicion of vitamin D toxicity, prescribed and over-the-counter medications should be carefully examined. Initial strategies to reduce vitamin D levels should focus on reducing dietary or supplemental sources. Although there is currently no evidence of large-scale trials, the evidence suggests that clinicians might consider strategies to reduce active vitamin D levels if Hypercalcemia persists, by inhibiting the activity of 1-hydroxylase (Figure 3) .11,12 If patients are asymptomatic, clinicians may choose to monitor levels early because vitamin D is very fat soluble and may return to normal for some time.
The simplified pathway of vitamin D metabolism with a suggested approach to the management of hypervitaminosis D. The key steps are as follows: Limit sun exposure; Stop oral vitamin D supplements; Use drugs such as corticosteroids, ketoconazole and hydroxychloroquine to block the activity of 1α-hydroxylase; Stop oral calcium supplements to reduce the burden of hypercalcemia associated with hypervitaminosis D. The main enzymes involved in the metabolic pathway are indicated in green.5–7,11,12
Image courtesy of Bottle Credit: Creativity Credit Pills: BSGStudio
Several drugs have been used successfully to treat hypercalcemia by reducing the active form of vitamin D. Glucocorticoids, ketoconazole, and hydroxychloroquine have all been used in cases of hypercalcemia-related sarcoïdose.1,9 The opinion of an expert suggests that these drugs reduce the activity of 1α-hydroxylase and can be used to treat hypercalcemia by reducing 1,25 dihydroxyvitamin D3 niveaux.11,12 Because our patient was reluctant to use glucocorticoid therapy, we used hydroxychloroquine as an alternative to lower her 1.25 dihydroxyvitamin D.3 levels and, in turn, its calcium levels.
Our experience tells us that patients and clinicians should be better informed about the risks associated with unhindered use of vitamin D. Given the new findings of the US Task Force on Preventive Services, 4 Canadian guidelines current trends in its use in low-risk individuals should be reviewed.
Patients with CYP24A1 mutations may present an increased risk of vitamin D toxicity, and clinicians may consider genetic testing if the toxicity of vitamin D develops at doses less than 10,000 IU per day. Although the toxicity of vitamin D is rare, early recognition can prevent chronic complications associated with hypercalcemia. In symptomatic patients, it is suggested to stop the supplements with glucocorticoid treatment. In cases where glucocorticoid therapy is not preferred or is contraindicated, ketoconazole or hydroxychloroquine are reasonable alternatives.
The case section presents brief case reports that convey clear and practical lessons. Preference is given to joint presentations of important rare conditions and important and unusual presentations of common problems. Articles begin with a case presentation (500 words maximum), followed by a discussion of the underlying condition (1000 words maximum). Visual elements (for example, tables of differential diagnosis, clinical features or diagnostic approach) are encouraged. The consent of patients for the publication of their story is a necessity. See information for authors at www.cmaj.ca.
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