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DRI Dietary Reference Intakes Calcium Vitamin D G Cases Studies of Vitamin D Toxicity
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DRI Dietary Reference Intakes Calcium Vitamin D TABLE G-1 Case Studies of Vitamin D Toxicity Study Patient/Population Preparation; Dose Duration Children Djamil and Tu-Tunji. 1931. Lancet letter to the editor 2-yr-old male Vigantol (irradiated ergosterol); 3 tsp 1 d 1947. BMJ letter to editor Not specified Cod liver oil Ross. 1952. Journal of Pediatrics :815-822 4 infants ages 8-14 mo Irradited ergosterol containing an estimated 30,000–40,000 IU vitamin Daily for 8-12 mo Jacqz et al. 1985 Infants with hypercalcemia (2 cases with vitamin D toxicity) Vitamin D and calcium supplementation Case 1: 3 mo old Case 2: 7 mo old 300 μg D3 Besbas et al. 1989. Turkish J Pediatrics 31:239-244 Case 1: 3 mo old Vitamin D: 45,000 IU/d 45 d Case 2: 4 mo old Vitamin D: 60,000 IU/d 30 d Dent. 1964. BMJ letter to editor 6 yr old Vitamin D (Calciferol Tablets B.P.): 1.25 mg. (~50,000 IU)/d 9 mo Counts et al. 1975. Ann Internal Med 82:196-200 4-yr-old male Vitamin D2 (Drisdol): 50,000 up to 100,000 IU/d 2 mo following bilateral nephrectomy DeWind. 1960. Arch Dis Child 36:373-380 5.5 yr old Vitamin D: 100,000 IU + cod liver oil-2 T + multivitamin daily × 2–3 mo; and continued intake of tx vitamin D for 1 yr after hospitalization Barrueto et al. 2005. Pediatrics 116:e453-e456 2-yr-old male Vitamin D (ergocalciferol): 2,400,000 IU 4 d
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DRI Dietary Reference Intakes Calcium Vitamin D Serum Calcium Serum 25(OH)D Symptoms/Health Effects Edema and albuminuria Response from editor: A toxic dose of more than 200,000 units would only be achieved with ingestion of 2.65 L cod liver oil/d 18–19 mg/dL All presented with anorexia, weight loss, weakness; 2 infants recovered within 6–9 mo following removal of vitamin D; 2 infants died: autopsy showed fibrotic changes in vascular tissue, calcification of other tissues was noted, particularly lung Both cases presented with anorexia, diarrhea, and vomiting 10.5 mg/dL 129 ng/ml 10.5 mg/dL 126 ng/ml 19.5 mg/dL Calcium phosphate crystals in urine; bilateral medullary nephrocalcinosis; vomiting and lethargy; both pts recovered without incident 17.6 mg/dL Extreme thirst, hypercalcemia, symptoms of diabetes insipidus 17.2 mg/dL 635 ng/ml Leg pain, cessation of growth resulting from bone resorption; serum calcium, accompanied by nausea and vomiting. Tx with Ca-free dialysate failed to reduce serum Ca; prednisolone for 7 d; calcitonin tx stabilized serum Ca 17 mg/dL Nausea and non-tender lumps over both tibias; X-rays showed alternating patterns of increased and decreased bone density. Loss of bone density and tissue calcification continued despite removal of vitamin D and the pt died 14.4 mg/dL 470 ng/ml Constipation and colic; persistent hypertension; no renal, cardiac, neurological symptoms noted. Acute toxicity treated with furosemide, calcitonin, and hydrocortisol
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DRI Dietary Reference Intakes Calcium Vitamin D Study Patient/Population Preparation; Dose Duration Adults Puig. 1998. Ann Internal Med 128(7):601-602 66-yr-old female Vitamin D: 200 IU + 1,000 mg calcium/twice daily 3 yr Rizzoli et al. 1994. Bone 15:193-198 7 adults ages 55–84 Vitamin D3: 30,000–60,000 IU/d 3 weeks to 7.5 yr Davies and Adams. 1976. The Lancet Case 1: 59-yr-old female post-thyroidectomy for 40 yr Vitamin D: 50,000–100,000 IU/d >30 yr Case 2: 71-yr-old female with Paget’s disease 150,000 IU/d 7 yr Case 3: 51-yr-old female 100,000 IU/d 10 yr 1950. BMJ letter to editor Vitamin D2: 100,000 IU/d 3 weeks Streck et al. 1979. Arch Intern Med 139:974-977 49-yr-old female post-thyroidectomy Vitamin D: 100,000 units/d; plus high calcium diet 3.8 yr Sterling and Rupp. 1967. Acta Endocrinologica 54:380-384 69-yr-old male with carcinoma of the larynx Vitamin D (Calciferol): 100,000 units/d 3 weeks Aub. 1951. Amer Prac 2(11):976-981 59-yr-old female Vitamin D: 150,000 units/d 6–8 weeks Vieth et al. 2002. Lancet 359:672 29- and 63-yr-old related males Vitamin D poisoning: 12.6 mg D3/g crystalline sugar (~1,700,000 IU/d) 7 mo
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DRI Dietary Reference Intakes Calcium Vitamin D Serum Calcium Serum 25(OH)D Symptoms/Health Effects 4.04 mmol/L (16.2 mg/dL) 696 nmol/L (278.8 ng/ml) Anemia and dehydration; toxicity treated with milk-free diet 3.30 mmol/L (mean) (13.2 mg/dL) (range = 2.52–4.59 mmol/L) (10.8–18.4 mg/dL) 710 nmol/L (mean) (284.5 ng/ml) (range = 221–1692 nmol/L) (88.5–677.9 ng/ml) Asthenia, anorexia, nausea, polydipsia, polyuria; hypercalciuria; PTH levels were low normal. Discontinuation of vitamin D normalized calcemia in 3 d and calcidiol levels in 3 mo; bisphosphonate was used to inhibit bone resorption Pts reported nausea, vomiting; case 3 had extensive arterial and ligamentous calcification; tx with corticosteroids and withdrawal of vitamin D 3.1 mmol/L (12.4 mg/dL 4.5 mmol/L (18 mg/dL) 450 nmol/L (180.3 ng/ml) 3.75 mmol/L (15 mg/dL) 400 nmol/L (160.3 ng/ml) Pt reported feeling well. Response from editor: Feeling well occurs early in toxicity. Toxic dose varies from 200,000–400,000 IU daily for 10 d. 12.8 mg/dL; 283 ng/mL Tx with prednisone resolved hypercalcemia via inhibition of bone resorption of calcium (Urinary calcium: 493–600 mg/24 hr) 3.8–5.1 mEq/L (15.2–20.4 mg/dL) Nausea, anorexia, polyuria that progressed to dehydration and coma. Removal of vitamin D and tx with corticosteroids resolved elevated calcium and CV abnormality 14.3 mg/dL Weight loss, memory loss; evidence of renal damage and corneal calcification. Tx not discussed 3.82 mmol/L (15.3 mg/dL) 1,555 nmol/L (623 ng/ml) Anorexia, fever, chills, vomiting, increased thirst; 5 kg weight loss; conjunctivitis, acute renal failure, PTH <1 pmol/L. Tx with IV hydrocortisone, sodium phosphate, and pamidronic acid; both patients survived.
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DRI Dietary Reference Intakes Calcium Vitamin D Study Patient/Population Preparation; Dose Duration Lilienfeld-Toal et al. 1978. Klin Wschr 56:715-717 70 yr old Vitamin D3: 15 mg/d 3 weeks Selby et al. (1995) 6 patients (most were hypoparathyroid) 2.5–5.0 mg/d, (80,000 IU to 200,000 IU D2)/d 2–13 yr Irnell (1969) Acta Med Scand. 185:147-152, 1969) 34-yr old 270,000 IU/d 10 d 45,000 IU/d 6 yr Accidental or Industrial Poisoning Scanlon et al. 1995. Am J Public Health 85:1418-1422 234 survey respondents Milk over-fortified with vitamin D at 70–600X concentration; (>50 IU/100 g) Intake range: (oz/d) < 5.5 5.5–11.0 11.1–19.6 ≥ 19.7 Blank et al. 1995. Am J Public Health 85:656-659 Hospital discharge, lab, and health dept data from cases of hypervitaminosis D Milk over-fortified with vitamin D + other risk factors, i.e., use supplements; sun sensitivity, history of cancer ~3 yr Jacobus et al. 1992. New Engl J Med 326:1173-1177 8 individuals ages 8 mo to 82 yr consumed milk excessively fortified with vitamin D Milk over-fortified with cholecalciferol at concentrations of 396,400 and 376,800 IU/ml Variable exposure Thomson and Johnson. 1986. Postgrad Med J 62:1025-1028 7 family members; 3 adults and 4 children ages 1.5 to 14 yr Unknown food source containing excessively high vitamin D Single exposure Pettifor et al. 1995. Ann Intern Med 122:511-513 10 family members and 1 servant; age range 8-69 yr ingested oil containing a veterinary vitamin D concentrate Cholecalciferol concentrate in peanut oil = 2 million U/g Unknown exposure
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DRI Dietary Reference Intakes Calcium Vitamin D Serum Calcium Serum 25(OH)D Symptoms/Health Effects 6.1 mval/L 498 nmol/L (200 ng/ml) Fatigue and psychotic symptoms; no evidence of 2° osteoporosis was found. Tx with vitamin D was interrupted; the increased body pool of calcium returned to normal when serum vitamin D levels decreased to 200 ng/ml 3.26 mmol/L (mean) (13.04 mg/dL) 842 nmol/L (mean) (337.3 ng/ml) Admitted for hypercalcemia; renal failure 6.6 mEq/L Patient exhibited symptoms of toxicity (tiredness, vomiting, diarrhrea, polyuria, weight loss, muscular weakness, headache) at 45,000 IU/d 8.5–9.6 mEq/L Linear regression model showed a 1 oz increase in milk intake was associated with 1.39 ng/ml increase in serum 25(OH)D. No association was found between milk intake and elevated serum calcium; there was an association with elevated serum 25(OH) D and urinary calcium mean (mg/dL) mean (ng/ml) 2.4 32.8 2.3 39.5 2.4 41.3 2.4 44.7 13.1 mg/dL (mean for 35 cases) 224 ng/ml (mean for 35 cases) Consumption of milk from sources other than the over-fortified milk was not associated with hypervitaminosis D 7 of 8 had hypercalcemia; 1 had hypercalcuria with normocalcemia Mean for all cases: 731 ± 434 nmol/L (293 ± 174 ng/ml) Vitamin D3 concentrate in milk that was up to 580 times in excess resulted in elevated serum vitamin D3, but not D2 in consumers. All consumers of the milk had elevated 25(OH)D levels and most had hypercalcemia 2.72–4.08 nmol/L (10.9–16.3 mg/dL) 832–1,287 nmol/L (333.0–515.6 ng/ml) Serum calcium levels returned to normal within 24 d but 25(OH)D levels remained elevated for 1 yr; 1,25 (OH)D was not significantly elevated in the adults 3.46–4.61 nmol/L (13.8–18.4 mg/dL) 847–1,652 nmol/L (339.3–661.9 ng/ml) Cholecalciferol poisoning did not elevate total 1-25 (OH)2D in 8 and only marginally in 3 of intoxicated patients; but did elevate free 1-25 (OH)2D in all
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DRI Dietary Reference Intakes Calcium Vitamin D Study Patient/Population Preparation; Dose Duration Hodges. 1985. British Med J 290:748-749. 32-yr-old male working with crystalline vitamin D in a laboratory setting Unknown exposure Intermittent exposure: 32 d in 1981; 11 d in 1982; 22 d in 1983 Klontz. 2007. New Engl J Med 357:308-309 58-yr-old female diagnosed with diabetes and rheumatoid arthritis Vitamin D3 overdose in a supplement; 186,906 IU/6 capsules ~2 mo Down et al. 1979. Postgrad Med J 55:897-902 3 family members; 2 adults ages 24 yr and 1 infant aged 11 mo Cholecalciferol concentrate in nut oil = 5 million IU/ml Single exposure Chiricone et al. 2003. J Nephrol 15:917-921 Case reports: Multivitamin preparation per injection; 100,000 IU vitamin D/vial 62-yr-old male 3 vials/d per 20 d/3 mo: total exposure estimate = 18,000,000 IU 55-yr-old female 3 vials/d per 20 d/1.5 mo total exposure estimate = 9,000,000 IU
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DRI Dietary Reference Intakes Calcium Vitamin D Serum Calcium Serum 25(OH)D Symptoms/Health Effects 3.5–3.7 mmol/L (~14 mg/dL) 496 ng/ml Polydypsia, polyuria, anorexia, nausea; tx with IV saline, furosemide; hydrocortisone 3.75 mmol/L (15 mg/dL) 1,171 nmol/L (469.2 ng/ml) Fatigue, constipation, back pain, forgetfulness, nausea, vomiting; tx with IV saline, furosemide, and pamidronate 3.95 mmol/L (15.8 mg/dL) 58–60 IU/ml (145–150 ng/ml) Both adults developed renal failure. The female aborted a 10-week fetus at 3 weeks post-diagnosis for hypervitaminosis D. Plasma vitamin D levels were 60 IU/ml 5 weeks post-diagnosis; nephrocalcinosis persisted in the adult male but neither had long-term renal impairment (mean for adults at 5 weeks post-exposure) (5 weeks post-exposure) Renal colic, confusion, lethargy, and weakness; reported passing small stones; tx with IV saline, furosemide, glucocorticoids 15.3 mg/dL >150 ng/ml 11.3 mg/dL >150 ng/ml
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