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Cases Studies of Vitamin D Toxicity



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G Cases Studies of Vitamin D Toxicity 1025

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1026 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D TABLE G-1 Case Studies of Vitamin D Toxicity Study Patient/Population Preparation; Dose Duration Children Djamil and 2-yr-old male Vigantol (irradiated 1d Tu-Tunji. 1931. ergosterol); 3 tsp Lancet letter to the editor 1947. BMJ letter to Not specified Cod liver oil editor Ross. 1952. Journal 4 infants ages 8-14 Irradited ergosterol Daily for 8-12 mo of Pediatrics mo containing an estimated :815-822 30,000–40,000 IU vitamin Jacqz et al. 1985 Infants with Vitamin D and calcium hypercalcemia (2 supplementation cases with vitamin D toxicity) Case 1: 3 mo old 300 mg D3 Case 2: 7 mo old Besbas et al. Case 1: 3 mo old Vitamin D: 45,000 IU/d 45 d 1989. Turkish J Pediatrics Case 2: 4 mo old Vitamin D: 60,000 IU/d 30 d 31:239-244 Dent. 1964. BMJ 6 yr old Vitamin D (Calciferol 9 mo letter to editor Tablets B.P.): 1.25 mg. (~50,000 IU)/d Counts et al. 1975. 4-yr-old male Vitamin D2 (Drisdol): 2 mo following Ann Internal Med 50,000 up to 100,000 bilateral 82:196-200 IU/d nephrectomy DeWind. 1960. 5.5 yr old Vitamin D: 100,000 IU daily × 2–3 mo; and Arch Dis Child + cod liver oil-2 T + continued intake of 36:373-380 multivitamin tx vitamin D for 1 yr after hospitalization Barrueto et al. 2-yr-old male Vitamin D 4d 2005. Pediatrics (ergocalciferol): 116:e453-e456 2,400,000 IU

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1027 APPENDIX G 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; 17.6 mg/dL both pts recovered without incident 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 continued

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1028 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D TABLE G-1 Continued Study Patient/Population Preparation; Dose Duration Adults Puig. 1998. Ann 66-yr-old female Vitamin D: 200 IU + 3 yr Internal Med 1,000 mg calcium/twice 128(7):601-602 daily Rizzoli et al. 1994. 7 adults ages 55–84 Vitamin D3: 30,000– 3 weeks to 7.5 yr Bone 15:193-198 60,000 IU/d Davies and Adams. Case 1: 59-yr-old Vitamin D: >30 yr 1976. The Lancet female post- 50,000–100,000 IU/d thyroidectomy for 40 yr Case 2: 71-yr-old 150,000 IU/d 7 yr female with Paget’s disease Case 3: 51-yr-old 100,000 IU/d 10 yr female 1950. BMJ letter to Vitamin D2: 100,000 3 weeks editor IU/d Streck et al. 1979. 49-yr-old female Vitamin D: 100,000 3.8 yr Arch Intern Med post-thyroidectomy units/d; plus high 139:974-977 calcium diet Sterling and 69-yr-old male with Vitamin D (Calciferol): 3 weeks Rupp. 1967. Acta carcinoma of the 100,000 units/d Endocrinologica larynx 54:380-384 Aub. 1951. Amer 59-yr-old female Vitamin D: 150,000 6–8 weeks Prac 2(11):976-981 units/d Vieth et al. 2002. 29- and 63-yr-old Vitamin D poisoning: 7 mo Lancet 359:672 related males 12.6 mg D3/g crystalline sugar (~1,700,000 IU/d)

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1029 APPENDIX G Serum Calcium Serum 25(OH)D Symptoms/Health Effects 4.04 mmol/L 696 nmol/L Anemia and dehydration; toxicity treated with milk- (16.2 mg/dL) (278.8 ng/ml) free diet 3.30 mmol/L 710 nmol/L Asthenia, anorexia, nausea, polydipsia, polyuria; (mean) (mean) hypercalciuria; PTH levels were low normal. (13.2 mg/dL) (284.5 ng/ml) Discontinuation of vitamin D normalized calcemia in (range = 2.52– (range = 221– 3 d and calcidiol levels in 3 mo; bisphosphonate was 4.59 mmol/L) 1692 nmol/L) used to inhibit bone resorption (10.8–18.4 mg/ (88.5–677.9 dL) ng/ml) Pts reported nausea, vomiting; case 3 had extensive 3.1 mmol/L arterial and ligamentous calcification; tx with (12.4 mg/dL corticosteroids and withdrawal of vitamin D 4.5 mmol/L 450 nmol/L (18 mg/dL) (180.3 ng/ml) 3.75 mmol/L 400 nmol/L (15 mg/dL) (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 Nausea, anorexia, polyuria that progressed to (15.2–20.4 dehydration and coma. Removal of vitamin D and tx mg/dL) 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 1,555 nmol/L Anorexia, fever, chills, vomiting, increased thirst; (15.3 mg/dL) (623 ng/ml) 5 kg weight loss; conjunctivitis, acute renal failure, PTH <1 pmol/L. Tx with IV hydrocortisone, sodium phosphate, and pamidronic acid; both patients survived. continued

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1030 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D TABLE G-1 Continued Study Patient/Population Preparation; Dose Duration Lilienfeld-Toal 70 yr old Vitamin D3: 15 mg/d 3 weeks et al. 1978. Klin Wschr 56:715-717 Selby et al. (1995) 6 patients 2.5–5.0 mg/d, (80,000 IU 2–13 yr (most were to 200,000 IU D2)/d hypoparathyroid) Irnell (1969) 34-yr old 270,000 IU/d 10 d Acta Med Scand. 45,000 IU/d 6 yr 185:147-152, 1969) Accidental or Industrial Poisoning Scanlon 234 survey Milk over-fortified with Intake range: et al. 1995. Am respondents vitamin D at 70–600X (oz/d) concentration; (>50 < 5.5 J Public Health 85:1418-1422 IU/100 g) 5.5–11.0 11.1–19.6 ≥ 19.7 Blank et al. 1995. Hospital discharge, Milk over-fortified ~3 yr Am J Public lab, and health with vitamin D + other Health 85:656-659 dept data risk factors, i.e., use from cases of supplements; sun hypervitaminosis D sensitivity, history of cancer Jacobus et al. 1992. 8 individuals ages Milk over-fortified Variable exposure New Engl J Med 8 mo to 82 yr with cholecalciferol 326:1173-1177 consumed milk at concentrations of excessively fortified 396,400 and 376,800 with vitamin D IU/ml Thomson and 7 family members; Unknown food source Single exposure Johnson. 1986. 3 adults and 4 containing excessively Postgrad Med J children ages 1.5 high vitamin D 62:1025-1028 to 14 yr Pettifor et al. 1995. 10 family members Cholecalciferol Unknown exposure Ann Intern Med and 1 servant; concentrate in peanut oil 122:511-513 age range 8-69 = 2 million U/g yr ingested oil containing a veterinary vitamin D concentrate

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1031 APPENDIX G Serum Calcium Serum 25(OH)D Symptoms/Health Effects 6.1 mval/L 498 nmol/L Fatigue and psychotic symptoms; no evidence of (200 ng/ml) 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 842 nmol/L Admitted for hypercalcemia; renal failure (mean) (mean) (13.04 mg/dL) (337.3 ng/ml) 6.6 mEq/L Patient exhibited symptoms of toxicity (tiredness, vomiting, diarrhrea, polyuria, weight loss, muscular 8.5–9.6 mEq/L weakness, headache) at 45,000 IU/d Linear regression model showed a 1 oz increase in mean (mg/dL) mean (ng/ml) milk intake was associated with 1.39 ng/ml increase 2.4 32.8 in serum 25(OH)D. No association was found 2.3 39.5 between milk intake and elevated serum calcium; 2.4 41.3 there was an association with elevated serum 25(OH) 2.4 44.7 D and urinary calcium 13.1 mg/dL 224 ng/ml Consumption of milk from sources other than (mean for 35 (mean for 35 the over-fortified milk was not associated with cases) cases) hypervitaminosis D 7 of 8 had Mean for all Vitamin D3 concentrate in milk that was up to 580 hypercalcemia; cases: 731 ± 434 times in excess resulted in elevated serum vitamin 1 had nmol/L (293 D3, but not D2 in consumers. All consumers of the hypercalcuria ± 174 ng/ml) milk had elevated 25(OH)D levels and most had with hypercalcemia normocalcemia 2.72– 4.08 832–1,287 Serum calcium levels returned to normal within 24 d nmol/L nmol/L but 25(OH)D levels remained elevated for 1 yr; 1,25 (10.9–16.3 mg/ (333.0– (OH)D was not significantly elevated in the adults dL) 515.6 ng/ml) 3.46–4.61 847–1,652 Cholecalciferol poisoning did not elevate total 1-25 nmol/L nmol/L (OH)2D in 8 and only marginally in 3 of intoxicated (13.8–18.4 mg/ (339.3– patients; but did elevate free 1-25 (OH)2D in all dL) 661.9 ng/ml) continued

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1032 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D TABLE G-1 Continued Study Patient/Population Preparation; Dose Duration Hodges. 1985. 32-yr-old male Unknown exposure Intermittent British Med J working with exposure: 32 d in 290:748-749. crystalline vitamin 1981; 11 d in 1982; D in a laboratory 22 d in 1983 setting Klontz. 2007. 58-yr-old female Vitamin D3 overdose in ~2 mo New Engl J Med diagnosed with a supplement; 186,906 357:308-309 diabetes and IU/6 capsules rheumatoid arthritis Down et al. 1979. 3 family members; Cholecalciferol Single exposure Postgrad Med J 2 adults ages 24 yr concentrate in nut oil = 5 55:897-902 and 1 infant aged million IU/ml 11 mo Chiricone et al. Case reports: Multivitamin preparation 2003. J Nephrol per injection; 100,000 IU 62-yr-old male 3 vials/d per 20 15:917-921 vitamin D/vial 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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1033 APPENDIX G Serum Calcium Serum 25(OH)D Symptoms/Health Effects 3.5–3.7 mmol/L 496 ng/ml Polydypsia, polyuria, anorexia, nausea; tx with IV (~14 mg/dL) saline, furosemide; hydrocortisone 3.75 mmol/L 1,171 nmol/L Fatigue, constipation, back pain, forgetfulness, (15 mg/dL) (469.2 ng/ml) nausea, vomiting; tx with IV saline, furosemide, and pamidronate 3.95 mmol/L 58–60 IU/ml Both adults developed renal failure. The female (15.8 mg/dL) (145–150 ng/ aborted a 10-week fetus at 3 weeks post-diagnosis for ml) hypervitaminosis D. Plasma vitamin D levels were 60 IU/ml 5 weeks post-diagnosis; nephrocalcinosis (mean for (5 weeks persisted in the adult male but neither had long-term adults at 5 weeks post-exposure) renal impairment post-exposure) Renal colic, confusion, lethargy, and weakness; reported passing small stones; tx with IV saline, >150 ng/ml 15.3 mg/dL furosemide, glucocorticoids >150 ng/ml 11.3 mg/dL

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