short presentation describing the danger of vitamin D in overdose.

1. 1 Vitamin D intoxication in infant:a growing concern in Switzerlandfrom Case Report to Physiology to Prevention Moullet F, Hassib C, Humbert M, Cachat F Department of Pediatrics, PediatricNephrology Unit UniversityHospital, Lausanne, Switzerland 4/20/2011

2. Case presentation 1er enfant d’un couple kosovare NNT, RCIU dysharmonieux Multiples signes dysmorphiques Bilan malformatif: - US abdominal: Rein G ectopique fusionné - Caryotype: Trisomie partielle du chromosome 2 2 4/20/2011 vitamin D intoxication

4. US: rein G ectopique fusionné, rein D normal, pas de dilatation pyélo-calicielle, bonne croissance

5. CUM: RVU grade 1 ddc

6. Scintigraphie rénale: bonne fonction3 4/20/2011 vitamin D intoxication

7. Case presentation Bilan fonction rénale: Plasma : Na, K, P, Mg, créatinine, urée, urate dans la norme, Ca tot 2.94 mmol/l (N 2.15-2.70), PTH 42 ng/l (N 10-70) Urine: natriurie, phosphaturie, magnésurie dans la norme, pas de protéinurie, rapport Ca/créatinine: 2.23 mol/mol (N 0,07-1.50) 4 4/20/2011 vitamin D intoxication

8. Que faites-vous (chez un enfant asymptomatique)? 5 4/20/2011 vitamin D intoxication

10. hypercalcémie (Ca tot. 2.82 mmol/l)

11. hypercalciurie (Ca/créatinine 2.65 mol/mol)6 4/20/2011 vitamin D intoxication

12. Suite de la prise en charge? 7 4/20/2011 vitamin D intoxication

13. Case presentation 25-OH Vitamine D : 238 µg/l (N 8.4-52.3) 1,25 dihydroxy-vit D3 : 90 pmol/l (N 48-160) PTH 42 ng/l (N 10-70) il y a 2 semaines PO4 1.28 mmol/l (N); PAL 130 UI/l (N), Mg 0.76 mmol/l (N) 8 4/20/2011 vitamin D intoxication

14. Attitude? Arrêt de la supplémentation en Vitamine D 9 4/20/2011 vitamin D intoxication

15. Case presentation Contrôle 3 semaines après arrêt de la Vitamine D Plasma: Ca tot. 3.28 mmol/l, Ca ionisé 1.68 mmol/l Urine: Ca /créat: 2.66 mol/mol 10 4/20/2011 vitamin D intoxication

16. Case presentation Hospitalisation pour prise en charge. Bilan: 25-OH Vitamine D: 179 µg/l ( N 8,4-52.3) 1,25-Dihydroxy-Vit D3: 31 pmol/l (N 48-160) PTH: <3 ng/l 11 4/20/2011 vitamin D intoxication

18. Apport de Vit D3 (Cholécalciférol) : entre 1600 U et 10’000 U/j + apports laitiers: Aptamil 3 450 U Vit D/j12 4/20/2011 vitamin D intoxication

19. Case presentation hospitalisation du 31.03 au 02.04 puis du 04 au 06.04 Hydratation iv Régime sans Ca Pas apport Vit D po Normalisation lente et progressive de la calcémie Enfant cliniquement asymptomatique 13

20. Definition of hypercalcemia Ionized calcium > 1.35 mmol/l(5.4 mg/dl) or total calcium > 2.7 mmol/l(10.8 mg/dl) Repeatedat least twice Rule out extremelyhighalbumin, total protein, paraproteinlevel(pseudo-hypercalcemia) (increasedprotein-bound calcium, normal ionized calcium!) 14

21. Symptoms of hypercalcemia GI: nausea, vomiting, constipation, anorexia, abdominal pain, pancreatitis Neurologic: pseudo-tumorcerebri, depression, confusion, fatigue, coma, hypotonia Cardiovascular: hypertension, bradycardia, cardiacarrest, vascular calcification Renal: polyuria, dehydration, nephrocalcinosis Kidney stones Symptoms related to the severity of hypercalcemia often asymptomatic if total Ca < 3 mmol/l

22. Whichactors are Important? Physiological controls of calcium and phosphate metabolism From: Plum L. Vitamin D, diseases, and therapeuticopportunities. Nature Rev Drug Discovery2010;9:948-961

23. Physiological control of calcium (and phosphorus) Hormone BloodBone Gut Kidney PTHCa, PO4 osteoclast indirect effect Ca excretion resorbtionthrough PO4 excretion calcitriol CalcitriolCa, PO4 no direct Ca and PO4 no direct effect effect absorption CalcitoninCa, PO4 osteoclast no direct Ca excretion resorbtioneffect PO4 excretion From: Carroll M. A practical approach to hypercalcemia. Am Fam Phys 2003;67:1959-1966

24. Physiopathological mechanisms leading to (sustained) hypercalcemia Initiation of hypercalcemia Maintenance of hypercalcemia 4/20/2011 18 vitamin D intoxication

25. 1. Initiation of hypercalcemia Vitamin D intoxication Bone metastasis Bone disease Digestive Calcium intoxication Vitamin D intoxication Granulomatousliver disease Bone Overdose of calcium Overdose of vitamin D 19 Iatrogenic Genetic Williams syndrome 4/20/2011

26. 2. Maintenance of hypercalcemia Continuous vitamin D Exposure (variable) Slow release of vitamin D from fat tissue (days to weeks) Renal failure  chronic acidosis (variable) 20

27. 21 4/20/2011

28. In summary: the questions (youshouldaskyourself) atthis point (from the history point of view): Doesmy patient takevitamin D? Vitamin D intoxication Doesmy patient producevitamin D? Granulomatousdiseases, sarcoidosis Doesmy patient take calcium? Calcium intoxication Doesmy patient release calcium? Bonediseases 22

29. Laboratoryapproach to hypercalcemiawith a good understanding of the physiologycontrolling calcium metabolism 23 4/20/2011 vitamin D intoxication

30. Hypercalcemia PTH Increased Normal/decreased Loss of functionCaSR (SevereneonatalhyperPTH, FHH)  25(OH)D Heterogenous  25(OH)D  1,25(OH)D Janssen PTHrP Malignancy Vitamin A intox. Sarcoidosis Granulomatosis Fat necrosis Hypophophatasia Vitamin D intoxication Williams syndrome

31. In summary: the questions (youshouldaskyourself) atthis point (from the laboratory point of view): Whatis the PTH level of my patient? Whatis the 25(OH)Vitamin D level of my patient? Expectedlow PTH, high 25(OH)D and normal (/high)1,25(OH)D levels in case of hypervitaminosis D 25

32. Vitamin D intoxication:How does that happen?How can we prevent it? 26 4/20/2011 26 vitamin D intoxication

33. Vitamin D intoxication: how common is it? Number of cases reported to the ToxZentrum Zurich withacute or chronicvitamin D3 intoxication Sharp increase of bothacute and chronic VitD3 intoxication over the last decade Related to the differentcurrently availableforms of vitamin D?

34. Vitamin D intoxication: summary of reported cases in the literature Age cummulative dose duration of intoxication calcium level (mmol/l) IU 7 w 6 millions 200’000 IU/d x 30 d 4.05 3 m 1.2 millions 3000’000 IU/d x 4 d 4.6 3 m 2.56 millions 302’000 IU/d x 8 days 4.5 6 m 3 millions 300’000 IU/d x 10 d 4.2 2 y 2.4 millions 600’000 IU/d x 4 d 3.6 11 m 1.34 millions 300’000 IU/m x 3 m 4.5 400 IU/d x 11 m 4 m 600’000 600’000 IU in 3 w 3.7 7 y 4.5 millions 300’000 IU x 15 d 7 m 1.8 millions 600’000 IU x 3 8.8 4 m 333’240 unclear 4.28 From: Chambellan-Tison C. Hypercalcemie majeure secondaire à une intoxication par la vitamine D. Arch Péd 2007;14:1328-1332

35. Vitamin D intoxication: beware of the level, beware of the duration! Acute intoxication: Relativelywelldescribed From 40’000 IU per day for 3 to 4 months (= 3.6 millions to 4.8 millions) Most of the time > 1-2 million IU cummulative dose (see French experience) for symptoms to develop Chronic intoxication: Relativelyunclear From 2’000 to 4’000 IU per day for years 29 29

36. Vitamin D intoxication: why does that happen? Multitude of vitamin D availablewithdifferent dispensers and concentration 30 Double cause for medicationerror

37. How can we prevent it? What has been done? Medical Information (Forum médical suisse Journal) (2010) Pharmacist Information (pharmajournal) (2008 and 2010) Implementation of recommendations difficult Multitude of different concentrations and dispensersavailable CONFUSION! Over the countervitamins CONFUSION! Effective and presumedbeneficialeffects of vitamin D reported in the literature CONFUSION! BUT errorsstilloccurs ! 31

38. Real and presumed beneficial effects of vitamin as of 2010

39. What have we done so far?How can we improve public safety? 4/20/2011 33 vitamin D intoxication

40. Improvingimplementation / error prevention 1. Leaflet for medicaldoctors and nurses and midwifes for the prevention of vitamin D intoxication In close collaboration with the Central Pharmacy of the Hospital 2. Ward round togetherwith a pharmacisttwice a week

41. Thanks to Marie Humbert, PharmD, PHEL, Central Pharmacy Vevey, for carefulliteraturereview and leaflet conception and writing Christian Schaeli, PharmD, PHEL, for providing excellent service with a pharmacist for weeklyward round in the pediatric department All pediatricians for anouncing all cases of hypervitaminosis in their patients 4/20/2011 35 vitamin D intoxication