Hypercalcemia and vitamin d intoxication slideshare

1

Vitamin D intoxication in infant:

a growing concern in Switzerland

from Case Report to Physiology to Prevention

Moullet F, Hassib C, Humbert M, Cachat F

Department of Pediatrics, Pediatric Nephrology Unit

University Hospital, Lausanne, Switzerland

4/20/2011

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

24/20/2011 vitamin D intoxication

Case presentation

• Follow up 1 année

- TA: normale

- US: rein G ectopique fusionné, rein D normal, pas de

dilatation pyélo-calicielle, bonne croissance

- CUM: RVU grade 1 ddc

- Scintigraphie rénale: bonne fonction


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)


Que faites-vous (chez un enfant asymptomatique)?


Case presentation

• Recontrôle 2 semaines plus tard

Persistance de:

hypercalcémie (Ca tot. 2.82 mmol/l)

hypercalciurie (Ca/créatinine 2.65 mol/mol)


Suite de la prise en charge?


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)


Attitude?

Arrêt de la supplémentation en Vitamine D


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


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


Case presentation

• Reprise d’anamnèse

Maman donne de l’Oleovit : 1 gtte = 400 U Vit D3 (4x plus

concentré que le Vide*), entre 4 gttes et une pipette (=

env. 25 gttes)/j

Apport de Vit D3 (Cholécalciférol) : entre 1600 U et

10’000 U/j + apports laitiers: Aptamil 3 450 U Vit D/j


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 asymptomatique13

Definition of hypercalcemia

• Ionized calcium > 1.35 mmol/l (5.4 mg/dl) or

total calcium > 2.7 mmol/l (10.8 mg/dl)

• Repeated at least twice

• Rule out extremely high albumin, total

protein, paraprotein level (pseudo-hypercalcemia)

(increased protein-bound calcium, normal ionized calcium!)14

Symptoms of hypercalcemia

• GI: nausea, vomiting, constipation, anorexia, abdominal pain, pancreatitis

• Neurologic: pseudo-tumor cerebri, depression, confusion, fatigue, coma,

hypotonia

• Cardiovascular: hypertension, bradycardia, cardiac arrest, vascular

calcification

• Renal: polyuria, dehydration, nephrocalcinosis

Kidney stones

Symptoms related to the severity of hypercalcemia

often asymptomatic if total Ca < 3 mmol/l

From: Plum L. Vitamin D, diseases, and therapeutic opportunities. Nature Rev Drug Discovery 2010;9:948-961

Physiological

controls of calcium

and phosphate

metabolism

Which actors are

Important?

Physiological control of calcium (and

phosphorus)

Hormone Blood Bone Gut Kidney

PTH Ca, PO4 osteoclast indirect effect Ca excretion

resorbtion through PO4 excretion

calcitriol

Calcitriol Ca, PO4 no direct Ca and PO4 no direct effect

effect absorption

Calcitonin Ca, PO4 osteoclast no direct Ca excretion

resorbtion effect PO4 excretion

From: Carroll M. A practical approach to hypercalcemia. Am Fam Phys 2003;67:1959-1966

Physiopathological mechanisms

leading to (sustained) hypercalcemia

Initiation of hypercalcemia

Maintenance of hypercalcemia

4/20/2011 18vitamin D intoxication

19

1. Initiation of hypercalcemia

Calcium intoxication

Vitamin D intoxication

Granulomatous liver

disease

Vitamin D intoxication

Bone metastasis

Bone disease

Overdose of calcium

Overdose of vitamin D

Williams syndrome4/20/2011

Slow release of vitamin

D from fat tissue(days to weeks) Continuous vitamin D

Exposure(variable)

Renal failure

chronic acidosis(variable)

2. Maintenance of hypercalcemia

20

http://www.histol.chuvashia.com/images/connective/fat-02.jpg

http://www.wellbasics.com/images/Vitamin-D-Drops.gif

214/20/2011

In summary: the questions (you should ask

yourself) at this point (from the history point of

view):

• Does my patient take vitamin D?

• Vitamin D intoxication

• Does my patient produce vitamin D?

• Granulomatous diseases, sarcoidosis

• Does my patient take calcium?

• Calcium intoxication

• Does my patient release calcium?

• Bone diseases

22

Laboratory approach to

hypercalcemia

with a good understanding of the physiology controlling

calcium metabolism


Hypercalcemia

PTH

25(OH)D 1,25(OH)D

Increased Normal/decreased

Loss of function CaSR(Severe neonatal hyperPTH, FHH)

Vitamin D

intoxication

Sarcoidosis

Granulomatosis

Fat necrosis

Hypophophatasia

Heterogenous

Williams syndrome

25(OH)D

Janssen

PTHrP

Malignancy

Vitamin A intox.

• What is the PTH level of my patient?

• What is the 25(OH)Vitamin D level of my

patient?

• Expected low PTH, high 25(OH)D and normal (/high)1,25(OH)D

levels in case of hypervitaminosis D

In summary: the questions (you should ask

yourself) at this point (from the laboratory point

of view):

25

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Vitamin D intoxication:

How does that happen?

How can we prevent it?


Vitamin D intoxication: how common is

it?

0

20

40

60

80

100

120

140

160

180

200

2000 2002 2004 2006 2008 2010

aigu (flacon)

aigu (posologie)

chronique

Number of cases reported to the ToxZentrum Zurich

with acute or chronic vitamin D3 intoxication

Sharp increase of

both acute and

chronic VitD3

intoxication over

the last decade

Related to the different currently

available forms of vitamin D?

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

• Acute intoxication: • Relatively well described

• 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: • Relatively unclear

• From 2’000 to 4’000 IU per day for years29

Vitamin D intoxication: beware of the

level, beware of the duration!

29

Vitamin D intoxication: why does that

happen?

Multitude of vitamin D

available with different

dispensers and concentration 30

Double cause for

medication error

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 dispensers available

– CONFUSION!

• Over the counter vitamins– CONFUSION!

• Effective and presumed beneficial effects of vitamin D reported in the literature

– CONFUSION!

BUT errors still occurs !

31

Real and presumed beneficial effects of

vitamin as of 2010

Vitamin D

02000400060008000

100001200014000160001800020000

1960-

1970

1970-

1980

1980-

1990

1990-

2000

2000-

2010

Vitamin D

What have we done so far?

How can we improve public safety?


Contexte : Depuis 2000 en Suisse, les cas de surdosages par solutions de vitamine D3 chez l’enfant sont en

constante augmentation1.

Rappels : Indications : Prévention et traitement du rachitisme.

Posologies usuelles :

Prévention rachitisme : Nouveau né : 400 UI/jour et Prématurés : 400 à 800 UI /jour jusqu’à la fin de la

1ère

année de vie.

Traitement du rachitisme : 5000 UI à 10 000 UI/jour 1 semaine, puis 5000 UI/jour 6 semaines, puis 200 à

5000 UI /jour plusieurs mois (avec suppléments calciques si nécessaire).

VITAMINE D3 buvables chez l’enfant :

Eviter les surdosages

Ces spécialités sont souvent présentes dans les pharmacies internationales.4

En Suisse2,3

VIDE 3 Vitamine D3 Streuli Vitamine D3 Wild

Principe Actif Cholécalciférol

(4500 UI/ml)°

1 goutte = 100 UI

Cholécalciférol

(4000 UI/ml)°

1 goutte = 100 UI

Cholécalciférol

(20 000 UI/ml)

1 goutte = 667 UI

Excipient Ethanol 65% Ethanol 49% Huile (triglycéride

chaine moyenne)

Forme galénique Flacon compte-goutte

10 ml

Flacon compte-goutte

10 ml

Flacon avec Pipette

compte-goutte 10 ml

Prix (Chf)

/Remboursé (Ass. de base)

4.60

OUI

3.85

NON

22.50

NON

Posologie usuelle en

prévention du rachitisme 4 gouttes/jour 4 gouttes/jour 1 goutte/jour

Administration Mélanger avec une

boisson/aliment.

Mélanger avec

liquide.

Mélanger au lait/

bouillie.

Présentation

Version: 1.0

Date : 07.04.2011 (MHC )

Improving implementation / error

prevention

1. Leaflet for medical doctors

and nurses and midwifes for

the prevention of vitamin D

intoxication

In close collaboration with the

Central Pharmacy of the

Hospital

2. Ward round together with a

pharmacist twice a week

• Thanks to

– Marie Humbert, PharmD, PHEL, Central PharmacyVevey, for careful literature review and leafletconception and writing

– Christian Schaeli, PharmD, PHEL, for providingexcellent service with a pharmacist for weekly wardround in the pediatric department

– All pediatricians for anouncing all cases of hypervitaminosis in their patients


Date post:	03-Jul-2015
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Hypercalcemia and vitamin d intoxication slideshare

Health & Medicine