Saggese

Giuseppe Saggese

Vit-Ormone D: stato dell’arte

Caserta, 25 febbraio 2016

 Cenni storici

 Stato vitaminico e fattori di rischio

 Azioni scheletriche

 Azioni extra-scheletriche

 Profilassi con vitamina D

Vit-Ormone D: stato dell’arte

1634: prima comparsa del termine “rickets”

End of 19

century – first decades of 20

century

Treatment of rickets – Meidling Hospital, Wien

Outdoor treatment in the shadow

Outdoor treatment in the sun

(Rickets before the discovery of Vitamin D. O’Riordan JL et al, Sept 2014)

End of 19

century – first decades of 20

century

Prevetion of rickets

Cod liver oil

Edward Mellanby intuì il ruolo dei fattori dietetici nell’eziopatogenesi del rachitismo. Alimenti “… ricchi di vitamina A”, come l’olio di fegato di merluzzo, contenevano un “fattore antirachitico” .

1919

1921 Elmer McCollum identificò questo

fattore antirachitico come una nuova vitamina liposolubile, la quarta fino ad allora scoperta e per questo chiamata vitamina D.

End of 19

century – first decades of 20

century

Cenni storici

 Stato vitaminico e fattori di rischio

 Azioni scheletriche

 Azioni extra-scheletriche

 Profilassi con vitamina D

Vit-Ormone D: stato dell’arte

D2, D3

DBP (vitamin D biding protein)

D2, D3

Vitamin D endocrine system

(Holick. NEJM 2007)

25-OH-D, ng/ml

PTH, pg/ml

Vitamin D status in children and adolescents

(Dept. of Pediatrics, University of Pisa, n = 652, 2-21 yrs)

( Saggese G.et al Eur J Ped 2013)

Inverse relationship between PTH

and 25-OH-D levels

No hyperPTH in the individuals with 25-OH-D >30 ng/ml

We propose > 30 ng/ml as “sufficient”, 20-30 ng/ml as

“insufficient” and < 20 ng/ml as “deficient” 25-OH-D levels.

PTH as a functional indicator of vitamin D sufficiency in children

(n = 1,370; M=51%; age 1-16 yrs; supplemented 55%; Canada 43.4°N)

(Maguire JL et al, Feb 2014)

A nonlinear relationship was found between 25-OH-D and PTH, with a 25-OH-D plateau at 107 nmol/L (40

ng/ml, p< .001) above which PTH is minimized in young children

25-hydroxyvitamin D levels higher than currently recommended for young children may be required to

minimize PTH.

Vitamin D status (25-OH-D, ng/ml) in pediatric age Author’s proposed cut-off

Author Year Country n Age Severe

deficiencyDeficiency Insufficiency Sufficiency

Maguire, JAMA pediatrics 2013 Canada (Toronto) 1 898 1-5 - < 10 - > 30

Dong, Pediatrics 2010 USA 559 14-18 - < 20 21-29 > 30

Ganji, J Nutr 2012 USA (NHANES) 10 197 2-19 - - - > 30

Gordon, Arch Pediatr Adolesc Med 2008 USA 365 0,6-2,0 < 8 < 20 20-30 > 30

Kumar, Pediatrics 2009 USA (NHANES) 6 275 1-21 - < 15 15-29 > 30

Mansbach, Pediatrics 2009 USA (NHANES) 3 951 1-11 - < 20 20-30 > 30

Saintonge, Pediatrics 2009 USA (NHANES III) 2 692 12-19 - < 20 - -

Karalius, J Pediatr Endocrinol Metab 2014 USA (NHANES) 2 877 6-18 - < 12 < 16 > 20

Flores, Nutrition 2013 Mexico 1 025 2-12 < 8 8.0-19.9 20.0-29.9 > 30

Santos, BMC Ped 2012 Brazil 234 7-18 - < 20 20-29 > 30

González-Gross, Br J Nutr 2012 Europe 1 006 12,5-17,5 < 11 11-20 20-30 > 30

Absoud, Plos One 2001 Great Britain 1 102 4-18 - < 10 10-20 -

Hill, British Journal of Nutrition 2008 Ireland 1 015 12-15 < 10 < 20 - > 20

Andersen, Eur J Clin Nutr 2013 Denmark 54 11-13 - < 10 - > 20

Vierucci, Eur J Pediatr 2013 Italy 652 2-21 < 10 < 20 20-30 > 30

Rodríguez-Rodríguez, Minerva Pediatr 2011 Spain 102 9-13 < 12 < 20 - -

Djennane, Osteopor Int 2014 Algeria 435 5-15 - < 20 - > 20

Akman, Pediatrics Int 2011 Turkey 849 1-16 - < 20 20-30 > 30

Zhu, BMC Public Health 2012 China 6 008 0,1-16 < 10 < 20 20-30 > 30

Kim, Public Health Nutr 2012 Korea 2 062 10-18 - < 11 < 20 > 30

Lee, Public Health Nutr 2013 Korea 1 510 12-18 - < 20 - -

Nam, Public Health Nutr 2012 Korea (KNHANES) 1 504 12-18 - - < 20 > 20

Han, Pediatr Gastroenterol Hepatol

Nutr 2013 Korea 397 7-15 - - < 30 > 30

Houghton, Am J Clin Nutr 2010 New Zealand 193 12-22 - < 10 < 20 -

Determining Vitamin D status: comparison between available assays

• High-performance liquid chromatography (HPLC, Tandem Mass)

• Radioimmunoassay (RIA)

• Chemiluminescent immunoassay (CLIA)

There are substantial inter-assay differences between common commercially available assays for assessing vitamin D status.

N = 204

Age: 57.5 ± 9.7 yr

A single individual might be deemed deficient or sufficient, depending on the laboratory where the blood is tested.

Mean serum 25-OH-D by assay Cumulative proportion of subjects classified as insufficient (25-OH-D < 20 ng/ml) by assay

(Snellman G et al. Plos One 2010)

20,5 24,7

17,4

33,6 35,0

32,5

45,9 40,3

50,1

0 20 40 60 80 100

Entire sample Children Adolescents

Deficiency Insufficiency Sufficiency

Vitamin D status in italian children and adolescents

Dept. of Pediatrics, University of Pisa (n = 652*, 2-21 yrs)

p=0.02

n = 652 n = 283 n = 369

(25-OH-D < 20 ng/ml) (25-OH-D: 20-30 ng/ml) (25-OH-D ≥ 30 ng/ml)

62 patients (9.5%) had severe vitamin D deficiency

(25-OH-D < 10 ng/ml)

*Not supplemented in the year preceding the study

,Saggese G, et al. 2013

UDINE (46°N) n = 93 (0.2-18

years) 25-OH-D (ng/ml):

< 20 54.8%

VERONA (45°N) n = 59 (9-12 years)

25-OH-D (ng/ml):

• < 20 42.4%

• 20-30 45.8%

VERONA (45°N) n = 192 (0-18 years)

25-OH-D (ng/ml):

< 11 6.2%

Prevalence of hypovitaminosis D in Italy

(Marrone G et al. Eur J Nutr 2011)

(Chinellato I et al. Eur Respir J 2011)

PARMA (44°N) n = 270 (12-21 years)

25-OH-D (ng/ml):

• < 20 19.3%

• 20-30 36.3%

(Lippi G et al. Aging Clin Exp Res 2012 ) (Lippi G et al. CMAJ 2007)

PADOVA (45°N) n = 58 (1.1-15.3 years)

25-OH-D (ng/ml):

• < 20 50.0%

• 20-30 27.0%

(Mazzoleni S et al. Int J Pediatr Endocr 2012 )

PISA (43°N) n = 652 (2-21 years)

25-OH-D (ng/ml):

• < 20 45.7%

• 20-30 33.7%

ROMA (42°N) HELENA study n = 104 (12.6-17.4

years) 25-OH-D (ng/ml):

< 20 26.4%

(González-Gross M et al. Br J Nutr 2012;) (Vierucci F et al. Eur J Pediatr2013)

NOVARA (45°N) n = 62 (newborns)

25-OH-D (ng/ml):

75.6% < 20 ng/ml

(Cadario F et al. Ital J Pediatr 2013)

FIRENZE (43°N) n = 679 (0-18 years)

25-OH-D (ng/ml):

• < 20 55.4%

• 20-30 33.3%

(Stagi S et al. Italian J Pediatr In press)

PALERMO (37°N) n = 80 (4,6-16,0 years)

25-OH-D (ng/ml):

< 20 40%

20-30 35%

(Ciresi et al.)

Prevalence of hypovitaminosis D around the world

Studies adopting 30 ng/ml as cut-off of normality

(% of subjects with Vitamin D levels below 30 ng/ml : insufficient + deficient)

Europe, n = 1 006 (12.5-17.5 years)

80%

(Gonzales-Gross, Br J Nutr 2012)

Brazil, n = 234 (7-18 years)

91%

(Santos, BMC Ped 2012)

USA, n = 9 045 (12-19 years)

75 - 79%

(NHANES 1994-98, 2001-06, J Nutr 2012)

Korea, n = 2 062 (10 – 18 years)

96%

(Kim, Publ Health Nutr 2013) China, n = 6 008 (0.1-16 years) 94% 6-12 years, 100% 12-16 years

(Zhu, BMC Public Health 2012)

USA, n = 6 275 (1-21 years)

61%

(NHANES 2001-04, Pediatrics 2009)

USA, n = 3 951 (1-11 years)

95%

(NHANES 2001-06, Pediatrics 2009)

Algeria, n = 435 (5-15 years)

58% (September) – 65% ^(March)

(Djennane, Osteoporos Int 2014) Lebanon, n = 231 (0-18 years)

84%

(Hoteit, Metabolism 2014)

90 - 95%

5 - 10%

Ipovitaminosi D. Fattori di rischio

Contenuto di vitamina D (UI/100 g) nei più comuni alimenti

• Latte vaccino intero 3 - 40 / L

• Yogurt 89

• Emmenthal 44

• Parmigiano 28

• Burro 35

• Margarina fortificata 60 /

cucchiaio

• Fegato di manzo 40 - 70

• Carne di maiale 40 - 50

• Dentice, merluzzo, orata, palombo, 300 - 1500

sogliola, trota, salmone, aringhe

 Allattamento al seno esclusivo, senza supplementazione

 Adolescenza

 Obesità

 Esposizione solare ridotta o inefficiente

• latitudine

• stagione

• stile di vita

• creme solari

• abbigliamento (abitudini culturali)

• etnia

Ipovitaminosi D: fattori di rischio

23.5° N

23.5° S 66.5° N

Latitudine e sintesi cutanea di vitamina D

(Arabi A et al. Nat Rev Endocrinol 2010)

Pre-vit. D3, photosynthesis %

(Saggese G et al. It J Ped 1992)

Photosynthesis of pre-vitamin D3 from 7-dehydrocholesterol during the year, in vitro,in Pisa (latitude 43°N)

During winter and early spring adequate vitamin D status can be assured by body vitamin D stores or supplementation

Sun exposure and vitamin D status

…

Exposure of arms and legs for 5 to 30 minutes (depending on time of day, season, latitude, and skin pigmentation) twice a week is often adequate .

(Holick MF. 2007)

• Pediatricians should inform parents on the risks related to UVR exposition.

• Children’s outdoor activities should be planned to minimize peak- intensity midday sun (10AM to 4PM). Infants younger than 6 months should be kept out of direct sunlight.

• Shade, clothing and broad rimmed hats are the best sun protection measures for infants. Sunscreens should be applied to areas of the skin not protected by clothing (SPF > 15, applied every 2 hrs).

(Pediatrics, 2012)

( Gilaberte Y et al. 2014 ⁾

Sun exposure outside of peak sun times (10:00 AM to

3:00 PM in the spring, summer, and fall) has a limited

impact on the cutaneous synthesis of vitamin D

(Nature 2011)

northern USA (45°N)

Everyday outdoor exposure for children with skin type III and skin type IV rarely provides their minimum vitamin D3 needs (~ 600 IU/day), and children with skin type V may never meet their minimum daily vitamin D needs.

Solar UV doses of young Americans and vitamin D production

(Godar DE et al. Environmental Health Perspectives 2012)

Fattori di rischio di ipovitaminosi D in età pediatrica

 Allattamento al seno esclusivo, senza supplementazione

 Adolescenza

 Obesità

 Esposizione solare ridotta o inefficiente

• Latitudine

• Stagione

• Stile di vita

• Crema solare

• Abbigliamento (abitudini culturali)

• Etnia

Antirachitic activity of breast milk

ng / L IU / L Vitamin D 57.0 + 12 2.3 + 0.5

25-OH-D 239.8 + 30.9 47.9 + 6.2 Total antirachitic activity - 50.2 + 6.7

(Saggese G. et al. Riv Ped 39: 81, 1989)

Vitamin D status: breastfeeding vs formula feeding

(Department of Pediatrics, University of Pisa) 46 unweaned infants

(1 – 7 months)

• 25-OH-D levels were significantly different according to

supplementation and type of feeding.

• Exclusively breastfed infants are at higher risk of vitamin D

deficiency.

Breastfed not supplemented Formula fed

without additional supplementatiom

p<0.0004

Supplemented independently of type of feeding

9.4 ± 7.7 20.7 ± 5.0.

38.5 ± 15.3

Rickets in a High Social Class of Renaissance Italy:

the Medici children

Exploration of the Medici Chapels in the Basilica of San Lorenzo in Florence

Burials of 9 juvenile members of the Medici family

(16th–17th centuries).

(Giuffra V. et al. Int. J. Osteoarcheol 2013) (Watson T, Nature News 2013)

Don Filippino, son of Joan of Austria: antero-posterior X-ray projection of the skull (increased biparietal

diameter, high frontal bone and frontal bossing , wide coronal suture), deformed tibia and fibula

prolonged breastfeeding

Documentary sources &

13C and ¹⁵N bone collagen analysis



weaning around 2 years old

Fattori di rischio di ipovitaminosi D in età pediatrica

 Allattamento al seno esclusivo, senza supplementazione

 Adolescenza

 Obesità

 Esposizione solare ridotta o inefficiente

• Latitudine

• Stagione

• Stile di vita

• Crema solare

• Abbigliamento (abitudini culturali)

• Etnia non caucasica

20,5 24,7

17,4

33,6 35,0

32,5

45,9 40,3

50,1

0 20 40 60 80 100

Entire sample Children Adolescents

Deficiency Insufficiency Sufficiency

Vitamin D status in Italian children and adolescents

Dept. of Pediatrics, University of Pisa (n = 652, 2-21 yrs)

p=0.02

n = 652 n = 283 n = 369

(25-OH-D < 20 ng/ml) (25-OH-D: 20-30 ng/ml)

(25-OH-D ≥ 30 ng/ml)

(Vierucci F, Saggese G. et al. Eur J Ped 2013)

Vitamin D status during adolescence

(Hill TR et al, Br J Nutr 2008)

36%

(N = 1,015)

(Saintonge S et al, Pediatrics 2009)

14%

(N = 2,955)

Deficiency : 25-OH-D < 20 ng/ml

54.7%

(N = 2,062)

(Kim SH et al, Publ Health Nutr 2012)

(Santos BR et al, BMC Pediatrics 2012)

36.3%

(N = 234)

49.9%

(N = 427)

(Vierucci F, Del Pistoia M, Fanos M, Erba P, Saggese G. Ital J Pediatr Jun 2014)

Prevalence of hypovitaminosis D and predictors of vitamin D status in Italian healthy adolescents

Risk factors for hypovitaminosis D during adolescence

• Lifestyle: reduced sun exposure due to sedentary lifestyle (excessive computer use, TV), reduced time spent outdoor

• Obesity

• Chronic diseases

• Increased demand for calcium and phosphorus for growth

0 10 20 30 40 50 60 70 80 90 100

20 gg - 2 2 11 11 17 Adulti

Years

* p < 0.001 vs 2-11 years and adults

25/1,25

450/1 25/1,25

450/1

25/1,25

850/1 25/1,25

1000/1

*

*

(Saggese G et al. Riv Ital Ped, 1986)

1,25 (OH) 2D, pg/ml

1,25-dihydroxyVitamin D levels in children and adolescents

- -

20 days - 2 Adults

Clinical presentation of Vitamin D deficiency

(25-OH-D < 20 ng/ml) in children and adolescents

In older children and adolescents, low vitamin D levels mostly result in nonspecific subtle complaints.

(Torun E et al. JPEM 2015)

1-3 yrs 4-6 yrs 7-11 yrs 12-17 yrs

• Vitamin D deficiency is highly prevalent in overweight and obese children.

• The particularly high prevalence in severely obese suggests that targeted screening and treatment guidance is needed.

Prevalence of vitamin D deficiency among overweight and obese US children (NHANES 2003-2006).n. 12.292 (6-18 yrs)

(Pediatrics, 2013)

Cenni storici

Stato vitaminico e fattori di rischio

 Azioni scheletriche

 Azioni extra-scheletriche

 Profilassi con vitamina D

Vit-Ormone D: stato dell’arte

Vitamin D skeletal actions

 Rickets

 Bone mass acquisition

(Rauch F, Endocr Dev, 2003)

RICKETS

Rickets

Control

Mineralized bone

Unmineralized osteoid

Polso e mano Arti inferiori

Rachitismo

Lesioni radiologiche

RACHITISMO

Solco di Harrison

"Braccialetto" e "Caviglia rachitica“RA

18 cm 8 cm

Congenital rickets in a term newborn

(Tuoni C. et al. Medico e Bambino 2011)

• Mehdi : 25-OH-D: 9 ng/ml

• Mother : 25-OH-D : 8 ng/ml

• Medhi: born at term from cesarean section, Algerian origin (veiled mother).

• Wide anterior and posterior fontanelle.

• Platibasia, rachitic rosary.

• Veiled mother

• No vit. D supplem. in pregnancy

• Conceived in winter

(

Munns C.F. et al. J Clin Endocrinol Metab, dec 2015)

Nutritional rickets (NR), secondary to vitamin D

deficiency and/or dietary calcium deficiency, remains a

significant global, public health problem despite the

availability of supplementation and numerous

published guidelines for its prevention. This is

concerning because NR can have a major impact on the

health of infants, children, and adolescents, with

ramifications that persist into adulthood.

Vitamin D skeletal actions

 Rickets

 Bone mass acquisition

(Saggese G. et al, Min Pediatr 1986)

BMD, g/cm2

2-3 4-5 6-7 8-9 10-1112-1314-1516-1718-19 Years

Radial bone mineral density during childhood and adolescence

measured by single-photon absorptiometry (SPA)

Changes in bone mass with age

(Cooper C. 1990)

Males

Females PEAK BONE MASS

Picco di massa ossea

L'acquisizione di un ottimale picco di massa ossea rappresenta uno dei fattori più importanti per la prevenzione dell’osteoporosi.

Significato clinico

"Livello più elevato di massa ossea raggiungibile durante la vita come

risultato di una crescita normale”

Physical activity

Genetic factors

Nutritional factors Calcium

ACQUISITION

OF

BONE MASS

Vitamin D

The effect of maternal vitamin D concentration on fetal bone

• Fetus from vitamin D sufficient mothers have higher femur volume.

• Maternal vitamin D concentrations are significant predictors of femoral volume.

(Ioannou C et al. JCEM Nov 2012)

• n. 357 pregnant women

• fetal 3D ultrasound and maternal 25-OH-D levels were assessed at 34 wk

25-OH-D (ng/ml)

< 30 > 30

Femur volume adjusted for GA (ml)

Maternal 25-hydroxyvitamin D level and fetal bone growth assessed by ultrasound

(Galthen M. et al. Ultrasound Obstet Gynecol, 2014)

A systematic review

750 pubblications , 5 selected for inclusion in final review

Parameters studied:

humerus lenght (HL) and femour lenght (FL) and their Z-scores, femoral volume, femoral distal metaphyseal cross-sectional area (CSA), femoral proximal methaphyseal diameter (PMD), femoral mid-shaft diameter and crown-rump lenght^.

Low maternal 25(OH)D levels may affect fetal bone growth (FL, HL Z-scores), especially in cases of

simultaneous low calcium intake.

Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years

• N = 198 children (M = 104)

• Serum 25(OH)D levels measured at 34 weeks

• Singleton pregnancy, at term

• BMD assessment (DXA) at

9 yrs

(Javaid MK et al. Lancet 2006)

At 9 yr children BMD was positively related with 34 w maternal 25(OH)D.

Maternal vitamin D status seems to influence the programming of the acquisition of bone mass of the child.

Whole Body DXA

Children arealBMD (g/cm2 )

Lumbar spine DXA

Children arealBMD (g/cm2 )

Maternal serum 25(OH)D levels in late pregnancy (ng/ml)

N = 341 mother and offspring pairs

• Maternal serum samples at 18 wks gestation

• BMC and BMD measured by DXA in offspring at 20 yrs

Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age

Vitamin D deficiency in pregnant women is associated

with lower peak bone mass in their offspring at 20 yrs of age.

This may increase fracture risk in the offspring in later life

(Zhu K et al. JBMR 2013)

In the 132 offspring whose mothers had 25-OH-D levels <50 nmol/L (20 ng/ml) at 18 weeks gestation, total body BMC and BMD were significantly lower than in the offspring of women whose had 25OHD ≥ 50 nmol/L

Model 3 = adjustment for season of sampling, maternal factors and offspring factors (sex, birth weight, and age, height, lean mass and fat mass at 20 y)

J Clin Densitom, Mar 2015 Objective: associations between vitamin D status, bone mineral

content (BMC), areal bone mineral density (aBMD), and markers of calcium homeostasis in preschool-aged children.

Children: n=488; age range: 1,8-6,0 y

Higher vitamin D status (>75 nmol/L) is linked to

higher BMC and aBMD of forearm and whole body

in preschool-aged children (p<0,036).

The relation between 25-hydroxyvitamin-D with peak bone mineral density and body composition in healthy young adults

(n = 464, age 17-31 yrs)

° °

* ^

° p<0.05; *p<0.01; ^p<0.001

• 25-OH-D levels were related to the achievement of peak bone mass.

• Vitamin D status was negatively associated with body fat in females and positively with lean body mass in males^.

Correlation coefficients between 25-OH-D and DXA variables

(Boot AM et al. J Pediatr Endocr Met 2011)

Sufficient vitamin D status has a positive influence on bone mass and muscle strength in adolescent girls

(n = 301, 15.0 ± 0.4 yr)

Adequate vitamin D status is important in enhancing muscle strength and in attaining higher peak bone mass.

(Foo LH et al. J Nutr 2009)

• Sufficiency (25-OH-D > 20 ng/ml): 11.0%

• Deficiency (25-OH-D: 10-20 ng/ml): 57.8%

• Severe deficiency (25-OH-D < 10 ng/ml): 31.2%

2100 2150 2200 2250 2300 2350 2400 2450

Severe deficeincy Deficiency Sufficiency

Total body BMC

21,5 22,0 22,5 23,0 23,5 24,0 24,5 25,0 25,5

Severe deficeincy Deficiency Sufficiency

Handgrip muscle strenght

p<0.001 p=0.014

g K

g

“Mechanostat theory” (Frost, 1994)

Muscolo

Massa

ossea

“Mechanostat theory” (Frost,1994)

Vitamin D

Muscolo

• livelli intracellulari di calcio

• proteine contrattili

Massa

ossea

Cenni storici

Stato vitaminico e fattori di rischio

 Azioni scheletriche

 Azioni extra-scheletriche

 Profilassi con vitamina D

Vit-Ormone D: stato dell’arte

Extraskeletal actions of vitamin D

(Holick MF. NEJM 2007)

1,25(OH)₂D:

•

•

differentiation; induces apoptosis and inhibits

angiogenesis (reducing risk of cancer);

•

immunomodulatory action, reducing risk of

autoimmune diseases;

•

brain

1,25(OH)

D

• endocrine action

• paracrine action

• autocrine action

Vitamin D effects on the immune system

(Mora JR et al. Nat Rev Immunol 2008)

Influence of vitamin D status and vitamin D3 supplementation on Genome Wide

Expression of white blood cells.

A randomized double-blind clinical trial

• Any improvement in vitamin D status will significantly affect expression of genes linked to cancer, autoimmune disorders and cardiovascular disease.

• This study reveals for the first time molecular finger prints that help explain the extraskeletal health benefits of vitamin D^.

• 400 IU (n = 3) or 2.000 IU (n = 5) of vitamin D3 daily for 2 months.

• 1.5 fold alteration in the expression of 291 genes.

(Holick M., et al. PLoS One , 2013)

Extraskeletal Actions of vitamin D

Psoriasis

28-year old man with a more than 20-year history of psoriasis.

(Courtesy dr. Holick MF., 1979)

Condizioni pediatriche che possono essere associate a Ipovitaminosi D

• Malattie autoimmuni

(diabete mellito tipo 1, artrite idiopatica

giovanile)

• Obesità

• Sindrome Metabolica, Diabete Mellito Tipo 2

• Infezioni

(influenza, bronchiolite,

polmonite, TBC)

• Asma

• Dermatite atopica

• Allergia

alimentare

Cord blood 25(OH)D levels and the subsequent risk of lower respiratory tract infections (LRTI) in the first year of life:

the Ulm Birth Cohort Study

 Vitamin D deficiency at birth was associated with increased risk of LRTI during the first year, particularly in infants born in fall.

 Especially children born in fall might benefit from an intervention to increase cord blood vitamin D values in order to reduce risk of subsequent LRTI.

(Luczynska A. et al. Eur J Epidemiol, May 2014)

777 mother-infant pairs

Questionnaire completed by the child’s physician during the 1 year follow-up period Association between cord blood 25(OH)D concentration and risk of LRTI using predefined cutpoints of 25-OH-D concentrations. RR risk ratio, CI confidence interval

• A double-blind, single-center, randomized clinical trial

• OBJECTIVE: to determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring.

•623 women were recruited at 24 weeks of pregnancy.

•Follow-up of the children (N = 581) was completed when the youngest child reached age 3 yr

•Vitamin D3 (2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D3 as part of usual

pregnancy care.

The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years, but the number of wheezing episodes was significantly lower in the children of mothers with vitamin D supplementation.

January 2016

End point in children during the first 3 years Vitamina D3 group (2.800 IU)

control group (400 IU)

p

Persistent wheeze (n. 47) 16% (n. 57) 20% NS

Episodes of troublesome lung symptoms 5.9 % 7.2 % 0,02

(Chawes Bo L. et al.)

• A randomized, double-blind, placebo-controlled trial conducted in 3 centers across the United States

• OBJECTIVE: To determine whether prenatal vitamin D (cholecalciferol) supplementation can prevent asthma or recurrent wheeze in early childhood.

• 881 pregnant women between (18-39 yrs) at high risk of having children with asthma were randomized at 10 to 18 weeks’ gestation.

• 440 women were randomized to receive daily 4.000 IU vitamin D + a prenatal vitamin containing 400 IU vitamin D

• 436 women were randomized to receive a placebo + a prenatal vitamin containing 400 IU vitamin D.

• 806 infant were included in the analyses for the 3-year

January 2016

In pregnant women at risk of having a child with asthma, with supplementation of 4400 IU/d of vitamin D, the incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1%, but this did not meet statistical significance.

Longer follow-up of the children is ongoing to determine whether the difference is clinically important.

4.400-IU group (n. 405) 400-IU group (n. 401) p

asthma or recurrent wheeze in born infant (n. 98) 24,3% (n. 120) 30,4% NS (p = 0,051) 25-OH D levels of 30 ng/mL or higher in the

women

(n. 289) 74.9% (n. 133) 34.0% p < 0,001

(Litonjua A.A. et al.)

Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren

• Randomized, double-blind, placebo- controlled trial conducted from

December 2008 through March 2009 comparing vitamin D

supplementation (1.200 IU/die) with placebo.

• N = 430 (10.2 yr; range 6-15)

• 56% previous diagnosis of asthma

Vitamin D supplementation during the winter season 1) reduced the incidence of influenza A and 2) prevented asthma attacks in children with asthma.

(Urashima, M et al. Am J Clin Nutr 2010) 0

2 4 6 8 10 12 14 16 18 20

Vitamin D Placebo

Asthma attacks in patients with asthma

%

Cases of influenza A

p<0.01 p<0.05

Randomised, double-blind, placebo-controlled trial

Aims

to evaluate whether a deficit in vitamin D (VD) is associated with an increased risk of recurrent acute otitis media (AOM),

to evaluate whether VD supplementation is effective in reducing the number of AOM episodes in otitis-prone children.

58 children received placebo + 58 children were treated with VD

Conclusions

 The likelihood of AOM was significantly reduced in the patients whose serum VD concentrations were ≥30 ng/mL.

 The number of children experiencing ≥1 AOM episode during the study period was significantly lower in the treatment group (26 versus 38; P = 0.03).

 There was a marked difference in the number of children who developed uncomplicated AOM (P < 0.001). (Pediatr Infect Dis J , Oct 2013)

11 placebo-controlled studies of 5.660 patients 5 conducted on the pediatric population

Vitamin dose: 1.600 IU/day

IR prevention

IR prevention and therapy

Results indicate that vitamin D has a protective effect against RTI (lower and upper), and dosing once-daily seems most effective than bolus doses (1-3 months).

Due to heterogeneity of included studies and possible publication bias, results should be interpreted with caution.

Plos One, June 2013

• 145 enrolled infants

• Vitamin D-deficient infants were younger than infants with 25-OH-VitD 20 ng/mL (2,8vs4,5 months, respectively;

p=0,04) and were less likely to consume infant’s formula (42,9%vs87,0%, respectively; p<0,01).

• The following indicators of acute bronchiolitis severity did not differ between infants who were vitamin D-deficient and nondeficient: duration of hospitalization (p=0,053), lowest oxygen saturation (p=0,45), and bronchiolitis severity score (p=0,97), even after adjusting for age, and for infant’s formula consumption.

Among this cohort of infants that were hospitalized for RSV bronchiolitis, vitamin D status at the time of bronchiolitis was not

associated with indicators of acute bronchiolitis severity.

(Beigelman A et al, J of Ped Inf Dis Society, 2014)

Does vitamin D supplementation prevent acute respiratory tract infections?

in children?

Arch Dis Child, September 2015

Salma Rashid Ali, Helen McDevitt

 Studies have suggested an association between low serum vitamin D levels and an increased risk of respiratory tract infections; however, evidence for a causal association is inconclusive (grade B).

 Prescription of vitamin D supplements should not be undertaken unless vitamin D deficiency is demonstrated, or new trials are completed (grade B).

Evidence suggests that higher serum levels of 25(OH)D are associated with a reduced risk of asthma exacerbations, but there is little evidence to suggest an association with asthma incidence, prevalence or severity.

2015

Meta-analysis of 4 studies, which measured asthma exacerbations in children:

high serum 25(OH)D concentrations were associated with reduced

asthma exacerbation (RR = 0.64, 0.5–0.81).

Aim: Systematic review of 23 articles investigated the relationship between serum 25(OH)D and asthma.

18 studies conducted on children and adolescents, whose ages ranged from birth to 20 years.

 Meta-analysis suggested a statistically significant reduction (RR 0.41, CI 0.27-0.63) in asthma exacerbation with high dose vitamin D therapy.

 These results should be confirmed through larger well-designed randomised controlled trials.

• 5 studies were identified that met study eligibility and assessed final data synthesis.

• Range trial size was 17-430 participants and the average daily dose of cholecalciferol ranged from 500 to 2.000 IU/day.

• Overall study methodological quality was high, but some heterogeneity in population and vitamin D dosing regimen was evident.

Journal Asthma, May 2015

Objectives: to evaluate the efficacy and safety of vitamin D supplementation as a treatment or adjunct treatment for asthma.

Randomized controlled trials provide some low- quality evidence to

support vitamin D

supplementation for the reduction of asthma exacerbations.

Evidence on the

benefits of vitamin D supplementation for other asthma-related outcomes in children is either limited or

inconclusive.

8 RCTs, 573 children aged 3 to 18 years

Vitamin D and increasing incidence with latitude of type 1 diabetes Evidence for an association?

(Hyppönen E. Diabetes Obes Metab 2010) Latitude (°)

Diabetes incidence rate per 100.000

(n° 9)

(n° 8)

(n° 3) 9 studies accepted for analysis

6 studies: case-control

1.860 cases,6.243 controls 3 studies: cohort design

171 cases, 14.264 controls Follow-up: from 5 to 31 years

Most cases aged < 18 years old

2 studies: age range between 0 and 30 years old

The findings of this meta-analysis suggest that vitamin D intake during early life (first year/childhood) is associated with a reduced risk of type 1 diabetes. There was not enough evidence supporting an association between maternal intake of vitamin D and type 1 diabetes risk in the offspring.

The pooled odds ratio for type 1 diabetes comparing vitamin D supplementation with non supplementation during early life was 0.71 (95% confidence interval [CI], 0.51–0.98)

Cenni storici

Stato vitaminico e fattori di rischio

 Azioni scheletriche

 Azioni extra-scheletriche

 Profilassi con vitamina D

Vit-Ormone D: stato dell’arte

Health benefits and disease incidence prevention related to serum 25-OH-D levels

(Holick MF. Vitamin D: Physiology, Molecular Biology, and Clinical Applications., 2010)

 30 ng/ml

< 20 ng/ml

Livelli di 25-OH-D

Ipovitaminosi D e conseguenze cliniche

20-30 ng/ml

Azioni scheletriche

Azioni extra-scheletriche

(ipovitaminosi D: “fattore modificabile di rischio”) sufficienza

deficienza insufficienza

Vitamin D Recommended Dietary Allowance

in the first year of life

Age groups ^{IOM 2011}

IU/die

AAP 2012 IU/die

LARN 2012 IU/die

ES 2011 IU/die

Infants

(AI)

0 - 6

months 400 400 * - 400 – 1.000

6 - 12

months 400 400 * 400 400 – 1.000

Subjects at risk for vitamin D deficiency

* Every infant who do not ingest at least 1 L of Vitamin D–fortified milk (containing at least 400 IU/L) daily initiating within days of birth.

Type 1 infant formulas Type 2 infant formulas

 Indipendente dal tipo di allattamento.

 Inizio: a partire dai primi giorni di vita.

 Modalità di somministrazione: in gocce per il più facile calcolo delle dosi ed il volume ridotto.

 Forme di vitamina D da utilizzare: D2 e D3 ugualmente efficaci.

 Non devono essere utilizzati i metaboliti della vitamina D.

Espongono a rischio di ipercalcemia e non sono in grado di mantenere e/o ripristinare le scorte di vitamina D.

Profilassi durante il 1° anno di vita

Vitamin D, the placenta and pregnancy

(Liu NQ, Hewison M. Arch of Biochem and Piophysics 2012)

Cord blood 25-OH-D: 80-100% of mother values Neonatal 25-OH-D: 50-70% of mother values

Placenta

 Indipendente dal tipo di allattamento.

 Inizio: a partire dai primi giorni di vita.

 Modalità di somministrazione: in gocce per il più facile calcolo delle dosi ed il volume ridotto.

 Forme di vitamina D da utilizzare: D2 e D3 ugualmente efficaci.

 Non devono essere utilizzati i metaboliti della vitamina D.

Espongono a rischio di ipercalcemia e non sono in grado di mantenere e/o ripristinare le scorte di vitamina D.

Profilassi durante il 1° anno di vita

Fabbisogni Vitamina D tra 1 e 18 anni

Fabbisogni Vitamina D tra 1 e 18 anni

Tutti i bambini e

adolescenti devono

essere sottoposti a

profilassi?

Dopo il 1° anno di vita, lo stato vitaminico è influenzato da:

 esposizione alla luce solare

 presenza di condizioni di rischio

Profilassi dopo il 1° anno di vita, nel bambino e nell’adolescente

Il mantenimento di un adeguato stato vitaminico è

importante durante tutta l’età pediatrica, fino

all’adolescenza per l’effetto della vitamina D sui

processi di acquisizione della massa ossea

Profilassi dopo il 1° anno di vita, nel bambino e nell’adolescente

Alcune Società Scientifiche consigliano la profilassi solo nei soggetti con fattori di rischio:

- ridotta esposizione solare: profilassi da novembre ad aprile

- condizioni patologiche permanenti: profilassi per tutto l’anno

Altre Società raccomandano una profilassi

continuativa anche nei soggetti sani, in

particolare nel periodo adolescenziale (Society

for Adolescent Health and Medicine).

Profilassi dopo il 1° anno di vita, nel bambino e nell’adolescente

Modalità di somministrazione - giornaliera (600 UI/mese)

- dosi intermittenti: 18.000-30.000 UI/mese

10.000-15.000 UI/15 giorni

Non devono essere somministrati i metaboliti

della vitamina D

 Il dosaggio routinario dei livelli di 25(OH)D non è consigliato prima di iniziare o durante la profilassi con vitamina D.

 Si consiglia la valutazione dei livelli di 25(OH)D (basale ed annualmente) solo nei soggetti affetti da specifiche condizioni patologiche o in trattamento con farmaci interferenti con il metabolismo della vitamina D che richiedono profilassi continuativa.

Profilassi e dosaggio della vitamina D

EAR % (Estimated Average Requirement) RDA % (Recommended Dietary Allowance)

Intake di calcio espresso come percentuale dei fabbisogni raccomandati (IOM 2010)

Clinica Pediatrica Università di Pisa (n = 272; M = 124)

0 10 20 30 40 50 60 70 80 90 100

Tutti M F Tutti M F Tutti M F

Bambini Adolescenti Giovani adulti

EAR% RDA%

%

n = 225 (9.0-18.0 aa) n = 117 (4.0-8.9 aa)

EAR: 800 mg/die RDA: 1000 mg/die

EAR: 1100 mg/die RDA: 1300 mg/die

Ca and P supply for the fetus during gestation

During the third trimester of gestation, the supply of calcium for the fetus is up to 100-120 mg/kg/day, and phophorus up to 75 mg/kg/die

(Thandrayen K, Pettifor JM. Endocrinol Metab Clin North Am 2010)

Christopher S. Kovacs

Physiological Reviews Published 1 October 2015 Bone Development and Mineral Homeostasis in the Fetus and Neonate:

Roles of the Calciotropic and Phosphotropic Hormones

Physiological evolution of bone mineral density during the last trimester of gestation and during the first year of life in term and preterm infants

(Rigo J et al. J of Pediatrics 2006)