1. Vitamin D in Jordanian Infants
Najwa Khuri-Bulos
Professor of Pediatrics and Infectious Disease
Jordan University Hospital

2. Outline about vitamin D
Sources of vitamin D
Classical action on bone
Non classical functions
Normal vitamin D intake
Pts at risk of vitamin D deficiency
Clinical manifestations of vitamin D deficiency
Laboratory diagnosis of vitamin D deficiency
Treatment
Status of vitamin D in jordan with special reference to children
Prevention of vitamin D deficiency

3. Vitamin D Rickets first described in the 17th century
Relationship to fat soluble vitamin and dietary vitamin D in early 20th century .
This is the only vitamin that is synthesized by human body by interaction of skin with sunshine
Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D

5. Vitamin D pathways for the two sources of vitamin D

6. Definition Vitamin D2, Ergosterol plant sources
Vitamin D3 Cholecalciferol from skin
also manufactured from lanolin
25,0H vitamin D Calcidiol
1,25 OH vitamin D Calcitriol

7. Vitamin D actions Vitamin D promotes calcium absorption in the gut
Maintains adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and prevents hypocalcemic tetany.
It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts

8. Vitamin D actions Actions on bone Increased Bone density
Increased calcium and PO4 deposition
Decreased osteoporotic fracture

9. Vitamin D actions Immune response Increased regulatory T cell
Increased oxidative burst
Increased Cathelicidin
Decreased cytokine release

10. Vitamin D actions Pregnancy ?Decreased pre eclampsia
Decreased myopathy
Decreased calcium malabsorption
Decreased bone loss
?Decreased risk of CS
Mulligan et al,
American Journal of Obstetric and Gynecology, 2010

11. Vitamin D action Pancreas Decreased insulin resistance
Decreased type 1 diabetes
Increased insulin secretion

12. Vitamin D actions Children Decreased SGA Decreased risk of rickets
Decreased risk of hypocalcemia
Infantile cardiomyopathy if deficient
Decreased severity of RSV infection
Increased incidence of asthma if deficient

13. Sources of vitamin D Normal diets < 10%
Must be synthesized by the skin or taken as dietary supplement
Skin, must have direct exposure to sunshine minutes at noon hours
Exposure not acceptable behind glass
No sun block applied
Dark skin people need more exposure to have same level of vitamin D

14. Vitamin D in the newborn
Highly correlated with vitamin D in the pregnant mother. Fetus totally dependent on maternal sources of vitamin D and Calcium
After birth, Breast milk is a very poor source of vitamin D, only Units/Litre
Hence Must supplement infants very early in life
Infants need 400 IU/ per day
Even formula fed babies need vitamin D supplementation

15. Vitamin D status 1 nmole/litre = 0.4 ngm /ml
Vitamin D levels are Inversely related to parathormone levels
These level off at nanograms determined to be the adequate range
Calcium absorption increased at > 30 nanograms

16. Vitamin D 25 OH levels and vitamin D status
Definition
<20ng/ml <50 mm/L Deficient
20-30ng/ml mm/L Insufficient
>30- ng/ml >75 mm/L Normal, optimal
>150 ng/ml >375 mm/L Toxic

17. Vitamin D sources Dietary Supplementation Sunlight
Wavelength penetrates the skin and converts 7 dehydrocholesterol to previtamin D3
Any excess of these is destroyed by sunlight. There is no toxicity from sun exposure.
Vitamin D from the skin and dietary sources is metabolized by the liver to become 25 OH and the final 1 hydroxylation step occurs in the kidney to lead to 1, 25 OH vitamin D which is the active form
This final renal step is highly regulated by parathormone and serum calcium and PO4 levels

18. Sun exposure and vitamin D
Ultraviolet (UV) B radiation with a wavelength of 290–320 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to previtamin D3, which in turn becomes vitamin D3.

19. Adequate intake of vitamin D per day
Infants <12 month IU
Children >1 yr IU
Adults, pregnant IU
>70 yrs IU
Mainly obtained from fish and fortified foods or exposure to sunshine
1 ug=40 units

20. People at risk of vitamin D deficiency
Breast fed infants
Older adults
People with limited sun exposure
People with dark skin
People with fat malabsorption
People with BMI>30

21. Causes of vitamin D deficiency in children and adolescents
Reduced intake or synthesis of vitamin D3
Being born to a vitamin D-deficient mother; dark-skinned women, or women of who actively avoid exposure to sunlight or are veiled
Prolonged breastfeeding
Dark skin colour
Reduced sun exposure — chronic illness or hospitalisation, intellectual disability, and excessive use of sunscreen
Low intake of foods containing vitamin D

22. Causes of vitamin D deficiency in children and adolescents
Abnormal gut function or malabsorption
Small-bowel disorders (eg, coeliac disease)
Pancreatic insufficiency (eg, cystic fibrosis)
Biliary obstruction (eg, biliary atresia)

23. Causes of vitamin D deficiency in children and adolescents
Reduced synthesis or increased degradation of 25-OHD or 1,25-(OH)2D
Chronic liver or renal disease
Drugs: rifampicin, isoniazid and anticonvulsants

24. Osseous signs of vitamin D deficiency (common to less common)
Swelling of wrists and ankles
Rachitic rosary (enlarged costochondral joints felt lateral to the nipple line)
Genu varum, genu valgum or windswept deformities of the knee
Frontal bossing
Limb pain and fracture
Craniotabes (softening of skull bones, usually evident on palpation of cranial sutures in the first 3 months)
Hypocalcaemia — seizures, carpopedal spasm
Myopathy, delayed motor development
Delayed fontanelle closure
Delayed tooth eruption
Enamel hypoplasia
Raised intracranial pressure
secondary hyperparathyroidism

25. Radiological features
Cupping, splaying and fraying of the metaphysis of the ulna, radius and costochondral junction
Coarse trabecular pattern of metaphysis
Osteopenia
Fractures

31. Treatment of Hypocalcemia
< 1 month of age
10% calcium gluconate: 0.5 mL/kg (max 20 mL) intravenously over 30–60 minutes.
Calcium: 40–80 mg/kg/day (1–2 mmol/kg/day) orally in 4–6 doses,
Calcitriol ( vitamin D3) : 50–100 ng/kg/day or in 2–3 doses until serum calcium level is > 2.1 mmol/L or 8 mg/L

32. Treatment of vitamin D deficiency
ACUTE Management
Age
< 1 month
Vitamin D: 1000 IU (25 μg) daily for 3 months.
Maintenance
Vitamin D: 400 IU (10 μg) daily or 150 000 IU (3750 μg) at the start of autumn.‡
Monitoring
1 month: Serum calcium and alkaline phosphatase.
1-12 months
Vitamin D: 3000 IU (75 μg) daily for 3 months, or 300 000 IU (7500 μg) over 1–7 day
3 months: Serum calcium, magnesium, phosphate, alkaline phosphatase, calcidiol, parathyroid hormone. Wrist x-ray to assess healing of rickets.
Annual: Calcidiol.
>12 months
Vitamin D: 5000 IU (125 μg) daily for 3 months, or 500 000 IU (15 000 μg) over 1–7 days.
Calcitriol , 1, 25 OH vitamin D, Calcidiol, 25 oh vitamin D

33. Adequate calcium intake
Age
Calcium intake
0-6 months
210 mg
6-12 months
270 mg
1-3 years
300 mg
4-8 years
800 mg
9-18 years
1300 mg

34. Recent Studies on vitamin D in Jordanians
2011, Batieha Et al Ann Nutr Met
37% females were deficient
5.6% of males were deficient
2010 Abdul Razzak , Pediatric International
28% deficient, 16% severe
Association with breast feeding was found
National micronutrient survey 2010
women deficient < 12 ng/ml > 50%
children 1-6 yrs< 11 ng/ml 10-20%
Takruri, Khuri-Bulos et al , JMJ, 1-6 yrs also 30% insufficient

35. Study on newborn and pregnant mothers and vitamin D
Ongoing study of vitamin D in newborn
More than 3000 vitamin D levels obtained in the first day of life
Range from ng/ml
Cut off for this is 20 ng/ml
99.8 were vitamin D deficient below 10 ng/ml
Mean was 3 ng/ml !!!
100 Mothers who were tested also had decreased vitamin D level. Almost uniformly less than 10ng/ml

36. Vitamin D levels in newborns in Jordan
Overwhelming majority >99% are deficient < 15 nanograms/ml

37. What should be done
Increased sun exposure, not consistent with current social norms
Supplementation of the different age groups
Fortification of food items, most useful
Which food item?? Oil preferable but flour more feasible since it is cheaper and is the main staple food
For infants must give vitamin d drops
Pregnant women should be studied further and supplementation during pregnancy must be done

38. Thank you

40. Vitamin D activity
Activated T lymphocytes and macrophages have increased VDR This stimulates antibody mediated and phagocyte mediated cytotoxicity
Clinical association with asthma and RSV if cord blood vitamin D is deficient
Increased risk of cesarian section also with vitamin D deficiency

41. Metabolism of 25-Hydroxyvitamin D to 1,25-Dihydroxyvitamin D for Nonskeletal Functions.
Figure 2. Metabolism of 25-Hydroxyvitamin D to 1,25-Dihydroxyvitamin D for Nonskeletal Functions. When a macrophage or monocyte is stimulated through its toll-like receptor 2/1 (TLR2/1) by an infectious agent such as Mycobacterium tuberculosis or its lipopolysaccharide, the signal up-regulates the expression of vitamin D receptor (VDR) and 25-hydroxyvitamin D-1α-hydroxylase (1-OHase). A 25-hydroxyvitamin D [25(OH)D] level of 30 ng per milliliter (75 nmol per liter) or higher provides adequate substrate for 1-OHase to convert 25(OH)D to its active form, 1,25 dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D travels to the nucleus, where it increases the expression of cathelicidin, a peptide capable of promoting innate immunity and inducing the destruction of infectious agents such as M. tuberculosis. It is also likely that the 1,25(OH)2D produced in monocytes or macrophages is released to act locally on activated T lymphocytes, which regulate cytokine synthesis, and activated B lymphocytes, which regulate immunoglobulin synthesis. When the 25(OH)D level is approximately 30 ng per milliliter, the risk of many common cancers is reduced. It is believed that the local production of 1,25(OH)2D in the breast, colon, prostate, and other tissues regulates a variety of genes that control proliferation, including p21 and p27, as well as genes that inhibit angiogenesis and induce differentiation and apoptosis. Once 1,25(OH)2D completes the task of maintaining normal cellular proliferation and differentiation, it induces expression of the enzyme 25-hydroxyvitamin D-24-hydroxylase (24-OHase), which enhances the catabolism of 1,25(OH)2D to the biologically inert calcitroic acid. Thus, locally produced 1,25(OH)2D does not enter the circulation and has no influence on calcium metabolism. The parathyroid glands have 1-OHase activity, and the local production of 1,25(OH)2D inhibits the expression and synthesis of parathyroid hormone. The 1,25(OH)2D produced in the kidney enters the circulation and can down-regulate renin production in the kidney and stimulate insulin secretion in the beta islet cells of the pancreas.
Holick MF. N Engl J Med 2007;357:

42. Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism.
Figure 1. Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism. During exposure to solar ultraviolet B (UVB) radiation, 7-dehydrocholesterol in the skin is converted to previtamin D3, which is immediately converted to vitamin D3 in a heat-dependent process. Excessive exposure to sunlight degrades previtamin D3 and vitamin D3 into inactive photoproducts. Vitamin D2 and vitamin D3 from dietary sources are incorporated into chylomicrons and transported by the lymphatic system into the venous circulation. Vitamin D (hereafter “D” represents D2 or D3) made in the skin or ingested in the diet can be stored in and then released from fat cells. Vitamin D in the circulation is bound to the vitamin D–binding protein, which transports it to the liver, where vitamin D is converted by vitamin D-25-hydroxylase to 25-hydroxyvitamin D [25(OH)D]. This is the major circulating form of vitamin D that is used by clinicians to determine vitamin D status. (Although most laboratories report the normal range to be 20 to 100 ng per milliliter [50 to 250 nmol per liter], the preferred range is 30 to 60 ng per milliliter [75 to 150 nmol per liter].) This form of vitamin D is biologically inactive and must be converted in the kidneys by 25-hydroxyvitamin D-1α-hydroxylase (1-OHase) to the biologically active form — 1,25-dihydroxyvitamin D [1,25(OH)2D]. Serum phosphorus, calcium, fibroblast growth factor 23 (FGF-23), and other factors can either increase (+) or decrease (–) the renal production of 1,25(OH)2D. 1,25(OH)2D decreases its own synthesis through negative feedback and decreases the synthesis and secretion of parathyroid hormone by the parathyroid glands. 1,25(OH)2D increases the expression of 25-hydroxyvitamin D-24-hydroxylase (24-OHase) to catabolize 1,25(OH)2D to the water-soluble, biologically inactive calcitroic acid, which is excreted in the bile. 1,25(OH)2D enhances intestinal calcium absorption in the small intestine by interacting with the vitamin D receptor–retinoic acid x-receptor complex (VDR-RXR) to enhance the expression of the epithelial calcium channel (transient receptor potential cation channel, subfamily V, member 6 [TRPV6]) and calbindin 9K, a calcium-binding protein (CaBP). 1,25(OH)2D is recognized by its receptor in osteoblasts, causing an increase in the expression of the receptor activator of nuclear factor-κB ligand (RANKL). RANK, the receptor for RANKL on preosteoclasts, binds RANKL, which induces preosteoclasts to become mature osteoclasts. Mature osteoclasts remove calcium and phosphorus from the bone, maintaining calcium and phosphorus levels in the blood. Adequate calcium (Ca2+) and phosphorus (HPO4 2−) levels promote the mineralization of the skeleton.
Holick MF. N Engl J Med 2007;357:

43. The immune system and Vitamin D
Calcitriol (I,25, OH) has immune modulating function
First described with sarcoidosis
Calcitriol produced by macrophages in the granulomas lead to hypercalcemia
Calcitriol also inhibits proliferation of MTB in cells
This is not subject to feedback as is the kidney
Vitamin D deficiency has been shown to increase the risk of infection especially respiratory infection

44. Vitamin D functions
Vitamin D has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation
Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D
Serum concentration of 25(OH)D is the best indicator of vitamin D status. It reflects vitamin D produced cutaneously and that obtained from food and supplements and has a fairly long circulating half-life of 15 days

45. Sun exposure and vitamin D
Complete cloud reduces UV energy by 50%; shade
UVB radiation does not penetrate glass, so exposure to sunshine indoors through a window does not produce vitamin D
Sunscreens with a sun protection factor (SPF) of 8 or more appear to block vitamin D-producing UV rays