Cholecalciferol (D3) - sources Vitamin D. Endogenous - synthesis in the skin

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1 Department of Pediatrics and Developmental Disorders Medical University of Bialystok Vitamin D metabolism and clinical manifestation of its deficit Pawel Abramowicz M.D., Ph.D. Jerzy Konstantynowicz MD, PhD, Assoc. Prof. Vitamin D Refers to a group of 5 fat-soluble secosteroids The two major forms are: Vit. D2 ergocalciferol (plants, mushrooms) Vit. D3 cholecalciferol (animal sources) Vitamin D without a subscript refers to either D 2 or D 3 or both. These are known collectively as calciferol. [ Cholecalciferol (D3) - sources Endogenous - synthesis in the skin Exogenous - natural dietary sources - vitamin D fortified products - dietary supplements 1

2 Synthesis in the skin Major (90%), natural and safe source 7DHC (7- dehydrocholesterol) PREVITAMIN D3 UVB light at wavelenghts nm photochemically converts 7DHC into cholecalciferol CHOLECALCIFEROL VITAMIN D3 Similarly, ergosterol is converted to ergocalciferol (vitamin D2) Synthesis in the skin Skin exposure to the sunlight fully provide daily requirement for vitamin D. 10,000 to 20,000 IU of vitamin D are produced in 30 minutes of whole-body exposure. Sunscreen with a sun protection factor (SPF) of 8 decreases vitamin D synthetic capacity by 95%, whereas sunscreen with an SPF15 by 98%. Skin synthesis in our geographical latitudes is effective only between May and September and only if exposure occurs between 10.oo and 15.oo Factors which reduce vitamin D biosynthesis in the skin Age (prematurity, elderly) Dark pigmentation of the skin Geographical and climatic factors Lifestyle, cultural and religious habits. Sunscreens use 2

3 Dietary sources of vit.d Dietary sources of vit.d! Exogenous sources Dietary supplements Currently, 26 pharmaceutical drugs containing cholecalciferol are available They are performed in various dosage forms such as: Drops Twist-off capsules Capsules Tablets Spray 3

4 Dietary products due to Polish feeding habits are poor source of vitamin D Vitamin D metabolic activation 7-dehydrocholesterol PREVITAMIN D3 1. UV SKIN FOOD 25-hydroxylase CHOLECALCIFEROL VITAMIN D3 25--hydroksycholecalciferol OH D ά-hydroxylase Active form of vit.d CALCITRIOL 1,25(OH)2D3 PTH hypocalcemia hypophosphatemia 4

5 Liver 25 hydroxylase in hepatocytes converts cholecalciferol to calcidiol 25(OH)D3 CALCIDIOL, CALCIFEDIOL - active metabolite of long half-life time (~ 3 wks.) - 25OHD indicate person's vitamin D status. Kidney 1-alfa-HYDROXYLATION - 1α-hydroxylase converts calcidiol to the biologically active form of vitamin D 1,25(OH) 2 D 3 - CALCITRIOL 1-hydroxylation of 25(OH)D 3 occurs mainly in renal proximal tubules, and also in many other tissues (peripheral 1α-hydroxylases) 1,25(OH) 2 D 3 activity Mechanisms classic non-classic - calcemic: supports calcium and phosphorus homeostasis - auto- and paracrine activity in many tissues and cells; pleiotropic effects. 5

6 Classic 1,25(OH) 2 D 3 activity Active vitamin D bonds to the VDR in the: - intestine - kidney - bone - parathyroid gland and leads to the maintenance of calcium and phosphorus levels Intestinal activity of 1,25(OH) 2 D 3 Promoting of calcium absorption - Increase calcium influx into the enterocyte - Facilitate transport of calcium through basement membrane of enterocyte into the circulation Skeletal activity of 1,25(OH) 2 D 3 Supports effective mineralization of osteoid tissue by keeping serum concentration of Ca and P in balance. Stimulates collagen secretion by osteoblasts. Collagen fibers constitute a fremework for hydroxyapatite (mineral substance) accumulation. 6

7 Renal activity of 1,25(OH) 2 D 3 Protects from excesive urinary calcium and phosphorus excretion Stimulates calcium reabsorption Non-classic pleiotropic activity of 1,25(OH)2D3 - is involved in cell proliferation and differentiation. - has antiproliferative and proapoptotic activity - regulates hormonal secretion - regulates reproductive functions - affects the immune system VDRs Present in over 30 tissues and organs - bone - skin - intestine - muscles - kidneys - brain - parathyroid glands - immune system - endocrine system - heart - reproductive system - breast - gonads, prostate - other 7

8 THE VITAMIN D AUTOCRINE/PARACRINE SYSTEM? Janssens W et al (2009) Am J Respir Crit Care Med 179: VITAMIN D DEFICIENCY Vitamin D status based on a serum calcidiol conc. (25OHD) Status Serum 25(OH)D nmol/l ng/ml Management Deficiency Should be treated medically Insufficiency > Continue/increase supplementation Optimal > Continue supplementation High optimal > Continue/decrease dose Potentially toxic > Toxic level >500 >200 Discontinue until obtaining target serum 25(OH)D concentration May need specific medical intervention to correct toxic effects 8

9 DEFICYT NORMA Risk factors for vitamin D deficiency Age prematurity, beeing elderly Dark skin Obesity Poor dietary supply (in infants being exclusively or primarily breast-fed, vegetarians, milk-free diet) Chronic conditions (liver, kidney diseases and inflammatory bowel disease, fat malabsorption syndromes) 9

10 Risk factors for vitamin D deficiency Antiepileptic drugs alter liver metabolism Living in cold climates and having little sun exposure Covering all or almost all of one's skin while outdoors Liberal use of high-spf sunscreens Air pollutions Vitamin D deficiency clinical effects Nutritional rickets Osteomalacia (when growth is completed) Hypocalcemic seizures in neonates Non-characteristic bone and muscle pain Predispose to osteopenia/osteoporosis Tooth enamel hypoplasia Rickets lat. Rachitis Defective mineralization of bones before epiphyseal closure due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium 10

11 Rickets Predominantly presents during intensive growth: 3 month 3 years. Signs and symptoms of rickets include skeletal and extraskeletal manifestation Extraskeletal (systemic) symptoms anxiety sleeplessness excessive sweating, predominantly of the head muscle weakness: distended (protruding) abdomen, constipation delayed psychomotoric development delayed teething delayed fontanelle closure growth disturbance tetany (overt or latent) susceptibility to infections Rickets skeletal symptoms Softening and flattening of the skull (craniotabes) frontal bossing (prodruding forehead) widening of wrists due to metaphyseal cartilage hyperplasia rickety bracelets costochondral swelling of ribs = rickety rosary bell-shaped chest spinal deformity: kyphoscoliosis or lumbar lordosis bowed legs = genu varum knock-knees = genu valgum pelvic deformity Harrison s groove (sulcus) 11

12 Remember Isolated skeletal symptom of rickets as craniotabes or extraskeletal (f.ex. excessive sweating) don t indicate for rickets without serum 25OHD assessment. Radiography Wrist X-ray: cupping and fraying of the metaphyseal region 12

13 Serum chemistry Decreased phosphorus level Calcium usually normal - hypocalcemia at the beginning is compensated by PTH activity. Increased alkaline phosphatase activity Decreased 25(OH)D3 level 1,25(OH2)D3 (if measured) is increased contrregulation) Increased PTH secondary hyperparathyroidism Increased urine calcium excretion Vitamin D deficits in adults In adults (after epiphyseal closure) vit.d deficiency leads to a similar condition: RICKETS OSTEOMALACIA No skeletal deformities Hypocalcemic tetany is possible. Severe demineralization of the skeleton Skeletal pains Myopathy Pathological fractures RICKETS - treatment Improve diet Increase calcium supply Expose (safely) to the sunlight Refill vitamin D3 deficiency pharmacologically 13

14 Recommended therapeutic doses of vitamin D for the treatment of rickets Infants: IU daily Older children: IU daily The duration of treatment usually varies from 1 3 months, depending on the severity of symptoms and vitamin D deficiency. Treatment - effects The first changes are seen on the radiograms within 7 days Craniotabes should disappear after 3 weeks. Flattening of the skull can persist even 1 year Phosphatemia normalizes within about 2-3 weeks. Alkaline phosphatase level back to the normal ranges within 2-3 months. Poor treatment effects? Consider: Poor compliance Other (congenital) types of rickets: Vitamin D-dependent type 1 Vitamin D-dependent type 2 Hypophosphatemic rickets (Vitamin D-resistant) 14

15 Vitamin D overdose - toxicity The threshold for vitamin D toxicity has not been established In healthy adults, sustained intake of more than 50,000 IU / day can produce overt toxicity after several months Supplementing (chronic) with high doses of vit.d Single intake IU of vit.d (whole bottle of vit.d preparation) does not induce symptomatic toxicity providing that further supplementation is stopped. Symptoms of vitamin D overdose Hypercalcemia is a strong indication of vitamin D toxicity: - increase in urination (polyuria) and proteinuria - muscle weakness - arrythmia - excesive thirst (polydipsia) - nausea, vomiting - abdominal pain - irritability, insomnia - If hypercalcemia is not treated, it results in excess deposits of calcium in soft tissues and organs (calcinosis) - ultimately renal failure Management Discontinue vitamin D supply and restrict calcium intake. Maintain fluid balance Glucocorticosteroids inhibit Ca absorption Diuretics (Furosemid) 15

16 Prophylaxis of Vit.D deficiency Promoting of the sunlight exposure Well balanced diet optimal Ca, P and vit.d3 intake Active life style Avoiding of environmental risk factors Effective pharmacological supplementation Practical guidelines for the supplementation of vit.d and the treatment of its deficits in Central Europe Free access online: Recommended Vitamin D Daily Intakes in the general population NEONATES AND INFANTS Supplementation should be introduced from the first days of life irrespective of nutritional option (breastfeeding or formula-based nutrition) 400 IU from 0 up to age 6 months IU between 6 to 12 months of age depending on daily vitamin D intake from diet. 16

17 Recommended Vitamin D Daily Intakes in the general population CHILDREN AND ADOLESCENTS (1 18 yrs) IU depending on body weight is recommended between September and April or throughout the whole year if sufficient skin synthesis of vitamin D is not ensured in the summer. Recommended Daily Intakes in groups at risk of vitamin D deficiency. PREMATURE INFANTS Supplementation should be introduced from the first days of life (as soon as enteral feeding is possible) IU until accomplishing the corrected gestational age of 40 weeks should be warranted. Thereafter, the recommendations as for normal-term infants are adequate. Recommended Daily Intakes in groups at risk of vitamin D deficiency. OBESE CHILDREN AND ADOLESCENTS (BMI > 90th percentile for age and gender using local reference in a given country) IU, depending on severity of obesity is recommended between September and April or throughout the whole year if sufficient skin synthesis of vitamin D is not ensured in the summer. 17

18 SUMMARY Moderate vitamin D deficiency is a global health problem. Vitamin D is essential in many physiological processes and has irreplaceable metabolic functions. Vitamin D is necessary in all age groups. Supplementation is practically the only effective source of Vitamin D due to insufficient endogenous (skin) synthesis in our geographical latitude. Prophylaxis of Vitamin D deficiency should be included in the priorities of physicians, medical professionals and healthcare policy-makers. 18