1. The Return of Vitamin D Deficiency and Rickets By Paul Breyer, M.D.

2. Lecture Content n History n Normal Calcium Physiology n Evaluation n Case Study n Discussion n Treatment

3. History n n 4000 B.C. No evidence of rickets in Egyptian mummies n n 1582 Reusner first described rickets n n 1650 Francis Glisson published De rachitide – –Severe bone deforming disease – –Growth retardation – –Enlargement of epiphyses of the long bones – –Deformities of the legs – –Bending of the spine – –Weak and toneless muscles n n 1822 Sniadecki recognized the importance of sun exposure for the prevention and cure

4. History n 1906 Frederick G. Hopkins developed concept of accessory foodstuffs n 1912 Casimir Funk named them vitamines n 1919 Huldschinski demonstrated the antirachitic effect of ultraviolet light n 1922 McCollum and Steenbock discovered the antirachitic Vitamin D n 1924 Hess and Steenbock showed the antirachitic effect of ultraviolet light was due to activating a provitamin into Vitamin D n 1927 Windaus indentified the provitamin as ergosterol. n Large scale elimination of Rickets followed the addition of Vitamin D to milk

5. Calcium Physiology n Calcium –Levels tightly controlled (8.4-10.6 mg/dl) –Critical functions n Bone formationNeuronal conduction n Cardiac rhythmBlood coagulation n Enzyme functionSecond messenger n Mitotic divisionMuscle contraction –Active ionized state 40-50% –Inactive protein bound 45% n 0.8 mg/dl reduction in total Ca for every 1.0 g/dl decrease in albumin

6. Calcium Physiology n Calcium absorption –Primarily in duodenum –Vitamin D regulated active transport –Diffusional transport - concentration n Calcium excretion –Renal tubules reabsorb >97% filtered Ca –Urine Ca / Cr ratio should be <0.25 –Fecal >> renal

7. Calcium Physiology n Bone accretion –Infants 270 mg / day (RDA 270 mg) –Adolescents 400 mg / day (RDA 1300 mg) n Calcium regulation –Parathyroid hormone (PTH) –Vitamin D –Calcitonin (minor role) –Other hormones (estrogen, thyroid, cortisol, growth hormone)

8. Parathyroid Hormone n PTH Production –Pre-prohormone 115 aminoacids –Cleaved to 84 aa final form (intact PTH) –Intact PTH level reflect steady state –Binding at PTH receptor splits hormone n Inactive C-terminal PTH n Active N-terminal PTH –PTH receptor G protein coupled receptor n Activates adenylate cyclase (cAMP)

9. Parathyroid Hormone n PTH Regulation –Calcium level n Low Ca level stimulates PTH secretion n High Ca level suppresses PTH secretion –Magnesium level n Low Mg levels impair secretion of PTH and blunts tissue responsiveness to PTH –Phosphorus level n Does not directly effect PTH secretion n Hyperphosphatemia may increase PTH due to phosphorus-induced suppression of calcium

10. Parathyroid Hormone n PTH action –Kidney (loop of Henle, distal tubule) n Moment to moment regulation of serum Ca n Increases Ca reabsorption, phosphorus wasting Increases synthesis of 1,25-OH 2 Vitamin D via direct stimulation of 1  -hydroxylase activity Increases synthesis of 1,25-OH 2 Vitamin D via direct stimulation of 1  -hydroxylase activity –Bone (osteoclasts) n For regulation of serum Ca levels in hours n Leads to bone dissolution (Ca/Phos release) n Synergistic with 1,25-OH 2 Vitamin D

11. Vitamin D Metabolism n Skin source –UV B light (290-315) plus body heat converts 7- dehydrocholesterol to Vitamin D3 (cholecalciferol) –10-15 minutes of full body exposure in summer will generates 10,000 - 20,000 IU within 24 hours –Decreased UV absorption in dark pigmented persons leads to less vitamin D3 production (5-10 times more exposure needed to generate similar amounts). n Dietary source –Mammal Vitamin D3 and plant Vitamin D2 (ergocalciferol) absorbed with chylomicrons in duodenum n Storage –Stored in fat or bound to Vit D binding protein

12. Vitamin D Metabolism n Liver (Vitamin D transported to liver) –Hydroxylated at carbon 25 in hepatic mitochondria forms 25-OH vitamin D (calcidiol) –Serum concentration best reflects stores n Kidney (25-OH Vit D to kidney on DBP) –Enzyme 1  -hydroxylase at proximal tubule –Forms 1,25-OH 2 Vit D (calcitriol) most active –Enzyme activity increased by PTH, hypo- calcemia (PTH) and hypophosphatemia –Activity decreased by calcitriol, phosphorus

13. Vitamin D Metabolism n Vitamin D actions –Stimulates intestinal absorption of calcium and phosphorus –Enhances bone mineralization –With PTH mobilizes Ca and Phos from bone –With PTH increases reabsorption of calcium at distal tubule

14. Calcium Metabolism

15. Vitamin D Abormalities n Nutritional deficiency –Reduced sunlight exposure –Dark pigmented skin –Breast fed infants (15-50 IU/L) –Low birth weight infants –Malabsorption, hepatobiliary dysfunction –Anticonvulsant drugs (phenytoin) –Low 25-OH Vitamin D, low calcium, high PTH –Leads to both a low Ca and low Phos

16. Vitamin D Abormalities n Metabolic errors –1  hydroxylase deficiency (AR) –Vitamin D dependent rickets –Normal 25-OH Vitamin D, low 1, 25 OH2 Vitamin D –Abnormal receptor for 1, 25-OH2 Vitamin D –Vitamin D resistant rickets - severe –Alopecia –High 1,25-OH 2 vitamin D n Chronic renal disease –1  hydroxlase deficiency

17. Signs and Symptoms n May be asymptomatic or symptomatic n Hypocalcemia –Tetany, cramps, paresthesias –Stridor from laryngospasm –Seizures (grand mal, petit mal, focal) n Rachitic deformities –Widening of wrists and ankles –Rachitic rosary –Bowing of lower extremities (once weight bearing) –Fractures

18. Rachitic Deformities

19. Evaluation n History –Twitching, carpopedal spasm, laryngospasm, seizure –Medications –Diet –Sun exposure n Physical examination –Vital signs, height and weight, growth velocity –Hyperreflexia –Tetany –Rachitic deformities –Chvostek’s sign (twitching after tapping facial nerve) –Trousseau sign(carpopedal spasm cuff above SBP x 3min)

20. Trousseau sign

21. Evaluation n Laboratory studies –Total & ionized calcium levels –Magnesium, phosphorus –Alkaline phosphatase –Intact PTH –25-OH and 1,25-OH 2 Vitamin D levels

22. Evaluation cont. n Radiographic studies –Rickets survey –Classic appearance n Electrocardiogram –Prolonged QTc interval

23. Case Study n A 4 and ½ month infant boy presented to our emergency room with a seizure n The seizure was a generalized clonic seizure that lasted a minute and subsequently left the infant sleepy. n No history of illness, fever, trauma, ingestions or previous seizure activity.

24. Case Study cont. n Prior to this episode, the child was in excellent health n The child has been exclusively breast fed. n The physical exam was remarkable for an African American boy with normal weight and length. n His respiratory, cardiac and neurological exams were normal.

25. Case Study cont. n The initial laboratory studies –Normal glucose of 88 mg/dL (60 – 100) –Low total calcium of 6.4 mg/dL (9.0 - 11.0) –Low ionized calcium of 0.88 mmol/L (1.1 - 1.35) –Low phosphorus of 4.0 mg/dL (5.0 - 9.5) –Normal magnesium, normal albumin –Elevated alkaline phosphatase of 1029 U/L (127 – 438)

26. Case Study cont. n Upon further examination –widening of his wrists bilaterally –no obvious bowing of his lower extremities. n Additional laboratory studies –Low 25-hydroxyvitamin D level (<4 ng/mL) –Elevated intact parathyroid (iPTH) level ( 333 pg/mL ) –Normal 1, 25-dihydroxyvitamin D level (39 pg/mL) n Rickets survey abnormal with typical features

27. Rickets Survey

28. Vitamin D Deficiency Rickets n Stage 1 –When 25(OH)Vit D concentrations are inadequate, intestinal absorption of calcium is decreased. –In this first brief stage, there is a decrease in serum calcium concentration but the serum phosphorus and alkaline phosphatase levels remain normal.

29. Vitamin D Deficiency Rickets n Stage 2 –The low serum calcium stimulates PTH secretion. –Causing increased bone mobilization of both calcium and phosphorus, as well as increased tubular reabsorption of calcium and decreased reabsorption of phosphorus at the kidney. –The PTH also increases 1-hydroxylase activity in the kidney converting any available 25(OH)D to the more active form 1,25(OH)2D. –The serum calcium levels are now normal but the serum phosphorus levels are now low due to the renal excretion.

30. Vitamin D Deficiency Rickets n Stage 3 –The bone stores of calcium fall, the serum alkaline phosphatase climbs and the serum calcium levels can no longer be maintained. –Both the serum calcium and serum phosphorus levels are low and the alkaline phosphatase is high. –The PTH level is high, the 25(OH)D concentration is very low and the 1,25(OH)2D concentration is either low, normal or high. –Most children present to the hospital or clinic in this third stage of rickets.

31. Discussion n Vitamin D deficiency rickets is a sunlight deficiency disease n The fortification of milk with vitamin D was thought to have conquered it n Unfortunately Rickets has made a comeback n The cause in the U.S. is the lack of appreciation that human milk contains very little Vitamin D n This plus decreased sun exposure due to sunblocks or dark pigmented skin have compounded the problem.

32. Vitamin D Deficiency Rickets n Peak incidence is between 3- 18 months of age n The usual age range for diagnosis was 4-54 months with the majority being < 30 months old. n Approximately 83 % of children with rickets are African American and 96% are breast fed.

33. Vitamin D Deficiency Rickets n The higher incidence of rickets in breast fed infants is because breast milk is an inadequate source of vitamin D alone. n The vitamin D content of breast milk from a mother with adequate vitamin D status is approximately 22 IU/L n Which is well below the now recommended 400 IU/d for all infants (AAP) n Most breast fed infants must obtain the additional vitamin D from sunlight exposure.

34. Vitamin D Deficiency Rickets n Infants who spend minimal time outside or were born in fall will have minimal sun exposure leading to inadequate vitamin D levels. n Infants using topical sunscreens or infants with dark skin pigmentation are at risk for deficiency because of the decrease in UVB absorption. n In the skin, melanin is in competition for the UV B radiation with 7-dehydrocholesterol and can diminish the production of vitamin D by more than 90%.

35. Vitamin D Deficiency Rickets n To prevent rickets the American Academy of Pediatrics (AAP) recently recommended a minimal intake of 400 IU/d vitamin D (up from 200) for all infants beginning the first few days after birth. n The AAP recommends a vitamin D supplement of 400 IU for exclusively or partially breast-fed infants or formula-fed infants who do not consume at least 32 ounces of a vitamin D- fortified formula (U.S. formulas contain 400 IU/L).

36. Treatment of Vitamin D Deficiency Rickets n The treatment of vitamin D deficiency rickets requires pharmacologic doses of vitamin D to build up the body stores and correct the deficiency. n A total of 200,000 - 600,000 IU of Drisdol [25(OH)D] with adequate dietary calcium will effectively treat and cure rickets. n These doses can be given as a one time high- dose bolus (compliance issues) or as a daily dose of 2,000 – 10,000 IU/d for 3 to 6 months. I start with 8,000 - 10,000 IU (Drisdol 8000 IU/mL).

37. Treatment of Vitamin D Deficiency n If hypocalcemic, I add calcium carbonate (50 –100 mg elemental Ca/ Kg/ day. n Monitor calcium level weekly, once corrected stop the calcium supplement if dietary intake is adequate. n Monitor monthly alkaline phosphatase levels (usually see normalization in 2 to 4 months depending on the severity of the rickets). n Monitor calcium, phosphorus, urine calcium/creatinine ratio monthly as well.

38. Treatment of Vitamin D Deficiency n Once rickets healed, continue the child on 400 IU of vitamin D daily if still breast feeding to maintain normal vitamin D levels and prevent a recurrence in their rickets. n Can repeat radiograph in 3 months n Monitor 25 (OH)-D levels yearly

39. Summary n With the resurgence of vitamin D deficiency rickets and the risk for serious morbidity, there is an urgent need for heightened awareness among our health care providers and families. n High-risk infants and now older children who do not receive 400 IU of Vitamin D daily should start vitamin D supplement as early as possible n High-risk infants and now older children who do not receive 400 IU of Vitamin D daily should start vitamin D supplement as early as possible.