The Return of Vitamin D Deficiency and Rickets

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

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

3. History • 4000 B.C. No evidence of rickets in Egyptian mummies • 1582 Reusner first described rickets • 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 • 1822 Sniadecki recognized the importance of sun exposure for the prevention and cure

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

5. Calcium Physiology • Calcium • Levels tightly controlled (8.4-10.6 mg/dl) • Critical functions • Bone formation Neuronal conduction • Cardiac rhythm Blood coagulation • Enzyme function Second messenger • Mitotic division Muscle contraction • Active ionized state 40-50% • Inactive protein bound 45% • 0.8 mg/dl reduction in total Ca for every 1.0 g/dl decrease in albumin

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

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

8. Parathyroid Hormone • 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 • Inactive C-terminal PTH • Active N-terminal PTH • PTH receptor G protein coupled receptor • Activates adenylate cyclase (cAMP)

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

10. Parathyroid Hormone • PTH action • Kidney (loop of Henle, distal tubule) • Moment to moment regulation of serum Ca • Increases Ca reabsorption, phosphorus wasting • Increases synthesis of 1,25-OH2 Vitamin D via direct stimulation of 1a-hydroxylase activity • Bone (osteoclasts) • For regulation of serum Ca levels in hours • Leads to bone dissolution (Ca/Phos release) • Synergistic with 1,25-OH2 Vitamin D

11. Vitamin D Metabolism • 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). • Dietary source • Mammal Vitamin D3 and plant Vitamin D2 (ergocalciferol) absorbed with chylomicrons in duodenum • Storage • Stored in fat or bound to Vit D binding protein

12. Vitamin D Metabolism • Liver (Vitamin D transported to liver) • Hydroxylated at carbon 25 in hepatic mitochondria forms 25-OH vitamin D (calcidiol) • Serum concentration best reflects stores • Kidney (25-OH Vit D to kidney on DBP) • Enzyme 1a-hydroxylase at proximal tubule • Forms 1,25-OH2 Vit D (calcitriol) most active • Enzyme activity increased by PTH, hypo- calcemia (PTH) and hypophosphatemia • Activity decreased by calcitriol, phosphorus

13. Vitamin D Metabolism • 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 • 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 • Metabolic errors • 1a 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-OH2 vitamin D • Chronic renal disease • 1a hydroxlase deficiency

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

18. Rachitic Deformities

19. Evaluation • History • Twitching, carpopedal spasm, laryngospasm, seizure • Medications • Diet • Sun exposure • 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 • Laboratory studies • Total & ionized calcium levels • Magnesium, phosphorus • Alkaline phosphatase • Intact PTH • 25-OH and 1,25-OH2 Vitamin D levels

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

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

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

25. Case Study cont. • 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. • Upon further examination • widening of his wrists bilaterally • no obvious bowing of his lower extremities. • 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) • Rickets survey abnormal with typical features

27. Rickets Survey

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

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

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

34. Vitamin D Deficiency Rickets • Infants who spend minimal time outside or were born in fall will have minimal sun exposure leading to inadequate vitamin D levels. • Infants using topical sunscreens or infants with dark skin pigmentation are at risk for deficiency because of the decrease in UVB absorption. • 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 • 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. • 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 • The treatment of vitamin D deficiency rickets requires pharmacologic doses of vitamin D to build up the body stores and correct the deficiency. • A total of 200,000 - 600,000 IU of Drisdol [25(OH)D] with adequate dietary calcium will effectively treat and cure rickets. • 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 • If hypocalcemic, I add calcium carbonate (50 –100 mg elemental Ca/ Kg/ day. • Monitor calcium level weekly, once corrected stop the calcium supplement if dietary intake is adequate. • Monitor monthly alkaline phosphatase levels (usually see normalization in 2 to 4 months depending on the severity of the rickets). • Monitor calcium, phosphorus, urine calcium/creatinine ratio monthly as well.

38. Treatment of Vitamin D Deficiency • 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. • Can repeat radiograph in 3 months • Monitor 25 (OH)-D levels yearly

39. Summary • 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. • 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.