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LTC Karen S. Vogt Pediatric Endocrinology, WRNMMCB March 2013

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Presentation on theme: "LTC Karen S. Vogt Pediatric Endocrinology, WRNMMCB March 2013"— Presentation transcript:

1 LTC Karen S. Vogt Pediatric Endocrinology, WRNMMCB March 2013
Rickets

2 PREP 2013 Content Specifications
Understand the necessity of adequate vitamin D intake in children and adolescents Understand the necessity of calcium and phosphorous intake in children and adolescents Know that hypocalcemia with hypophosphatemia suggests vitamin D deficiency

3 PREP 2013 Content Specifications
Understand the mechanism of rickets in children with hepatic disease Plan the treatment of a child with familial hypophosphatemic rickets

4 Outline Case Nutritional rickets and Vitamin D deficiecy Prevention
Other types of rickets PREP Questions

5 Case 9 month old female presents in January for her well baby visit
Lorelai Lingad 3913

6

7 History Birth: PMH: healthy Immunizations: up-to-date
C-section at 34 weeks for placental abruption Required PRBC transfusion x2 PDA - closed after indomethacin x 1 18 day NICU stay PMH: healthy Immunizations: up-to-date

8 More History Diet: exclusively breastfed until 6 months of age, now taking stage 2 baby foods and soft table foods Meds: Poly-vi-sol in first 3 months of life, no current meds Development: sits unsupported when placed, pulls to stand, cannot get from lying to sitting, immature pincer grasp, waves bye-bye, plays peek-a-boo, consonant babbling

9 History and Physical Exam
Family History: parents healthy, mom no longer taking prenatal vitamins, mom is Filipino, dad is half caucasian/half Filipino Physical Exam : Unremarkable

10 Plan…. Weight check in one month
Mom comes back in 2 weeks for concern for difficulty feeding Less appetite for solids than previously and no weight gain from well visit

11 Labs TSH, CRP, Celiac Panel – unremarkable
Fecal fat, reducing substances and alpha-1-antitrypsin – normal Sweat test – normal CMP- Alk Phos 736 U/L ( ) Calcium mg/dl ( ) Albumin g/dl (3.5-5)

12 Labs CBC - WBC 12.6 Hgb 10.8 Hct Plt MCV (70-86)

13 Pediatric Endocrinology Consult
More History: Mom drinks no milk, occasional cheese, doesn’t like yogurt Infant light skinned and born in early spring Minimal time in the sun per mom – spent most of summer indoors PE: subtle wrist widening, slight concavity of lateral chest walls, mild generalized low tone

14 More Labs…. Alk Phos: 568 U/L (150-420) Calcium: 8.8 mg/dl (8.7-10.4)
Albumin: g/dl (3.5-5) Corrected Ca: mg/dl ( ) Phosphorus: 2.5 mg/dl ( ) PTH: pg/ml (13-75) 25 OH Vit D: < 4.0 ng/ml

15 Fraying and cupping of metaphysis of long bones of the knee and wrists most prominent in the distal femur

16 Fraying and cupping of metaphysis of long bones of the knee and wrists most prominent in the distal femur

17 Fraying and cupping of metaphysis of long bones of the knee and wrists most prominent in the distal femur

18 Fraying and cupping of metaphysis of long bones of the knee and wrists most prominent in the distal femur

19 Diagnosis Rickets due to vitamin D deficiency Treatment:
Ergocalciferol (Drisdol® 8000 IU/ml) IU daily Calcium carbonate 40 mg/kg/day div bid

20 Pediatrics Aug 2008:122:

21 Rickets - Definition Failure in the mineralization of newly synthesized bone matrix (osteoid) in growing bone Due to deficiencies in calcium, phosphorous, or both Most common cause is Vitamin D deficiency

22 Definitions Osteomalacia – equivalent in mature bone
Contrast to osteoporosis Low bone mass due to decreased mineralization and decreased bone matrix

23 Vitamin D Synthesis

24 Vitamin D - Sources Dietary UVB exposure
Ergocalciferol (D2) – plant source Cholecalciferol (D3) – animal source UVB exposure Promotes conversion of 7-dehydrocholesterol to cholecalciferol (D3) in the skin nm

25 Vitamin D Metabolism Vitamin D is converted to 25(OH)D by 25-hydroxylase in the liver 25(OH)D A.k.a calcidiol Inactive form Reflects total body stores (2-3 week ½ life) Do not confuse calcidiol with D2; Most abundant circulating vitamin D metabolite

26 Vitamin D Metabolism 25(OH)D is converted to 1,25(OH)2 D by 1α-hydroxylase in the kidney 1,25-OH2 D A.k.a calcitriol Active form More tightly regulated (4-6 hour ½ life) Do not confuse calcitriol with D3

27 1α-hydroxylase (kidney)
Stimulated by PTH Low phosphorous levels

28 1,25-OH2 Vitamin D Acts on the vitamin D receptor (nuclear receptor) at the target organs Major effect: absorption of calcium and phosphorous from the GI tract Immunomodulary effects

29 Parathyroid Hormone (PTH)
Actions: keep serum calcium normal Bone – stimulates reabsorption Kidney: Stimulates 1α-hydroxylase Increases calcium reabsorption Increases phosphate excretion Stimulated by decreased serum calcium levels Hypomagnesemia impairs its secretion

30 Alkaline Phosphatase Produced by active osteoblasts, which form unmineralized matrix Levels increase with increased osteoblast activity

31 Pathophysiology Deficient GI absorption of :
Calcium → hypocalcemia → ↑PTH: Release of calcium and phosphorous from bones Activation of 1α-hydroxylase → increased formation of 1,25-OH2 D Increase in renal phosphate loss Phosphorous

32 Pathophysiology Net effect: decreased calcium and phosphorous available for bone mineralization Osteoid continues to form without mineralization Expansion of the growth plate Metaphyseal irregularities, fraying, flaring Bones become “soft” and less rigid

33 Increasing Prevalence of Vitamin D Deficiency Rickets
Reasons for increasing prevalence Exclusive breastfeeding Breastfeeding moms with insufficient vitamin D stores Increasing use of sunscreen Less time spent outdoors Pediatrics 2008;122:

34 Patient Risk Factors Prematurity
Exclusive breastfeeing for 6 months (although was on poly-vi-sol for the first 3 months) Probable vitamin D deficient breastfeeding mother Winter season Minimal sun exposure

35 Other Risk Factors – Vit D deficiency
Nutritional Dark skin Malabsorption Obesity (sequestration in body fat) Liver or kidney disease

36 Drugs Anticonvulsants Glucocorticoids HIV medications Rifampin
Isoniazide Ketoconazole

37 Clinical Presentation - Rickets
Incidental finding LE bowing Delayed walking Failure to thrive Bone pain Pathologic fracture Hypocalcemia (to include seizure) Weakness Pneumonia, other respiratory infection Anorexia Restlessness/irritability

38 Frontal Bossing

39 Rachitic Rosary

40 Chest Deformity Harrison’s groove

41 Leg Bowing - genu varus

42 Wide Wrists

43 Wide Ankles

44 Physical Exam Findings
Poor growth or weight gain Delayed anterior fontanelle closure Teeth: delayed eruption, enamel defects Generalized muscular weakness/hypotonia

45 Radiographic Findings
Wrist and/or knee films usually Metaphyseal fraying, widening, flaring, cupping Periosteum separated from the diaphysis Generalized osteopenia

46 Associated Lab Findings
Iron deficiency anemia Renal Fanconi syndrome Anemia – from nutritional iron deficiency; Renal Fanconi Syndrome due to increased PTH

47 Vitamin D Deficiency Screening
Who? Nonspecific symptoms: poor growth, gross motor delays, unusual irritability Dark skin infants in higher latitudes in the winter and spring Children taking chronic glucocorticoids or anticonvulsants Chronic diseases associated with malabsorption Frequent fractures and low BMD Pediatrics 2008;122:

48 Vitamin D Deficiency Screening
How? Serum Alkaline Phosphatase (ALP) If elevated: 25 OH Vitamin D, PTH, Calcium and Phosphorus Films: Wrist Knee Pediatrics 2008;122:

49 Treatment of Vitamin D Insufficiency or Deficiency
< 1 month of age: IU/day 1-12 months of age: IU/ day > 12 months of age: >5000 IU/day Teens/adults: 50,ooo IU/week x 8 weeks Consider Stoss therapy if compliance a concern (100,000 – 600,000 IU over 1-5 days) Pediatrics 2008;122:

50 Vitamin D Preparations
Ergocalciferol = D2 (Drisdol®, Calciferol®) Drops (8000 IU/mL) Capsules (50,000 IU) Injection (500,000 IU) – no longer available Cholecalciferol = D3 Capsules (5000 IU) Drisdol is 200 IU/drop, 40 drops/ml; all on our formulary (except injection)

51 What about Calcium?? Simultaneous calcium supplementation necessary
Concern for “Hungry Bone” hypocalcemia 30-75 mg/kg/day divided TID – elemental calcium Symptomatic hypocalcemia requires parenteral calcium replacement Calcitriol (Rocaltrol®) can help treat hypocalcemia associated with rickets but does NOT build up vitamin D stores Pediatrics 2008;122:

52 Treatment Caveats Vitamin D is fat soluble so must not overtreat
Hypercalcemia Weakness Polyuria Nephrocalcinosis

53 Monitoring Therapy 1 Month: Calcium, Phosphorus, ALP
3 Months: Calcium, Phosphorus, ALP PTH, 25 OH Vit D, Urine calcium/creatinine ratio Recheck films Check 25 OH Vit D at one year and then annually Pediatrics 2008;122:

54 Rickets Follow-up Alk phos may increase initially due to increased bone formation Healing is usually complete by 4 months Lack of response to treatment may indicate a different etiology (or lack of adherence) Once healed, continue a maintenance dose of at least 600 IU vitamin D daily (often more)

55 Reported Associations with Vit D Deficiency
Cardiovascular disease, BMI, Insulin resistance Autoimmune disease Cancers – breast, prostate, colon Asthma Schizophrenia, Mood disorders Tuberculosis Analogs used to treat psoriasis

56 What is a normal 25(OH)D level?
No established reference range in children 2008 AAP Review > 20 ng/ml IOM Report 2012 > 20 ng/ml Endocrine Society 2011 CPG Deficiency < 20 ng/ml Insufficiency < 30 ng/ml AAP recommendations - Levels somewhat arbitrary; Adult levels: calcium absorption, bone density

57 Prevention Adequate dietary intake of calcium and vitamin D
Adequate sunlight exposure

58 AAP Clinical Report (2008) Vitamin D supplementation (400 IU) for:
Breast-fed or partially breast-fed infants beginning in the first few days of life Infants receiving <1000 ml formula/day (33 oz) Older children/adolescents who don’t obtain 400 IU/day of Vit D through diet (milk, other foods) IOM Nov 2010 recommends 600 IU for children and adolescents (RDA) IOM Nov 2010 recommends 600 IU for children/adolescents Pediatrics 2008;122:

59 Vitamin D Content Breastmilk 15-50 IU/L Infant formula 400 IU/L
Vit D sufficient mother Infant formula 400 IU/L Prenatal vitamins 400 IU

60 IOM Report: Dietary Reference Intakes for Calcium and Vitamin D
Released Nov 2010 Supplementation for healthy infants, children, and adults Prevention Not treatment recommendations Assumed little to no sun exposure

61 IOM – Vitamin D RDA Infants (0-12 months) 400 IU
Children/Adolescents 600 IU Adults (19-70 years) 600 IU Upper level intakes 0-6 months 1000 IU 6-12 months 1500 IU 1-3 y/o IU 4-8 y/o IU 9-70 y/o 4000 IU IOM Report Nov 2010

62 IOM – Calcium per Day AGE RDA UPPER INTAKE LEVEL 0-6 months
200 mg (AI) 1000 mg 6-12 months 260 mg (AI) 1500 mg 1-3 years 700 mg 2500 mg 4-8 years 9-18 years 1300 mg 3000 mg Adults years IOM Report Nov 2010

63 Dietary Sources of Vitamin D
Fish oils (salmon, mackerel, sardines) Cod liver oil Liver and organ meats Egg yolks IU/yolk Fortified milk/juice IU/L Fortified cereals 40 IU/serving

64 Dietary Sources of Calcium
MG CALCIUM Milk (2%) 285 Per cup Plain low-fat yogurt 415 Per cup Cheese 220 Per oz Tofu 163 Per ¼ firm block Sardines 325 Per 3 oz Salmon 181 Per 3 oz Spinach 250 Per cup Almonds 126 Per 1/3 cup

65 Sunlight Exposure – Vit D
UVB nm – highest at 1200 noon ( ) Minimal Erythema Dose (MED, slight pink skin) → 10,000-20,000 IU vitamin D 40% body to ¼ MED → approx 1000 IU vitamin D Pediatrics 2008;122:

66 Vitamin D Preparations
Formulary Cholecalciferol = D3 D-Vi-Sol® (400 IU/ml) Poly-Vi-Sol® (400 IU/mL) 400 IU tab 1000 IU tab OTC Most standard multivitamins (400 IU) Viactiv® chews (500 IU D3/chew) Many other OTC vitamin D supplements D3 may be more potent and longer lasting

67 Calcium Preparations - Formulary
Calcium Carbonate – with food Oral suspension (500 mg/5 mL) 500 mg tab 600 mg/tab IU D3 Calcium Citrate – absorbed with/without food 200 mg tab Citracal® (315 mg/tab IU vit D3)

68 Calcium Preparations Tums® Viactiv® chews (500 mg + 500 IU vit D3)
Reg 500 mg/tab Extra Strength 750 mg/tab Viactiv® chews (500 mg IU vit D3)

69 Other Types of Rickets 1α-hydroxylase deficiency
Vitamin D receptor mutation Associated alopecia totalis X-linked hypophosphatemic rickets Other inherited hypophosphatemic rickets

70 X-linked Hypophosphatemic Rickets
Renal phosphate wasting Defective 1α-hydroxylase activity in kidney Due to PHEX mutation  increased levels of FGF-23 X-linked dominant Low serum phos, low/inappropriately normal 1,25-dihydroxyvitamin D Treatment: phosphorous replacement, calcitriol (Rocaltrol®)

71 Key Points - Vitamin D Prevention of vitamin D deficiency is key
Don’t forget about sunlight exposure Supplement all breast-fed infants with 400 IU vitamin D within the first few days Vitamin D RDA 600 IU for children and adolescents (IOM Report) Vitamin D may be important for more than just bone health If rickets is not responding to vitamin D treatment, consider other causes

72 PREP Question 1 A 12 year old boy presents to your office for follow-up after his third wrist fracture in 3 years. As part of his evaluation in the emergency department, a complete metabolic panel was obtained and revealed a low calcium (7.5 mg/dL), low phosphorous (2.8 mg/dL), normal magnesium (1.9 mg/dL), and normal albumin (4 g/dL).

73 PREP Question 1 With the exception of his fractures, the boy has had no other medical problems and has not been taking any long-term medications. His height and weight are both at the 75th percentile. His physical exam is unremarkable except for his casted left wrist. Of the following, the MOST appropriate next step in this boy’s evaluation and management is to measure:

74 PREP Question 1 Ionized calcium Serum 1,25-dihydroxyvitamin D
Serum 25-hydroxyvitamin D Serum parathyroid hormone Urine N-telopeptide

75 PREP Question 2 A 14 y/o boy suffers a nondisplaced fracture of his left radius and ulna while playing soccer. He had a similar injury to his radius and ulna 9 months ago. Physical exam reveals SMR 2 pubic hair and testicular volume of 6 ml. A thorough review of his dietary history suggests that his daily intake of calcium and phosphorous are 800 mg each. He takes 400 IU of vitamin D supplement daily.

76 PREP Question 2 Serum calcium measures 7.9 mg/dL, serum phosphorous measures 2.7 mg/dL, and 25-hydroxyvitamin D measures 55 ng/mL (normal 30-80). Of the following, the most appropriate recommendation for this boy is to increase his:

77 PREP Question 2 Calcium and phosphorous intake to 1300 mg/day
Calcium intake to 1000 mg/day Phosphorous intake to 1000 mg/day Vitamin D supplementation to 2000 IU/day

78 PREP Question 3 A 7-month-old child presents for a follow-up visit after undergoing a Kasai procedure for biliary atresia at 6 weeks of age. The mother states that the boy is irritable when his right arm is moved. On physical exam, the infant is jaundiced. You detect tenderness in the anterior radial head. Radiography of the affected region demonstrates metaphyseal fraying and a fracture.

79 PREP Question 3 The MOST appropriate laboratory studies to obtain next are: Calcium, phosphorous, bone densitometry (DEXA scan) Calcium, phosphorous, urinary calcium-to-creatinine ratio Calcium, phosphorous, 25-hydroxyvitamin D Calcium, phosphorous, magnesium Magnesium, phosphorous, parathyroid hormone

80 PREP Question 4 You diagnose familial hypophosphatemic rickets in a boy who presents with rickets and whose mother had rickets as a child and required osteotomies as an adult. You explain to the parents that treatment can help the boy reach normal height and lessen his rachitic bone changes. Of the following, the most appropriate treatment is:

81 PREP Question 4 Daily injections of human growth hormone and oral calcium twice daily Oral calcitriol once daily Oral calcium twice daily with oral cholecalciferol once daily Oral neutral phosphate salts every 6 hours with calcitriol once or twice daily Oral neutral phosphate salts once daily

82 References * Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin d deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122: * Wagner CL, Greer FR. Prevention of rickets and vitamin d deficiency in infants, children, and adolescents. Pediatrics. 2008;122: Institute of Medicine Report on Dietary Reference Intakes for Calcium and Vitamin D. Released 30 Nov Available at Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357: Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab. 2010;95: Carpenter TO et al. A clinician’s guide to X-linked hypophosphatemia. JBMR. July 2011;26(7):


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