Rickets (nasrum seminar) nutritional and others

Rickets

1. Speaker Dr. Nasrum Jahan Assistant registrar Department of Pediatrics Kurmitola General Hospital

2. Case summery 1 Ayesha, 20 month old girl of nonconsnguineous parents, presented with – Widening of both wrist and ankle . Not growing well . Bowing of both lower limbs . On examination B ox shaped head , wide open anterior fontanelle . Pigeon shaped chest, Rachitic rosary . Coxa vera deformity . Hypotonia .

3. Case summery 2 Abu Bakar , 14 month old boy of non consanguineous parents presented with – Cough and respiratory distress for 10 days . Not growing well since birth . Polyuria and polydipsia since birth . On examination Box shaped head with frontal bossing, wide open anterior fontanelle . Features of pneumonia . Pigeon shaped chest, Rachitic rosary . Hypotonia ,protruded abdomen,hepatomegaly .

4. History of rickets The word “Rickets ” is derived from the old English word for "twist," or "wrick," Throughout history children with rickets could be identified by their bowed legs and knock knees, which gave them a twisted appearance. In 1645, English physician Daniel gave the earliest known description of the disease.

5. Epidemiology Developed countries - incidence < 1 in 200,000. North America - most commonly seen in children with relatively more pigmented skin, who are exclusively breastfed. Australia and Europe- mostly identified in immigrant populations from the Middle East and the Indian subcontinent.

6. Epidemiology - Continued Developing country- Africa , the Middle East, and parts of Asia rank among the world’s most heavily affected region. Africa - prevalence>10 % China - prevalence upto 25%

7. Rickets In Bangladesh Rickets is an emerging disease in Bangladesh. First reported by Social Assistance and rehabilitation of the Physically Vulnerable(SARPV- NGO) in 1991 in Chakaria, a sub-district of Cox’s Bazaar, a south-eastern coastal town. More than half a million children in Bangladesh could be suffering from rickets (IRIN Asia ). UNICEF reports that over 550,000 Bangladeshi children have rickets, and studies show Cox's Bazaar has the highest prevalence (8.7% show at least early symptoms ).

8. Rickets in coastal children The National Rickets Survey jan 2010 shows 1% children age 1-15 yrs have rickets.76.6% in Chittagong division.about 47,4% were deficient in Ca and vit D.

9. What is rickets ? Disease of growing bone, Before fusion of the epiphyses, Due to un-mineralized matrix at the growth plate.

10. Parts of a growing long bone Epiphysis Epiphyseal plate Metaphysis Diaphysis

11. Normal bone growth

12. In Rickets- Deranged b one g rowth Cartilage fail to complete normal cycle of proliferation and degeneration with subsequent failure of capillary penetration.so a frayed irregular epiphyseal line produce . Failure of osseous and cartilaginous matrix to mineralize in ZPC followed by deposition of new formed uncalcified osteoid results in a wide irregular frayed zone . Weight bearing and stress over uncalcified bone produce cupping.

13. Normal Metaphysis Epiphyseal plate is well demonstrated. Cartilage cells are orderly. Calcified matrix is regular.

14. Rachitic Metaphysis The degenerating cartilage, islands of capillaries, osteoblasts, and unmineralized osteoid compose broad, irregular, rachitic imtermediate zone.

15. Factors associated with calcium & phosphate metabolism and bone development: Vitamin D Parathyroid hormone Calcitonin

16. Forms of Vitamin D Vitamin D2 = ergocalciferol From plant and yeast. Vitamin D3 = cholecalciferol Synthesize in skin. 25(OH)D3 = calcidiol Relatively inactive, very stable. Reflects vitamin D status. 1,25(OH) 2 D3 = calcitriol ‘Active ’ metabolite, highest affinity + activity at nuclear VDR, short half-life.

17. Sources of Vitamin D Exposure to sunlight Fish oil Fatty fish Egg yolk Vit D fortified formula Milk Cereal Bread

18. Functions of Vitamin D Intestine : Calcium and phosphate absorption. Kidney : Calcium and phosphate reabsorption. Bone : Synthetic activity of osteoblast. Parathyroid gland : Negative feedback. Immune system : Important for Cell Mediated Immunity & co-ordination of the immune response.

19. Regulation of synthesis (Regulated by 1 α hydroxylase activity) Stimulatory Inhibitory Low S. Ca PTH Low PO 4 1,25(OH) 2 D3 High PO 4

20. Parathormone

21. CALCITONIN

22. Classification of Rickets Vitamin D Disorders: •Nutritional vit D deficiency •Congenital vit D deficiency •Secondary vit D deficiency – Malabsorption – Increased degradation – Decreased liver 25 hydroxylase • Vit D dependent rickets type 1 • Vit D dependent rickets type 2 • Chronic Kidney Diseases

23. Classification of Rickets ( Cont ’) Calcium Deficiency: •Low intake – Diet – Premature infant (rickets of prematurity) • Malabsorption – Primary disease – Dietary inhibitor of Ca absorption Phosphorus Deficiency : – Premature infant – Aluminum containing antacid

24. Renal Losses: X linked hypophosphatemic rickets Autosomal dominant hypophosphatemic rickets Autosomal recessive hypophosphatemic rickets Hereditary hypophosphatemic rickets with hypercalciurea Overproduction of fibroblast growth factor-23 • Tumor induced rickets • McCune-Albright syndrome • Epidermal nevus syndrome • Neurofibromatosis Fanconi syndrome Distal renal tubular acidosis Classification of Rickets ( Cont ’)

25. Clinical features Early sign Irritability , r estlessness Increased head sweating , particularly around the head ,which result in the occipital bone bare

26. Skeletal changes Relaxation of muscle and ligaments Active stage

27. Craniotabes 3-6 month old infants Ping- pong ball sensation Disappear by 1 year D/D- Hydrocephalus Congenital syphilis Osteogenesis imperfecta Skeletal Change: Head

28. Skeletal Change: Head Frontal and parital bossing D/D: Congenital haemolytic anaemia Scurvy Congenital syphilis Hurler syndrome Achondroplasia Ayesha and Abu bakar both had Frontal Bossing

29. Skeletal Change : Head Delayed fontanel closure D/D- Hydrocephalus Congenital hypothyroidism Osteogenesis imperfecta Achondroplasia Hypophosphatasia Abu bakar has wide open anterior fontanelle

30. Teeth Delayed dentition Dental caries Enamel hypoplasia Pulp defect Periodontal abscess.

31. Rachitic rosary Costochondral prominence or beading of the ribs D/D- Scorbutic rosary Chondrodysplasia Skeletal change: Chest

32. Harrison’s groove: A horizontal depression along the lower border of chest Skeletal change: Chest

33. Skeletal change: Chest Pigeon Chest deformity- The sternum with its adjacent cartilage appears to be projected forward.

34. Bow leg/Genu Vera Intercondylar distance >5 cm D/D- Physiological bowing Metaphyseal Dysplasia Blount’s disease Skeletal change: Extremity

35. Knock Knee/Genu vulgus Intermalleolar distance ˃10 cm Skeletal change: Extremity

36. Skeletal change: Extremity Windswept deformity Combination of both valgus and verus deformity

37. Bowing of tibia

38. Skeletal change: Spine

39. Muscle & Ligaments: Delayed motor milestones Hyperextensibility of the joints. Pott belly due to: - Hypotonia of the abdominal and intestinal muscles - Downward displacement of the liver & spleen

40. Skeletal change Ayesha has box shaped head , rachitic rosary, w idening of wrists and bowing of legs

41. Skeletal change Abu B akar has frontal bossing , rachitic rosary, w idening of wrists and protruded abdomen

42. Others Fatigue Bone pain, Repeated RTI Short stature Waddling gait Fracture ( Green stick fracture) Hypocalcaemic symptom: Carpopedal spasm Convulsion Laryngeal spasm- Stridor

43. Approach to a patient with rickets History : Age of onset Prematurity Feeding History including prolong breast feeding Exposure to sun light Mile stones of development Polyuria , polydipsia, H/O renal disease (Renal rickets) G.I . symptoms •Diarrhoea • Malabsorption

44. Jaundice or CLD H/o tetany Drugs : •Anti Convulsants( Phenobarbitone, Phenytoin) •Anti tubercular drugs e.g. Isoniazide, Rifampicin •Aluminum containing antacids Recurrent chest infection Time of Dentition, Dental Caries Maternal risk factors of nutritional vit D deficiency. Family History Consanguinity Sib death Maternal Short stature/Bow leg/ osteomalacia Approach to a patient with rickets ( Cont )

45. Head – Shape – Ant . Fontanel – OFC – Alopecia Face : pallor, jaundice Dental (Number of teeth, caries, enamel defect) Chest : harrison sulcus, rachitic rosary, sign of pneumonia Protuberant abdomen Anthropometry Skeletal changes, deformity Muscle bulk, tone, power Gait (waddling) Physical examination

46. Basic investigations to confirm Serum Calcium Serum inorganic phosphate S. Alkaline phosphatase S. PTH X rays- ends of long bones

47. S. Ca (8.5-10.5mg/dl ) : Low normal or decreased: – Vit D deficiency – Dietary Ca++ deficiency – VDDR, Type 1 – VDDR, Type 2 – CKD Normal: – Familial Hypoposphatemic rickets Biochemical changes

48. S. PO4 (5-7mg/dl) : Decreased in all type of rickets except CKD Alkaline phosphatase : Increased in all type of rickets PTH level ;( upto 10 -65 pg /ml) Increased In all types of rickets except - Familial Hypoposphatemic rickets - Dietary phosphate deficiency Biochemical changes (Cont.)

49. Rachitic index ( Ca++ ) X (PO 4 ) = >40 → exclude rickets 30 – 40 → suspected <30 → active rickets Biochemical changes (Cont.)

50. Second line Investigations: S . creatinine S . electrolyte Blood PH Urine Ca++ Urine PO 4 Urine Ca++ creatinine ratio LFT Urinalysis (Glycosuria, aminoaciduria) S . 25(OH)D3, 1,25(OH) 2 D 3

51. Earliest change: Disappearance of provisional zone of calcification Active rickets: Widening, cupping & fraying of distal ends of long bones Wide gap between epiphysis & metaphysis Density of the bone shaft is reduced Deformities Green stick fracture Periosteum may be raised Delayed bone age Classical radiological changes:

52. X-ray wrist joint X-ray Leg

53. Healing Rickets Line or zone of preparatory calcification (ZPC) is seen as a continuous dense line. Osteoid tissue between ZPC & diaphysis become mineralized.

54. Radiological Changes R x Vitamin D 3 + Calcium

55. Radiological Changes (Cont.) After 12days : ZPC appears. After 18days : ZPC & Rachitic metaphysis appears well defined. After 29days : ZPC, Rachitic metaphysis & shaft become united So, After 1 month metaphysis shows- Widening, cupping but no fraying

56. Healing rickets

57. Nutritional vitamin D deficiency

58. Etiology Due to poor intake and inadequate cutaneous synthesis Formula fed infants - receive adequate vit D even without cutaneous synthesis Breast fed infants - rely on cutaneous synthesis or vitamin D supplements, prolonged breast feeding without supplementary food . Decreased cutaneous synthesis Ineffectiveness of winter sun Avoidance of sunlight Increased skin pigmentation

59. Vit D deficiency Reduced intestinal absorption of calcium and phosphate Hypocalcemia Parathyroid hormone Excretion of urinary P Mobilization of Ca & P Failure of mineralization of Osteoid tissue Rickets

60. Usually present during the end of 1st yr and during the 2nd year . Breastfed infants of vitamin D deficient mother may present within 2 months. It is rare in later childhood. Age of presentation

61. Investigations Radiology : Classical radiological findings of rickets Laboratory findings: Calcium Normal/decrease Phosphate Decrease PTH Increase 1,25(OH)D Low, normal, or high 25(OH)D Low Alk Phosphatase Increase Urine Calcium Decrease Urine phosphate Increase

62. 2 strategies: “Stoss therapy”: 3-6 lakh IU of vit D orally or I.M as 2-4 dose over one day Or, Daily high dose vit D 2,000-5,000 IU/d over 4-6 wks. Followed by- Daily vitamin-D supplementation 400 IU/d (<1year) 600 IU/d (>1 year) Adequate intake of Ca & PO4 Treatment

63. Complications Recurrent espiratory tract infection . Tetany ,seizures. Short stature. Green stick fracture . Bone deformity.

64. Monitoring Serum calcium ,Serum phosphorous and ALP –at 1 and 3 months after initiating therapy . Serum PTH level every 3 monthly. X-ray wrist at – 2 weeks and 3 months to confirm healing .

65. Prognosis Good prognosis Lab result, normalized rapidly Radiological healing - within few months Many malformation improves. severe disease may have permanent deformities and Short stature does not resolve .

66. Vitamin D Refractory Rickets Lack of response to vitamin D (2 doses of 6,00,000 IU each, given 2 to 4 weeks apart) is the hallmark of vitamin D refractory rickets. Clue for diagnosis A family history of short stature Alopecia Poor dentition Bone abnormalities(lower limb) Consanguinity

67. Cause of Vitamin D Refractory Rickets Low calcium and high parathormone Vitamin D dependent rickets type IA Vitamin D dependent rickets type I B Vitamin D dependent rickets type II Decreased calcium intake Chronic renal failure

68. Low phosphorus normal parathormone FGF-23 excess AD hypophosphatemic rickets AR hypophosphatemic rickets type I AR hypophosphatemic rickets type II X-linked hypophosphatemic rickets Fibrous dysplasia (McCune Albright symdrome ) Epidermal nevus syndrome Tumor induced osteomalacia and rickets Cause of Vitamin D Refractory Rickets (Cont.)

69. Low phosphorus normal parathormone Renal phosphaturia with normal FGF-23 H ypophosphatemic rickets with hypercalciuria Dent Disease Lowe syndrome Fanconi -Bickel syndrome Fanconi syndrome Cause of Vitamin D Refractory Rickets (Cont.)

70. Workup of Refractory Rickets

71. Renal Osteodystrophy

72. Pathogenesis of rickets due to CKD Impairment of normal renal function Decrease formation of 1 alfa hydroxylase enzyme GFR No conversion of 25 hydroxycholecalciferol to 1, 25 dihydroxy cholecalciferol Decrease calcium absorbtion Decrease renal Phosphate excretion Decrease S. calcium Increase S. Pi Stimulate PTH Rickets as secondary effect Bone Buffer act Due to metabolic acidosis

73. Features Vomiting , lethargy, growth retardation Hypertension, anemia, with or without edema. Features of obstructive uropathy. Raised blood urea, creatinine, S. potassium Abnormalities in USG, MCU and DMSA scan. Chronic renal failure - Renal osteodystrophy

74. Treatment Low PO 4 diet. Calcium based PO 4 binder – Calcium Carbonate 50 – 60 mg/kg/day with meal or calcium acetate, calcium gluconate . Paracalcitriol and doxecalciferol 1 – alpha hydroxycholecalciferol 15 – 30 μ g/kg/day Vit D therapy-calcitriol 0.01- 0.05 μ g/kg/day. Calcium supplementation.

75. Renal tubular acidosis (RTA) Rickets commonly present in Distal RTA(type-1 ) which results from failure to secrete hydrogen ion from DRT It is characterized by persistent severe metabolic acidosis. The proximal tubular reabsorption of bicarbonate is normal. Hypercalciuria and nephrocalcinosis are typically present. Causes of hypercalciuria are: - increased calcium release from bone to buffer the systemic acidosis. - acidosis induced down regulation of renal calcium transport proteins . Urine PH cannot be reduced to below 5.5.

76. Pathogenesis of rickets due to RTA(type 1/distal RTA) Type 1 RTA Decrease secretion of Hydrogen ion in Distal convoluted tubule Down regulation of renal calcium transport protein Decrease calcium reabsorption Increase mobilization of calcium ion from bone to buffer systemic acidosis Rachitic manifestation

77. Features In infancy and early childhood: marked failure to thrive, weakness, polyuria and polydipsia. Recurrent vomiting, diarrhea with acidotic breathing. Metabolic acidosis with normal anion gap, hypokalemia , hyperchloremic . Normal blood urea and serum creatinine No proteinuria or glycosuria Distal Renal tubular acidosis

78. Lab findings ABG analysis: normal anion gap metabolic acidosis Serum electrolyte - Hypokalemia Hyperchloraemia Serum calcium – Hypocalcaemia Serum Phosphate – Hypophosphaetemia Urine pH > 5.5 Urinary calcium excretion: >4 mg/kg/day Urinary calcium/creatinine ratio: >0.2 Renal USG – Nephrocalcinosis

79. Treatment Correction of the acidosis with oral sodium HCO3 2-4mEq/kg/day or sodium citrate ( bicitra or shohl’s solution) Hypokalemia and urinary stone formation and nephrocalcinosis can be treated with potassium citrate. Thiazide diuretics to reduce hypercalciuria

80. X-linked Hypophosphatemic (XLH) Rickets

81. Most common among genetic Rickets (1/20000)

82. Clinical feature: Late presentation. Abnormalities of lower extremities and short stature are dominant feature. Delayed dentition and tooth abscess are common. Mother may have bowing of legs, short stature or fasting hypophosphatemia

83. Pathogenesis Defective PHEX gene in X chromosome Increase phosphatonin FGF 23 Inhibit phosphate reabsorption in PCT Increase phosphate excretion Hypophosphatemia Rachitic change

84. Treatment Oral Phosphorus (Joules solution/neutral phosphate tablet) 30-50 mg/kg or 1-3 gm elemental phosphorus divided in 4-5 doses & 1,25-D ( Calcitriol ) 30-70ng/kg/d bid to prevent hyperparathyroidism Joulie’s solution- Dibasic NaPO4 136gm/L & phosphoric acid 58.8 gm /L which contains 30mg iP /ml (1.6mmol) Prognosis Usually good Short stature may persist

85. Hereditary Hypophosphatemic rickets with hypercalciuria (HHRH) Autosomal recessive disorder Mutation in gene for Na-PO4 co transporter in PCT Reduce reabsorption of PO4 Hypophosphatemia Ricketic Changes

86. Features Rachitic leg abnormality are prominent syndrome Muscle weakness, bone pain Disproportionate short stature Hypophospetamia Increased calcitrol level Hypercalciuria , Nephrocalcinosis Low PTH Treatment: Oral phosphorus replacement(1-2.5 gm / day in divided dose)

87. Vitamin D dependent rickets type-1

88. Vitamin D dependent rickets type-2

89. VDDR Type 1 VDDR Type 2 Mode of inheritance and pathology Autosomal recessive , impaired 1-alpha hydroxylation . Autosomal recessive ; vitamin D receptor malfunction; end organ resistance. Presentation 1 st and 2 nd yr of life Severe: Early infancy Less severe: Until adulthood Clinical Features Classic clinical feature of rickets including symptomatic hypocalcemia 50-70% alopecia (areata/totalis) Ectodermal defects-epidermal cyst Investigation 25 D- Normal 1,25 D –Reduced 25 D – Normal 1,25 increased Treatment 1,25D(calcitriol)—0.25-2ug/day + calcium-long time. When healing- lower dose High dose of 1,25 D—2ug/day –upto 50-60ug/day + calcium1000-3000 mg/day Duration- 3-6 month trial

90. Rickets of prematurity Very premature infants(birth weight <1000gm ) are at risk. Other risk factors: cholestatic jaundice , prolonged use of parenteral nutrition ,soy milk ,medication such as diuretics, corticosteroids. 80 percent transfer of calcium and phosphorus from mother to fetus occurs during 3 rd trimester . Premature births interrupt this process. Presents at 1-4 months after birth. Infants can have nontraumatic fractures .

91. Congenital vitamin D deficiency Due to severe maternal vitamin D deficiency during pregnancy. Features: Symptomatic hypocalcemia , Neonatal hypocalcemic tetany , laryngeal spasm. IUGR , Bone ossification Classic rachitic change as early as 2 months. Treatment : Vitamin D supplementation and adequate calcium intake.

92. Rickets in CLD Defective absorption of vitamin D (as fat soluble ) Defective conversion from D3 to 25 (OH) D3 .

93. CASE 2 Abu bakar , Feature of rickets present with history of calorie deficit H/O polyuria, polydipsia No family history He has adequate sun exposure Mother also has history of adequate sun exposure Proper breastfeeding practice Did not response to vitamin D

94. Investigation Ayesha Abu bakar S ca ++ 9.5 mg/dl 9.2 mg/dl S ipo4 Rachitic index 2.1 mg/dl 19.9 1.6 mg/dl 14.7 ALP 2160u/l 895u/l S PTH raised Not done S . Eletrolyte normal Na+ -140 k+ -2.7 CL- 111

95. ABU BAKAR S.ALT and S. creatinine was normal . ABG analysis – showed normal anion gap(13) metabolic acidosis with hypokalaemia and hyperchloremia . USG of KUB region – showed renal parenchymal disease . CXR – suggestive of bronchopneumonia. For further evaluation this patient was referred to higher centre .

96. Prevention of Rickets Pay much attention to the health care of pregnant and lactating women, instruct them to take adequate amount of vit-D Advocate sunbathing. Advocate breast feeding, give supplementary food on time with vitamin fortified food. 400IU/day of vit-D for all infants and children beginning in the 1 st two month of life. Older children should receive 600 IU/day.

97. Thank You