1.Kamal kishor guptaresident of orthpaedics

2. VITAMIN D Humans & animal utilize only vitamin D3 &they can produce it inside their bodies fromcholesterol. Cholesterol is converted to 7-dehydro-cholesterol (7DC), which is a precursor ofvitamin D3. 3. VITAMIN D Exposure to the ultraviolet rays in the sunlight convert 7DC to cholecalciferol. Vitamin D3 is metabolically inactive until it is hydroxylated in the kidney & the liver to the active form 1,25 Dihydroxycholecalciferol. 1,25 DHC acts as a hormone rather than a vitamin, endocrine & paracrine properties. 4. Vitamin D: The Sunshine Vitamin Not always essential Body can make it ifexposed to enoughsunlight Made from cholesterol inthe skin 5. Formation of Vitamin D Skin (UV light) 7-dehydro cholesterol Vitamin D3 Ergosterol Vitamin D2 Liver OH-group added 25-Hydroxy vitamin D3 Storage form of vitamin (~3 months storage in liver) Kidney OH-group added by 1-hydroxylase 1,25-dihydroxy vitamin D3 Active form of vitamin D, a steroid hormone OH-group added by 24-hydroxylase 24,25-dihydroxy vitamin D3 Inactive form of vitamin D, ready for excretion 6. FUNCTIONSCalcium metabolism: vitamin D enhances caabsorption in the gut & renal tubules.Cell differentiation: particularly of collagen& skin epitheliumImmunity: important for Cell MediatedImmunity & coordination of the immuneresponse. 7. Vitamin D - Functions Bone development Calcium absorption (small intestine) Calcium resorption (bone and kidney) Maintain blood calcium levels Phosphorus absorption (small intestine) Hormone Regulation of gene expression Cell growth 8. Vitamin D Functions 9. Vitamin D Affects Absorption ofDietary Ca 1,25-(OH)2 Dbinds tovitamin Dreceptor (VDR)in nucleus Increase incalbindin(Ca-bindingprotein)Groff & Gropper, 2000 10. Vitamin D Affects Absorption of DietaryPhosphorus 1,25-(OH)2 D3 increases activity ofalkaline phosphatase Hydrolyses phosphate ester bonds Releases phosphorus Increase in phosphate carriers 11. Vitamin D deficiency 12. Etiology 1. Lack of sunshine due to: 1) Lack of outdoor activities 2) Lack of ultraviolet light in fall and winter 3) Too much cloud, dust vapour and smoke 13. Etiology 2. Improper feeding: 1) Inadequate intake of Vitamin DBreast milk 0-10IU/100mlCows milk 0.3-4IU/100mlEgg yolk25IU/average yolkHerring1500IU/100g 2) Improper Ca and P ratio 14. Etiology 3. Fast growth, increased requirement Relative deficiency 4. Diseases and drug:Liver diseases, renal diseasesGastrointestinal diseasesAntiepilepticGlucocorticosteroid 15. GROUPS AT RISKInfantsElderlyDark skinnedCovered womenKidney failure patientsPatients with chronic liver diseaseFat malabsorption disordersGenetic types of ricketsPatients on anticonvulsant drugs 16. Parathyroid Hormone (PTH) Calcium-sensor protein in the thyroid gland Detects low plasma calcium concentrations Effects of parathyroid hormone Urine / kidneys Increases calcium reabsorption Increases phosphorus excretion Stimulates 1-hydroxylase activity in the kidneys 25-OH D 1,25-(OH)2 D PTH required for resorption of Ca from bone Activates a calcium pump on the osteocyticmembrane Activates osteoclasts 17. Pathogenesis PTHHigh secretionP in urineDecalcification of old boneP in bloodCa in blood normal or low slightlyCa, P product Rickets 18. Pathogenesis Low secretion of PTHFailure of decalcification of boneLow serum Ca level Rachitic tetany 19. Vitamin D deficiencyDeficiency of vitamin D leads to: Rickets in small children. Osteomalacia Osteoporosis 20. RICKETS : Defective mineralization of growingbone before epiphyseal fusionRENAL OSTEODYSTROPHY : Alteration inskeletal growth & remodelling in CRFOSTEOMALACIA : Defective mineralization ofbone after epiphyseal fusionOSREOPOROSIS : Proportionate loss of bonevolume & mineralsOSTEOPENIA OF PREMATURITY : Post natalinadequate bone mineralization in preterm babies 21. - Causes of Rickets VITAMIN D DISORDERS CALCIUM DEFICIENCY PHOSPHORUS DEFICIENCY RENAL LOSSES DISTAL RENAL TUBULAR ACIDOSIS 22. VITAMIN D DISORDERS Nutritional vitamin D deficiency Congenital vitamin D deficiency Secondary vitamin D deficiencyMalabsorption Increased degradation Decreased liver 25-hydroxylase Vitamin Ddependent rickets type 1Vitamin Ddependent rickets type 2 Chronicrenal failure 23. CALCIUM DEFICIENCY Low intake Diet Premature infants (rickets of prematurity) MalabsorptionPrimary diseaseDietary inhibitors of calcium absorption 24. PHOSPHORUS DEFICIENCY Inadequate intake Premature infants (rickets of prematurity) Aluminum-containing antacids 25. RENAL LOSSES X-linked hypophosphatemic rickets[*] Autosomal dominant hypophosphatemic rickets[*] Hereditary hypophosphatemic rickets withhypercalciuria Overproduction of phosphatoninTumor-induced rickets[*]McCune-Albright syndrome[*]Epidermal nevus syndrome[*]Neurofibromatosis[*] Fanconi syndrome Dent disease DISTAL RENAL TUBULAR ACIDOSIS 26. NUTRITIONAL VITAMIN DDEFICIENCY Most common cause globelyEtiology poor intake - Neonate -Infant -on formula diet-on breast milk- inadequate cutaneous synthesis 27. NUTRITIONAL VITAMIN DDEFICIENCY Clinical ManifestationThe clinical features are typical of ricketswith a significant minority presenting with symptoms of hypocalcemiaprolonged laryngospasm occasionally fatal.these children have an increased risk of pneumonia and muscle weakness, adding to a delay in motor . developments. 28. CONGENITAL VITAMIN DDEFICIENCY. severe maternal vitamin D deficiency duringpregnancy Maternal risk factors poor dietary intake of vitamin D, lack of adequate sun exposure closely spaced pregnancies presentationsymptomatic hypocalcemia, intrauterine growth retardation decreased bone ossification, classic rachitic changes 29. SECONDARY VITAMIN DDEFICIENCY. inadequate absorption -cholestatic liver disease,-defects in bile acid metabolism,- cystic fibrosis - other causes of pancreaticdysfunction, celiac disease, andCrohn disease -intestinal lymphangiectasia -after intestinal resection decreased hydroxylation in the liver,-insufficient enzymeactivity more than 90% increased degradation - medications, by inducing the P450 system,--anticonvulsants, such as phenobarbital or phenytoin; -antituberculosis medicationsisoniazid and rifampin 30. VITAMIN DDEPENDENTRICKETS, TYPE 1. autosomal recessive disorder, mutations in the gene encoding renal 1-hydroxylase preventing conversion of 25-D into 1,25-D. present during the 1st 2 yr of life classic features of rickets includingsymptomatic hypocalcemia. They have normal levels of 25-D, but low levels of1,25-D (see Table 48-4 31. VITAMIN DDEPENDENTRICKETS, TYPE 2.mutations in the gene encoding the vitamin D receptor, Levels of 1,25-D are extremely elevated autosomal recessive disorderMost patients present during infancy, although less severely affected patients may not be diagnosed until adulthood.Less severe disease is associated with a partially functional vitamin D receptor. 5070% of children - alopecia, -more severe alopecia areata alopecia totalis. Epidermal cysts. 32. CHRONIC RENAL FAILURE decreased activity of 1-hydroxylase in the kidney, hyperphosphatemia as a result of decreased renalexcretio Along with inadequate calcium absorption andsecondary hyperparathyroidism, the rickets maybe worsened by the metabolic acidosis of chronicrenal failure. In addition, failure to thrive and growthretardation may be accentuated because of thedirect effect of chronic renal failure on the growthhormone axis. 33. PHOSPHOROUS DEFICIENCY INADEQUATE INTAKE.-rare ,severe anorexia -long-term use of aluminum-containing antacids PHOSPHATONIN.humoral mediator that decreases renaltubular reabsorption of phosphate and therefore decreasesserum phosphorus.decreases the activity of renal 1-hydroxylase,Fibroblast growth factor-23 (FGF-23) is themost well characterized phosphatonin 34. X-LINKED HYPOPHOSPHATEMICRICKETS. X-linked hypophosphatemic rickets (XLH) most common, with a prevalence of 1/20,000. The defective gene is on the X chromosome, butfemale carriers are affected, so it is an X-linkeddominant disorder . PHosphate-regulating gene with homology toEndopeptidases on the X chromosom PHEX gene role in inactivating a phosphatonin or phosphatonins.FGF-23 may be the target phosphatonin. 35. Clinical Manifestations. These patients have rickets, but abnormalities ofthe lower extremities and poor growth are thedominant features. Delayed dentition and tooth abscesses are alsocommon. Some patients have hypophosphatemia and shortstature without clinically evident bone disease. 36. AUTOSOMAL DOMINANTHYPOPHOSPHATEMIC RICKETS. Less common mutation in the gene encoding FGF-23. The mutation prevents degradation of FGF-23 byproteases, leading to increased levels of thisphosphatonin hypophosphatemia, and inhibition of the 1-hydroxylase in the kidney, causing a decrease in1,25-D synthesis. 37. HEREDITARY HYPOPHOSPHATEMICRICKETS WITH HYPERCALCiuRIA. The primary problem is a renal phosphate leakthat causes hypophosphatemia, which then stimulates production of 1,25-D. The high level of 1,25-D increases intestinalabsorption of calcium, suppressing PTH. Hypercalciuria ensues due to the high absorptionof calcium and the low level of PTH, whichnormally decreases renal excretion of calcium 38. OVERPRODUCTION OFPHOSPHATONIN Tumor-induced osteomalacia McCune-Albright syndrome , an entity that includesthe triad of polyostotic fibrous dysplasia,hyperpigmented macules, and polyendocrinopathy epidermal nevus syndrome, sporadic disorder consisting ofcongential epidermal nevi associated with anomalies ofother organ systems, especially the skeleton and centralnervous system Rickets due to phosphate wasting is an extremely rarecomplication in children with neurofibromatosis 39. FANCONI SYNDROME Fanconi syndrome is secondary to generalized dysfunction of therenal proximal tubules There are renal losses of phosphate, amino acids, bicarbonate,glucose, urate, and other molecules that are normally reabsorbedin the proximal tubule. hypophosphatemia -- phosphate lossesproximal renal tubular acidosis -- bicarbonate losses. The findings of aminoaciduria, glucosuria, and a low serum uricacid level are helpful diagnostically. genetic disorder cystinosis -wilson disease Secondary to heavy metal exposure-drug toxicity ,(ifosfamide, valproate,aminoglycosides 40. DENT DISEASE X-linked disorder ,,,,male mutations in the gene encoding a chloridechannel that is expressed in the kidney.hematuria, nephrolithiasis, nephrocalcinosis, rickets, and chronic renal failure. Almost all patients have low molecular weightproteinuria and hypercalciuria . Rickets occurs in approximately 25% ofpatients, and it responds to oral phosphorussupplements. 41. Aetiological classification enal causes RRenal osteodystrophyFamilial hypophosphataemic ricketsRenal tubular acidosisFanconi syndromePrimarySecondary - cystinosis, wilsons disease,lowe syndrome,tyrosinemiaVitamin D dependent type 1 ricketsVitamin D dependent type 2 rickets 42. Non renal causes Nutritional Intestinal malabsorption Hepatobiliary Metabolic anticonvulsant therapy Oncogenic- mesenchymal tumours Rickets of prematurity 43. Biochemical classification CALCIUM DEFICIENCY WITH SECONDARY HYPERPARATHYROIDISM Vitamin D deficiency rickets Rickets with malabsorptionhepatic diseaseanticonvulsant therapy Renal osteodystrophy Vitamin D dependent type 1 rickets 44. Primary phosphate deficiency(nosecondary hyperparathyroidism) Familial hypophosphatemic rickets. Fanconi syndrome Renal tubular acidosis Oncogenic hypophosphatemia Phosphate deficiency - malabsorption, low phosphate level. 45. End organ resistance to 1,25Dihydroxy Vit D3 Vitamin D dependent type 2 rickets. 46. Bones. What do they need to bestrong? calcium/ PO4 Vit D PTH Ph 47. Pathophysiology of rickets Low active vitamin D levels Hyperparathyroidism Metabolic Acidosis Hypophosphatemia Multiple factors in renal disease AnorexiaDiet restrictionUremic toxins 48. Age of presentation VITAMIN D DEFICIENCY RICKETS 6 to 18 months. NON NUTRITIONAL RICKETS Beyond this age group. 49. Skeletal manifestations HEAD Craniotaes Delayed closure of anterior fontanelle Frontal and parietal bossing Delayed eruption of primary teeth Enamel defects and caries teeth 50. chest Rachitic rosary Harrison groove Respiratory infections and atelectasis 51. back Scoliosis Kyphosis Lordosis 52. Vitamin D Deficiency - Rickets 53. Skeletal manifestations EXTREMITIES Enlargement of long bones around wrists and ankles Bow legs, knock knees, anterior curving of legs Coxa vara and green stick fractures Deformities of spine, pelvis and leg rachiticdwarfism Lower extremities are extensively involved in Familialhypophosphatemic rickets. Upper limb more involved than lower limbs inHypocalcemic rickets. 54. chief complaint skeletal deformities, difficulty walking due to a combination ofdeformity failure to thrive and symptomatic hypocalcemia ( 55. Extra skeletal manifestations SEIZURES AND TETANY Secondary to hypocalcemia in Vit D deficiency rickets and VDDR type 1 HYPOTONIA AND DELAYED MOTOR DEVELOPMENT In rickets developing during infancy. PROTUBERANT ABDOMEN, BONE PAIN, WADDLING GAIT AND FATIGUE. In older children presenting with rickets 56. Extra Skeletal manifestations. Features of primary problems Features of hepatic diseaserenal failurerecurrent vomiting.acidotic breathing or failure to thrive. ASYMPTOMATIC Radiologists detect in X ray chest film taken for adifferent reason in a child. 57. Investigations, BASIC INVESTIGATIONS TO CONFIRM RICKETS Serum Ca, P and SAP X rays of ends of long bones at knees or wrists CLASSICAL RADIOLOGICAL CHANGES Disappearance of provisional zone of calcification Widening, fraying, cupping of the distal ends of shaft. 58. radiology most easily visualized on posteroanteriorradiographs of the wrist ,knee ,chest Decreased calcification leads to thickening of thegrowth plate. The edge of the metaphysis loses its sharpborder, which is described as fraying. In addition, the edge of the metaphysis changesfrom a convex or flat surface to a more concavesurface. This is termed cupping, 59. and is most easily seen at the distal ends of theradius, ulna, and fibula. There is widening of thedistal end of the metaphysis, corresponding tothe clinical observation of thickened wrists andankles, as well as the rachitic rosary. Other radiologic features include coarsetrabeculation of the diaphysis and generalizedrarefaction 60. Second level investigations Blood urea, creatinine, electrolytes, ABG Tubular reabsorption of phosphate( Trp) Urine analysis for specificgravity, glucose, protein, aminoacids, potassium and calcium. USG abdomen LFT, malabsorption and IEM studies 61. Tertiary level investigations Estimation of vitamin D metabolites todifferentiate VDDR type 1 from type 2 Receptor vitamin D interaction in vitrostudy to assess VDDR type 2 Bone mineral content Bone densitometry 62. VIT D LEVEL IN SERUM - 25 (OH) D3 level ng/ml DEFICIENT < 10 INSUFFICIENT10 - 20 OPTIMAL 20 - 60 HIGH60 - 90 TOXIC >90 63. Practical approach to child withrickets. Level 1. Is it true rickets or rickets like states ? Do preliminary investigations Serum calcium, phosphate, SAP Have a close look at the x rays Consider the following conditions Hypophosphatasia, Metaphyseal dysplasia 64. Level 1 is it true rickets or ricketslike states ? Features Radiological signs similar to rickets. But growth plateare not wide with differential involvement of bones in ajoint. Eg. Femur shows changes but tibia is normal. Levels of serum Ca, P and SAP normal. DiagnosisMetaphysial dysplasia. 65. Features .---- Clinical signs or rickets are present but x rays show tonguelike radiolucency projecting from growth plate intometaphysis whereas in rickets growth plate is uniformlywide. SAP levels are low but S. ca, P Levels are normal. Diagnosis -- Hypophasphatasia 66. Practical approach to rickets Level 2 is it nutritional or non nutritional ? Look for clues in the history or examination- prematurity neonatal cholestasis anticonvulsant therapy chronic renal disease 67. Level 1.. Is it nutritional or nonnutritional? Useful clues Jaundice -hepatobiliary disease metabolic disorders Cataract -galactosemia, wilsons Positive family history - metabolic disease, RTA Mental retardation, seizures -Galactosemia,drug induced rickets in primaryCNS problem Alopecia - VDDR type 2. 68. Level 2.. Is it nutritional or nonnutritional? In the absence of clues Presume and treat it as vit D deficiency rickets. Give vitamin D2 (inj. arachitol) 600000 units 2 doses at two to three weeks interval . Improvement occurs in nutritional rickets. Healing is indicated by the presence of provisional zone of calcification. Non healing favours a non nutritional cause. 69. Level 2.. Is it nutritional or nonnutritional? Features of non nutritional causes Presentation before six months or after two years ofage Associated failure to thrive Positive family history Obvious clues mentioned earlier Failure of vitamin D therapy 70. Level 3. if it is non nutritional and lack anyobvious clues it could be either due to GIor renal cause Features . Recurrent diarrhea, oily stools. Recurrent abdominal pain and distension. Anemia, hypoproteinemia. Multiple vitamin and mineral deficiencies. Diagonosis - Malabsorption with rickets. 71. If it is non nutritional and lack any obviousclues it could be either due to GI or renalcause Features Hepatobiliary findings. Raised serum billirubin, low serum albumin andprolonged prothrombin time. Diagnosis - Hepatic rickets 72. Level 3.. If it is non nutritional and lack anyobvious clues it could be either due to GIor renal cause Features Failure to thrive, rec. vomiting, lethargy, acidoticbreathing. Hypertension, anemia with or without edema. Positive findings in urine analysis. Abnormalities in electrolytes, blood urea andcreatinine. Renal abnormalities in ultrasound abdomen. Diagnosis Renal rickets. 73. Level 4.. If it is rickets due to renal causes whatis the underlying renal problem that led torickets.? Depends on the clinical features of chronic renalfailure and on laboratory investigations. Do urine analysis..blood for electrolytes, urea and creatinine.blood gas analysis.ultrasonography of abdomen. 74. Features Vomiting , lethargy, growth retardation Hypertension, anemia, with or without edema. Features of obstructive uropathy. Raised blood urea, creatinine.. S. potassium may be high. Abnormalities in USG, MCU and DMSA scan. Diagnosis Chronic renal failure - renal osteodystrophy. 75. Features Recurrent vomiting, diarrhoea with acidotic breathing. Positive family history. Metabolic acidosis with normal aniongap, hypokalemia, and raised serum chloride Normal blood urea and serum creatinine. No proteinuria or glycosuria. Diagnosis - Renal tubular acidosis. 76. Features. Severe form of rickets with stunting and deformity. Features mentioned in RTA. Proteinura, glycosuria present. Normal or slightly increased B.urea and S.creatinine. Features of underlying causes such as cystinosis. diagnosis. - Fanconi syndrome. 77. Features Lower limb deformity, stunted growth. Often with family history. Frequent dental abscess and early decay. Low serum phosphate and low TRP. Diagnosis Familial hypophosphataemic rickets(FHR). 78. Level 5.. Child with rickets, noclues so far, what else? Features Often presenting in early infancy. Hypocalcemic tetany. Improvement with vitamin D therapy and recurrence of symptoms on discontinuation. Diagnosis - vitamin D dependent rickets type1 79. Features Alopecia with or without any response to any form ofvitamin D High serum levels of 1,25 dihydroxy vitamin D. Diagnosis vitamin D dependent rickets type2 1,25(OH)2 vit D level is high in contrast to VDDR type 1 where it is low. 80. Types of rickets and treatment Vit D deficiency rickets 1 alpha vit D3 or vit D2(arachitol) 6,00,000 IU every two to three weeks IM 2 to 3 doses. (STOSS REGIMEN) VDDR 1 1,25 vit D 0.25 to 1.0 mcg/day orally. VDDR 2 1,25 vit D or 1 alpha Vit D 6 mcg/kg/day (total of 30 to 60 mcg orally) with calcium supplements. 81. RENAL OSTEODYSTROPHY Low phospharous diet [low phosphate formulas toinfants]. Phosphate binders to enhance fecal excretion calcium carbonate & calcium acetate, newer non-calcium based binders sevelamer [Aluminum basedbinders should be avoided].Vit. D therapy : If 25 (OH) D levels are low treat with ergocalciferol. If 25 (OH) D levels are normal but PTH is high, treat with calcitriol or 1,25 (OH) D 0.01-0.05 mg/kg/24hr 82. FANCONIS SYNDROME Treating the cause Eliminating heavy metal exposure, chelationtherapy. Discontinuation of toxic drug. Cystemine in cystinosis. Avoiding tyrosine in tyrosinemia. Bicarbonate & phosphorous supplementation [tocorrect acidosis and hypophosphatemia] Oral calcitriol. 83. RTA 3-5 meq/kg/day of alkali in distal RTA 5-15 meq/kg/day of alkali in proximal RTA K supplementation accoding to S.k level 84. RICKETS OF PREMATURITY Calcium 100 mg/kg/day Po4 50mg/kg/day Vit D according to daily requirement for 3 months 85. FAMILIAL HYPOPHOSPHATEMICRICKETS Replacement of po4 every 4 to 6 hourly 1 alpha Vit D 86. Rickets in wrist - uncalcified lowerends of bones areporous, ragged, and saucer-shaped(A) Rickets in 3 month old infantA (B) Healing after 28days of treatment(C) After 41 daysB C of treatment 87. Prevention 1. Pay much attention to the health care ofpregnant and lactating women, instructthem to take adequate amount of vitaminD. 2. Advocate sunbathing 3.Advocate breast feeding, givesupplementary food on time 88. Prevention 4. Vitamin D supplementation:In prematures, twins and weak babies, give Vitamin D 800IU per day,For term babies and infants the demand of Vitamin D is 400IU per day,For those babies who cant maintain a daily supplementation, inject muscularly Vitamin D3 10000-200000 IU. 89. Prevention 5. Calcium supplementation: 0.5-1gm/day, for premature, weak babies and babies fed mainly with cereal 90. Sources of Vitamin D Sunlight is the most important source Fish liver oil Fish & sea food (herring & salmon) Eggs Plants do not contain vitamin D3 91. Vitamin D - Sources Not found naturally in manyfoods Synthesized in body Plants (ergosterol) Sun-cured forages Fluid milk products arefortified with vitamin D Oily fish Egg yolk Butter Liver Difficult for vegetarians 92. TOXICITYHypervitaminosis Dcauses hypercalcemia, which manifest as:Nausea & vomitingExcessive thirst & polyuriaSevere itchingJoint & muscle painsDisorientation & coma. 93. Vitamin D Toxicity Calcification of soft tissue Lungs, heart, blood vessels Hardening of arteries (calcification) Hypercalcemia Normal is ~ 10 mg/dl Excess blood calcium leads to stone formation inkidneys Lack of appetite Excessive thirst and urination