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.
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.
Vitamin D: The Sunshine Vitamin Not always essential Body can make it if exposed to enough sunlight Made from cholesterol in the skin
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
FUNCTIONS•Calcium metabolism: vitamin D enhances caabsorption in the gut & renal tubules.•Cell differentiation: particularly of collagen& skin epithelium•Immunity: important for Cell MediatedImmunity & coordination of the immuneresponse.
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
GROUPS AT RISK•Infants•Elderly•Dark skinned•Covered women•Kidney failure patients•Patients with chronic liver disease•Fat malabsorption disorders•Genetic types of rickets•Patients on anticonvulsant drugs
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 osteocytic membrane Activates osteoclasts
Pathogenesis PTH High secretion P in urine Decalcification of old bone P in blood Ca in blood normal or low slightly Ca, P product Rickets
Pathogenesis Low secretion of PTH Failure of decalcification of bone Low serum Ca level Rachitic tetany
Vitamin D deficiency•Deficiency of vitamin D leads to: Rickets in small children. Osteomalacia Osteoporosis
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
- Causes of Rickets VITAMIN D DISORDERS CALCIUM DEFICIENCY PHOSPHORUS DEFICIENCY RENAL LOSSES DISTAL RENAL TUBULAR ACIDOSIS
VITAMIN D DISORDERS Nutritional vitamin D deficiency Congenital vitamin D deficiency Secondary vitamin D deficiency Malabsorption Increased degradation Decreased liver 25-hydroxylase Vitamin D–dependent rickets type 1 Vitamin D–dependent rickets type 2 Chronic renal failure
CALCIUM DEFICIENCY Low intake Diet Premature infants (rickets of prematurity) Malabsorption Primary disease Dietary inhibitors of calcium absorption
NUTRITIONAL VITAMIN DDEFICIENCY Most common cause globelyEtiology –poor intake - Neonate -Infant -on formula diet -on breast milk - inadequate cutaneous synthesis
NUTRITIONAL VITAMIN DDEFICIENCY Clinical Manifestation The clinical features are typical of rickets with a significant minority presenting with symptoms of hypocalcemia prolonged laryngospasm occasionally fatal. these children have an increased risk of pneumonia and muscle weakness, adding to a delay in motor . developments.
CONGENITAL VITAMIN DDEFICIENCY. severe maternal vitamin D deficiency during pregnancy Maternal risk factors poor dietary intake of vitamin D, lack of adequate sun exposure closely spaced pregnancies presentation symptomatic hypocalcemia, intrauterine growth retardation decreased bone ossification, classic rachitic changes
SECONDARY VITAMIN DDEFICIENCY. inadequate absorption -cholestatic liver disease, -defects in bile acid metabolism, - cystic fibrosis - other causes of pancreatic dysfunction, celiac disease, and Crohn disease -intestinal lymphangiectasia -after intestinal resection decreased hydroxylation in the liver,-insufficient enzyme activity more than 90% increased degradation - medications, by inducing the P450 system,- -anticonvulsants, such as phenobarbital or phenytoin; -antituberculosis medications isoniazid and rifampin
VITAMIN D–DEPENDENTRICKETS, TYPE 1. autosomal recessive disorder, mutations in the gene encoding renal 1α- hydroxylase preventing conversion of 25-D into 1,25-D. present during the 1st 2 yr of life classic features of rickets including symptomatic hypocalcemia. They have normal levels of 25-D, but low levels of 1,25-D (see Table 48-4
VITAMIN D–DEPENDENTRICKETS, 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. 50–70% of children - alopecia, -more severe alopecia areata alopecia totalis. Epidermal cysts.
CHRONIC RENAL FAILURE decreased activity of 1α-hydroxylase in the kidney, hyperphosphatemia as a result of decreased renal excretio Along with inadequate calcium absorption and secondary hyperparathyroidism, the rickets may be worsened by the metabolic acidosis of chronic renal failure. In addition, failure to thrive and growth retardation may be accentuated because of the direct effect of chronic renal failure on the growth hormone axis.
PHOSPHOROUS DEFICIENCY INADEQUATE INTAKE. -rare ,severe anorexia -long-term use of aluminum- containing antacids PHOSPHATONIN. humoral mediator that decreases renal tubular reabsorption of phosphate and therefore decreases serum phosphorus. decreases the activity of renal 1α-hydroxylase, Fibroblast growth factor-23 (FGF-23) is the most well characterized phosphatonin
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, but female carriers are affected, so it is an X-linked dominant disorder . PHosphate-regulating gene with homology to Endopeptidases on the X chromosom –PHEX gene role in inactivating a phosphatonin or phosphatonins. FGF-23 may be the target phosphatonin.
Clinical Manifestations. These patients have rickets, but abnormalities of the lower extremities and poor growth are the dominant features. Delayed dentition and tooth abscesses are also common. Some patients have hypophosphatemia and short stature without clinically evident bone disease.
AUTOSOMAL DOMINANTHYPOPHOSPHATEMIC RICKETS. Less common mutation in the gene encoding FGF-23. The mutation prevents degradation of FGF-23 by proteases, leading to increased levels of this phosphatonin hypophosphatemia, and inhibition of the 1α- hydroxylase in the kidney, causing a decrease in 1,25-D synthesis.
HEREDITARY HYPOPHOSPHATEMICRICKETS WITH HYPERCALCiuRIA. The primary problem is a renal phosphate leak that causes hypophosphatemia, which then stimulates production of 1,25-D. The high level of 1,25-D increases intestinal absorption of calcium, suppressing PTH. Hypercalciuria ensues due to the high absorption of calcium and the low level of PTH, which normally decreases renal excretion of calcium
OVERPRODUCTION OFPHOSPHATONIN Tumor-induced osteomalacia McCune-Albright syndrome , an entity that includes the triad of polyostotic fibrous dysplasia, hyperpigmented macules, and polyendocrinopathy epidermal nevus syndrome, sporadic disorder consisting of congential epidermal nevi associated with anomalies of other organ systems, especially the skeleton and central nervous system Rickets due to phosphate wasting is an extremely rare complication in children with neurofibromatosis
FANCONI SYNDROME Fanconi syndrome is secondary to generalized dysfunction of the renal proximal tubules There are renal losses of phosphate, amino acids, bicarbonate, glucose, urate, and other molecules that are normally reabsorbed in the proximal tubule. hypophosphatemia -- phosphate losses proximal renal tubular acidosis -- bicarbonate losses. The findings of aminoaciduria, glucosuria, and a low serum uric acid level are helpful diagnostically. genetic disorder –cystinosis -wilson disease Secondary to –heavy metal exposure -drug toxicity ,(ifosfamide, valproate, aminoglycosides
DENT DISEASE X-linked disorder ,,,,male mutations in the gene encoding a chloride channel that is expressed in the kidney. hematuria, nephrolithiasis, nephrocalcinosis, ric kets, and chronic renal failure. Almost all patients have low molecular weight proteinuria and hypercalciuria . Rickets occurs in approximately 25% of patients, and it responds to oral phosphorus supplements.
Aetiological classification – enal causes –RRenal osteodystrophyFamilial hypophosphataemic ricketsRenal tubular acidosisFanconi syndrome Primary Secondary - cystinosis, wilsons disease,lowe syndrome,tyrosinemiaVitamin D dependent type 1 ricketsVitamin D dependent type 2 rickets
Non renal causes – Nutritional Intestinal – malabsorption Hepatobiliary Metabolic – anticonvulsant therapy Oncogenic- mesenchymal tumours Rickets of prematurity
Biochemical classification – CALCIUM DEFICIENCY WITH SECONDARY HYPERPARATHYROIDISM – Vitamin D deficiency rickets Rickets with malabsorption hepatic disease anticonvulsant therapy Renal osteodystrophy Vitamin D dependent type 1 rickets
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 – rachitic dwarfism Lower extremities are extensively involved in Familial hypophosphatemic rickets. Upper limb more involved than lower limbs in Hypocalcemic rickets.
chief complaint skeletal deformities, difficulty walking due to a combination of deformity failure to thrive and symptomatic hypocalcemia (
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
Extra – Skeletal manifestations. Features of primary problems Features of hepatic disease renal failure recurrent vomiting. acidotic breathing or failure to thrive. ASYMPTOMATIC Radiologists detect in X ray chest film taken for a different reason in a child.
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.
radiology most easily visualized on posteroanterior radiographs of the wrist ,knee ,chest Decreased calcification leads to thickening of the growth plate. The edge of the metaphysis loses its sharp border, which is described as fraying. In addition, the edge of the metaphysis changes from a convex or flat surface to a more concave surface. This is termed cupping,
and is most easily seen at the distal ends of the radius, ulna, and fibula. There is widening of the distal end of the metaphysis, corresponding to the clinical observation of thickened wrists and ankles, as well as the rachitic rosary. Other radiologic features include coarse trabeculation of the diaphysis and generalized rarefaction
Second level investigations Blood urea, creatinine, electrolytes, ABG Tubular reabsorption of phosphate( Trp) Urine analysis for specific gravity, glucose, protein, aminoacids, potass ium and calcium. USG abdomen LFT, malabsorption and IEM studies
Tertiary level investigations Estimation of vitamin D metabolites to differentiate VDDR type 1 from type 2 Receptor vitamin D interaction – in vitro study to assess VDDR type 2 Bone mineral content Bone densitometry
VIT D LEVEL IN SERUM - 25 (OH) D3 level ng/ml DEFICIENT < 10 INSUFFICIENT 10 - 20 OPTIMAL 20 - 60 HIGH 60 - 90 TOXIC >90
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
Level 1 – is it true rickets or ricketslike states ? Features Radiological signs similar to rickets. But growth plate are not wide with differential involvement of bones in a joint. Eg. Femur shows changes but tibia is normal. Levels of serum Ca, P and SAP normal. Diagnosis Metaphysial dysplasia.
Features .---- Clinical signs or rickets are present but x rays show tongue like radiolucency projecting from growth plate into metaphysis whereas in rickets growth plate is uniformly wide. SAP levels are low but S. ca, P Levels are normal. Diagnosis -- Hypophasphatasia
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
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 primary CNS problem Alopecia - VDDR type 2.
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.
Level 2.. Is it nutritional or nonnutritional? Features of non nutritional causes Presentation before six months or after two years of age Associated failure to thrive Positive family history Obvious clues mentioned earlier Failure of vitamin D therapy
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.
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 and prolonged prothrombin time. Diagnosis - Hepatic rickets
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, acidotic breathing. Hypertension, anemia with or without edema. Positive findings in urine analysis. Abnormalities in electrolytes, blood urea and creatinine. Renal abnormalities in ultrasound abdomen. Diagnosis –Renal rickets.
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 renal failure and on laboratory investigations. Do urine analysis.. blood for electrolytes, urea and creatinine. blood gas analysis. ultrasonography of abdomen.
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.
Features… Recurrent vomiting, diarrhoea with acidotic breathing. Positive family history. Metabolic acidosis with normal anion gap, hypokalemia, and raised serum chloride Normal blood urea and serum creatinine. No proteinuria or glycosuria. Diagnosis - Renal tubular acidosis.
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.
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).
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
Features… Alopecia with or without any response to any form of vitamin 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.
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.
RENAL OSTEODYSTROPHY Low phospharous diet [low phosphate formulas to infants]. Phosphate binders to enhance fecal excretion – calcium carbonate & calcium acetate, newer non- calcium based binders – sevelamer [Aluminum based binders 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
FANCONI’S SYNDROME Treating the cause Eliminating heavy metal exposure, chelation therapy. Discontinuation of toxic drug. Cystemine in cystinosis. Avoiding tyrosine in tyrosinemia. Bicarbonate & phosphorous supplementation [to correct acidosis and hypophosphatemia] Oral calcitriol.
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
RICKETS OF PREMATURITY Calcium 100 mg/kg/day Po4 50mg/kg/day Vit D according to daily requirement for 3 months
FAMILIAL HYPOPHOSPHATEMICRICKETS Replacement of po4 every 4 to 6 hourly 1 alpha Vit D
Rickets in wrist - uncalcified lower ends of bones are porous, ragged, and saucer-shaped (A) Rickets in 3 month old infantA (B) Healing after 28 days of treatment (C) After 41 daysB C of treatment
Prevention 1. Pay much attention to the health care of pregnant and lactating women, instruct them to take adequate amount of vitamin D. 2. Advocate sunbathing 3.Advocate breast feeding, give supplementary food on time
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 can’t maintain a daily supplementation, inject muscularly Vitamin D3 10000-200000 IU.
Prevention 5. Calcium supplementation: 0.5-1gm/day, for premature, weak babies and babies fed mainly with cereal
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
Vitamin D - Sources Not found naturally in many foods Synthesized in body Plants (ergosterol) Sun-cured forages Fluid milk products are fortified with vitamin D Oily fish Egg yolk Butter Liver Difficult for vegetarians
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 in kidneys Lack of appetite Excessive thirst and urination