EKA AGUSTIA RINI

RICKETSDisorder of mineralization of the bone matrix / osteoid in growing boneInvolved : growth plate Newly trabecular formed Cortical boneOsteomalacia After cessation of growth Involves only a bone, not the growth plate

Risk factors Living in northern latitudes (>30o);Dark skinned children;Decreased exposure to sunlightMaternal vitamin D deficiency;Diets low in calcium, phosphorus and vit. DProlonged parenteral nutrition in infancy with an inadequate supply of intravenous calcium and phosphate;Intestinal malabsorption

Defective production of 1,25(OH)2D3Hereditary type I vitamin D-resistant (or dependent) rickets (mutation which abolishes activity of renal hydroxylase);Familial (X-linked ) hypophosphataemic rickets renal tubular defect in phosphate transport;Chronic renal disease;Fanconi syndrome (renal loss of phosphate)Target organ resistance to 1,25(OH)2D3- hereditary vitamin D-dependent rickets type II (due to mutations in vitamin D receptor gene).

Calcium homeostasis - PTH actionSerumCa2+1,25-(OH)2D-ve feedbackIncreased ResorptionIncreasedCa AbsorptionDecreasedCa Clearance

Vitamin D MetabolismCalcium absorption

PTH Response to Hypocalcemia PTH 1,25-(OH)2D -ve feedbackIncrease

Role of CalciumBone GrowthBlood Clotting Maintenance of trans membrane potentialCell replicationStimulus-contraction & stimulus-contracting couplingSecond messenger process

Intestine:

Increases calcium binding proteinActive transport in the jejunal cellsPhosphorus ions absorption through specific phosphate carrierAlkaline phosphatase (AP) synthesisATP-ase sensibility to calcium ions

Factors in Calcium HomeostasisCa++ sensing receptor (CaSR) membrane protein that binds Ca++ determines the set-point for PTH secretion.Parathyroid hormone (PTH) 84 amino acid peptide increases calcium concentration calcium reabsorption in the kidney calcium resorption from bone intestinal calcium absorption via renal formation 1,25-diOH-D).

Factors in Calcium HomeostasisVitamin D (1,25-diOH-D). absorption / reabsorption of calcium (intestines, bone, and kidney). Calcitonin. 32 amino acid peptide Secretion if serum calcium (antagonist PTH)inhibits osteoclast activity bone calcium resorption

Calcium metabolism

Calcium Distribution in PlasmaTotal Calcium~2.0 mmol/LIonised Calcium~1.0 mmol/LBound Calcium~0.95 mmol/LComplexed Calcium~0.05 mmol/L

Pathophysiology of CalciumDisorders of homeostatic regulatorsPTHvitamin DDisorders of the skeletonbone metastasesDisorders of effector organsgut - malabsorptionkidneyDiet

Breast milk contains 30-50IU/liter, cows milk 20-30IU/l, egg yolk contains 20-50IU/10gr.80% of the vitamin D is absorbed in the small intestine in the present of normal biliary secretion.Vitamin D reaches the blood through thoracic duct along with chilomicrons.

Calcium regulation in the blood is as follows:Vitamin D2 in the food (exogenous) + vitamin D3 (skin, endogenous) =>liver microsomes=>25(OH) D3 => Mitochondrial kidney tubules membrane activated 3 forms:24,25 (OH)2 D3; 1,24,25 (OH)2 D3; 1,25 (OH)2 D3 !!! last more active.In placental macrophage of pregnancy women are present 1,25(OH)2 D3

Serum calcium : narrow physiological range Result of complex interaction process vitamin D, parathyroid hormone (PTH), and the calcium sensing receptor.Serum calcium50% free (ionized)40% protein bound (80% albumin & 20% globulin)10% complexed (phosphate, citrate, bicarbonate, lactate)

Physiology of PTH

Bone Resorption: free Ca2+, orthophosphate, Mg, citrate, hydroxyproline,osteocalcin.GIT Calcium absorption indirectly through vit D metabolismKidney phosphate excretion via proximal tubulesInhibits bicarbonate reabsorption metabolic acidosis favours calcium ionization bone resorption & dissociation of calcium from plasma protein binding sites

Causes of rickets

Vit. D deficiencyLack of adequate sunlightUnsupplemented breast-fed infant.Total parenteral nutrition (TPN)Ca deficiencyLack of dietary CaInadequate Ca in TPNPhosphat def.Breast-fed infantInadequate PO4 in TPN

Causes of rickets

Vit. D deficiencyLack of adequate sunlightConsumption of diet low in fortified foodsUnsupplemented breast-fed infant.Total parenteral nutrition (TPN)UV / increased sunlight exposureVit D2

Vit D2 for premature

Vit D2 in TPN / oralCa deficiencyLack of dietary CaInadequate Ca in TPNCa 700 mg/dayCa in prmature / TPNPhosphat def.Breast-fed infantInadequate PO4 in TPN

CLINICAL MANIFESTATIONS Rickets may develop in any age of an infant, more frequent at 3-6mo, early in prematures.The first signs of hypocalcaemia are CNS changes- excitation, restlessness, excessive sweated during sleep and feeding, tremors of the chin and extremities.

Skin and muscle changes- pallor, occipital alopecia, fragile nails and hair, muscular hypotony,motor retardation.Complications- apnoea, stridor, low calcium level with neuromuscular irritability (tetany).CNS changes are sometimes interpreted as CNS trauma and the administration of the

ACUTE SIGNS Have acute and subacute clinical signs Craniotabes acute sign of rickets, osteolyses detected by pressing firmly over the occipital or posterior parietal bones, ping-pong ball sensation will be felt. Large anterior fontanella, with hyperflexible borders, cranial deformation with asymmetric occipital flattening.

SUBACUTE SIGNSSubacute signs are all the following: frontal and temporal bossingFalse closure of sutures (increase protein matrix), in the X-ray craniostenosis is absent.Maxilla in the form of trapezium, abnormal dentition.

Late dental evolution, enamel defects in the temporary and permanent dentition.Enlargement of costo-chondral junctions-rickets rosaryThorax, sternum deformation, softened lower rib cage at the site of attachment of the diaphragm- Harrison groove.

Subacute signsSpinal column- scoliosis, lordosis, kyphosis.Pelvis deformity, entrance is narrowed (add to cesarean section in females)Extremities- palpated wrist expansion from rickets, tibia anterior convexity, bowlegs or knock kness legs.Deformities of the spine, pelvis and legs result in reduced stature, rachitic dwarfism.Delayed psychomotor development (heat holding, sitting, standing due to hypotonia).

LABORATORY DATA Serum calcium level (N=2.2-2.6mmol/l). At the level 500mmol/l.Thyrocalcitonin can be appreciated (N=23.6+3.3pM/l)Serum parathyroid hormone (N=598+5.0pM/l)In urine: Aminoaciduria >1.0mg/kg/dayUrinary excretion of 35 cyclic AMPDecreased calcium excretion (N=50-150mg/24h)

Radiological findings Only in difficult diagnostic cases.X-ray of the distal ulna and radius: concave (cupping) ends; normally sharply, Fraying rachitic metaphyses and a widened epiphyseal plate.Osteoporosis of clavicle, costal bones, humerus.Greenstick fractures.Thinning of the cortex, diaphysis and the cranial bones.

EVOLUTION The evolution is slow with spontaneous healing at the age of 2-3 years.If treated can be cured in 2-3mo with the normalization of the skeletal and the cellular system.Gibbous, palatal deformity and the narrow pelvis may persist.

DIFFERENTIAL DIAGNOSIS Osteogenesis imperfecta, chondrodystrophy, congenital diseases- CMV, rubella, syphilis.Chronic digestive and malabsorption disorders.Hereditary Fanconis disease, phosphorus diabetes, renal tubular acidosis.

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RadiologyThinning of cortexWidening, cuping metaphysesDecreased bone density

Biochemistry

Ca serum : low / NALP increasedPTH increased

PROPHILAXIS IN RICKETS Specific antenatal prophylactic dose administration : 500-1000IU/day of vitamin D3 solution at the 28-th week of pregnancy. The total dose administered is 135000-180000IU. In term infants prophylactic intake of vitamin D2700IU/d started at 10 days of age during the first 2 years of life; in premature the dose may increase to 1000IU/day.

PROPHILAXIS IN RICKETS WHO recommendation for rickets prophilaxis in a children coming from unfavorable conditions and who have difficult access to hospitals is 200000IU vitamin D2 i/muscular,On the 7day, 2, 4, 6 month- total dose 800000IU. In case of the necessary prolongation 700IU/day till 24mo are given.

SPECIFIC TREATMENT IN RICHETS The treatment is with vitamin D3 depending on the grade.In grade I- 2000-4000IU/day for 4-6weeks, totally 120000-180000IU.In grade II- 4000-6000IU/day for 4-6 weeks, totally 180000-230000IU.In grade III- 8000-12000IU/day for 6-8 weeks, totally 400000-700000IU.

SPECIFIC TREATMENT IN RICHETS Along with vitamin D, calcium is also administered (40 mg/kg/day for a term baby,80 mg/kg/day for a premature baby); also indicate vitamin B&C preparations. From the 7-th day of the treatment massage can be started. Intramuscular administration of ATP solution in case of myotonia 1ml/day is preferred.

Vit D. def;TPN : 0,5 ug/kg/dayOral: 400-800 IU dailyCa deficiency;Premature: 75-150 mg/dlOral :200 mg/kg/dayIV : solution 20 mg/dl

RICKETS COMPLICATIONS Rickets tetany in result of low concentration of serum calcium (

HYPERVITAMINOSIS DSymptoms develop in hypersensitivity to vitamin D children or after1-3mo of high doses intakes of vitamin D; they include hypotonia, anorexia, vomiting, irritability, constipation, polydipsia, polyuria, sleep disorder, dehydration. High serum level of acetone, nitrogen and Ca>2.9mmol/l are found. Increase calcium concentration in urine may provoke incontinence, renal damage and calcification.

*Maintenance of serum calcium levels in thephysiological range is a complex process thatreflects the function of, and interaction between,vitamin D, parathyroid hormone (PTH), and thecalcium sensing receptor.