eka agustia rini. rickets disorder of mineralization of the bone matrix / osteoid in growing bone ...
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EKA AGUSTIA RINI
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RICKETS Disorder of mineralization of
the bone matrix / osteoid in growing bone
Involved : growth plate Newly trabecular formed Cortical bone
Osteomalacia After cessation of growth
Involves only a bone, not the growth plate
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Risk factors
Living in northern latitudes (>30o); Dark skinned children; Decreased exposure to sunlight Maternal vitamin D deficiency; Diets low in calcium, phosphorus and vit. D Prolonged parenteral nutrition in infancy with
an inadequate supply of intravenous calcium and phosphate;
Intestinal malabsorption
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Defective production of 1,25(OH)2D3 Hereditary 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).
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Calcium homeostasis - PTH action
SerumCa2+
SerumCa2+
1,25-(OH)1,25-(OH)22DD1,25-(OH)1,25-(OH)22DD
-ve feedback
Increased ResorptionIncreased Resorption
IncreasedCa Absorption
IncreasedCa Absorption
DecreasedCa ClearanceDecreased
Ca Clearance
PTHPTH
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Vitamin D Metabolism
7 Dehydrocholesterol
Skin VitD3 (cholecalciferol)
25-OH-D3(calcidiol)
VitD3
1,25-(OH)2-D3(calcitriol)
25-OH-D3(calcidiol)
Resorption
Calcium absorption
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Resorption Resorption
PTH Response to Hypocalcemia
PlasmaPlasmaPlasmaPlasmaCa2+
PTH PTH
Renal Excretion Renal Excretion Renal Excretion Renal Excretion
Ca2+
Renal Excretion Renal Excretion Renal Excretion Renal Excretion
H2PO4-1,25-(OH)1,25-(OH)22D D
GIT absorption GIT absorption GIT absorption GIT absorption
Ca2+
-ve feedback-ve feedback
IncreaseIncreasePlasmaPlasmaPlasmaPlasmaCa2+
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Role of Calcium
Bone Growth Blood Clotting Maintenance of trans membrane potential Cell replication Stimulus-contraction & stimulus-contracting
coupling Second messenger process
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Intestine:
Increases calcium binding protein Active transport in the jejunal cells Phosphorus ions absorption through
specific phosphate carrier Alkaline phosphatase (AP) synthesis ATP-ase sensibility to calcium ions
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Factors in Calcium Homeostasis Ca++ 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).
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Factors in Calcium Homeostasis Vitamin 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
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Calcium metabolism
GutGut
SkeletonSkeleton
KidneyKidney
Plasma/ICFPlasma/ICF
2.20 mmol/L(30mmol)
25 Mol (99%)25 Mol (99%)
300 mmol/day300 mmol/day
290 mmol/day290 mmol/day
10 mmol/day10 mmol/day
3 mmol/d3 mmol/d
25 mmol/day25 mmol/day
15 mmol/day15 mmol/day
13 mmol/d13 mmol/d
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Calcium Distribution in Plasma
Total Calcium~2.0 mmol/L
Ionised Calcium~1.0 mmol/L
Bound Calcium~0.95 mmol/L
Complexed Calcium~0.05 mmol/L
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Pathophysiology of Calcium
Disorders of homeostatic regulators PTH vitamin D
Disorders of the skeleton bone metastases
Disorders of effector organs gut - malabsorption kidney
Diet
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Breast milk contains 30-50IU/liter, cow’s 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.
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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
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Serum calcium : narrow physiological range
Result of complex interaction process vitamin D, parathyroid hormone (PTH), and the calcium sensing receptor.
Serum calcium 50% free (ionized) 40% protein bound (80% albumin &
20% globulin) 10% complexed (phosphate, citrate,
bicarbonate, lactate)
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Physiology of PTH
Bone Resorption: free Ca2+, orthophosphate, Mg, citrate, hydroxyproline,osteocalcin.
GIT Calcium absorption indirectly through vit D metabolism
Kidney
phosphate excretion via proximal tubulesInhibits bicarbonate reabsorption metabolic acidosis favours calcium ionization bone resorption & dissociation of calcium from plasma protein binding sites
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Causes of rickets
Vit. D deficiency Lack of adequate sunlight
Unsupplemented breast-fed infant.
Total parenteral nutrition (TPN)
Ca deficiency Lack of dietary Ca
Inadequate Ca in TPN
Phosphat def. Breast-fed infant
Inadequate PO4 in TPN
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Causes of ricketsVit. D deficiency
Lack of adequate sunlight
Consumption of diet low in fortified foods
Unsupplemented breast-fed infant.
Total parenteral nutrition (TPN)
UV / increased sunlight exposure
Vit D2
Vit D2 for premature
Vit D2 in TPN / oral
Ca deficiency
Lack of dietary Ca
Inadequate Ca in TPN
Ca 700 mg/dayCa in prmature / TPN
Phosphat def.
Breast-fed infant
Inadequate PO4 in TPN
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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.
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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
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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.
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SUBACUTE SIGNS
Subacute signs are all the following: frontal and temporal bossing
False closure of sutures (increase protein matrix), in the X-ray craniostenosis is absent.
Maxilla in the form of trapezium, abnormal dentition.
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Late dental evolution, enamel defects in the temporary and permanent dentition.
Enlargement of costo-chondral junctions-“rickets rosary”
Thorax, sternum deformation, softened lower rib cage at the site of attachment of the diaphragm- Harrison groove.
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Subacute signs
Spinal 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).
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LABORATORY DATA
1. Serum calcium level (N=2.2-2.6mmol/l). At the level <2.0mmol/l convulsions sets in.
2. Phosphorus normal (1.5-1.8mmol/l). Normal ratio of Ca : P= 2:1; in rickets become 3:1; 4:1.
3. Serum 25(OH)D3 (N=28+2.1ng/ml); and 1,25(OH)2D3(N=0.035+0.003ng/ml)
4. Serum alkaline phosphatase is elevated >500mmol/l.5. Thyrocalcitonin can be appreciated
(N=23.6+3.3pM/l)Serum parathyroid hormone (N=598+5.0pM/l)In urine: Aminoaciduria >1.0mg/kg/day
• Urinary excretion of 3’5’ cyclic AMP• Decreased calcium excretion (N=50-150mg/24h)
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Radiological findings
Only in difficult diagnostic cases.1. X-ray of the distal ulna and radius:
concave (cupping) ends; normally sharply, Fraying rachitic metaphyses and a widened epiphyseal plate.
2. Osteoporosis of clavicle, costal bones, humerus.
3. Greenstick fractures.4. Thinning of the cortex, diaphysis and
the cranial bones.
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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.
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DIFFERENTIAL DIAGNOSIS
1. Osteogenesis imperfecta, chondrodystrophy, congenital diseases- CMV, rubella, syphilis.
2. Chronic digestive and malabsorption disorders.
3. Hereditary Fanconi’s disease, phosphorus diabetes, renal tubular acidosis.
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Slide 3 of 21
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Radiology
Thinning of cortexWidening, cuping metaphysesDecreased bone density
Biochemistry
Ca serum : low / NALP increasedPTH increased
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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 D2 700IU/d started at 10 days of age during the first 2 years of life; in premature the dose may increase to 1000IU/day.
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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.
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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.
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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.
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Vit D. def;TPN : 0,5 ug/kg/dayOral: 400-800 IU daily
Ca deficiency;Premature: 75-150 mg/dlOral :200 mg/kg/dayIV : solution 20 mg/dl
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RICKETS COMPLICATIONS
1. Rickets tetany in result of low concentration of serum calcium (<2mmol/l), failure of the PTH compensation and muscular irritability occur.
2. Hypervitaminosis D
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HYPERVITAMINOSIS D
Symptoms 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.