MBD CAN BE PREDICTED? Dr. Emad Shatla MD / MRCPCH / FRCPCH Senior Consultant Neonatology Head of NICU Head of Pediatrics Sohar Hospital - OMAN

Transcription

1 MBD METABOLIC BONE DISEASE CAN BE PREDICTED? Dr. Emad Shatla MD / MRCPCH / FRCPCH Senior Consultant Neonatology Head of NICU Head of Pediatrics Sohar Hospital - OMAN

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5 Preterm 27 weeks 6 weeks old Osteopenia of prematurity X ray Vit D,PTH,. Bone profile, Ca, P, ALP,

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8 There are three special types of cells that are found only in the bone. OSTEOCLASTS Dissolve the bone. They come from the bone marrow and are related to white blood cells. They are formed from two or more cells that fuse together, usually have more than one nucleus. OSTEOBLASTS It forms new bone,come from the bone marrow and have only one nucleus. They control calcium and mineral deposition. The old osteoblasts are also called LINING CELLS. They regulate passage of calcium into and out of the bone. OSTEOCYTES They come from osteoblasts. Some of the osteoblasts turn into osteocytes while the new bone is being formed can sense pressures.

9 Alkaline Phosphatase Alkaline phosphatases (ALPs) are a group of enzymes that are present in many different tissues. e.g. bone and liver.( Intestine, placenta, tumour ) in vitro activity at a ph of 10. reference range of 35 to 125 IU per liter in an adult population.

10 Total BALP can be further separated into isoforms that are specific for cortical and trabecular bone, respectively. The role of ALP in the skeleton in the mineralization process. involved The clearance of ALP from serum may be transiently impaired after viral infections in children (transient Hyperphosphatasemia), leading to excessively high total ALP. Cholestasis ---- ALP

11 Backstrom and colleagues suggested that Serum alkaline phosphatase levels higher than 900 U.I/l associated with a serum phosphate level lower than 1.8 mmol/l have a diagnostic sensitivity of 100% and specificity of 70%. Dick H. Kleyn The reliability of alkaline phosphatase to predict the status of bone mineralization are still conflicting? Serum level of calcium is usually within the normal range.

12 This figure indicates that the activity of alkaline phosphatase is decreases with the advancement of GA

13 Osteocalcin Osteocalcin is secreted by osteoblasts It is secreted and incorporated into the organic bone matrix during the matrix mineralization phase. Some newly synthesized Osteocalcin reaches the bloodstream. Osteocalcin, or( bone gammacarboxyglutamic acid containing Protein ) (BGLAP) It has gla domains, its synthesis is vitamin K dependent. Reference Range: 18 years or older ng/ml Osteocalcin is metabolized primarily by the kidneys. It has been observed that higher serumosteocalcin levels are relatively well correlated with increases in bone mineral density (BMD).

14 Bone Mineral Density Test Bone density testing can be done several ways. The most common and accurate way uses a dual-energy x-ray absorptiometry (DEXA) scan. DEXA uses low-dose x-rays. (You receive more radiation with a chest x-ray.)

15 There are two types of DEXA scans: Central DEXA. You lie on a soft table. The scanner passes over your lower spine and hip. Peripheral DEXA (p-dexa). These smaller machines measure the bone density in your wrist, fingers, leg, or heel.

16 Osteocalcin Diagnostic use of this molecule is hampered by its significant I n s t a b i l i t y Found in the circulation In small amount Difficulties in distinguishing between the various molecular forms.

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19 Low Osteocalcin levels are associated with insulin resistance, diabetes and metabolic syndrome in observational studies. New therapeutic approaches to diabetes and heart disease may be anticipated if this bone-derived protein is involved in the regulation of glucose metabolism and cardiovascular risk. J Diabetes Investig Jul; 7(4): Published online 2015 Dec 16. doi: /jdi.12439

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21 Parathyroid Hormone (PTH) The placenta is impermeable to parathyroid hormone (PTH), PTHrP, and calcitonin. but!!!!!!!!! Vitamin D (1) or (1,25) are transported across the placenta, and free vitamin D concentrations in foetal blood are similar to or higher than maternal values. PTH serum calcium concentrations directly by increasing bone resorption and renal calcium reabsorption and indirectly by increasing renal synthesis of 1,25(OH)2D3.

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23 In humans, maternal hyper-parathyroidism may lead to stillbirth or neonatal hypo-calcemia secondary to suppression of fetal PTH. Maternal hypoparathyroidism leads to increased levels of fetal PTH via fetal parathyroid hyperplasia, and generalized skeletal demineralization Ginekol Pol. 2005

24 PARATHYROID HORMONE-RELATED PEPTIDE (PTHRP) There is increasing evidence that PTHrP is the major determinant of placental calcium transport in animals, and that levels of PTHrP are increased in response to a low fetal plasma calcium level. The role of PTHrP is less well characterized in human pregnancy, but may be produced in the placenta, and is present in breast milk.

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26 Vit. D Reducing the risk of multiple sclerosis, according to a 2006 study published in the Journal of the American Medical Association Decreasing the chance of developing heart disease, according to 2008 findings published in Circulation journal Helping to reduce the likelihood of developing the flu, according to 2010 research published in the American Journal of Clinical Nutrition Also has role in: Hypertension Depression Obesity Rheumatoid arthritis Diabetes Autoimmune disorders Osteoporosis

27 What I should do???? Urine R/E CBC

28 The period of greater skeletal development is during the intrauterine life and specifically during the last trimester. The bone volume increases significantly with gestational age and the high net bone formation activity is mainly due to modelling, with a rapidly increasing trabecular thickness (the trabecular thickening rate being approximately 240 times faster in the foetus than in the children).

29 The prevalence of MBD varies depending on gestational age, birthweight and kind of alimentation. Magnitude of the problem it occurs in up to 55% of babies born with weight under 1000 g,and 23% of infants weighing < 1500 g frequent in babies under 28 weeks of gestation.

30 MBD remains silent until a severe demineralisation occurs. The most evident clinical findings of osteopenia are deformity of the skull (diastasis of the suture, enlargement of the sagittal fontanelle and frontal bosses, craniotabe). Also,thickening of the of the wrists, rib and long bones fractures. Softening and/or fractures of the ribs can cause pulmonary changes and respiratory distress, typically between 6 and 16 weeks of age.

31 The mineralization process is determined by synthesis of the organic bone matrix by osteoblasts (osteoid) onto which calcium and phosphate salts are deposited. This process increases exponentially between 24 and 37 weeks of gestation, reaching the 80% of mineral accretion in the third trimester.

32 The main determinant of skeletal mineralization in utero appears to be the foetal plasma calcium concentration and this is mainly influenced by fetal PTH activity. Lack of parathyroid in fetal mice leads to low foetal calcium and skeletal mineralization.

33 NEWBORN The supply of calcium and phosphorus halts abruptly at birth when the umbilical cord is cut. Whole blood ionized calcium falls rapidly, reaching a nadir of 1.2 mmol/l by around 16 hours of age. Paradoxically, plasma calcitonin rises rapidly after birth in infants.

34 In the adult, calcitonin is secreted in response to hyper-calcemia, and in response to elevated plasma gastrin concentrations. The infant surge in plasma calcitonin peaks at approximately 12 hours after birth and is greater in preterm infants than in term small for gestational age (SGA) infants. The surge can be ameliorated in preterm infants by the provision of large supplements (2 mmol/kg/day) of calcium.

35 Many factors affect calcium absorption including the maternal vitamin D status, solubility of calcium salts, quality and quantity of calcium, amount and type of lipids and, obviously, gut function. Calcium absorption from the intestine occurs both passively and through a vitamin-d dependent active transport mechanism. Italian Journal of Pediatrics 2009, 35:20

36 occurs within hours of birth commonly seen in preterm and very low birth weight infants, infants asphyxiated or depressed at birth, infants of diabetic mothers, and the intrauterine growth restricted infants. The mechanisms inadequate nutritional intake decreased responsiveness of parathyroid hormone to vitamin D increased calcitonin level metabolic acidosis increased urinary losses hypoalbuminemia increased endogenous phosphate load due to tissue catabolism

37 Late-onset neonatal hypocalcemia Occurs 3-7 days after birth. Vitamin D deficiency. Exogenous phosphate load. Primary immunodeficiency disorder: DiGeorge Syndrome. Gentamicin therapy.

38 Phosphorus Absorption of phosphorus takes place in the jejunum and depends on the dietary intake. The phosphorus supply regulates calcium absorption and retention: the higher is the phosphorus content of the diet, the higher is the calcium retention. Chronic damage to placenta phosphorus transport osteopenia (IUGR).

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40 Moreover, while in utero fetus experiments mechanical stimulation by kicking against the uterine wall, extra-uterine LIFE incubator. Immobilisation stimulates bone reabsorption by osteoclasts and urinary calcium excretion.

41 TOP 8 CALCIUM RICH FOODS 1) Raw Milk. 1 cup: 300 mg (30% DV) 2) Kale (cooked) 1 cup: 245 mg (24% DV) 3) Sardines (with bones) 2 ounces: 217 mg (21% DV) 4) Yogurt or Kefir. 6 oz: 300 mg (30% DV) 5) Broccoli. 1 ½ cup cooked: 93 mg (9% DV) 6) Watercress. 1 cup: 41 mg (4% DV) 7) Cheese. 1 oz: 224 mg (22% DV) 8) Bok Choy.

42 Recent work in human subjects has shown placenta The level of mrna expression of an active placental calcium transporter (PMCA 3), on the basal membrane of the placenta, is positively correlated with whole body bone mineral content (BMC) in the offspring at birth. These observations may suggest a possible mechanism for the influence of maternal vitamin D status on placental calcium transport and intrauterine bone mineral accrual. The plasma membrane Ca2+ ATPase (PMCA).

43 NEONATAL MINERAL REQUIREMENTS Supplying calcium and phosphorus in parenteral nutrition is a challenge because of limited solubility of these two minerals. Calcium and phosphorus's solubility depends on: Presence of lipid PH Type and concentration of calcium salts Glucose concentration Temperature Type and concentration of amino acid

44 In parenteral nutrition calcium is administered as inorganic salt and phosphorus may be administered as inorganic sodium and potassium phosphate or glycerol-phosphate, which are quite soluble in water. The addition of cysteine to lower ph of the parenteral admixtures improves the solubility of calcium and phosphorus. Adding cysteine increased the amount of NaPhos that could be added to solutions.

45 The human milk content is inadequate for preterm requirements since the content of calcium and phosphorus in preterm human milk is 31 mg/100 kcal and 20 mg/ 100 kcal. Assuming calcium and phosphorus absorption of 70% and 80% respectively, this would provide only one-third of the in utero level of absorbed calcium and phosphorus. Low concentrations of calcium and phosphorus in the urine suggest an inadequate intake.

46 Markers of nutritional status should be assessed baseline, and then weekly during the initial phase; once the newborn is stable, assessment must be done at the starting of total enteral nutrition and every 2 3 weeks. Parenteral administration of mg of calcium/kg/day can prevent early neonatal hypo-calcaemia in preterm infants The best calcium to phosphorus ratio for bone mineralization is 1.7:1. Ca +P P+Ca p Ca

47 Clinical Features and Diagnosis MBD Diagnosis of osteopenia is mainly done by serum analysis. Biochemically osteopenia is characterised by low serum levels of phosphorus and by an increase in serum levels of alkaline phosphatase that can reach values 5 times higher than the upper reference range used for adults.

48 If MBD is diagnosed and nutritional supplementation is started, a periodic assessment of laboratory data is necessary to evaluate the response to treatment also when babies are discharged from hospital.

49 Minerals and vitamin D recommended intakes in growing preterm infants. Requirements ESPGAN LSRO Atkinson Rigo Calcium (mg/kg/day) Phosphorus (mg/kg/day) Vitamin D (I.U./day) (I.U./kg/day)

50 Osteopenia has a good prognosis, provided that calcium, phosphates and vitamin D are appropriately administered to the babies. It is still controversial the need for high calcium and phosphorus intakes in preterm infants after hospital discharge. Few data are available about the optimal length, quantity and methods of providing supplemental minerals for preterm infants.

51 The determination of ALP and of P seems to be useful in assessing the risk of metabolic bone disease and serum analysis need to be performed periodically in order to assess response to nutritional treatment. Through DEXA and quantitative ultrasound it is also possible to determine the state of bone mineralization and therefore to plan a nutritional intervention.

52 Fracture Incidence in Low Birth Weight Infants Most common sites: Ribs Radius ulna Femur Koo WWK et al J Pediar Orthop 9:326,1989

53 Article: EARLY NEONATAL HYPOCALCEMIA IN INFANTS BORN TO MOTHERS WITH HIGH PREVALENCE OF HYPOVITAMINOSIS D AND RELATION TO BIRTH SIZE A. Soliman, Emad Shatla, A. Adel ABSTRACT: Conclusion This high incidence of neonatal hypocalcemia necessitates vitamin D supplementation to pregnant women in this population with high prevalence of vitamin D deficiency. Archives of Disease in Childhood 10/2014; 2.91 Impact Factor

54 Radiological manifestations of Neonatal Rickets Ashraf Soliman, Husam Salama, Emad Shatla, Elsaid Bedair Article: Clinical, biochemical, and radiological manifestations of vitamin D deficiency in newborns presented with hypocalcemia Indian journal of endocrinology and metabolism. 07/2013; 17(4):

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56 Emad Shatlaᶦ, A.Soliman². INCIDENCE OF EARLY NEONATAL HYPOCACEMIA IN INFANTS BORN IN QATAR TO MOTHER WITH HIGH PREVELENCE OF HYPOVITAMINOSIS D AND ITS RELATION TO ANTHROPOMETRIC DATA. 27 th international congress of pediatrics Melboume, Australia 2013; August:

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58 Guidelines for the Treatment of Osteopenia of Prematurity Prescribe: Elemental calcium mmol/kg/day and Elemental phosphate 2-3 mmol/kg/day to be given in divided doses. Ensure an adequate intake of calcium and phosphate from feeds fortified breastmilk / preterm formula. Weekly monitoring for infants.

59 Weekly bloods including bone profile for all preterm. If persistently rising alkaline phosphatase (>500IU/L) despite prophylaxis, consider calculating the urinary tubular reabsorption of phosphate (TRP). If TRP >95%, this suggests that phosphate supplementation is still insufficient and increasing or adding phosphate supplementation is appropriate. TRP % = (1 - ( Urine phosphate / Urinary Creatinine ) x ( Plasma Creatinine / Plasma phosphate )) x 100.

60 World J Methodol Sep 26; 5(3):

61 Conclusion An adequate nutritional intake of calcium, phosphorus and vitamin D and passive physical exercise may prevent abnormal bone-remodelling activity during first weeks of life and may optimize growth potential of preterm infants. It is important to recognize the biochemical signs of osteopenia in an early stage in order to be able to precociously implement the dietary intake and reduce the risk of bones fractures.

62 98% of the calcium and 80% of the phosphorus in the body are in the skeleton. The metabolic homeostasis of calcium, phosphorus, and magnesium and mineralization of the skeleton are complex.

63 References Belkacemi L, Bedard I, Simoneau L, Lafond J. Calcium channels, transporters and exchangers in placenta: a review. Cell Calcium 2005;37:1e8. Stauffer TP, Hilfiker H, Carafoli E, Strehler EE. Quantitative analysis of alternative splicing options of human plasma membrane calcium pump genes. J Biol Chem 1993;268:25993e6003. Glazier JD, Atkinson DE, Thornburg KL, et al. Gestational changes in Ca2þ transport across rat placenta and mrna for calbindin9k and Ca(2þ)-ATPase. Am J Physiol 1992;263:R930e5. Kip SN, Strehler EE. Vitamin D3 upregulates plasma membrane Ca2þ-ATPase expression and potentiates apico-basal Ca2þ flux in MDCK cells. Am J Physiol Renal Physiol 2004;286:F363e9

64 Kovacs CS. Skeletal physiology: fetus and neonate. In: Favus MJ, editor. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington: ASBMR; p. 65e71. Care AD, Caple IW, Abbas SK, Pickard DW. The effect of fetal thyroparathyroidectomy on the transport of calcium across the ovine placenta to the fetus. Placenta 1986;7:417e24. Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM. Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci USA 1996;93:15233e8. Kovacs CS, Manley NR, Moseley JM, Martin TJ, Kronenberg HM. Fetal parathyroids are not required to maintain placental calcium transport. J Clin Invest 2001;107:1007e15. Ardawi MS, Nasrat HA, HS BAA. Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol 1997;137:402e9.

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