Disorders of Calcium & Phosphorus Metabolism

1. Departments of Pediatrics University of Udine and LSUHSC Schools of Medicine Disorders of Calcium & Phosphorus Metabolism Alfred Tenore, MD Alfonso Vargas, MD

2. Outline I. Introduction A. Minerals (Ca, P, Mg) B. Hormones (PTH, Vit D, Calcitonin) II. Metabolic Action of Hormones A. PTH B. Vitamin D C. Calcitonin III. Hypercalcemia A. Differential diagnosis B. Symptoms C. Treatment IV. Hypocalcemia A. Generalities B. Symptoms C. Clinical Entities V. Rickets

3. Introduction A. Homeostasis of calcium and phosphorus is maintained by a highly integrated and complex endocrine system 1. Calcium a. Essential for major cellular functions normal muscle contraction membrane functions and permeability blood coagulation secretion of peptide hormones numerous enzymatic reactions b. Normal serum range is unaffected by: sex rate of growth climatic conditions

4. Introduction 2. Phosphorus a. Fundamental for cell bioenergetics b. Important for activation of most hormone receptors c. Serum concentration is influenced by: age sex dietary intake physical exercise nyctohemoral variations

5. Introduction 3. Alkaline Phosphatase a. Synthesized by bone and liver b. In bone: produced by osteoblasts (bone forming) c. Elevated during periods of increased bone forming activity normal growth or growth spurts healing fractures d. Elevated where there is an increase in bone turnover (since osteoblastic activity is coupled with osteoclastic activity)

6. Introduction B. A close relationship exists between Ca and P fluxes 1. Any change in the extracellular concentration of one leads to an inverse change in the concentration of the other 2. The activity of ionic Ca++ in the extracellular fluid regulates the secretion (and biosynthesis) of PTH (and calcitonin) by a negative feedback mechanism

7. Metabolic Action of Calcium-Regulating Hormones PTH, Vitamin D(1,25(OH)2D3) and CT regulate the flow of calcium and phosphorus in and out of the extracellular fluid compartment through their actions on : ◊ Bone ◊ Intestine ◊ Kidney

8. PTH 1. Bone (minor effect) a. Increases alkaline phosphatase b. Increases the release of calcium c. Increases the release of phosphorus 2. Intestine (indirect effect *) a. Increases absorption of calcium b. Increases absorption of phosphorus *The effects are caused by vitamin 1,25(OH)2D3, whose synthesis is stimulated by PTH

9. PTH 3. Kidney (major effect) a. Increases cAMP as intracellular second messenger b. Increases excretion of phosphorus, as well as: bicarbonate sodium potassium c. Decreases the excretion of calcium, as well as: magnesium hydrogen b. Stimulates synthesis of 1,25(OH)2-D3

10. PTH 4. Net effect of PTH on the serum concentrations of Ca and P Net Effect Bone Intestine Kidney Ca    P  

11. Vitamin D 1. Bone (indirect effect) a. Increases the release of calcium b. Increases the release of phosphorus (This effect requires the presence of PTH) 2. Intestine (major effect) a. Increases absorption of calcium b. Increases absorption of phosphorus 3. Kidney (minor effect) a. Improves renal tubular reabsorption of calcium b. Increases renal tubular reabsorption of phosphorus

12. Vitamin D 4. Net effect of Vitamin D on the serum concentrations of Ca and P Net Effect Bone Intestine Kidney Ca    P 

13. Calcitonin (CT) 1. Bone (major effect) a. Inhibits re-absorption of calcium b. Inhibits re-absorption of phosphorus 2. Intestine (no specific effect) 3. Kidney (minor effect) a. Decreases renal tubular re-absorption of calcium b. Decreases renal tubular re-absorption of phosphorus

14. Calcitonin (CT) 4. Net effect of Calcitonin on the serum concentrations of Ca and P Net Effect Bone Intestine Kidney Ca —   P —  

15. SUMMARY  Net effects of the three hormones on the serum concentration of Ca and P Ca P Vitamin D   PTH   Calcitonin  

16. Hypercalcemia A. Rare in children B. Differential diagnosis : 1. Increased Intestinal Absorption a. Vitamin D intoxication b. Idiopathic infantile hypercalcemia (William S.) c. Sarcoidosis 2. Increased Bone Mobilization a. Hyperparathyroidism b. Hyperthyroidism c. Immobilization d. Vitamin A intoxication e. Metastatic tumors with osteolysis f. Multiple myeloma 3. Uncertain mechanism: Subacute fat necrosis

17. a. general malaise, fatigue b. psychoneurotic complaints c. weight loss d. pruritis Hypercalcemia C. Symptoms 1. Asymptomatic : 2. Non-specific : a. colic 3. Renal: b. polyuria, polydipsia a. epigastric pain 4. Gastrointestinal : b. constipation c. anorexia d. nausea - vomiting a. muscular weakness 5. Neuro-Muscular : b. lethargy c. confusion - stupor d. coma

18. D. Treatment Hypercalcemia 1. Removal through diuresis : a. intravenous hydration b. furosemide 1 mg/kg iv q 6-8 h 2. Block absorption : Prednisone 2 mg/kg/day 3. Increase binding: Inorganic oral phosphate 1–3 gm/day in 4 divided doses 4. Favor deposition : a. Salmon calcitonin 5-8 MRC U/kg q 6–12 h IV/IM b. Bisphosphonates 5. Mithramycin : (25 ug/kg as iv bolus)

19. Hypo-calcemia A. Generalities 1. “True” versus“False” Hypocalcemia a. Consider the physiologically active fraction ( ionized calcium ) only Total Ca: (8.8-10.8 mg/dl) - (2.2-2.7mmol/L) Ionized Ca:(4.4-4.9 mg/dl) - (1.1-1.2mmol/L) plasma protein concentration: each decrease of 1 g/dl of albumin results in a decrease of 0.8 mg/dl (0.02 mmol/L) of calcium b. Consider the acid-base status of patient Alkalosis increases binding ( ionized Ca) Acidosis decreases binding ( ionized Ca)

20. Hypocalcemia A. Generalities 2. Think also of Magnesium a. As many as 80% of infants with “hypocalcemic” seizures may be hypomagnesemic b. In some infants the hypocalcemia may be difficult to correct until the hypomagnesemia is corrected

21. Hypocalcemia B. Clinical Features 1. paresthesia 2. neuromuscular irritability 3. muscle cramps 4. tetany 5. seizures

22. Hypocalcemia C. Clinical Entities 1. Neonatal a. Early distinctive feature of premature infants occurs in first 24 h of life corrects spontaneously (in most) after 5-10 days of life phosphate level not necessarily elevated Causes (single or in combination)

23. Hypocalcemia C. Clinical Entities 1. Neonatal a. Early Causes (single or in combination) sudden interruption of materno-fetal Ca flux (together with increased fetal need of Ca for growth) ◊ ◊ anoxia; birth trauma; acidosis; respiratory diffic. (cause cell break-down and increase in inorganic P) ◊ inadequate (immature) PTH response ◊ end-organ unresponsiveness to PTH ◊ transient neonatal hypercalcitoninemia ◊ inadequate maternal vitamin D

24. Hypocalcemia C. Clinical Entities 1. Neonatal b. “Late” mostly seen in term infants occurs from the 3rd day to 2 mos of life Levels of phosphorus are consistently elevated infants with perinatal hypoxia and/or acidosis are more prone hypoparathyroidism is the main etiological factor (in most cases it is transient)

25. Algorithm for the diagnosis and treatment of Neonatal Hypocalcemia Hypocalcemia HYPOCALCEMIA <48–72 hrs of age >3 days of age “EARLY” Neonatal Tetany “LATE” Neonatal Tetany Dietary management: Increase Ca and decrease P Calcium Treatment :

26. Hypocalcemia C. Clinical Entities 2. Older Children a. Hypoparathyroidism Classification ◊ Transient (neonatal – Immature PTH response) ◊ Reversible (due to Magnesium deficiency) ◊ Irreversible (permanent absence of PTH)  Congenital (Di George Syndrome) cardiac defect absent thymus and/or T-cell defects  Idiopathic (autoimmune – most frequent)

27. Hypocalcemia C. Clinical Entities 2. Older Children a. Hypoparathyroidism Laboratory findings Ca low P high PTH low ◊ Diagnostic triad ◊ ◊ Alk P’ase low Mg nl/low

28. Algorithm for the diagnosis and treatment of Childhood Hypocalcemia Hypocalcemia Ca  low P  high PTH LOW (hypoparathyroidism) HIGH (Pseudo-hypo- parathyroidism) Permanent (Congenital) (idiopathic) Transient (“Neonatal”) Reversible (Mg defic.) Treatment : Vit D (1,25) increase Ca decrease P Mg Vit D (if necessary)

29. Hypocalcemia C. Clinical Entities 2. Older Children b. Pseudo-Hypoparathyroidism (PHP) Classification Renalunresponsiveness & Boneunresponsiveness ◊ Renal responsiveness & Boneunresponsiveness ◊ Renalunresponsiveness & Boneresponsiveness ◊ Renal responsiveness & Bone responsiveness ◊

30. Hypocalcemia C. Clinical Entities unresponsiveness Totally – PHP Type 1 Partially – PHP Type 2 to endog PTH –Pseudo Idiop HP Renal UN-responsiveness Bone UN-responsiveness Pseudo Hypo-Hyper-P Ps Hyper-Hypo-P Bone Responsiveness Renal Responsiveness Pseudo-Pseudo-Hypo-P

31. Hypocalcemia C. Clinical Entities 2. Older Children a. Pseudo-Hypo-parathyroidism (PHP) Laboratory findings Ca low P high PTH high ◊ Diagnostic triad ◊ ◊ Alk P’ase low/high Mg nl

32. Hypocalcemia b. Pseudo-Hypoparathyroidism (PHP) Summary table of the various forms of “pseudo”-hypoparathyroidism

33. Hypo-calcemia Distinguishing features between Idiopathic and Pseudo-Hypoparathyroidism (PHP) Hypo-parathyroidism Idiopathic Pseudo Female : Male 1 : 1 2 : 1 Average age of onset (years) 16 8 % with moniliasis 16 0 % with papilledema 2 18 % with subcut. soft tissue calcifications 2 60 % with mental retardation 1 63 % with round face, short stat. (obesity) 0 50-75 % with short metacarpals (stubby fingers) 0 50-75

34. Rickets A. Definition : Defective mineralization of the osteoid tissue of the skeleton affecting: 1. Epiphyseal growth plates (“growing bones”) 2. Cortical & Trabecular bone where resorption (in relation to bone remodelling) is followed by deposition of osteoid that fails to mineralize where cartilage cells and unmineralized osteoid accumulates (“Rickets”) (“Osteomalacia”) giving rise to giving rise to  Bone deformities Bone fractures

35. Rickets Clinical and Imaging (X-rays)

36. Rickets B. The 3 Basic Etiologies : 1. Failure to form the active metabolite (1,25(OH)2D3) of Vit D a. dietary deficiency b. malabsorption “Vitamin D Deficiency” c. liver disease d. renal disease e. hereditary “Vitamin D Dependency” f. anticonvulsants 2. Excessive phosphate excretion a. Hypophosphatemic Rickets “Vitamin D Resistance” b. Fanconi Syndrome c. Lowe Syndrome 3. Accumulation of excess acid a. Distal renal tubular acidosis

37. Rickets C. Impaired Vitamin D metabolism is the major cause of rickets

38. Blood pH PHASE Ca P PTH AP Urine Bone 1° nl nl nl nl nl nl  2° nl    aa acidosis rickets  3°    aa   acidosis Florid Rickets D. “Vitamin D Deficiency” 1. The three stages in the development of Vitamin D Deficiency Rickets

39. Rickets D. “Vitamin D Deficiency” 2. Treatment a. 1000 – 2000 IU/day Vit D2-ErgoCalciferol b. Treat for several months until healing occurs c. The Institute of Medicine - IOM of the National Academy of Sciences and the American Academy of Pediatrics Committee on Nutrition advice 400 IU vitamin/day when healing is completed. today some experts recommend 1000 - 2000 IU/day for up to a year for complete bone healing and repletion of reserves

40. Rickets E. “Vitamin D Dependency” 1. Hereditary a. Vit DDependency Rickets (VDDR) Type 1 Autosomal recessive deficiency of 1-hydroxylase enzyme Treatment ◊ Vitamin D: 50,000-100,000 IU/d (1.25-2.5 mg/d) ◊ 25-OHD: 400 – 900 g/day ◊ 1,25(OH)2D: 0.5 – 1 g/day ◊ 1-OH vitamin D: 0.5 - 2 g/day b. VDDR Type 2 Autosomal recessive End-organ resistance to 1,25(OH)2D3

41. Rickets E. “Vitamin D Dependency” 2. Anticonvulsant - induced a. diphenylhydantoin b. phenobarbital c. Treatment Vitamin D: 800 – 2000 IU vitamin/day (in some up to 50,000 IU)

42. Rickets E. “Vitamin D Resistance” 1. “X-linked hypophosphatemic rickets” 2. kidney and intestine involved” 3. laboratory studies : a. Ca  normal b. P  low c. PTH  nl/high 4. Treatment : a. oral phosphate: 1 – 2 g elemental P/day b. 1-OH vitamin D: 0.01 – 0.02 ng/kg/day c. 1,25(OH)2D: 0.01 – 0.05 g/kg/day (up to 4 g/day)

43. decreased decreased elevated vit D deficiency decreased elevated elev/norm Renal failure (BUN & Creat) decreased elevated elevated elevated normal normal Vit D intoxication Hypoparathyroidism SUMMARY TABLE Abnormalities of calcium concentrations can be initially assessed by evaluating serum phosphate and alk. phosphatase Diagnostic considerations with abnormal Ca++ concentrations Calcium Phosphorus Alk Phosph Diagnosis elevated decreased ~elev/norm Hyperparathyroidism

44. Questions 1) Which of the following metabolic derangements would be the most likely diagnosis for a 36-hour-old infant weighing 1800 g who is irritable, has cardiac arrhythmias, apnea and seizures ? a) hypoglycemia b) hypocalcemia c) hyponatremia d) hypercalcemia e) hyperglycemia

45. Questions 1) Which of the following metabolic derangements would be the most likely diagnosis for a 36-hour-old infant weighing 1800 g who is irritable, has cardiac arrhythmias, apnea and seizures ? a) hypoglycemia b) hypocalcemia c) hyponatremia d) hypercalcemia e) hyperglycemia

46. Questions 2) Which of the following would a full-term child born to a mother with hyperparathyroidism most likely have ? a) hyperparathyroidism b) hypoparathyroidism c) Vitamin D dependency d) Di George syndrome e) magnesium deficiency

47. Questions 2) Which of the following would a full-term child born to a mother with hyperparathyroidism most likely have ? a) hyperparathyroidism b) hypoparathyroidism c) Vitamin D dependency d) Di George syndrome e) magnesium deficiency

48. Questions 3) All of the following are characteristic of hypoparathyroidism, except ? a) cataracts b) paresthesia c) delayed eruption of teeth d) pseudotumor cerebri e) hyperphosphaturia

49. Questions 3) All of the following are characteristic of hypoparathyroidism, except ? a) cataracts b) paresthesia c) delayed eruption of teeth d) pseudotumor cerebri e) hyperphosphaturia