1. Calcium Disorders Dr. Sohail Inam Consultant Endocrine & Diabetes Prince Sultan Military Medical City Riyadh

2. Calcium Major intracellular ion Important for cellular function – Intracellular signaling – Muscle action potential – Hormone secretion – Coagulation cascade Major store is the bone (90%)

3. Calcium Serum calcium is tightly regulated Normal total Ca 2.2-2.5 mmol/l (8.5-10 md/dl) – Ionized (free) – Bound (Albumin and other proteins) Corrected calcium for albumin

4. Serum Calcium Urine calcium 300 100 600 980010000 1000 Dietary Calcium Fecal Calcium 800 200 Values mg/day

5. Regulation of calcium Parathyroid hormone Vitamin D Calcitonin

6. Parathyroid gland PTH Calcium Phosphate Reabsorbs Calcium Excretes Phosphate Activates 1 alpha hydroxylase 25 OH D3 → 1,25 Dihydoxy D3

7. PTH Stimulation – Hypocalcaemia & hypomagnesaemia – Decrease 1,25 D3 – Hyperphosphatemia –  adrenergic stimulation Inhibition – Hypercalcemia – Increased 1,25 D3 – Hypophosphatemia

8. Vitamin D 291-315 nm

9. Vitamin D 25 OH D 1,25 dihydroxy D ↑Calcium ↑Phosphate ↑Absorption Calcium Phosphate 25 hydroxylase 1 alpha hydroxylase

10. 1 alpha Hydroxylase Activation –PTH –Low phosphate –Low calcium –IGF 1 Inhibition –1,25 (OH)2 D3 –High phosphate & High calcium –FGF23

11. Calcitonin Inhibits release of Ca from bone Increases Ca excretion by the kidney Stimulated by increase in Ca levels

12. Ca x PO4 PTH 1,25-D3 Serum Calcium Urine calcium PTH 1,25-D3 CT

14. HYPOCALCEMIA

15. Hypocalcemia Causes Hypoparathyroidism – Autoimmune – Surgical damage – Radiation damage – Infiltrative Psudohypoparathyroidism (PTH resistance) CaSR mutation

16. Hypocalcemia Causes Vitamin D – Deficiency – Inability to activate Vitamin D – Resistance Renal disease Magnesium deficiency – Decrease PTH release – PTH resistance

17. Hypocalcemia Causes Calcium sequestration – Pancreatitis – Osteoblastic metastasis – High phosphate – Hungry bone disease Drugs Critical illness

18. Hypocalcemia Symptoms Paresthesia – Peri-oral – Limbs Muscle cramps & carpopedal spasm Seizures Laryngeal spasm Cardiac Psychiatric

19. Hypocalcemia Signs Tetany – Carpopedal spasm – Chvestok’s sign – Trousseau's sign Papilledema Cataracts Extrapyramidal ECG- Prolonged QTc

20. Investigations Corrected calcium Phosphate Alkaline phosphatase Renal function Parathyroid hormone Vitamin D Magnesium

21. Hypocalcemia PTH Low Hypoparathyroidism CaSR mutations Magnesium deficiency Hungry bone syndrome PTH High Vitamin D disorders Renal disease PTH resistance Ca sequestration Sepsis Drugs Magnesium deficiency

22. Hypocalcemia Phosphate, Alkaline Phosphatase, Magnesium, Creatinine, Vitamin D PTH HighNormal or low ↑ Phosphate↓ Phosphate↑ Phosphate↓ Phosphate Renal failure PTH resistance Rhabdomyolysis Vitamin D disordersHypoparathyroidism CaSR mutations Hungry bone

23. Treatment Severe symptomatic hypocalcemia – IV calcium (slow infusion) Mild symptoms – Oral calcium Vitamin D – Active form – Inactive form

24. Treatment Specific Magnesium Hypoparathyroidism – Active form of vitamin D – PTH replacement Renal failure – Phosphate binders – Active form of Vitamin D

25. HYPERCALCEMIA

26. Hypercalcemia Mechanisms Excess PTH hormone PTHrP – Tumors (Malignancy) – Pregnancy & lactation Vitamin D mediated – Intoxication – Granulomatous disease – Hematological malignancies

27. Hypercalcemia Mechsnisms Excess Ca absorption (Milk Alkali) Increased osteoclast activation – Cytokines – Immobilization – Adrenal insufficiency – Thyrotoxicosis

28. ↑ Serum Calcium Urine calcium

29. Causes Hyperparathyroidism Malignancy Vitamin D intoxication Milk Alkali syndrome Granulomatous diseases Endocrine

30. Causes Immobilization Drugs Parenteral nutrition Familial hypocalciuric hypercalcemia

31. Clinical features Polyuria & polydipsia GIT – Anorexia – Abdominal pain – Constipation Neuropsychiatric Musculoskeletal

32. Clinical features Renal dysfunction – Nephrocalcinosis – Nephrolithiasis – Renal tubular acidosis Cardiovascular – Arrthymias – Cardiac arrest

33. Hypercalcemia High PTH Hyperparathyroidism Ectopic PTH secretion FHH Drugs Low PTH Malignancy Vitamin D excess Immobilization Milk Alkali Syndrome Granulomatous disease Endocrine

34. Hypercalcemia Confirm on repeat sample Measure PTH Normal or ↑ PTH 24 hour urine Calcium & creatinine FHHHyperparathyroidism Low PTH (<20pg/ml) Measure PTHrP, Vit D metabolites, TFT CXR, CT scan, Myeloma Clinical evaluation & medication history low Normal or high

35. Hypercalcemia Principles of Therapy Increase renal Ca excretion – Saline diuresis (± frusemide) – Calcitonin – Dialysis Reduce Ca efflux from bone – Calcitonin – Bisphosphonates – Denusamab Treat underling cause

36. Treatment Mild hypercalcemia (Ca <3) – Treat underlying cause Moderate hypercalcemia (Ca 3-3.49) – Hydration – Bisphosphonate – Treat underlying cause

37. Treatment Severe Hypercalcemia (severe symptoms, Ca>3.5) – IV hydration 0.9% NaCl – Calcitonin – Bisphosphonates – Low calcium bath dialysis – Treat underlying cause

38. Specific Treatment Hyperparathyroidism – Surgery – Non-surgical ablation – Conservative approach – Calcimimetics Steroids – Hematological malignancies – Vitamin D intoxication