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

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

Calcium Serum calcium is tightly regulated Normal total Ca mmol/l ( md/dl) – Ionized (free) – Bound (Albumin and other proteins) Corrected calcium for albumin

Serum Calcium Urine calcium Dietary Calcium Fecal Calcium Values mg/day

Regulation of calcium Parathyroid hormone Vitamin D Calcitonin

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

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

Vitamin D nm

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

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

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

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

HYPOCALCEMIA

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

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

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

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

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

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

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

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

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

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

HYPERCALCEMIA

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

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

↑ Serum Calcium Urine calcium

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

Causes Immobilization Drugs Parenteral nutrition Familial hypocalciuric hypercalcemia

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

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

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

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

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

Treatment Mild hypercalcemia (Ca <3) – Treat underlying cause Moderate hypercalcemia (Ca ) – Hydration – Bisphosphonate – Treat underlying cause

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

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