FY1 Calcium/Phosphate/ Magnesium Homeostasis

1. FY1 Calcium/Phosphate/ Magnesium Homeostasis Funmi Awopetu Senior Clinical Scientist King George Hospital

2. Ca/P/Mg • Intro • Calcium • Phosphate • Magnesium • Investigations

3. Calcium • 99% present in skeleton (reservoir) • Serum calcium 2.15-2.6 mmol/L • Functions of calcium • Intracellular signalling • Coagulation • Bone mineralization • Plasma membrane potential

4. Calcium Homeostasis Parathyroid gland Skeleton Intestine Ca++ Vitamin D Kidneys

5. Calcium Metabolism • Forms • Free – 50% • Bound – protein – 40% • Complexed – 10% • Hence adjusted for albumin • Acid base status • Calcium sensing receptor • PTH • Vitamin D • (calcitonin)

6. Adjusted Calcium Total Ca + ((44-Alb) x 0.015) • Advantages • Accounts for changes in alb conc • To calculate the expected Ca conc if the alb were normal • Limitations • Interpret with caution when H+ status abnormal • Not valid when alb very low eg <20

7. Errors in Calcium measurement • In Vitro • Inappropriate anticoagulants • Dilution with liquid heparin • Contamination with calcium • Spectrophotometric interference In vivo • Tourniquet use and venous occlusion • Changes in posture • Exercise • Hyperventilation • Alterations in protein binding / complex formation

8. PTH • 84 aa • Synthesised by parathyroid gland • Bio activity in aa 1-34 (fragments) • Intact PTH T1/2 3-4 mins • Inhibited by • Hypercalcaemia (secretion) • 1,25D (synthesis) • Normal levels 1.3 – 6.8 pmol/L

9. PTH • Bone resorption – to release Ca/P • Rapid release and longer term response – proliferation of osteoclasts • Kidney • distal tubule reabs of calcium (hypercalciuria) • Phosphaturia inhibits P reabs from prox tubule • Calcitriol ( intestine)

10. Vitamin D • Diet/UV sunlight (D2/D3) • 25 hydroxy D (liver) • 1,25 dihydroxy Vitamin D (kidney) – tightly regulated • Active form 1,25VitD • VitD action • Absorption of phosphate and calcium from intestine • PTH • 25OHD best measure – reflects sun and diet, long T1/2

11. Hypercalcaemia • Increased flux of Ca2+ into the ECF from skeleton, kidney or intestine • Lethargy • Nausea • Vomiting • Bones, moans, groans and stones • Polyuria • Symptoms dependent on rate of increase

12. Causes of Hypercalcaemia • Contamination • Primary hyperparathyroidism • Malignancy (skeletal involvement/PTHRP) • Endocrine disorders – hyper-/hypothyroidism/acute adrenal insufficiency • FHH 95% • Renal failure • Idiopathic hyperCa of infancy • Granulomatous disorders (eg sarcoidosis and TB) • Chlorthiazide diuretics • Lithium • Milk alkali syndrome • etc

13. Hyperparathyroidism • PTH Inappropriate to calcium level • Raised calcium with raised/normal PTH • ? Primary • ?Secondary/Tertiary • Primary - usually due to parathyroid adenoma (single/multiple) • Multiple - ? MEN • Treatment • High fluid intake • Surgery • Watch and wait • Side effects • Osteoporosis • Renal failure • Stones

14. FHH • Familial hypocalciuric hypercalcaemia • Autosomal dominant mutation in calcium sensing receptor  increased set point for calcium • Asymptomatic hypercalcaemia • Normal/slightly elevated PTH • Must differentiate from primary hyperparathyroidism • Low rate of calcium excretion in urine

15. Investigations • Bone profile • Renal function • PTH (>3 pmol/L inappropriate for hyperCa) • ? Primary HyperPTH or FHH • Urinary fractional calcium excretion • Fasting urine calcium x serum creatinine Urine creatinine < 25 umol/L FHH > 30 umol/L PHPT

16. Case • 51 year old woman investigated after ureteric colic shown on radiological examination to be due to Ca containing calculi. • Serum Calcium 2.95 mmol/L • Phosphate 0.7 mmol/L • PTH 10 pmol/L • Bone radiographs normal • Serum urea, albumin ALP normal

17. Hypocalcaemia • Symptoms • Chvosteks and Trousseau’s signs • Neuromuscular excitability • Tetany • Paresthesia • Seizures

18. Causes of hypocalcaemia • Contamination • Hypoalbuminaemia • Chronic renal failure • Magnesium deficiency • Hypoparathyroidism (/pseudo) • Vitamin D deficiency (or resistance) • Acute haemorrhagic and edematous pancreatitis • Hungry bone syndrome

19. Chronic Renal failure • Phosphate • Protein • 1, 25 Vit D • Skeletal resistance to Vitamin D

20. Investigations • Bone profile • Renal function • Mg • Vitamin D • ? History (eg surgery to neck) • ? PTH

21. Phosphate Metabolism • 85% present in skeleton • Serum inorganic phosphate 0.84-1.45 mmol/L • 10% protein bound, 35% complexed, rest free • Integrity of bone • Oxygen delivery • Muscle contraction • Role in ATP (energy), nucleotides, NADP, cell membranes, gene transcription, cell growth • Balance maintained primarily by kidneys

22. Hyperphosphataemia Decreased renal excretion • GFR • Reabsorption • hypoPTH • Acromegaly • Disodium etidronate • Cell Lysis • Rhabdomyolysis • Intravascular haemolysis • Cytotoxic therapy • Leukaemia • Lymphoma • Increased intake • Oral or IV • P containing laxatives/enemas • Vit D intoxication • Transcellular shift • Lactic acidosis • Respiratory acidosis • DKA

23. Hyperphosphataemia • Exclude spurious • delayed sample receipt • haemolysis (HM2) • anticoagulants EDTA/citrate – interfere with complex formation during analysis

24. Hypophosphataemia • Common • Muscle weakness • Respiratory failure • Decreased myocardial output • Rhabdomyolysis < 0.15mmol/L • Severe hypoP  haemolysis • Rickets/osteomalacia (chronic defy) • Wernicke’s encephalopathy

25. Hypophosphataemia • Decreased absorption • Increased loss • Vomiting • Diarrhoea • Phosphate binding antacids • Decreased absorption • Malabsorption syndrome • VitD defy • Poor diet Intracellular shift • Glucose • Insulin • Resp alkalosis • Refeeding • Lowered renal P threshold • Primary hyperPTH • Renal tubular defects • Familial hypophospataemia • Fanconi’s

26. Investigations • ? History • ? Contamination ? Repeat • Bone profile • Renal function • Mg • ? Vitamin D (?Ca) • ? PTH (?Ca)

27. Magnesium Metabolism • 55% present in skeleton • 1% of total body Mg extracellular • Serum Mg 0.7-1.0 mmol/L • Cofactor for enzymes • Required for ATP (MgATP) • Glycolysis • Cell replication • Protein biosynthesis • PTH increases renal tubular reabs of Mg • Homeostasis maintained - control of excretion

28. Hypermagnesaemia Symptoms • Depressed neuromuscular system • Depressed respiration • Cardiac arrest Causes • Excessive intake • Antacids • Enemas • Parenteral therapy • Mg administration (RF)

29. Hypomagnesaemia • Common in inpatients • Usu assoc with hypoK and hypoP • Increased neuromuscular excitability • Causes impaired PTH secretion • PTH end organ resistance • Oral K not retained if patient also Mg deficient • Assoc. with Ca defy with overlapping symptoms • HypoCa and HypoK unresponsive to supplementation should prompt Mg measurement

30. Hypomagnesaemia • GI • Prolonged nasogastric suction • Malabsorption • Bowel resection • Diarrhoea • Fistulas • Acute pancreatitis • Decreased intake • Chronic vomiting • Redistribution • DKA • Hungry bone disease • Renal loss • Chronic TPN • Osmotic diuresis (DM/mannitol) • Hypercalcaemia • Alcohol • Drugs – diuretics/aminoglycosides/cisplatin/cardiac glycosides • Metabolic acidosis (DKA/ETOH/starvation) • Renal disease

31. Questions?