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

Ca/P/Mg Intro Calcium Phosphate Magnesium Investigations

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 Protein binding – 80% albumin, 20% globulins Ca binds to –vely charged sites of proteins thus alkalosis leads to an increase in negative charge on proteins and more Ca binding to proteins – decreased free ca Complexes with lactate/phosphate/bicarbonate/citrate

Calcium Homeostasis Parathyroid gland Skeleton Intestine Ca++ Vitamin D Kidneys Bone is not metabolically inert there is a constant movement of calcium from bone and the ECF in bone remodelling

Calcium Metabolism Forms Hence adjusted for albumin Acid base status Free – 50% Bound – protein – 40% Complexed – 10% Hence adjusted for albumin Acid base status Calcium sensing receptor PTH Vitamin D (calcitonin) calcitonin – inhibits osteoclastic activity but ? Physiological role unknown.

Adjusted Calcium Total Ca + ((44-Alb) x 0.015) Advantages Limitations 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

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 HM4

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 Intact PTH assays may detect intact aswell as N terminal fragments 7-84aa.

PTH Bone resorption – to release Ca/P Kidney Calcitriol ( intestine) 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) Increased filtered load of calcium results in hypercalciuria despite increased reabsorption

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 Levels of 1,25 OHD do not decrease until defy is severe D2 - ergocalciferol

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 Ca > 3mmol/L  stones

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 Hypercalcaemia occurs in 10-20% of patients with cancer Tumours may produce humoral factors: Poor correlation between severity of hypercalcaemia and extent of metastatic bone involvement Patients with mild asymptomatic hyperca (<3mmol/L) may stay healthy for years without operation but increased risk of osteoporosis and renal failure. Should be reassessed regularly. High fluid intake to discourage renal calculus. Surgery is recommended if ca > 3mmol/L or marked hyoercalciuria/complications present, < 50yrs PTHRP – binds to PTH receptor Humoral factors – bone resorption 1,25 VitD Secondary/tertiary hyperPTH – chronic renal disease or vit d defy (decreased vit D)  hypocalcaemia) thyrotoxicosis – Hypercalcaemia due to increased osteoclast activity 10% of sarcoidosis develop hyperca due to increased 1 hydroxylation of 25OHD by macrophages in sarcoid granulomas

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 Secondary hyperparathyroidism occurs when the parathyroid glands become hyperplastic after long-term hyperstimulation and release of PTH. In secondary hyperparathyroidism, elevated PTH levels do not result in hypercalcemia. This has been classically attributed to an underlying state of hypocalcemia in those with chronic renal failure (CRF). With long-term hyperstimulation, the glands function autonomously and produce high levels of PTH even after correction of chronic hypocalcemia. Tertiary hyperparathyroidism refers to hypercalcemia caused by autonomous parathyroid function after long-term hyperstimulation. HyperPTH usu detected by biochemical screening Phosphate may be normal or low Plasma ALP is raised in 20-30% of cases.

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 Urine calcium excretion only required in the diagnosis of FHH

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 CaE – fasting urine calcium and creatinine and concurrent serum creatinine

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 HyperPH may present in many ways including stones – due to hypercalciuria. 10% have clinical evidence of bone disease at presentation. Many patients with hyperPTH detected by biochemical screening. Plasma phosphate may be normal or raised, particularly when there is renal damage. The plasma ALP is raised in 20-30% of cases. Inappropriateness of PTH to calcium level.

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

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 Hungry bone syndrome – healing phase of bone disease of hypercalcaemia caused by increase bone resorption eg treated hyperparathyroidism (surgical), hyperthyroidism, and haematological malignancies. Removal of the stimulus of bone resorption results in rapid uptake of calcium into bone. Vitamin D deficiency  secondary hyperparathyroidism Hypoparathyroidism – congenital or acquired Congenital – Di George syndrome, thymic aplasia, immune deficiency Pseudo hyperpth PTH effects mediated through formation of cyclic AMP. Type 1 pseudo hyperpth activation of adenylate cyclase defective cAMP not formed Type 2 cAMP formed, responses to it are blocked

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

Investigations Bone profile Renal function Mg Vitamin D ? History (eg surgery to neck) ? PTH CaE – fasting urine calcium and creatinine and concurrent serum creatinine

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 Glycolysis Ox’ phosphorylation Protein phosphorylation critical control mechanisms for various proteins and enzymes

Hyperphosphataemia Decreased renal excretion Cell Lysis 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 GH raises tubular reabsorption of Phos Raised Phosphate may cause a decrease in calcium thus tetany and seizures may be a presenting symptom. PTH  increased loss ECFV Expansion  increased loss Phosphate may lead ti secondary hyperPTH Chronic high P  soft tissue calcification (heart/lungs/liver

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

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

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

Investigations ? History ? Contamination ? Repeat Bone profile Renal function Mg ? Vitamin D (?Ca) ? PTH (?Ca) CaE – fasting urine calcium and creatinine and concurrent serum creatinine ?DM, insulin, cell lysis, medication

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

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

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 Mg competitively inhibits calcium entry into neurons. HypoMg common in patients with multiple electrolyte disturbances

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

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