CMP Lecture Notes Calcium, Magnesium, Phosphate PDF

Calcium Magnesium Phosphate Dr JJ Jordaan Chemical Pathology Registrar 1 2 https://apps.ankiweb.net/ 3 UCT Notes (2023) https://health.uct.ac.za/chemical-pathology/teaching/training-resources...

Calcium Magnesium Phosphate Dr JJ Jordaan Chemical Pathology Registrar 1 2 https://apps.ankiweb.net/ 3 UCT Notes (2023) https://health.uct.ac.za/chemical-pathology/teaching/training-resources 4 5 What are the functions of calcium? Fractions of calcium  ! * low albumin false low albumin may give Corrected/adjusted Calcium Most often used for low albumin: [Ca] + 0.02(40-albumin) Not always accurate, depends on methods used Volutary reading: https://www.myadlm.org/cln/articles/2019/june/ionized-versus-albumin-adjusted-total-calcium https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340960/  pH and ionised calcium Increase in pH = alkalosis Decreases ionised calcium measurement The hydrogen ions dissociate from albumin and the ionised calcium binds the vacant sites on the albumin acute acidosis increases ionised calcium Note that changes in ionised calcium result in symptoms of hypocalcaemia (in alkalosis) and hypercalcaemia (in acidosis) = disease states Measurement error can also occur and some labs therefore correct their ionised calcium for pH pH and ionised calcium What are the indications for measuring ionised calcium? Chronic kidney disease and dialysis Transplantation Extracorporeal transfusion Massive transfusion Critical illness Hyperparathyroidism Post-operative period following parathyroidectomy Severe pancreatitis Hypercalcaemia of malignancy  Pre-analytical variables affecting specimen collection for ionised calcium Serum * separator tube Stasis-free collection (SST) SST (yellow tube) maximally filled Transport on ice To reach lab within 30 min so that RBC can be separated within 1 hour (centrifugation) Tube should be kept sealed to avoid changes in pH and false measurement Marshall notes… Calcium flux Calcium flux ✔Representative calcium fluxes (mmol/24 h) in a healthy adult (70 kg body weight) in zero calcium balance ✔ The rapid exchange of calcium on bone surfaces and the exchange in soft tissues are not illustrated in this diagram. ✔ The major sites of action of parathyroid hormone (*) and 1,25(OH)2D (**) are indicated. (Modified from Wilkinson R. Absorption of calcium, phosphorus and magnesium. In: Nordin B E C (ed). Calcium, phosphate and magnesium metabolism. Edinburgh: Churchill Livingstone; 1976, with permission). Hormones regulating calcium homeostasis Parathyroid hormone (PTH) Vitamin D Calcitonin (minor) PTH precursors and cleavage products What are the active “bits”? Intact PTH 84aa N-terminal fragment 34aa 17 Actions of PTH target organs →bone →kidney →gut  Bone Rapid release of calcium ↑ plasma [Ca2+] ↑ osteoclastic resorption = ↑ production of FGF23 ↓ plasma [PO42−] "You en bon" Kidney ↑ Calcium reabsorption ↑ plasma [Ca2+] ↓ phosphate reabsorption ↓ plasma [PO42−] ↑ 1α-hydroxylation of 25-hydroxycholecalciferol ↑ calcium and ↑phosphate (increased activation of Vitamin D) absorption from gut ↓ bicarbonate reabsorption acidosis => ↑ Cast 19 What is the net effect of PTH? ↑ plasma 2+ [Ca ] ↓ plasma [PO4 2−] Mild acidosis Vitamin D Vitamin D (VD) metabolism > - "Stores" > - Active Circulating concentrations of VD metabolites  Clinical use for testing: nothing to do with CMP Calcitonin Medullary thyroid cancer malignancy of the parafollicular cells peptide hormone produced by the C cells(parafollicular) of the thyroid Secreted when plasma calcium concentration rises secreted in response to gut hormones Inhibits osteoclast activity and thus bone resorption (in experiments) Physiological role is uncertain: may antagonize calcitriol action on the bone thereby restoring normocalcaemia without bone demineralization, Neurotransmitter role in the gut and CNS Not to be confused with PROcalcitonin: acute phase protein, ↑ in infection, greater sensitivity and specificity for bacterial infection than CRP Fibroblast growth factor 23 (FGF23) FGF23 hormone is secreted by osteocytes when calcitriol↑ and phosphate ↑ Does not affect plasma calcium directly Increases loss of phosphate through the kidneys by inhibiting the sodium–phosphate cotransporter (Na+/Pi) Also, inhibits renal 1α-hydroxylase Net effect ↓ serum phosphate (hypophosphataemia) phosphaturia (phosphate is urine) ↓ serum calcitriol Fibroblast growth factor 23 (FGF23) ↓ plasma [PO4 2−] phosphate also sometime abbreviated as Pi: inorganic phosphate Homoeostatic responses to hypocalcaemia Hypocalcaemia stimulates the release of parathyroid hormone (PTH), which in turn stimulates calcitriol synthesis. These hormones act together to restore plasma calcium concentration to normal, independently of phosphate concentration. ECF, extracellular fluid; 25-OHCC Calcium homeostasis  Homoeostatic responses in hypophosphataemia In absence of parathyroid hormone (PTH) (secretion is not affected by phosphate) increase in calcitriol (active vit D) production caused by stimulation of 1α- hydroxylase: increase the plasma phosphate independently of calcium concentration. ↓FGF23 release from bone by hypophosphataemia also contributes to maintaining plasma phosphate concentration by allowing the renal tubules to reabsorb more phosphate. Causes of hypercalcaemia Primary hyperparathyroidism Sporadic Familial Malignant disease Humoral hypercalcaemia of malignancy (PTHrP) Widespread skeletal metastases (most commonly breast cancer) Haematological malignancy (multiple myeloma, adult T cell leukaemia/lymphoma) Less common Granulomatous diseases (e.g. sarcoidosis, tuberculosis, histoplasmosis, leprosy) Toxicity with vitamin D or its derivatives Persistent hyperparathyroidism after renal transplantation Severe thyrotoxicosis Uncommon causes of hypercalcaemia Clinical features of hypercalcaemia Describe how you would investigate hypercalcaemia. Primary HYPERparathyroidism 2+ ↑ Ca primary = problem with parathyroid gland most common in postmenopausal women renal impairment, and should be reassessed regularly causes: ◦ usually parathyroid adenoma ◦ less often diffuse hyperplasia of parathyroid glands ◦ rarely parathyroid carcinoma definitive treatment: surgical removal mild ( - vitamin D deficiency both conditions: decreased synthesis of calcitriol [active vit D aka 1,25-(OH) cholecalciferol] 2 leads to hypocalcaemia (↓Ca2+) appropriate physiological response: ↑ PTH increase in PTH may not normalize the plasma calcium 37 Tertiary HYPERparathyroidism Occasionally, patients with established kidney failure become hypercalcaemic, caused by the development of autonomous PTH secretion, presumably as a result of the prolonged hypocalcaemic stimulus. May manifest for the first time in a patient given a renal transplant who becomes able to metabolize vitamin D normally. This is termed tertiary hyperparathyroidism 38 voluntary reading Tietz, 6th 39 Now consider How would you investigate hypocalcaemia? Hyperphosphataemia Hyperphosphataemia common causes Common: renal insufficiency Tissue catabolism e.g. tumour lysis syndrome Hyperphosphataemia Hyperphosphataemia is important clinically because: It results in inhibition of the 1α-hydroxylation of 25- hydroxycholecalciferol in the kidneys (less active Vit D made) Phosphate may also combine with calcium, resulting in metastatic calcium deposits in the tissues and hypocalcaemia Management should be directed at the underlying cause Phosphate binders are commonly used Hypophosphataemia – clinical effects Common Mild – minimal clinical effect Severe (7.5 mmol/L) cause respiratory paralysis and cardiac arrest e.g. kidney failure Hypermagnesaemia (3–4 mmol/L) may be induced in the ICU to reduce bronchospasm in severe asthma or to reduce the risk of fitting in severe pre-eclampsia Thank you slides based on lecture by Prof Punchoo Voluntary reading (Tietz 6 th ed) 55 56 57 58 Questions? 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