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 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

4. 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

5. 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.

6. 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

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
HM4

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

9. 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

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

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
Ca > 3mmol/L  stones

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
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

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
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.

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
Urine calcium excretion only required in the diagnosis of FHH

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
CaE – fasting urine calcium and creatinine and concurrent serum creatinine

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
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.

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
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

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
CaE – fasting urine calcium and creatinine and concurrent serum creatinine

21. Phosphate Metabolism 85% present in skeleton
Serum inorganic phosphate 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

22. 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

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
Cardiomyopathy

25. 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

26. 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

27. Magnesium Metabolism 55% present in skeleton
1% of total body Mg extracellular
Serum Mg 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 Causes 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
Mg competitively inhibits calcium entry into neurons.
HypoMg common in patients with multiple electrolyte disturbances

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?