Calcium, Phosphate and Magnesium

• Calcium is the most abundant mineral in the body. The body contains about 1kg and 99% of it is stored in the skeleton
• Around 500mmol/24hr moves between bone and the ECF to supplement calcium homeostasis
• Approximately 7.5mmol/24hr moves between the bone and ECF in the course of bone remodelling
• In the kidneys, ionised calcium is filtered by the glomeruli, most is reabsorbed but normal kidney excretion of calcium is around 2.5-7.5mmol/24hr
• About 25mmol is ingested per day of which about 6 to 12 mmol is absorbed
• Because of fecal loss the minimum dietary requirement is 12.5mmol/L although this increases in growth, pregnancy and lactation
• Vitamin D in the form of 1,25-dihydroxycholecalciferol is required for adequate calcium absorption
• Much more calcium enters the gut from intestinal secretions than from the diet. Most fecal calcium consists of that which has not been reabsorbed from these secretions
• Calcium in the intestine can  be rendered insoluable by complexing with phosphate or fatty acids preventing absorption – oral phosphate can be used to reduce calcium absorption

 

Important functions of calcium;

• Structural – bones and teeth
• Neuromuscular – control of excitability, release of neurotransmitters, inhibition of muscle contraction
• Enzymic – conregulation for coagulation factors
• Signalling – intracellular secondary messenger

 

Bone

• Bone consists of osteoid, a collagenous organic matrix on which is deposited complex inorganic hydrated calcium salts known as hydroxyapatites
• 5% of bone in the adult is subject to remodelling
• Alkaline phosphatase is essential to the process, probably acting by releasing phosphate from pyrophosphate. It is a marker of osteoblastic function and increases in osteomalacia

 

Plasma calcium

• In the plasma calcium is present in 3 forms;
  • Bound to protein (mainly albumin) – around 50%
  • Complexed with citrate and phosphate
  • Free ions – only this form is physiologically active
• In alkalosis, hydrogen ions dissociate from albumin, and calcium binding to albumin increases – this can lead to symptoms of hypocalcaemia, even though the total calcium concentration hasn’t changed
• In acidosis, the opposite effect occurs and hypercalcaemia can appear to result. Acidosis increases the release of calcium from bones as well and prolonged acidosis may cause osteomalacia

 

• Plasma calcium can be measured as total calcium or ionised calcium (using an ion selective electrode). Measuring ionised calcium is quicker than measuring total calcium

 

Calculation of ‘corrected’ plasma concentration

• If plasma albumin concentration is [alb] g/L and measured total calcium is [Ca] mmol/L
• If [alb] < 40, corrected calcium = [Ca] + 0.02 x {40 – [alb]} mmol/L
• If [alb] > 45, corrected calcium = [Ca] + 0.02 x {[alb] – 45} mmol/L
• Care should be taken in interpreting such figures especially when H+ ion concentration is abnormal
• A common cause of apparent hyperproteinaemia and hence hypercalcaemia is venous stasis during blood sampling
• Although globulins contribute to calcium binding to a lesser extent than albumin, the increase in g-globulin in patients with multiple myeloma can increase total calcium concentration (Myeloma is normally accompanied by a hypercalcaemia due to the release of calcium mobilising substances by tumour cells)

 

Calcium regulating hormones

Parathyroid Hormone

• Synthesised as a large precursor, pro-pre-PTH, first cleavage removes 25 amino acids to produce pro-PTH, the second cleavage removes a further 6 amino acids to produce PTH itself
• Secreted by the parathyroids in response to a fall in plasma ionised calcium concentration
• Hypercalcaemia and calcitriol inhibit release of PTH
• The action of PTH tends to increase plasma calcium and decreased plasma phosphate levels

 

Actions of PTH

• Bone
  • Rapid release of calcium
  • Increased osteoclastic resorption (if prolonged, osteoblastic activity is increased causing an increase in plasma alkaline phosphatase activity)
• Kidney
  • Increased calcium reabsorption
  • Decreased phosphate reabsorption
  • Increased 1a-hydroxylation of 25-hydroxycholecalciferol (increases calcium and phosphate absorption from the gut)
  • Decreased bicarbonate reabsorption (which can lead to acidosis)

 

• Changes in phosphate concentration do not directly affect the release of PTH
• Mild hypomagnesaemia stimulates PTH but more severe hypomagnesaemia reduces it as the secretion of PTH is magnesium dependant

 

Calcitriol

• In the liver 25-hydroxylase catalyses the hydroxylation of cholecalciferol to 25-hydroxycholecalciferol, the rate of formation of which is affected by the supply of cholecaciferol derived from the skin and intestine
• Further hydroxylation of 25-hydroxycholecalciferol to 1,25-hydroxycholecalciferol occurs in the kidney via the action of the enzyme 1a-hydroxylase. This is the active form of vitamin D
• The activity of 1a-hydroxylase is increased by;
  • A low plasma phosphate concentration
  • An increase in plasma PTH concentration (possible as a consequence of its phosphate lowering effects)
  • Oestrogens, prolactin and growth hormone – important during pregnancy, lactation and growth
• 1,25 dihydroxycholecalciferol acts on intestinal muscosal cells to increase calcium reasborption
• In conjunction with PTH it stimulates release of calcium from bone
• When 1a-hydroxylation in the kidney is inhibited, 24-hydroxylation is increased. The product of this reaction 24,25-dihydroxycholecalciferol has no function

 

Calcitonin

• Produced by C cells of the thyroid
• Inhibits osteoclast acticity in vitro but it is unclear the affect it has in the body considering the lack of clinical syndrome in individuals who have a thymectomy
• Also calcium homeostasis is normal in patients who have a medullary carcinoma of the thyroid – a tumour which produces large amounts of calcitonin
• Calcitonin is increased in pregnancy but so is calcitriol. Calcitonin may block the action of calcitriol on the bone permitting increased uptake of calcium from the gut without loss of mineral from bone

 

Homeostatic response to hypocalcaemia

• Hypocalcaemia stimulates release of PTH which in turn stimulates calcitriol synthesis
• Results in increased uptake of calcium and phosphate from the gut and their release from the bone
• PTH causes phosphate to be excreted in the urine but causes as increase in the fraction of calcium reabsorbed by the kidney

 

Homeostatic response to hypophosphataemia

• Calcitriol is increased but PTH is not
• This results in increased uptake of calcium and phosphate from the gut. The increased calcium further inhibits PTH
• Calcitriol has less affect in the kidney compared with PTH to most of the excess calcium is excreted in the urine

 

Hypercalcaemia

Causes of hypercalcaemia;

• Common
  • Malignant disease (with or without bone metastases)
  • Primary hyperparathyroidism
• Less common
  • Thyrotoxicosis – due to increased osteoclastic activity
  • Vit D intoxication – caused by over vigorous treatment of hypocalcaemia
  • Thiazde diuretics – decreased renal calcium excretion
  • Sarcoidosis – due to 1-hydroxylation of hydroxycholecalciferol by macrophages in the sarcoid granuloma
  • Familial hypocalciuric hypercalcaemia – autosomal dominant trait due to mutation in the calcium sensor gene leading to an increase in the parathyroids set point for calcium
  • Renal transplantation (tertiary hyperparathyroidism)
• Uncommon
  • Milk-alkali treatment – ingestion of milk and antacids for the control of dyspepsis. Ingestion of alkali in particular decreases urinary excretion of calcium by and unknown mechanism
  • Lithium treatment – increase PTH secretion
  • TB
  • Immobilisation (especially in Paget’s disease) – decreased stimulus of bone formation and continuous resorption
  • Acute adrenal failure – due to fall in cortisol
  • Idiopathic hypercalcaemia of infancy – associated with elfin facies amd supravalvular aortic stenosis
  • Diuretic phase of acute renal failure

 

Clinical features;

• Weakness, tiredness and weight loss
• Mental changes – impaired concentration, drowsiness, personalitiy changes, coma
• Anorexia, nausea, vomiting and constipation
• Abdominal pain – rarely peptic ulceration due to calcium stimulation of gastrin secretion
• Polyuria, dehydration and renal failure – due to precipitation of calcium phosphate in the kidneys, leading to renal tubular calcification
• Renal calculi and nephrocalcinosis
• Short QT interval on ECG
• Cardiac arrhythmias and hypertension
• Corneal calcification and vascular calcification

 

• 90% of cases are caused by primary hyperparathyroidism and malignancy
• Clinically patients may complain of bony pain and have bony swellings
• Hypercalcaemia should be considered as one of the causes of the acute abdomen
• Hypercalcaemia not due to inappropriate PTH secretion suppresses release of the hormone and the plasma phosphate concentration tends to rise

 

Malignant Disease

• Non-metastatic hypercalcaemia caused by solid tumours is due to secretion by the tumour of PTH-related peptides (PTHrP) which is a peptide with N-terminal amino acid sequence with homology with PTH
• It acts as a growth factor in the fetus but is not detectable in significant amounts in adults except in the breast during lactation
• In patients with bone metastases there is often no correlation between the extent of metastases and the severity of disease
• In haematological malignancy, particularly melanoma, hypercalcaemia is due to release of osteoclast-activating cytokines by the tumour such as IL-1 and TNF-b
• Osteoclasts can also be activated by prostaglandins released from tumour metastases in bone, for example metastases from the breast

 

Primary hyperparathyroidism

• Prevalence 1 in 1000, most common in menopausal women
• Usually it is due to parathyroid adenoma or less commonly diffuse hyperplasia of the glands
• Very rarely it is due to parathyroid carcinoma
• Patients may present with renal or ureteric colic due to calculi as a result of the hypercalcaemia
• Plasma calcium may not be raised in concomitant renal disease, Vit D deficiency or hypoparathyroidism
• Generally it is associated with a hypophosphataemia, but this may not be the case if there is renal damage
• PTH is usually elevated
• Definitive treatment is surgery although patients with only mild hypercalcaemia may stay healthy for many years prior to surgery although they are at increased risk of renal impairment and osteoporosis
• A high fluid intake should be encouraged to discourage renal calculus formation

 

Secondary and tertiary hyperparathyroidism

• Chronic renal disease and Vit D deficiency cause secondary hyperparathyroidism. Both conditions are associated with decreased synthesis of calcitriol which causes hypocalcaemia, with a resulting increase in PTH production
• Tertiary hyperparathyroidism is seen if the parathyroid glands have been subjected to long standing and sustained positive feedback by low free-ionised calcium concentrations, they hypertrophy and hormone secretion becomes partly autonomous, this can occur after the reason for the original hypocalcaemia is removed for example by renal transplantation or correction of long standing Vit D deficiency

 

Investigations

• Plasma calcium levels
• Plasma phosphate levels in relation to that of urea
• Plasma alkaline phosphatase levels
• X-rays – hyperparathyroidism associated with subperiosteal bone reabsorption and bone cysts, primary lung tumour? Bone mets?
• Measure plasma PTH levels
• Little point measuring urine [Ca²⁺], as long as glomerular function is normal, hypercalciuria will occur regardless of the cause
• Isotope subtraction scanning of the neck may help to localise parathyroid adenoma before operation
• Steroid suppression test – large doses of cortisol reduce calcium concentrations except in primary and tertiary hyperparathyroidism (and in malignant disease with bony metastases)

 

Management

• Treat underlying cause if possible
• Rehydrate patient
• Frusemide can be used as it stimulates diuresis and inhibits calcium reabsorption by the kidney
• Calctonin
• Steroids
• Mithramycin – if due to malignancy. It inhibits calcium mobilisation from the bone
• Sodium phosphate – prevents reabsorption of calcium entering the gut lumen in intestinal secretions. May cause precipitation of calcium salts in the kidney and aggravate renal dysfunction
• Life threatening hypercalcaemia may be treated by dialysis or emergency parathyroidectomy
• The aim of treatment should be to lower calcium level to one which is not immediately dangerous and then to lower more slowly to normal levels. Too rapid a reduction may cause tetany or hypotension

 

Hypocalcaemia

Causes;

• Artefactual – blood collected into an EDTA tube
• Vitamin D deficiency – dietary, malabsorption, inadequate exposure to ultraviolet light
• Disordered Vitamin D metabolism – renal failure, anticonvulsant treatment
• 1a-hydroxylase deficiency
• Hypoparathyroidism
• Pseudohypoparathyroidism
• Magnesium deficiency
• Acute pancreatitis – due to reduced albumin
• Treatment of metabolic bone disease
• High phosphate intake (rare)
• Neonatal hypocalcaemia
• Massive transfusion of citrated blood

 

Clinical features;

• Behavioural disturbance and stupor
• Numbness and parasthesia
• Muscle cramps and spasms (tetany)
• Laryngeal stidor
• Convulsions
• Cataracts (chronic hypocalcaemia)
• Basal ganglia calcification
• Chvostek’s sign positive – contraction of facial muscles on tapping of the facial nerve
• Trousseau’s sign positive – carpal spasm when the sphygmomanometer cuff is applied to the upper arm and inflated midway between systolic and diastolic blood pressure for 3 mins
• Prolonged QT interval on ECG

 

• Majority of cases due to deficiency or impaired metabolism of Vit D, renal failure, hypoparathyroidism and hypomagnesaemia
• Clinical features relate to increased neural and muscular excitability

 

Vitamin D deficiency

• Causes osteomalacia in adults and rickets in children
• May be due to inadequate endogenous synthesis or dietary supply of vitamin D, or to malabsorption
• This results in a decreased amount of 25-hydroxycholecalciferol available for calcitriol synthesis leading to decreased absorption of calcium and phosphate from the gut
• Vitamin D deficiency is a cause of secondary parahyperthyroidism

 

 

 

Impaired Vitamin D metabolism

• Phenobarbitone and phenytoin alter metabolism of Vit D in the liver. They also directly inhibit intestinal calcium absorption
• In some forms of chronic liver disease such as primary biliary cirrhosis, hypocalcaemia and metabolic bone disease with some features of osteomalacia can develop
• There are also inherited forms of Vit D metabolism

 

Renal Disease

• Possible due to impairment of 1a-hydroxylation of 25-hydroxycholecalciferol and Vitamin D function
• Also hyperphosphataemia due to decreased GFR inhibits the action of 1a-hydroxylation

 

Hypoparathyroidism

• Can be congenital or aquired
• The congenital form may be associated with Di George syndrome
• Acquired causes include;
  • Idiopathic
  • Autoimmune
  • Surgery – thyroidectomy
  • Haemochromatosis
  • Infiltrative conditions
• Pseudohypoparathyroidism superficially resembles hypoparathyroidism but the plasma concentrations of PTH are elevated. There are 2 types, both of which are hereditary and related to cAMP formation and action

 

The hypocalcaemia of ‘shock’

• Seen following surgery or acute pancreatitis and is due to hypoalbuminaemia with a consequent fall in plasma total calcium concentration

 

Magnesium Deficiency

• Bone salts contain magnesium and well as calcium and the two ions tend to move in and out of bone together
• Cells contain magnesium at much higher concentrations than the ECF and magnesium, phosphate and potassium tend to enter and leave cells under the same conditions
• Magnesium is required for both PTH secretion and its action on target tissues therefore magnesium deficiency can cause hypocalcaemia and render patients insensitive to the treatment of hypocalcaemia with Vit D or calcium
• Seen in patients with malabsorption, severe prolonged diarrhoea or through intestinal fistulae
• Always measure magnesium in patients with hypocalcaemia
• In the absence of hypocalcaemia, hypomagnesaemia may cause tetany

 

Management

• Treat with calcium gluconate until symptoms are controlled
• Correct any co-existing magnesium deficiency
• Persistant hypocalcaemia should be treated with calcium supplements of Vit D or both depending on the cause

 

 

 

Hyperphosphataemia

Causes;

• Renal failure (most common)
• Hypoparathyroidism
• Pseudohypoparathyroidism
• Acromegaly
• Excessive phosphate intake – seen in infants feed undiluted cows milk
• Vitamin D intoxication
• Catabolic states e.g. tumour lysis syndrome

 

• Hyperphosphataemia is clinically important as it inhibits 1-hydroxylation of 25-cholecalciferol in the kidney
• The normal plasma phosphate concentration of phosphate is higher in children than adults

 

Management

• Treat underlying cause
• Give oral calcium or aluminium salts to bind phosphate in the gut and reduce its absorption

 

Hypophosphataemia

• Common biochemical finding. Mild hypophosphataemia is of little consequence but severe hypophosphataemia can have important consequences by limiting the formation of essential phosphate containing compounds such as ATP
• It can also cause osteomalacia and rickets
• Can be due to decreased intestinal absorption, increased renal excretion or redistribution
• Causes;
  • Vitamin D deficiency
  • Primary hyperparathyroidism
  • Enteral/parenteral nutrition with inadequate phosphate
  • Diabetic ketoacidosis (recovery phase)
  • Alcohol withdrawl (rare)
  • Renal tubular disease
  • Phosphate binding agents such as magnesium or aluminium salts (rare)
  • Respiratory alkalosis – stimulates phosphofructokinase an the formation of phosphorylated glycolytic intermediates

 

Management

• Administer phosphate but don’t give I.V. phosphate in patients who are hypercalcaemia or oligouric