Disorder Of Calcium, Phosphate And Magnesium

Question 1

Approximately 99% of the body’s calcium is present in the bone, mainly as

Answer 1

the mineral hydroxyapatite, where it is combined with phosphate.

Question 2

◦Abnormal total calcium measurements often arise from:

Answer 2

Albumin
an increase or decrease in the unbound or ionised calcium

Question 3

major calcium‐ binding protein is

Answer 3

Albumin

Question 4

What are the 3 ORGANS and 3 HORMONES involved in Calcium metabolism?

Answer 4

PTH
Calcitonin
Calcitrol

Kidney
GIT
Bone
(Parathyroid gland)

Question 5

Factors affecting Ca intake (food, absorption)

Answer 5

Diet, 1,25-dihydroxycholecalciferol (1,25-DHCC, also called calcitriol)

Question 6

Factors affecting Ca loss (urine & faeces):

Answer 6

◦Urinary Ca excretion

◦Ca in the intestine may form insoluble, poorly absorbed complexes with oxalate, phosphate or fatty acids. An excess of fatty acids in the intestinal lumen in steatorrhoea may contribute to Ca malabsorption.

Question 7

Urinary Ca excretion depends on what?

Answer 7

1. the amount of Ca reaching the glomeruli
2. the glomerular filtration rate (GFR)
3. Renal tubular function.

Question 8

What hormones increase urinary calcium reabsorption?

Answer 8

Parathyroid hormone (PTH) and calcitriol increase urinary calcium reabsorption.

Question 9

BIOLOGIC FUNCTIONS of Calcium

Answer 9

◦Mechanical/structural role e.g., Bone & teeth
◦Reservoir role: acts as a reservoir that helps to stabilise ECF Ca2+.
◦Neuromuscular role for normal excitability of nerve and muscle.
◦Enzymatic role required in the activation of the clotting and complement cascades
◦Signalling role: increase in cytosolic Ca2+ serves as a signal for several cell processes, which include cell shape change, cell motility, metabolic changes (hormones), secretory activity and cell division.

Question 10

The 3 Components of calcium in plasma and their percentage

Answer 10

Calcium is present in plasma in 3 forms, in equilibrium with one another

lonised calcium, Ca2+
50-65%
Calcium bound to plasma
proteins - mainly albumin
30-45%
Calcium complexed with
citrate, etc.
5-10%

Question 11

Which calcium component is physiologically important

Answer 11

Plasma Ca2+

Question 12

How is plasma Ca2+ regulated in humans?

Answer 12

PTH and 1,25-DHCC: both act to increase plasma Ca2+ and hence plasma calcium. The body’s responds to a fall in plasma Ca2+, in terms of changes in PTH and 1,25‐DHCC production.

Question 13

Major factors in the control of Calcium Metabolism

Answer 13

◦PTH
◦1,25‐dihydroxycholecalciferol (1,25‐ DHCC)
◦Calcium-sensing receptor (CaSR)
◦Parathyroid hormone-related protein (PTHRP) ???

Question 14

Minor factors in the control of Calcium Metabolism

Answer 14

• Calcitonin???
◦Growth hormone,
◦Glucocorticoids (e.g. cortisol),
◦Prolactin
◦Sex hormones and
◦Thyroid hormones -

Question 15

PTH on the control of calcium metabolism

Answer 15

◦PTH is the principal acute regulator of plasma Ca2+. The active hormone is secreted in response to a fall in plasma Ca2+, and its actions are directed to increase plasma Ca2+. An increase in plasma Ca2+ suppresses PTH secretion.

Question 16

The biological actions of PTH include

Answer 16

In bone, PTH stimulates osteoclastic bone resorption, so releasing both free ionized calcium and phosphate into the ECF; this action increases the plasma concentrations of both calcium and phosphate. In synergy with Calcitriol.

Biochemical measures of both increased osteoblast activity (e.g. increased serum ALP activity) and increased osteoclast activity (e.g. raised urinary hydroxyproline & deoxypyridinoline excretion) may be evident.
• In the kidney, PTH increases the distal tubular reabsorption of calcium. It also reduces proximal tubular phosphate reabsorption and promotes activity of the 1α‐hydroxylation of 25‐HCC.

Formation of 1,25‐DHCC indirectly increases the absorption of calcium from the small intestine.

PTH decreases renal tubular reabsorption of phosphate, causing phosphaturia and increases reabsorption of calcium; this action tends to increase the plasma calcium concentration but to decrease the phosphate.

Question 17

CONTROL OF Ca METABOLISM: 1,25‐DHCC, or Calcitriol

Answer 17

◦Most Vit D3 (cholecalciferol) is synthesised by the action of ultraviolet light on 7‐dehydrocholesterol in the skin. Vit D3 is also present naturally in food (a rich source is fish oils), while Vit D2 (ergosterol) is added to margarine.

Endogenous synthesis of vitamin D3 is important. Deficiency can develop if exposure to sunlight is inadequate, or because of inadequate dietary intake, but is usually a result of the combined effects of these two factors.

Question 18

In the body, Vit D3 and Vit D2 undergo two hydroxylation steps before attaining full physiological activity

Answer 18

• 25‐Hydroxylation: occurs in the liver, with the production of 25‐hydroxycholecalciferol (25‐HCC, or calcidiol). The main form of Vit D circulating in the plasma is 25‐HCC, bound to a specific transport protein; it is carried to the kidney for further metabolism. Plasma 25‐HCC is the Vit D metabolite routinely measured. It is the main circulating form and store of the vitamin.

• 1α‐Hydroxylation of 25‐HCC: takes place in the kidney, with the production of 1,25‐DHCC; the most active biological form of vitamin D.

Renal 1α‐ hydroxylation is increased by low plasma phosphate, high PTH and where there is a tendency to hypocalcaemia, whatever the cause.

The reverse circumstances direct metabolism of 25‐HCC towards the formation of 24,25‐DHCC, which has no clearly established physiological function.

Question 19

The principal action of 1,25‐DHCC
What is the result of its deficiency?

Answer 19

The principal action of 1,25‐DHCC is to induce synthesis of a Ca2+-binding protein in the intestinal epithelial cell necessary for the absorption of calcium from the small intestine (greatest absorption in duodenum).

Deficiency of 1,25‐DHCC leads to defective bone mineralisation. Maintenance of both ECF Ca2+, and ECF phosphate by 1,25‐DHCC may be a key factor in normal mineralization

Question 20

CONTROL OF Ca METABOLISM: Calcium-sensing receptor (CaSR)

Answer 20

◦This is a G protein coupled receptor. This allows the parathyroid cells and the ascending loop of Henle epithelial cells to respond to changes in extracellular calcium. The parathyroid cell surface is rich in CaSR, which allows PTH secretion to be adjusted rapidly depending on the calcium concentration.

Question 21

Defects in the CaSR gene
Including active and inactive mutations

Answer 21

◦Defects in the CaSR gene are responsible for various rare defects of calcium homeostasis.

◦Inactivating mutations include familial benign hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism;

◦Activating mutations include autosomal dominant hypocalcaemia with hypercalciuria.

Question 22

CONTROL OF Ca METABOLISM: Calcitonin and its function

Answer 22

◦Calcitonin (produced in the C cells of the thyroid gland) can decrease plasma Ca2+, by reducing osteoclast activity AND decreasing renal reabsorption of calcium and phosphate.

But its actions are transient, and chronic excess or deficiency is not associated with disordered calcium or bone metabolism.

◦It is used as a tumour marker for medullary thyroid cancer (MTC) which arises from the parafollicular, calcitonin‐producing cells (C cells) of the thyroid gland, and accounts for about 10% of thyroid cancers.

◦Exogenous calcitonin has been used to treat hypercalcaemia and Paget’s disease of bone.

Question 23

CONTROL OF Ca METABOLISM:
Parathyroid hormone-related protein (PTHrP)

Answer 23

◦This is a peptide hormone that has a similar amino acid sequence at the biologically active end of the peptide, therefore activating the same receptors as PTH.

The function of PTHrP is uncertain, but it may be important in calcium metabolism in the fetus. The gene that codes for PTHrP is widely distributed in body tissues but is normally repressed.

◦However, it may become derepressed in certain tumours, causing humoral hypercalcaemia of malignancy.

Question 24

HYPERCALCAEMIA

Answer 24

◦Increased plasma Ca is a potentially serious problem that can lead to renal damage, cardiac arrhythmias and general ill‐health.

The most common causes are primary hyperparathyroidism and malignant disease, although the likelihood of these diagnoses will vary depending on the patient population. In asymptomatic ambulatory patients with hypercalcaemia, primary hyperparathyroidism may account for up to 80% of cases whereas in sick hospitalised hypercalcaemic patients, malignancy‐associated hypercalcaemia is more likely.

◦In countries with more limited access to health care or screening laboratory testing of calcium levels, primary hyperparathyroidism often presents in its severe form with skeletal complications in contrast to the asymptomatic form that is common in developed countries. Vit D deficiency is paradoxically common in some countries despite extensive sunlight (e.g., India, Nigeria) due to avoidance of sun exposure and poor dietary Vit D intake.

Question 25

AETIOPATHOGENESIS of hypercalcemia

Answer 25

1. Excessive PTH production
2. Hypercalcemia of malignancy
3. Excessive 1,25-DHCC production
4. Primary increase in bone resorption
5. Excessive calcium intake
6. Miscellaneous

Question 26

Excessive PTH production (in hypercalcemia)

Answer 26

Primary hyperparathyroidism (adenoma, hyperplasia, rarely carcinoma)

Tertiary hyperparathyroidism (long-term stimulation of PTH secretion in renal insufficiency)

Ectopic PTH secretion (very rare)

Inactivating mutations in the CaSR or in G proteins (Familial hypocalciuric hypercalcaemia, FHH)

Alterations in CaSR function (lithium therapy)

Question 27

Hypercalcemia of malignancy

Answer 27

Overproduction of PTHrP (many solid tumors)
Lytic skeletal metastases (breast, myeloma)

Question 28

Excessive 1,25-DHCC production (in hypercalcemia)

Answer 28

Granulomatous diseases (sarcoidosis, tuberculosis, silicosis)
Lymphomas
Vitamin D intoxication

Question 29

Primary increase in bone resorption (in hypercalcemia)

Answer 29

Hyperthyroidism
Immobilization

Question 30

Excessive calcium intake (in hypercalcemia)

Answer 30

Milk-alkali syndrome
Total parenteral nutrition

Question 31

Other causes (in hypercalcemia)

Answer 31

h.Endocrine disorders (adrenal insufficiency, phaeochromocytoma, VIPoma)
i.Medications (thiazides, vitamin A, antiestrogens)

The causes of hyper

Question 32

Other causes

Answer 32

h.Endocrine disorders (adrenal insufficiency, phaeochromocytoma, VIPoma)
i.Medications (thiazides, vitamin A, antiestrogens)

The causes of hyper

Question 33

Clinical features of hypercalcemia

Answer 33

• Neurological symptoms (inability to concentrate, depression, confusion)
• Generalised muscle weakness
• Anorexia, nausea, vomiting, constipation
• Polyuria with polydipsia
• Nephrocalcinosis, nephrolithiasis • ECG changes (shortened Q-T interval), with
bradycardia, first-degree block
• Pancreatitis, peptic ulcer

Question 34

INVESTIGATIONS in hypercalcemia

Answer 34

◦Measurement of plasma calcium and albumin, inorganic phosphate (Pi) and Alkaline phosphatase (ALP), and sometimes magnesium, PTH and vitamin D metabolites underlies diagnosis.

◦Other investigations will seek to confirm aetiology of the disorder.

Question 35

HYPERCALCAEMIA - treatment

Answer 35

◦Mild, asymptomatic hypercalcemia does not require immediate therapy, and management should be dictated by the underlying diagnosis.

◦Significant, symptomatic hypercalcemia usually requires therapeutic intervention independent of the aetiology of hypercalcemia.

◦Initial therapy is normal saline volume expansion and once well hydrated, with furosemide, which has the effect of blocking calcium reabsorption whilst promoting diuresis. If needed, dialysis is also an option.

◦In the long-term bisphosphonates can be given, which help trap Ca2+ in bone and inhibit bone resorption.

◦Steroids and calcitonin

◦As with all diseases, treat the cause; i.e., parathyroidectomy for primary

Question 36

HYPOCALCAEMIA

Answer 36

◦If potentially misleading hypocalcaemia due to either contamination of the sample with EDTA (from a full blood count tube) or decreased plasma albumin is first excluded, then the hypocalcaemia must be pathological and must result from a decrease in plasma Ca2+.

◦Tetany is the symptom that classically suggests the presence of a low plasma Ca2+. It may occur in any of the pathological conditions listed in causes of hypocalcaemia, and may also be caused by a rapid fall in plasma H+ (e.g. acute respiratory alkalosis produced by hyperventilation or IV infusion of NaHCO3). Occasionally it is due to a low plasma Mg2+ in the absence of low plasma Ca2+, and rarely it is due to a sudden increase in plasma phosphate.

Question 37

HYPOCALCAEMIA

Answer 37

◦If potentially misleading hypocalcaemia due to either contamination of the sample with EDTA (from a full blood count tube) or decreased plasma albumin is first excluded, then the hypocalcaemia must be pathological and must result from a decrease in plasma Ca2+.

◦Tetany is the symptom that classically suggests the presence of a low plasma Ca2+. It may occur in any of the pathological conditions listed in causes of hypocalcaemia, and may also be caused by a rapid fall in plasma H+ (e.g. acute respiratory alkalosis produced by hyperventilation or IV infusion of NaHCO3). Occasionally it is due to a low plasma Mg2+ in the absence of low plasma Ca2+, and rarely it is due to a sudden increase in plasma phosphate.

Question 38

Causes of hypocalcemia

Answer 38

1. Drugs and chemicals
2. Hypoalbuminaemic states
3. Hypocalcaemia usually with hypophosphataemia
4. Hypocalcaemia usually with hyperphosphataemia
5. Miscellaneous causes (rarer)

Question 39

Drugs and chemicals (in hypocalcemia)

Answer 39

◦Furosemide
◦Enzyme-inducing drugs, e.g. phenytoin
◦Ethylene glycol poisoning (rare)

Question 40

Drugs and chemicals (in hypocalcemia)

Answer 40

◦Furosemide
◦Enzyme-inducing drugs, e.g. phenytoin
◦Ethylene glycol poisoning (rare)

Question 41

Hypocalcaemia usually with hypophosphataemia

Answer 41

Vitamin D deficiency
◦Rickets/Osteomalacia
◦Malabsorption states

Question 42

Hypocalcaemia usually with hyperphosphataemia

Answer 42

◦Chronic kidney disease
◦Hypoparathyrodism (low PTH levels)
◦Idiopathic or autoimmune
◦Surgical removal of parathyroid glands
◦Congenital absence of parathyroid glands, e.g. DiGeorge’s syn
◦Infiltration of parathyroids, e.g. tumours, haemochromatosis
◦Pseudohypoparathyroidism (rare)
◦Parathyroid hormone (PTH) resistance (raised PTH levels)

Question 43

Miscellaneous causes (rarer) (of hypocalcemia)

Answer 43

◦Acute pancreatitis
◦Sepsis
◦High calcitonin levels
◦Rhabdomyolysis
◦Severe hypomagnesaemia
◦Autosomal dominant hypercalciuric hypocalcaemia

Question 44

Clinical features of hypocalcemia

Answer 44

• Enhanced neuromuscular irritability (positive
Chvostek’s sign and Trousseau’s sign); tetany
• Numbness, tingling (fingers, toes, circumoral)
• Muscle cramps (legs, feet, lower back)
• Seizures
• Irritability, personality changes
• ECG changes (prolonged Q-T interval) • Basal ganglia calcification; subcapsular cataracts
(especially with low PTH)

Question 45

What is Trousseau’s sign?

Answer 45

Trousseau’s sign is a spasm of the hand and forearm that occurs when the upper arm is compressed, for example by a blood pressure cuff.

Question 46

What is Chvostek’s sign?

Answer 46

Tapping of the cheekbone can cause a spasm of the face muscles, referred to as the Chvostek’s sign.

Question 47

INVESTIGATIONS of hypocalcemia

Answer 47

◦Measurement of plasma calcium and albumin, inorganic phosphate and Alkaline phosphatase (ALP), and sometimes magnesium, PTH and vitamin D metabolites underlies diagnosis.

◦Other investigations will seek to confirm aetiology of the disorder.

Question 48

HYPOCALCAEMIA - treatment
What are the life threatening symptoms?

Answer 48

◦Apparent hypocalcaemia, due to low plasma albumin concentrations, should not be treated. Always look at the albumin-adjusted calcium value.

◦Asymptomatic true hypocalcaemia, or that causing only mild clinical symptoms, can usually be treated effectively with oral calcium supplements & vitamin D supplements. It is difficult to give enough oral calcium by itself to make a lasting and significant difference to plasma calcium concentrations. If a normal diet is being taken, vitamin D, by increasing the absorption of calcium from the intestine, is usually adequate without calcium supplements.

1,25-Dihydroxycholecalciferol and alfacalcidol (1-α-hydroxycholecalciferol) are most commonly used as they have short half-lives, particularly if there is hypoparathyroidism or a defect in vitamin D metabolism.

It is important to monitor the plasma calcium closely to avoid inducing hypercalcaemia and hypercalciuria by ensuring a normal urinary excretion of calcium.

Hypocalcaemia with life-threatening symptoms
◦If there are cardiac arrhythmias, seizures or severe tetany including laryngospasm shown to be due to hypocalcaemia, intravenous calcium, usually as 10 mL of 10% calcium gluconate, should be given over about 5 min.
◦Rx can then begin as above, depending upon the aetiology of the hypocalcaemia.

◦Post-operative hypocalcaemia
◦Hypocalcaemia during the first week after a thyroidectomy or parathyroidectomy should be treated only if there is tetany, and usually with calcium replacement, which, unlike vitamin D supplements, has a rapid effect and a short half-life. Persistent hypocalcaemia may indicate that the parathyroid glands are permanently damaged and that long-standing, or even life-long, vitamin D supplementation is necessary. Parathyroid bone disease may result in ‘hungry bones’ and prolonged post-operative hypocalcaemia.

INVESTIGATIONS

Question 49

INVESTIGATIONS for hypocalcemia

Answer 49

◦Measurement of plasma calcium and albumin, inorganic phosphate and Alkaline phosphatase (ALP), and sometimes magnesium, PTH and vitamin D metabolites underlies the diagnosis of most disorders of calcium metabolism.
◦Other investigations will seek to confirm aetiology of the hypercalcaemia and hypocalcaemia. E.g.,Hormones (TFT -Hyperthyroidism), Genetic studies (FHH), etc.
◦Plasma calcium
◦Because of technical difficulties associated with the measurement of Ca2+, clinical biochemistry laboratories only measure plasma calcium routinely, despite the physiologically important fraction being Ca2+.
◦Effect of plasma albumin
◦Effect of plasma H+

Question 50

Effect of plasma albumin (in investigation of hypocalcemia)

Answer 50

◦The most common methods for measuring calcium determine its total concentration.
◦Because albumin is the principal binding protein for calcium, a fall in plasma albumin will lead to a fall in bound calcium and a decrease in total calcium (and vice versa).

Under these circumstances, the unbound plasma Ca2+, the physiologically important fraction, will be maintained at normal levels by PTH.

◦A raised plasma albumin may potentially lead to misleading increases in plasma calcium as a result of abnormal calcium binding. Often due to incorrect venepuncture technique.

◦To avoid misdiagnosis of hypocalcaemia or hypercalcaemia, plasma albumin should always be measured at the same time as plasma calcium.

◦The plasma calcium (in mmol/L) can be ‘adjusted’ () to take account of an abnormal albumin (in g/L) using this formula

◦‘Adjusted [calcium]’ = measured [calcium] + 0.02 x (40 - [albumin])

◦The alternative is to measure the free (ionized) calcium directly; this can be done using an ion selective electrode.

Question 51

Effect of plasma albumin

Answer 51

◦The most common methods for measuring calcium determine its total concentration.
◦Because albumin is the principal binding protein for calcium, a fall in plasma albumin will lead to a fall in bound calcium and a decrease in total calcium (and vice versa). Under these circumstances, the unbound plasma Ca2+, the physiologically important fraction, will be maintained at normal levels by PTH.
◦A raised plasma albumin may potentially lead to misleading increases in plasma calcium as a result of abnormal calcium binding. Often due to incorrect venepuncture technique.
◦To avoid misdiagnosis of hypocalcaemia or hypercalcaemia, plasma albumin should always be measured at the same time as plasma calcium.
◦The plasma calcium (in mmol/L) can be ‘adjusted’ () to take account of an abnormal albumin (in g/L) using this formula
◦‘Adjusted [calcium]’ = measured [calcium] + 0.02 x (40 - [albumin])
◦The alternative is to measure the free (ionized) calcium directly; this can be done using an ion selective electrode.

Question 52

Effect of plasma H+

Answer 52

◦In acidosis, the protonation of albumin reduces its ability to bind calcium, leading to an increase in unbound Ca2+, and vice versa, without any change in total calcium. Thus, hyperventilation with respiratory alkalosis can reduce Ca2+, with the development of tetany. In chronic states of acidosis or alkalosis, PTH acts to readjust the Ca2+, back to normal.

Question 53

Plasma phosphate

Answer 53

Plasma phosphate shows considerable diurnal variation; concentration reduces following meals. Different reference intervals should be used for different age groups.

Question 54

Alkaline phosphatase (ALP)

Answer 54

◦For physiological reasons, there are considerable variations in this enzyme’s activity in childhood, adolescence and pregnancy. The bone isoenzyme of ALP activity is increased in plasma from patients with diseases in which there is increased osteoblastic activity, e.g., hyperparathyroidism, Paget’s disease, rickets and osteomalacia, and carcinoma with osteoblastic metastases.

Question 55

Inorganic phosphate in the plasma exists in 3 forms

Answer 55

• free inorganic phosphate: ~80%
• protein-bound phosphate: ~15%
• complexed with calcium or magnesium: ~5%

Question 56

Phosphate can be found where and in what percentages?

Answer 56

Phosphate is a divalent anion; ≈ 80% (bony skeleton) and 20% (soft tissues and muscle), largely in an intracellular location as phosphate compounds.

Question 57

Discuss phosphate

Answer 57

In the ECF, phosphate is mostly inorganic (Pi), where it exists as a mixture of HPO24- and H2PO-4 at physiological pH.

◦The daily phosphate intake is about 30 mmol, with ≈ 80% being absorbed in the jejunum. Protein-rich food is a major source of phosphate intake, as are cereals and nuts.

The output is largely renal, with more than 90% being excreted by this route. Most of the phosphate filtered at the glomeruli is reabsorbed by the proximal tubules.

Gastrointestinal loss of phosphate accounts for only 10% of the body’s phosphate excretion.

Question 58

How does PTH control phosphate levels?

Answer 58

In bone, PTH (in synergy with calcitriol) stimulates osteoclastic bone resorption, releasing both free (ionized) calcium and phosphate into the ECF; this action increases the plasma concentrations of both calcium and phosphate.

◦In kidney, PTH reduces proximal tubular P reabsorption leading to phosphaturia.
or increased plasma 1,25(OH)2D

Question 59

How does 1,25‐dihydroxycholecalciferol (1,25‐DHCC) control phosphate levels?

Answer 59

◦To maintain electroneutrality, the transport of calcium ions by the intestinal epithelial cells is accompanied by inorganic phosphate; thus calcitriol also stimulates the intestinal absorption of phosphate.

◦In synergy with PTH, it stimulates osteoclastic bone resorption, releasing both free (ionized) calcium and phosphate

Question 60

How do Fibroblast growth factor (FGF) 23 control phosphate levels?

Answer 60

◦FGF23 increases fractional excretion of P by the kidneys. It also decreases production of 1,25(OH)2D, by decreasing the activity of the enzyme responsible for its formation. Both of these lead to decreased plasma P concentrations.
◦FGF23 is secreted in response to sustained increased plasma phosphate

Question 61

PHOSPHATE – Biologic Functions

Answer 61

1.Structural role as a component of phospholipids, phosphoproteins, nucleic acids (e.g. in DNA) and nucleotides (e.g. ATP).

2.Buffering intracellularly and extracellular buffering of hydrogen ions in urine.

3.Role in cellular metabolic pathways e.g. glycolysis & oxidative phosphorylation (major component of intermediate metabolites like G-6-P)

4.Cell signalling and enzyme activation/regulation by phosphorylation

5.Excitation–stimulus response coupling and nervous system conduction

6.Role in the optimal function of leucocytes (e.g. chemotaxis & phagocytosis) and for platelets in clot retraction.

Question 62

DISORDERS OF PHOSPHATE METABOLISM and their AETIOPATHOGENESIS

Answer 62

◦HYPERPHOSPHOTAEMIA
◦HYPOPHOSPHOTAEMIA

◦AETIOPATHOGENESIS
1.Intracellular shift/redistribution
2.Intake/absorption
3.Increased/reduced renal loss
4.Genetic
5.Miscellaneous

Question 63

HYPERPHOSPHOTAEMIA - CAUSES

Answer 63

1. Cellular redistribution
2. Increased intake
3. Reduced Renal excretion
4. Genetic: Pseudohyoparathyroidism
5. Miscellaneous

Question 64

Cellular redistribution (as a cause of hyperphosphatemia)

Answer 64

◦Artefact due to in vitro haemolysis or old blood sample
◦Acidaemia
◦Increased tissue breakdown e.g. rhabdomyolysis
◦Tumour lysis syndrome
◦Diabetic ketoacidosis

Question 65

Increased intake (as a cause of hyperphosphatemia)

Answer 65

Inappropriately high phosphate intake, usually intravenously or if undiluted cows milk is given to infants, Excess vitamin D intake via supplementation

Question 66

Reduced Renal excretion (in hyperphosphatemia)

Answer 66

Acute kidney injury or chronic kidney disease (commonest)
◦hypoparathyroidism (low PTH)
◦pseudohypoparathyroidism (resistance to PTH)
◦Vit D toxicity

Question 67

Genetic (in hyperphosphatemia)

Answer 67

Pseudohyoparathyroidism

Question 68

Miscellaneous (hyperphosphatemia)

Answer 68

Malignant hyperpyrexia
Crush injuries

Question 69

HYPERPHOSPHOTAEMIA – CLINICAL FEATURES

Answer 69

◦The majority of the clinical effects are the result of hypocalcaemia, especially in severe hyperphosphataemia ( >3.0 mmol/L). The reason for this is that calcium/phosphate precipitation into the tissues can ensue when the phosphate and calcium plasma concentrations exceed their solubility product. Thus, metastatic calcification is a clinical consequence of hyperphosphataemia.

Question 70

Investigations for hyperphosphatemia

Answer 70

INVESTIGATIONS
◦Measurement of plasma inorganic phosphate, calcium (with albumin) and Alkaline phosphatase (ALP), and sometimes magnesium, PTH and vitamin D metabolites underlies diagnosis.
◦Other investigations will seek to confirm aetiology of the disorder.
◦urea/creatinine and
◦urinary phosphate, etc.

Question 71

HYPERPHOSPHOTAEMIA - Rx

Answer 71

◦Directed at the cause
◦Oral phosphate-binding agents (e.g. magnesium hydroxide or calcium carbonate.
◦Haemodialysis or peritoneal dialysis may be indicated (In AKI or CKD and persistently severe hyperphosphataemia)

Question 72

HYPOPHOSPHOTAEMIA - CAUSES

Answer 72

1. Cellular redistribution (Commonest cause)
2. Decreased intake
3. Renal tubular loss
4. Genetic: X-linked hypophosphataemic Rickets
5. Miscellaneous

Question 73

Cellular redistribution (Commonest cause) in hypophosphatemia

Answer 73

◦Intravenous glucose/ Hyperalimentation
Alkalaemia (metabolic or respiratory alkalosis)
◦Administration of insulin/ Recovery from DKA
◦Re-feeding syndrome

Question 74

Decreased intake, (in hypophosphatemia)

Answer 74

◦total parenteral nutrition,
◦Chronic alcoholism or
◦Malabsorption states e.g. Vit D def
◦Oral phosphate binders

Question 75

Renal tubular loss (in hypophosphatemia)

Answer 75

◦Hyperparathyroidism (Pry/Sec. Pry hyperparathyroidism results in increased renal excretion),
◦Post renal transplant
◦Isolated phosphate disorder
◦Hypophosphataemic osteomalacia
◦X-linked hypophosphataemia
◦Oncogenic hypophosphataemia
◦Paracetamol poisoning
◦As part of Fanconi’s syndrome

Question 76

Genetic (in hypophosphatemia)

Answer 76

X-linked hypophosphataemic Rickets

Question 77

Miscellaneous (in hypophosphatemia)

Answer 77

Post-trauma or myocardial infarction or operation, Liver disease, Septicaemia

Question 78

HYPOPHOSPHOTAEMIA – CLINICAL FEATURES

Answer 78

◦The majority of the clinical effects are seen in severe hypophosphataemia (< 0.30 mmol/L)
◦Rhabdomyolysis, impaired skeletal muscle function, including weakness and myopathy.
◦Impaired diaphragmatic contractility, which may help to explain the difficulty in weaning patients off mechanical ventilators.
◦Cardiomyopathy is another possible complication of severe hypophosphataemia.
◦Hypophosphataemia can evoke seizures, perturbed mental state and paraesthesiae, as well as renal tubular impairment. If prolonged, it can lead to osteomalacia.
The haematological effects include thrombocytopenia, impaired clotting processes and also reduced leucocyte function. Haemolysis can also occur, as can erythrocyte 2,3-DPG depletion, resulting in a shift in the haemoglobin/oxygen dissociation curve to the left, that is, haemoglobin has a greater affinity for oxygen.

Question 79

INVESTIGATIONS for HYPOPHOSPHOTAEMIA

Answer 79

◦Measurement of plasma inorganic phosphate (and urinary phosphate), calcium (with albumin) and Alkaline phosphatase (ALP), and sometimes magnesium, PTH and vitamin D metabolites underlies diagnosis.
◦urinary phosphate – High values in patients with hypophosphtaemia reveal excessive urinary loss, whereas low/normal values are indicative of phosphate losses via the GIT

◦Other investigations will seek to confirm aetiology of the disorder

Question 80

HYPOPHOSPHOTAEMIA - Rx

Answer 80

◦Treatment is usually not necessary unless the plasma phosphate concentration is < 0.30 mmol/L or the patient is symptomatic.
Sometimes oral phosphate salts have been used, although diarrhoea can be a problem.

◦If intravenous phosphate replacement is indicated (indication?), the following regimens can be used, namely 9 mmol of monobasic potassium phosphate in half-normal saline by continuous intravenous infusion over 12 h, or Polyfusor phosphate 50 mmol over 24 h. They should not be given to patients with hypercalcaemia, because of the risk of metastatic calcification, or to patients with hyperkalaemia.

◦Treat the cause and replace orally (cow’s milk) or parenterally. Do not give phosphate IV to a patient with hypercalcaemia or oliguria.

Question 81

MAGNESIUM – Introduction, Metabolism & Control

3 forms magnesium exists

Answer 81

◦Mg is the 2nd most abundant intracellular cation. Essential for the activity of many enzymes (esp phosphotransferases).
◦Bone contains about 50%-75% of the body’s Mg, muscle & soft tissue contain remaining with a small proportion in the ECF(≈1%). So, plasma measurements of magnesium are not reliable indicators of the body status.
◦Mg exists in the plasma in 3 different forms:
◦• free ionized magnesium (Mg 2+ ): ~55%
◦• protein-bound magnesium (mainly albumin): ~32%
◦• complexed (with phosphate or citrate): ~13%

Answer 82

Dietary intake of Mg is ≈12 mmol (300 mg) daily. Green vegetables, cereals, nuts and meat are good sources. Significant amounts are contained in gastric and biliary secretions.
◦Mg is largely absorbed in the upper small intestine but the large intestine may also be important; unlike Ca, its absorption is not vitamin D dependent.
◦As much as 70% of Mg from dietary intake is not absorbed but eliminated in the faeces. The reminder is excreted via the kidneys, and about 65% of glomerular-filtered Mg is reabsorbed in the loop of Henle.

Question 83

MAGNESIUM – Control

Answer 83

◦Factors concerned with the control of magnesium absorption have not been defined, but may involve active transport across the intestinal mucosa by a process involving vitamin D.

◦Renal conservation of magnesium is at least partly controlled by PTH (Mg is required for synthesis and secretion of PTH) and aldosterone. PTH can increase magnesium reabsorption, although hypercalcaemia can increase the renal excretion of magnesium.

◦Insulin and calcitonin are important.

Question 84

MAGNESIUM – Biologic Functions

Answer 84

1.essential cofactor to many enzymes (≈ 300, energy metabolism, and protein & nucleic acid synthesis)
2.important for optimal cell function (normal cell permeability and neuromuscular function)
3.important for membrane function
4.act as an antagonist to calcium in cellular responses
5.has a structural role within the cell (required to maintain the structures of ribosomes, nucleic acids, and some proteins)
6.required for synthesis and secretion of PTH.

Question 85

DISORDERS OF MAGNESIUM METABOLISM

Answer 85

◦HYPERMAGNESAEMIA
◦HYPOMAGNESAEMIA

Question 86

HYPERMAGNESAEMIA - CAUSES

Answer 86

1. Increased intake of magnesium
2. Impaired renal excretion of magnesium
3. Miscellaneous causes

Question 87

Increased intake of magnesium (in hypermagnesemia)

Answer 87

Antacids, milk–alkali syndrome
Purgatives
Parenteral nutrition

Question 88

Impaired renal excretion of magnesium (in hypermagnesemia)

Answer 88

Acute kidney injury and chronic kidney disease
Familial hypocalciuric hypercalcaemia
Lithium treatment

Question 89

Miscellaneous causes (in hypermagnesemia)

Answer 89

Hypothyroidism
Adrenal insufficiency

Question 90

Miscellaneous causes

Answer 90

Hypothyroidism
Adrenal insufficiency

Question 91

HYPERMAGNESAEMIA – CLINICAL FEATURES

Answer 91

◦Clinical features do not usually manifest until the plasma magnesium concentration exceeds 2 mmol/L.
◦This includes cardiac arrhythmias, such as heart block and inhibition of atrioventricular conduction leading to cardiac arrest, seizures, altered nerve conduction, reduced tendon reflexes, paralytic ileus, nausea, respiratory depression and hypotension.

Question 92

INVESTIGATIONS of HYPERMAGNESAEMIA

Answer 92

◦Measurement of magnesium, calcium (with albumin), plasma inorganic phosphate,
◦Other investigations will seek to confirm aetiology of the disorder.
◦Renal function tests - renal disease. The patient can then be assessed for
◦TFTs - Hypothyroidism and
◦Mineralocorticoid deficiency - Addison’s disease.
◦Urine Ca - hypocalciuric hypercalcaemia

Question 93

HYPERMAGNESAEMIA - Rx

Answer 93

◦If there is severe hypermagnesaemia;
◦10 mL of 10% calcium gluconate given slowly intravenously may relieve symptoms.
◦Insulin and glucose infusion can be used too.
◦Failing this, and if there is impaired renal function, dialysis may be indicated

Question 94

HYPOMAGNESAEMIA –
CAUSES

Answer 94

1.Redistribution of magnesium between cells
2.Reduced intake of magnesium
3.Poor magnesium absorption
4.Increased renal loss of magnesium
5.Drugs
6.Miscellaneous causes

Question 95

HYPOMAGNESAEMIA –
CAUSES

Answer 95

1.Redistribution of magnesium between cells
2.Reduced intake of magnesium
3.Poor magnesium absorption
4.Increased renal loss of magnesium
5.Drugs
6.Miscellaneous causes

Question 96

Redistribution of magnesium between cells

Answer 96

Excess of catecholamines
Refeeding syndrome
Hungry bone syndrome

Question 97

Reduced intake of magnesium

Answer 97

Parenteral nutrition
Starvation/undernutrition

Question 98

Poor magnesium absorption

Answer 98

Intestinal resection
Gastrointestinal fistulae
Malabsorption states

Question 99

Increased renal loss of magnesium

Answer 99

Post-renal transplantation
Dialysis
Bartter’s and Gitelman’s syndromes

Question 100

Drugs

Answer 100

Diuretics
Proton pump inhibitors, e.g. omeprazole
Cytotoxics
Aminoglycosides
β2 -adrenergic agonists
Ciclosporin and tacrolimus
Pamidronate, pentamidine, amphotericin B, foscarnet

Question 101

Miscellaneous causes

Answer 101

Alcoholism
Hypercalcaemia
Hyperthyroidism
Hyperaldosteronism
Diabetes mellitus

Question 102

HYPOMAGNESAEMIA – CLINICAL FEATURES

Answer 102

◦The symptoms of hypomagnesaemia are very similar to those of hypocalcaemia. If the plasma calcium concentrations (allowing for that of albumin) and blood pH are normal in a patient with tetany, the plasma magnesium concentration should be assayed.
◦Hypomagnesaemia can result in cardiac arrhythmias, including torsade de pointes, and digoxin sensitivity.
◦Other symptoms include abdominal discomfort, anorexia, and neuromuscular sequelae (e.g., tremor, paraesthesiae, vertigo, tetany, seizures, irritability, confusion, weakness and ataxia).
◦Severe hypomagnesaemia can lead to hypocalcaemia due to decreased PTH release and activity.
◦Long-term magnesium deficiency may be a risk factor for coronary artery disease, perhaps increasing atherosclerosis and platelet aggregation. Reduced magnesium intake maybe associated with hypertension and insulin resistance.

Question 103

HYPOMAGNESAEMIA - Rx

Answer 103

◦Severe hypomagnesaemia, less than 0.5 mmol/L or if it is symptomatic, can be corrected by
◦Oral magnesium salts (these may be poorly absorbed and lead to gastrointestinal upset).
◦Oral magnesium gluconate 12 mmol/day to a maximum of 48 mmol/L, if required, in 2 or 4 divided doses.
◦Intravenous replacement as magnesium sulphate (0.5 mmol/kg/day) intravenous infusion. Close monitoring of plasma Mg is necessary.
◦The Rx of hypomagnesaemia may facilitate the Rx of refractory hypokalaemia and hypocalcaemia.

Question 104

INVESTIGATIONS

Answer 104

◦Measurement of plasma magnesium, calcium (with albumin), inorganic phosphate,
◦Urinary magnesium measurements over 1 mmol/day in patients with hypomagnesaemia reveal excessive urinary loss, whereas values below 1 mmol/day are indicative of magnesium losses via the GIT
◦Other investigations will seek to confirm aetiology of the disorder.
◦Plasma potassium measurements may reveal hypokalaemia in patients with hypomagnesaemia may give an indication as to the cause of the hypomagnesaemia, eg, hyperaldosteronism or diuretic therapy.
◦TFT, etc

Question 105

LABORATORY CONSIDERATIONS

Answer 105

◦1.Precautions in Specimen collection for Ca measurement
◦Never use EDTA, citrates, or oxalates as an anticoagulant because they bind calcium.
Specimen: PLASMA (LiH bottle) OR non-hemolysed SERUM (plain bottle)
◦Avoid prolonged tourniquet time
◦Take Albumin specimen to calculate albumin adjusted Ca (aka corrected Ca)
◦Free (ionized) calcium best measured with a specimen not exposed to air. Measure pH too.
◦2. Others
◦Hemolysis affect Pi & Mg; PLASMA (LiH bottle) OR non-hemolysed SERUM (plain bottle)
◦Anticoagulants like EDTA, citrate, and oxalate form complexes with Mg & should not be used.
◦Anticoagulants such as EDTA, citrate, and oxalate have the disadvantage in that they interfere in the formation of the phosphomolybdate complex used in Pi analysis.
◦Fasting specimen preferred for Pi.
◦PTH and Vit D3 preferred specimen is SERUM; morning specimens preferably esp for PTH.
◦Diurnal variation affects PTH (↑ in PM).
◦Plasma 25‐DHCC is the Vit D metabolite routinely measured. Main circulating form & store.