Week 2 Calcium

Question 1

What are the difference between intracellular and extracellular calcium?

Answer 1

• Intracellular Ca2+ is maintained at very low concentrations (less than 1 μmol/L).
• Reversible increases allow Ca2+ ions to bind to proteins to influence many key cell processes
• Extracellular Ca2+ is present at much higher concentration (about 1 mmol/L).
• To allow normal bone mineralisation
• To maintain normal activity of excitable tissue

Question 2

When you measure plasma/ serum calcium what are the two componants you detect?

Answer 2

• Ionised Ca2+ which is physiologically active
• Ca2+ which is ‘bound’ mainly to albumin and is not physiologically active

Question 3

What is the major Ca2+ binding protein is plasma?

Answer 3

Albumin

Question 4

How do you measure extracellular ionised calcium?

Answer 4

Measuring both albumin and total calcium is required to assess extracellular ionised Ca2+ status

Question 5

What proportion of the bodies calcium is stored in the skeleton?

Answer 5

Skeleton contains ~98% of body calcium

Question 6

Draw out calcium homeostasis

Answer 6

Question 7

Describe how calcitriol contributes to bone turnover?

Answer 7

Even though calcitriol promotes osteoclast action and therefor breaks down bone.

A deficiency in it results in bone loss because it is needed for calcium absorption in the intestine and kidneys, so without it PTH goes into averdrive and breaks down more bone than is nessecary in order to maintain calcium.

There is also less calcium for bone calcification.

It also supports osteoblasts. It seems to have involvement in both side of bone remodeling

Question 8

What does Alkaline phosphatase (ALP) do in bone mineralisation?

Answer 8

It is expressed ont he surface of osteoblasts.

Releases inorganic phosphate ions (PO43-) from diverse molecules (hydrolysis)
Hydrolyses pyrophosphate, a key inhibitor of mineralisation

Question 9

What is the mineral componant of bone?

Answer 9

hydroxyapatite: Ca10(PO4)6 (OH)2

Key: it is calcium AND phosphate

Question 10

Describe the actions of osteoblasts/clasts and rankL and OPG

Answer 10

Question 11

How do osteoclasts secrete H+?

Answer 11

By expressing plenty of carbonic anhydrase II for H+ generation

Question 12

What is osteopetrosis?

Answer 12

A disease caused by a failure of osteoclast bone resorbtion.

Also known as: ‘Marble bone disease’
Inherited bone disease
Increased bone mass

NOT Osteoporosis

Question 13

Describe the process of vitamin d activation

Answer 13

Vitamin D is either ingested or made in the skin form a cholesterol precurser

Enzymes in the liver then turn it into 25(OH)vitamin D. This is the thing we measure to assess vitamin D deficiency.

It is then hydroxylated by 1α-hydroxylase to 1,25(OH)2 vitamin D (calcitriol) in the kidney. This is regulated by PTH.

Question 14

What happens when a vitamin D receptor is bound to in the intestine?

Answer 14

In the intestine, a calcium-binding protein (calbindin-D9k) is synthesised which promotes absorption of both calcium and phosphate

Question 15

Three actions of calcitriol?

Answer 15

Promotes osteoclast action

Promotes intestinal absorption of calcium and phosphate

Promote renal reabsorption of calcium (weaker than PTH hence why PTH is still faster acting)

Question 16

Differences in overall effect of calcitriol and PTH

Answer 16

• PTH responsible for minute-by-minute plasma Ca2+ regulation
• Calcitriol responsible for longer term plasma Ca2+ regulation
• PTH tends to decrease plasma phosphate
• Calcitriol raises plasma phosphate

Question 17

Clinical manifestations of hypercalaemia?

Answer 17

• Muscle weakness (striated and smooth); possible competition with inward Na+ movement
• Central effects (anorexia, nausea, mood change, depression)
• Renal effects (impaired water concentration; renal stone formation)
• Bone involvement (cause-dependent)
• Abdominal pain
• ECG changes (shortened QT interval)

‘Stones, bones, abdominal moans and psychic groans’

Question 18

What is factitious hypercalcaemia?

Answer 18

Non-pathological raised [calcium] due to high plasma [albumin]

Question 19

Causes of factitious hypercalcaemia?

Answer 19

Venous stasis
Dehydration
IV albumin

Question 20

Difference between primary and secondary hyperparathyroidism

Answer 20

1y hyperparathyroidism is an autonomous and inappropriate overproduction of PTH leading to hypercalcaemia.

2y hyperparathyroidism is an appropriate increase in PTH in response to hypocalcaemia.

Question 21

What is the most common cause of primary hyperparathyroidism?

Answer 21

90% solitary adenoma -> hyperplasia

Question 22

Clinical sign of primary hyperparathyroidism

Answer 22

• Raised Ca2+ with inappropriately increased PTH
• Phosphate and bicarbonate tend to be low in serum (increased renal excretion)
• Alkaline phosphatase normal or moderately increased in more severe disease

Question 23

Treatment for moderate-severe primary hyperparathyroidism?

Answer 23

Acutely:

Patients may need treatment of their high ionised calcium. Ivolves re-hydration drugs.

Definitive treatment is removal of parathyroid adenoma (surgery)

Question 24

Treatment for mild hyperparathyroidism

Answer 24

Mild cases may be managed by repeated follow-up of serum calcium/PTH

Question 25

Drugs for treating hypercalcaemia

Answer 25

* Bisphosphonates (inhibit osteoclast action and bone resorption); after re-hydration this is key drug for longer-term control * Furosemide (inhibits distal Ca2+ reabsorption; requires care and patient must be hydrated first) * Calcitonin (inhibits osteoclast action); tolerance may develop but useful for immediate, short-term management * Glucocorticoids (inhibit vitamin D conversion to calcitriol; can prolong calcitonin action)

Question 26

What does malignancy have to do with hypercacaemia?

Answer 26

* Commonest cause of hypercalcaemia in hospitalised patients * Up to 20-30% cancer patients may develop hypercalcaemia during course of illness * Two broad reasons: 1. Endocrine factors secreted by malignant cells acting on bone 2. Metastatic tumour deposits in bone locally stimulating bone resorption via osteoclast activation

Question 27

Causes of hypercacaemia other than 1o hyperparathyroidism and malignancy

Answer 27

* Granulomatous disease e.g. sarcoidosis * Exogenous vitamin D excess * Familial hypocalciuric hypercalcemia * Drugs (e.g. Li, thiazide diuretics) * Some endocrine diseases (thyrotoxicosis, Addison’s disease) * Immobilization

Question 28

Three most common causes of hypercalcaemia

Answer 28

* factitious hypercalcaemia * primary hyperparathyroidism * malignancy

Question 29

Order of treatment for hypercalcaemia

Answer 29

1. Rehydrate 2. Bring down calcium with drugs - most common bisphosphonates 3. Treat underlying cause

Question 30

Clinical manifestations of hypocalcaemia

Answer 30

Neuromuscular: * Numbness and paraesthesiae (‘tingling’) in fingertips, toes, around mouth * Anxiety and fatigue * Muscle cramps, carpo-pedal spasm, bronchial or laryngeal spasm * Seizures Mental state * Personality change * Mental confusion, psychoneurosis * Impaired intellectual ability * ECG changes, eye problems

Question 31

What causes the neuromuscular features of hypocalcaemia?

Answer 31

Predominantly due to an increase in neuromuscular excitability (increased inward Na+ movement?)

Question 32

Two named signs of hypocalcaemia

Answer 32

Question 33

Causes of factitious hypocalcaemia

Answer 33

Consequence of low plasma [albumin] e.g.: 1. Acute phase response (low albumin) 2. Malnutrition or malabsorption (protein deficiency in diet) 3. Liver disease (reduced liver synthesis albumin) 4. Nephrotic syndrome (albumin lost in urine)

Question 34

Common causes of hypocalcaemia

Answer 34

* Facticious hypocalcaemia * Vit D deficiency * Hypoparathyroidism

Question 35

Causes of vit d deficiency

Answer 35

* Lack of sunlight * Inadequate dietary source * Malabsorption * Chronic renal disease (relatively common) * Chronic liver disease (rare) * Defective 1-OHase (v. rare) * Defective 1,25- D3 receptor (v.rare)

Question 36

Clinical features of vit D deficiency

Answer 36

* Low 25-D3 and 1,25-D3 (usually) * Low Ca2+ (may be normal in early stages) * High PTH (2y hyperparathyroidism) * Phosphate tends to be low * Often raised ALP

Question 37

Causes of hypoparathyroidism

Answer 37

Acquired * Surgical damage or removal (relatively common; usually transient) * Suppressed secretion (e.g. low Mg2+, maternal hypercalcaemia) Inherited * Developmental parathyroid problems * Genetic/familial disorders e.g. DiGeorge syndrome

Question 38

Biochemistry of hypoparathyroidism

Answer 38

* Low Ca2+ * Inappropriately low PTH * Phosphate may be increased

Question 39

Osteoporosis vs Osteomalacia

Answer 39

Question 40

What happens to calcium on osteoporosis?

Answer 40

Routine biochemistry unaffected.

Question 41

Treatment of hypocalcaemia

Answer 41

* In acute situations IV calcium may be required * Normally oral calcium and vitamin D are given (Mg sometimes)

Question 42

How must vit D be given if there is renal impairment?

Answer 42

Vit D must be given as the 1OH form if renal function is impaired

Question 43

What's going on in osteomalacia?

Answer 43

* Osteoid laid down by osteoblasts is not adequately calcified * Osteoid content in bone increases at the expense of normal calcified osteoid (bone matrix) * Bones are softened, weak and susceptible to fracture Not quite sure how but the lack of vitamin D (and probably increase in PTH). Vit D is needed for bone calcification. (as well as promoting osteoclast activity)