DISORDERS OF CALCIUM HOMEOSTASIS Flashcards
How is calcium excreted?
Kidneys
Where is the vast majority of calcium held in the body?
99% is stored in bone
What are the roles of calcium in the body?
Bone mineralisation Muscle contraction Processes involving exocytosis (eg synaptic transmission and hormone release) Enzymatic reactions Intracellular signalling Nerve conduction Blood clotting
How is calcium transported in the blood?
40% bound to albumin
10% bound to other proteins
50% unbound ionised form (physiologically active and the only form that can be secreted via kidneys)
What are the normal levels of unbound ionised calcium in the blood?
1.0-1.25 mmol/L
How does blood pH affect unbound ionised calcium levels in the blood?
Low pH - release of calcium from binding proteins
High pH - increased binding to proteins
What is the daily required amount of calcium for an adult?
1g
1.2g if pregnant
What hormone increases absorption of calcium from the gut?
Vitamin D
Which group tend to have a negative calcium balance (output outweighs input)?
Post-menopausal women
What are the normal ranges of total serum calcium?
2.12 - 2.65 mmol/L
What factor must be taken into account when calculating levels of unbound calcium?
Albumin level. Diseases that lower albumin can increase unbound calcium levels causing symptoms and signs of hypercalcaemia.
Where is parathyroid hormone produced?
In the chief cells of the parathyroid gland
Where are the parathyroid glands found? How many are there?
Often varies between 2 and 6 (normally 4) glands each found on the posterior surfaces of the lateral lobes of the thyroid gland
What is the effect of parathyroid hormone on calcium levels?
Increase serum calcium levels
What stimulates the release of parathyroid hormone?
Falling calcium levels
Increased levels of phosphate
What are the effects of parathyroid hormone on the kidney?
Increase calcium reabsorption by stimulating active uptake in DCT and thick ascending limb
Increase of phosphate ion excretion by inhibiting uptake in PCT and DCT
Stimulation of 1α-hydroxylase, an enzyme that activates vitamin D
What are the effects of parathyroid hormone on the bones?
Indirect stimulation of osteoclasts (binding to osteoblasts increases binding of RANK to RANKL which stimulates osteoclast proliferation) thereby breaking down bone.
What are the effects of parathyroid hormone on the intestine?
Very little direct effect
The indirect effect is the activation of vitamin D in the kidney which produces calcitriol. Calcitriol promotes absorption of both calcium and phosphate in the gut.
What is the overall effect of parathyroid hormone on serum levels of calcium and phosphate?
Increase calcium
Reduce phosphate
What are the two ways we obtain vitamin D3 (cholecalciferol)?
Ingestion (dairy food)
Formed in the skin from cholesterol with UV light
Where do the two stages of vitamin D3 activation occur?
Vitamin D3 –> 25 (OH) vitamin D3 - occurs in liver
25 (OH) vitamin D3 –> 1,25 (OH)2 vitamin D3 (Calcitriol) - occurs in kidney (this is the stage which is upregulated by PTH
How are all forms of vitamin D3 transported in the blood?
Plasma protein - transcalciferin
What is the effect of calcitriol on the intestines?
Active absorption of calcium and phosphote from the duodenum and jejunum
What is the effect of calcitriol on the kidneys?
Increased calcium reabsorption in the PCT and DCT
Increased phosphate reabsorption in the PCT
Inhibition of 1α-hydroxylase, the enzyme involved in activating vitamin D (negative feedback)
What is the effect of calcitriol on the bones?
Direct stimulates osteoblasts
Indirectly stimulates osteoclasts
Where is calcitonin secreted from?
Parafollicular cells (C cells) of the thyroid gland
What triggers the secretion of calcitonin?
High levels of serum calcium
What is the effect of calcitonin on the kidneys?
Inhibits calcium reabsorption and phosphate
What is the effect of calcitonin on the bones?
Direct inhibition of osteoclasts
What is the clinical significance of calcitonin deficiency or excess?
Very little
What is the therapeutic use of calcitonin?
Vertebral fractures
Paget’s disease
What is the difference between primary and secondary hyperparathyroidism?
Primary is when the cause is excessive PTH release. In secondary hyperparathyroidism the high PTH is a result of low calcium.
What are the main causes of primary hyperparathyroidism?
Parathyroid gland adenoma
Diffuse parathyroid gland hyperplasia
Which group are particularly affected by primary hyperthyroidism?
Postmenopausal women
What are the clinical features of primary hyperparathryoidism?
Unexpected bone weakness
Symptoms of hypercalcaemia
Dehydration
Severe thirst
What are the complications of prolonged primary hyperparathyroidism?
Osteomalacia in adults
Rickets in childhood
Complications of hypercalcaemia
What are the signs, symptoms and complications of hypercalcaemia?
‘Bones, stones, abdominal groans and psychic moans’
Painful fragile bones Renal calculi Polyuria Renal failure Vomiting Peptic ulceration Abdominal pain Constipation General weakness Mental confusion Headache Convulsions and coma Corneal calcification Cardiac arrythmias Ectopic calcification (heart, liver, pancreas)
What investigations would you perform in someone with suspected primary hyperparathyroidism?
Blood tests - U&Es, PTH levels, renal function
X-ray of hands and long bones
DEXA scan of bones - osteoporosis
Radio-isotope scanning or ultrasound of parathyroid glands to detect adenomas - parathyroid Sestamibi (uptake) scan
24 hour urinary calcium - young patients who present with increase in serum calcium and PTH need to have familial hypocalciuric hypercalcaemia excluded
X-ray of abdomen to look for nephrocalcinosis or renal calculi
What are the treatment options for someone with primary hyperparathyroidism?
Restrict dietary calcium and vitamin D, and encourage adequate hydration
Drug treatment - calcitonin, bisphosphonates, cinacalcet - drug treatment is used in those who do not fulfil criteria for surgery
Surgical removal of parathyroid gland
What are the indications and major contraindications for the surgical removal of parathyroid gland in someone with primary hyperparathyroidism?
Under 50
Serum calcium >3 mmol/L
Contraindication - familial hypocalciuric hypercalcaemia
What is familial hypocalciuric hypercalcaemia?
A mutation which causes loss of function of the calcium sensing receptor. It causes hyperparathyroidism and hypercalcaemia although actually symptoms are rarely seen. No calcium is lost in the urine, so patients do not suffer from renal stones.
What are the common complications of parathyroid surgery?
Hypocalcaemia
Recurrent laryngeal nerve injury
Bleeding and haematoma formation
What are the two main causes of hypocalcaemia leading to secondary hyperparathyroidism?
Chronic renal failure
Vitamin D deficiency or malabsorption of Ca
What is renal osteodystrophy?
A complication of chronic renal disease characterised by secondary hyperparathyroidism, osteomalacia and vitamin D deficiency.
What is the underlying mechanism of renal osteodystrophy?
Kidney failure causes impaired 1α-hydroxylase activity. This leads to reduced vitamin D activation and less calcium reabsorption. This along with impaired phosphate clearance by the kidney leads to high amount of PTH. PTH induced resorption of calcium from the bone leads to osteomalacia, bone marrow fibrosis and cyst formation.
How are those with secondary hyperparathyroidism managed?
Correct the cause of the hypocalcaemia:
Dietary modification and/or phosphate binders
Vitamin D analogues
Modification of dialysis
Cinacalcet (calcimimetic) - not recommended for those with end-stage kidney disease
What is tertiary hyperparathryoidism?
A complications of secondary hyperparathyroidism. The hyperplasia of the parathyroid glands during the period of prolonged hypocalcaemia means that once the underlying cause has been treated, PTH secretion becomes excessive and leads to the same complications as primary hyperparathyroidism. Most commonly seen in patients with renal failure on dialysis.
What are the clinical features of hypocalcaemia?
SPASMODIC-4
Spasms (carpopedal spasm with blood pressure cuff = Trousseau’s sign)
Paraesthesiae in hands, feet and around eyes
Anxious, irritable, irrational
Seizures
Muscle tone increase - colic, wheeze, dysphagia
Orientation impaired
Dermatitis
Impetigo herpetiformis
Chovstek’s sign (mouth twitch when parotid gland is tapped)
Cataracts
Cardiomyopathy (long Q-T interval)
Choreoathetosis
What are the main causes of hypoparathyroidism?
Complication of thyroid or parathyroid surgery Congenital deficiency - DiGeorge syndrome Idiopathic hypoparathyroidism (autoimmune) Pseudohypoparathyroidism - PTH resistance
What happens to levels of calcium and phosphate in hypoparathyroidism?
Reduced calcium
Raised phosphate
What is the mnemonic for remembering the causes of hypocalcaemia?
HARVARD
Hypoparathyroidism Acute pancreatitis Renal failure Vitamin D deficiency Alkalosis Rhabdomyolysis and tumour lysis syndrome Drugs - bisphosphonates
Why do rhabdomyolysis and tumour lysis syndrome cause hypocalcaemia?
Because the intracellular phosphate released from the broken down cells bind to the free ionised calcium.
How is hypoparathyroidism treated?
Severe hypocalcaemia is a life threatening condition and needs immediate treatment with IV calcium gluconate.
Long term treatment includes vitamin D analogs and calcium supplements. The N-terminal fragment of parathyroid hormone (PTH 1-34) is used as PTH replacement therapy.
What is pseudopseudohypoparathyroidism?
The haploinsufficiency of pseudohypoparathyroidism. They present with skeletal problems but have a normal blood picture in terms of PTH, calcium and phosphate.
How do you treat hypercalcaemia?
This can be an emergency. ABCDE Cardiac monitor - arrythmias Hydrate them - water is effective treatment for hypercalcaemia Monitor urine output - kidney injury
If calcium still high after 24 hours of treatment, bisphosphonate infusion which sends calcium back into bones
If granulomatous disease is suspected as cause give glucocorticosteroids
Chronic hypercalcamia - furosemide plus fluids
How does granlumatous disease such as sarcoidosis lead to hypercalcaemia?
Activates Vitamin D
