Clinical Calcium Homeostasis Flashcards
Give examples of dietary sources of calcium.
- Milk, cheese and other dairy foods
- Green leafy vegetables– such as broccoli, cabbage and okra, but not spinach
- Soya beans
- Tofu
- Nuts
- Bread and anything made with fortified flour
- Fish where you eat the bones– such as sardines and pilchards
What are the functions of calcium
- Bone formation
- Cell division & growth
- Muscle contraction
- Neurotransmitter release
What happens to the calcium we intake?
Dietary intake 1000mg
- 800mg faeces
- 1.0% cells
- 0.1% ECF
- 200mg kidneys
- 98.9% bone
What proportion of calcium is bound in plasma?
- 45% bound (mainly to albumin)
- 10% non-ionised or complexed to citrate, PO4 etc.
- 45% ionised
What is the normal calcium range?
Normal range 2.20-2.60 mmol/l
How do we calculate free calcium?
- Increased albumin decreases free calcium
- Decreased albumin increases free calcium
- Adjust Ca2+ by 0.1mmol/l for each 5g/l reduction in albumin from 40g/l
What conditions lead to hypercalcaemia?
Acidosis increases ionised calcium thus predisposing to hypercalcaemia
What are good food sources of vitamin D?
- Oily fish– such as salmon, sardines and mackerel
- Eggs
- Fortified fat spreads
- Fortified breakfast -Cereals
- Some powdered milks
Where are the parathyroid glands located?
Posterior to the thyroid gland in the neck
How many parathyroid glands are there?
4
What kind of cells are in the parathyroid glands?
Chief cells
What do the parathyroid glands do?
Secrete PTH
What cells in the parathyroid gland respond directly to changes in calcium concentrations?
Chief cells
What happens to PTH when calcium rises?
Decreases
What happens to PTH when calcium falls?
Increases
When is PTH secreted?
PTH is secreted in response to a fall in calcium
How are alterations in ECF Ca levels transmitted into the parathyroid glands?
Alterations in ECF Ca2+ levels are transmitted into the parathyroid cells via calcium-sensing receptor (CaSR)
What are the direct effects of PTH?
PTH has direct effects that promote reabsorbtion of calcium from renal tubules & bone
What does PTH mediate?
The renal conversion of vitamin D from its inactive to active form
What enzyme activates vitamin D?
25(OH) vitamin D 1α-hydroxylase
Why do some patients need activated vitamin D?
If they have renal failure they are unable to convert inactive vitamin D to active vitamin D
When do symptoms of hypocalcaemia typically develop?
Symptoms of hypocalcaemia typically develop when adjusted serum calcium levels fall below 1.9mmol/L. However this threshold does vary and is dependent on the rate of fall.
What acute neuromuscular irritability (tetany) is associated with hypocalcaemia?
- Paresthesia
- Muscle twitching
- Carpopedal spasm
- Trosseau’s sign
- Chovstek’s sign
- Seizures
- Laryngoscope
- Bronchospasm
What acute cardiovascular symptoms are associated with hypocalcaemia?
- Prolonged QT interval
- Hypotension
- Heart failure
- Arrhythmia
- Papilloedema
What chronic symptoms are associated with hypocalcaemia?
- Ectopic calcification (basal ganglia)
- Extrapyramidal signs
- Parkinsonism
- Dementia
- Subcapsular cataracts
- Abnormal dentition
- Dry skin
What hypoparathyroisim causes of hypocalcaemia are there?
- Disruption of parathyroid gland due to total thyroidectomy. May be temporary or permanent
- Following selective parathyroidectomy (usually transient and mild)
- Mg deficiency
- Cytotoxic drug-induced hypocalcaemia
- Pancreatitis, rhabdomyolysis and large volume blood transfusions
What are the high PTH causes of hypocalcaemia?
- Vitamin D deficiency or resistance
- Pseudohypoparathyroidism
- Hypomagnesemia
- Renal disease
- Tumour lysis
- Acute pancreatitis
- Acute respiratory alkalosis
What drugs can cause hypocalcaemia?
- Inhibitors of bone resorption (bisphosphonates, calcitonin, denosumab)
- Cinacalcet
- Calcium chelators (EDTA, citrate, phosphate)
- Foscarnet (due to intravascular complexing with calcium)
- Phenytoin (due to conversion of vitamin D to inactive metabolites
- Fluoride poisoning
What history is important in hypocalcaemia?
- Symptoms
- Ca and vitamin D intake
- Neck surgery
- Autoimmune disorders
- Medications
- Family history
What should be looked for on examination of hypocalcaemia?
Neck scars
What investigations should be carried out for hypocalcaemia?
- ECG
- Serum calcium
- Albumin
- Phosphate
- PTH
- U+Es
- Vitamin D
- Magnesium
How should hypocalcaemia be investigated if the PTH is low or normal?
Check magnesium
- Low: magnesium deficiency
- Normal: hypoparathyroidism or calcium sensing receptor defect (rare)
How should hypocalcaemia be investigated if the PTH is high?
Check urea and creatinine
- Normal: check vit D (normal vit D suggest pseudohypoparathyroidism, or calcium deficiency) (low vit D suggests vit D deficiency)
- High: renal failure
What are the levels of total calcium, ionised calcium, phosphate and PTH in: hypoalbuminaemia?
- Total calcium: low
- Ionised calcium: normal
- Phosphate: normal
- PTH: normal
What are the levels of total calcium, ionised calcium, phosphate and PTH in: alkalosis?
- Total calcium: normal
- Ionised calcium: low
- Phosphate: normal
- PTH: normal/high
What are the levels of total calcium, ionised calcium, phosphate and PTH in: chronic renal failure?
- Total calcium: low
- Ionised calcium: low
- Phosphate: high
- PTH: high
What are the levels of total calcium, ionised calcium, phosphate and PTH in: hypoparathyroidism?
- Total calcium:low
- Ionised calcium: low
- Phosphate: high
- PTH: low
What are the levels of total calcium, ionised calcium, phosphate and PTH in: pseudohypoparathyroidism?
- Total calcium: low
- Ionised calcium: low
- Phosphate: high
- PTH: high
What are the levels of total calcium, ionised calcium, phosphate and PTH in: acute pancreatitis?
- Total calcium: low
- Ionised calcium: low
- Phosphate: low/normal
- PTH: high
What are the levels of total calcium, ionised calcium, phosphate and PTH in: hypomagnesium?
- Total calcium: low
- Ionised calcium: low
- Phosphate: variable
- PTH: low or normal
What may hypoparathyroidism result from?
- Agenesis (e.g. DiGeorge syndrome)
- Destruction (neck surgery, autoimmune disease)
- Infiltration (haemochromatosis, Wilson’s disease)
- Reduced secretion of PTH (neonatal hypocalcaemia, hypomagnesaemia)
- Resistance to PTH
What is pseudohypoparathyroidism?
Pseudohypoparathyroidism, which presents in childhood, refers to a group of heterogenous disorders defined by target organ (kidney and bone) unresponsiveness to PTH.
What is pseudohypoparathyroidism characterised by?
It is characterised by hypocalcaemia, hyperphosphatemia and in contrast to hypoparathyroidism, elevated rather than reduced PTH concentrations
What can occur on some patients with pseudohypoparathyroidism?
Albright’s hereditary osteodystrophy (AHO)
What are the features of Albright’s hereditary osteodystrophy (AHO)?
- Obesity
- Short stature,
- Shortening of the metacarpal bones
What is AHO alone without abnormalities of calcium or PTH called?
Pseudo-pseudohypoparathyroidism
What is mild hypocalcaemia classed as?
Mild Hypocalcaemia (asymptomatic, >1.9mmo/L)
What is the treatment for mild hypocalcaemia?
- Commence oral calcium tablets
- If post thyroidectomy repeat calcium 24 hours later
- If vitamin D deficient, start vitamin D
- If low Mg, stop any precipitating drug and replace Mg
What is severe hypocalcaemia classed as?
Severe hypocalcaemia (symptomatic, <1.9mmol/L)
What is the treatment for severe hypocalcaemia?
- This is a medical emergency
- Administer IV calcium gluconate
- Initial bolus (10-20ml 10% calcium gluconate in 50-100ml of 5% dextrose IV over 10 minutes with ECH monitoring)
- Calcium gluconate infusion
- Treat the underlying cause
Why should alfacalcidol or calcitriol be prescribed in patients with severe renal impairment?
Vitamin D requires hydroxylation by the kidney to its active form, therefore the hydroxylated derivatives alfacalcidol or calcitriol should be prescribed if patients with severe renal impairment require vitamin D therapy
How should vitamin D replacement be administered?
- Advice regarding dietary sources
- Most tablets contain a combination of vitamin D and calcium
- Maintenance dose ~400-1000 international units
- Higher loading dose required (e.g. 3200 units daily for 12 weeks)
What is classified as mild hypercalcaemia?
<3.0mmol/L
Often asymptomatic and does usually require urgent correction
What is classified as moderate hypercalcaemia?
3.0-3.5mmol/L
May be well tolerated if it has risen slowly, but may be symptomatic and prompt treatment is usually indicated
What is classified as severe hypercalcaemia?
> 3.5mmol/L
Requires urgent correction due to risk of dysrhythmia and coma
Give examples of parathyroid mediated causes of hypercalcaemia.
-Primary hyperparathyroidism (sporadic)
-Inherited variants
Multiple endocrine neoplasia (MEN)
Familial isolated hyperparathyroidism
Hyperparathyroidism jaw tumour syndrome
-Familial hypocalciuric hypercalcaemia
-Tertiary hyperparathyroidism (renal
Give examples of non-parathyroid mediated causes of hypercalcaemia.
-Hypercalcaemia of malignancy
-PTHrp
-Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)
-Osteolytic bone metastases and local cytokines
-Vitamin D intoxication
-Chronic granulomatous disorders
• Sarcoid
• TB
• Berylliosis
• Histoplasmosis
• Wegner’s
Give examples of medications that can cause hypercalcaemia
- Thiazide diuretics
- Lithium
- Teriparatide
- Excessive vitamin A
- Theophylline toxicity
What miscellaneous causes of hypercalcaemia are there?
- Hyperthyroidism
- Acromegaly
- Pheochromocytoma
- Adrenal insufficiency
- Immobilisation
- Parenteral nutrition
- Milk alkali syndrome
What renal symptoms can hypercalcaemia cause?
- Polyuria
- Polydipsia
- Nephrolithiasis
- Nephrocalcinosis
- Distal renal tubular acidosis
- Nephrogenic diabetes insipidus
- Acute and chronic renal dysfunction
What GIT symptoms can hypercalcaemia cause?
- Anorexia
- Nausea and vomiting
- Bowel hypomotility and constipation
- Pancreatitis
- Peptic ulcer disease
What MSK symptoms can hypercalcaemia cause?
- Muscle weakness
- Bone pain
- Osteopenia/osteoporosis
What neurological symptoms can hypercalcaemia cause?
- Decreased concentration
- Fatigue
- Confusion
- Stupor, coma
What cardiovascular symptoms can hypercalcaemia cause?
• Shortening of the QT interval
• Bradycardia
Hypertension
What should you enquire about in a hypercalcaemia history?
- Symptoms of hypercalcaemia
- Systemic enquiry
- Medications
- Family history
What should you look for on examination of hypercalcaemia?
- Lymph nodes
- Concerns about malignancy (breast, lung, etc.)
What investigations should be carried out for hypercalcaemia?
- U+Es
- Ca
- PO4
- Alk phos
- Myeloma screen
- Serum ACE
- PTH
- Consider ECG
What is normally affected by primary hyperparathyroidism?
- F:M 3:1
- Incidence peaks 50-60 years
What can cause primary hyperparathyroidism?
Most cases are sporadic but has been associated with neck irradiation or prolonged lithium use
- 85% parathyroid adenoma
- 15% four gland hyperplasia - <1% MEN type 1 or 2A
- <1% parathyroid carcinoma
How do patients with primary hyperparathyroidism present?
Most patients are asymptomatic at diagnosis
What investigations should be carried out for primary hyperparathyroidism?
- Ca, PTH
- U+Es: check renal function
- Abdominal imaging: renal calculi
- DEX: osteoporosis
- 24 hour urine collection for calcium: Excl. FHH
- Vitamin D
- Parathyroid ultrasound
- SESTAMIBI
What are the indications for surgery in primary hyperparathyroidism?
The presence of any of the below features would be an indication for parathyroid surgery
- Presence of symptoms due to hypercalcaemia
- Serum calcium >0.25mmol/L above the upper limit of normal (2.85 in Aberdeen)
- Skeletal: osteoporosis on DEXA or vertebral
- Renal: eGFR /,60 or presence of kidney stones
- Age <50 years
How can primary hyperparathyroidism be managed medically?
- Generous fluid intake
- Cinacalcet (acts as calcimetic i.e. mimics effect of calcium on the calcium sensing receptor on chief cells, this leads to a fall in PTH and subsequently calcium levels)
What is familial hypocalciuric hypercalcaemia?
Autosomal dominant disorder of the calcium sensing receptor
How is familial hypocalciuric hypercalcaemia managed?
Benign so no therapy indicated
What may investigations of familial hypocalciuric hypercalcaemia show?
- PTH normal or slightly elevated
- No evidence of abnormal parathyroid tissue on ultrasound or isotope scan
- Positive family history so screen young family members for diagnosis
Describe hypercalcaemia caused by: local osteolytic hypercalcaemia
Frequency: 20%
Bone metastases: common, extensive
Causal agent: Cytokines, chemokines, PTHrP
Typical tumours: Breast cancer, multiple myeloma, lymphoma
Describe hypercalcaemia caused by: humoral hypercalcaemia of malignancy
Frequency: 80%
Bone metastases: minimal or absent
Causal agent: PTHrP
Typical tumours: Squamous cell cancer (e.g. head and neck, oesophagus, cervix or lung), renal, ovarian, endometrial & breast cancer
Describe hypercalcaemia caused by: 1,25 (OH)2 D-secreting lymphomas
Frequency: <1%
Bone metastases: variable Variable
Causal agent: 1,25 (OH)2D
Typical tumours: lymphoma (all types)
Describe hypercalcaemia caused by: ectopic hyperparathyroidism
Frequency: <1%
Bone metastases: variable
Causal agent: PTH
Typical tumours: variable
Describe MEN type 1 in hypercalcaemia
Associations
- Primary hyperparathyroidism
- Pancreatic
- Pituitary
- > 95% MEN 1 will have hyperparathyroidism
- MENIN mutation (chromosome 11)
- 2-4% of cases of PHP may be MEN1
- Usually presents in the 2nd to 4th decade of life
- Multigland involvement, high recurrence risk
Describe MEN type 2A in hypercalcaemia
Associations
- Medullary thyroid cancer
- Pheochromocytoma
- Primary hyperparathyroidism
- RET mutation
- 20-30% of MEN2A have hyperparathyroidism
- Usually milder disease than MEN1
How should those with hypercalcaemia be managed?
- Rehydration
- After rehydration, intravenous bisphosphonates
- Zolendronic acid 4 mg over 15 minutes
- Give more slowly and consider dose reduction if renal impairment
- Calcium will reach nadir at 2-4 days
Describe rehydration in the treatment of hypercalcaemia
- 0.9% saline 4-6 litres over 24 hours
- Monitor for fluid overload
- Consider dialysis if severe renal failure
What are the 2nd line treatments in hypercalcaemia?
- Glucocorticoids
- Calcitonin
- Calcimimetics
- Parathyroidectomy
When are glucocorticoids used in hypercalcaemia?
In lymphoma, other granulomatous disease or 250HD poisoning
When is calcitonin used in hypercalcaemia?
Can be considered if poor response to bisphosphonates
When are calcimimetic used in hypercalcaemia?
Licensed for hypercalcemia due to primary hyperparathyroidism, parathyroid carcinoma or renal failure
When is a parathyroidectomy used in hyperparathyroidism?
Can be considered in acute presentation of primary hyperparathyroidism if severe hypercalcaemia and poor response to other measures
What are the low PTH causes of hypothyroidism?
- Genetic disorders
- Post-surgical (thyroidectomy, parathyroidectomy, radical neck dissection)
- Autoimmune
- Infiltration of the parathyroid gland (granulomatous, iron overload, metastases)
- Radiation-induced destruction of parathyroid glands
- Hungry bone syndrome (post parathyroidectomy)
- HIV infection
