ENDOCRINE DISEASE III

hypocalcaemia and hypercalcaemia

how much calcium does the average person have

the average person has 1kg of calcium

• 99% in the skeleton

• <1% ionised calcium in ECF

  • cofactor in coagulation

  • skeletal mineralisation

  • membrane stabilisation (neuronal conduction)

which organs does calcium homeostasis rely on

• intestine (small) - absorbs dietary Ca

• kidney - adjusts how much Ca is excreted/ reabsorbed

• bone - primary Ca reservoir in the form of hydroxyapatite

if serum calcium decreases, how are normal Ca levels restored

• decreased in sCa²⁺ » parathyroid gland secretes PTH » increase in PTH »

  • ↑ bone resorption

  • ↑ Ca reabsorption in kidneys

  • ↑ Ca absorption in intestines

what are the other actions of parathyroid hormone in the kidneys

• INCREASES Ca REABSORPTION » serum Ca increases

• decreases phosphate reabsorption » lowers serum phosphate levels

• increases 1-alpha hydroxylation of vitamin D » increases levels of active form of vitamin D

what are the other actions of parathyroid hormone in the bones

• there is an immediate release of calcium and later release of calcium by an increase in bone resorption relative to bone formation

  • i.e. increase in bone remodelling

what are the other actions of parathyroid hormone in the intestines

• no direct effect

• increased 1,25-(OH)₂ vitamin D (active form of vitamin D) » increased calcium absorption

calcium homeostasis is an example of… and returns serum ionised Ca back to the set point of about…

calcium homeostasis is an example of negative feedback and returns erum ionised Ca back to the set point of about 1.1mmol/L

graph showing relationship between serum calcium and PTH

small changes in serum Ca results in big changes in PTH

PTH abnormalities can be categorised as…

• APPROPRIATE

  • maintains calcium balance

• INAPPROPRIATE

  • causes a calcium imbalance

what is hypocalcaemia

• a medical condition where the concentration of calcium in the blood serum drops below the normal range

low serum albumin causes…

low total serum calcium

but

not a low ionised calcium

corrected calcium = ?

corrected calcium = total serum calcium + 0.02 (40 - serum albumin)

state causes of hypocalcaemia (7)

• vitamin D deficiency/ osteomalacia

• hypoparathyroidism

• chronic renal failure

• magnesium deficiency

• pseudohypoparathyroidism

• acute pancreatitis

• multiple citrated blood transfusions

what can cause hypoparathyroidism (which causes hypocalcaemia)

• post surgery, radiation, autoimmune disease

• hereditary (autosomal dominant hypocalcaemia)

• syndromes (Di George, HDR)

• infiltration (Wilson’s disease, haemochromatosis)

what are the consequences of hypocalcaemia (7)

• parasthesia

• muscle spasm (hands and feet, larynx, premature labour)

  • Trousseau’s sign

  • Chvostek’s sign

• seizures

• basal ganglia calcification

• cataracts

• ECG abnormalities

• dental hypoplasia

muscle spasms: outline Chvostek’s sign

muscle spasms: outline Trousseau’s sign

how would an ECG of a patient with hypocalcaemia look like

long QT interval

what are some signs/ clues that a patient may have hypocalcaemia (7)

1. history of neck surgery

2. presence of other autoimmune conditions

3. history of congenital defects and immunodeficiency

4. family history to suggest genetic cause

5. drug history e.g. anti-epileptics

6. neck scar, candidiasis, vitiligo, generalised bronzing

7. growth failure, hearing loss

what does decreased PTH cause (4)

what are the signs of pseudopseudohypoparathyroidism (PPHP) (7)

• short stature

• obesity

• round face

• mild learning difficulties

• subcutaneous ossification

• short fourth metacarpals

• other hormone resistance

PPHP vs PHP table

pseudopseudohypoparathyroidism = normal Ca metabolism

mild VS severe hypocalcaemia

• mild hypocalcaemia

  • asymptomatic

  • calcium concentration > 1.9mmol/L

• severe hypocalcaemia

  • symptomatic

  • calcium concentration <1.9mmol/L

outline the treatment for mild hypocalcaemia

• commence oral calcium supplements (AdCal 3 tablets BD)

• post-thyroidectomy » Ca supplements and consider adding 1-alphacalcidol (0.25mcg/ day)

• if vitamin D deficiency » load with cholecalciferol for 12wks

• if hypomagnesaemia » replace Mg

outline the treatment for severe hypocalcaemia

• 10-20mls of 10% Ca gluconate over 10mins (in 50-100mls of 5% dextrose)

• dilute 100mls of 10% Ca gluconate in 1L of normal saline (at 50-100mls/h)

• post-operative hypocalcaemia/ hypoparathyroidism » 1-alphacalcidol 0.25mcg/ day

what should always be done when managing abnormal calcium levels

monitor adjusted calcium levels closely

what are differential diagnoses for hypercalcaemia (3)

is it really hypercalcaemia?

• tourniquet on for too long

• old sample and haemolysed

• recheck

what are the main causes of hypercalcaemia (10)

• malignancy - bone metastases, myeloma, PTHrP, lymphoma

• primary hyperparathyroidism

• thiazides

• thyrotoxicosis

• sarcoidosis

• familial hypocalciuric/ benign hypercalcaemia

• immobilisation

• milk-alkali

• adrenal insufficiency

• phaeochromocytoma

which two causes of hypercalcaemia are responsible for 90% of hypercalcaemia diagnoses

1. malignancy: bone metastases, myeloma, PTHrP, lymphoma

2. primary hyperparathyroidism

what is primary hyperparathyroidism

what are the symptoms of hypercalcaemia

• thirst, polyuria

• nausea

• constipation

• confusion coma

what are the consequences of hypercalcaemia

• pancreatitis

• gastric ulcer

• renal stones

• ECG abnormalities (short QT interval)

what are the signs of hypercalcaemia (5)

• confusion, hypotonia, hyporeflexic (absent muscle reflexes)

• dehydration

• signs of malignancy

• faecal impaction

• irregular pulse (arrhythmia, thyrotoxicosis)

give examples of signs of malignancy (5)

• enlarged liver

• clubbing

• thyroid mass

• breast lump

• lymph nodes

how should you approach identifying/ diagnosing hypercalcaemia (3° hyperparathyroidism)

• identify any drugs that may cause hypercalcaemia (thiazides, lithium vitamin D)

• identify whether renal failure is present » tertiary hyperparathyroidism

how should hypercalcaemia be investigated

• check serum PTH and if normal/ high » perform fractional calcium excretion

if a fractional calcium excretion test is done and the result is over 0.01mmol/L what does this indicate

• if PTH normal/ high and fractional calcium excretion > 0.01mmol/L » primary hyperparathyroidism

if a fractional calcium excretion test is done and the result is under 0.01mmol/L what does this indicate

• PTH normal/ high and fractional calcium excretion < 0.01mmol/L » familial hypocalciuric hypercalcaemia (FHH)

if serum PTH is low or suppressed, how should this be approached

exclude:

• malignancy

• hyperthyroidism

• Addison’s

• sarcoidosis

• granulomatous disorders

how do the bones, intestines and kidneys respond to PTH in malignancy

‘hypercalcaemia of malignancy’ = patients with cancer develop high calcium levels in the blood

how common is hypercalcaemia of malignancy and outline it

‘hypercalcaemia of malignancy’ = patients with cancer develop high calcium levels in the blood

• ≈ 20-30% of patients with cancer develop hypercalcaemia of malignancy

  • 80% of those are due to bony metastases (from breast, thyroid, kidney, lung, prostate cancers)

  • 20% of those are due to PTHrP release (others secrete vitamin D, ectopic PTH)

what other type of hypercalcaemia can occur in malignancy

osteoclastic hypercalcaemia

what is the most common cause of primary hyperparathyroidism

• 80% are due to a single benign adenoma

• 15-20% are due to four gland hyperplasia (all 4 parathyroid glands in the neck become large and overactive » excess PTH)

  • may be part of MEN I or MEN II

• <0.5% are malignant

what are consequences of primary hyperparathyroidism

• bones

  • osteitis fibrosa cystica (bone cysts)

  • osteoporosis

• kidney stones

• psychic groans

  • confusion

• abdominal moans

  • constipation

  • acute pancreatitis

what are the effects of increased PTH in 1° hyperparathyroidism

how is primary hyperparathyroidism managed

surgery

what are indications for surgery to treat primary hyperparathyroidism (6)

• serum calcium > 0.25mmol/L from upper limit

• creatinine clearance < 60ml/min

• T-score < -2.5 at any site

  • and/ or previous fragility fracture at spine, hip, radius, femoral neck

• 24h urine calcium > 400mg/day (>10mmol/day)

• nephrocalcinosis or nephrolithiasis

• < 50yo

what is secondary hyperparathyroidism

a condition where the parathyroid glands produce too much PTH in response to low blood calcium i.e. hypocalcaemia

• not due to a tumour like 1° hyperparathyroidism

what is tertiary hyperparathyroidism

a condition where the parathyroid glands become overactive and produce excess PTH which increases blood calcium levels » hypercalcaemia

• typically persisting after the underlying cause of 2° hyperparathyroidism e.g. chronic kidney disease has been addressed

what does 3° hyperparathyroidism lead to

• nodular hyperplasia: benign overgrowth of normal thyroid cells

• nodular autonomy: thyroid lump that produces T3 and T4 independent of the pituitary gland’s secretion of TSH

how is hypercalcaemia managed (6)

summary