Calcium disorders Flashcards
Describe the normal physiology of calcium
Calcium - distributed between bone and the intra- and extra-cellular compartments
Decreased extracellular calcium is detected by the calcium-sensing receptor (CaSR) on the parathyroid gland. The receptors is turned off causing PTH released
The parathyroid glands respond to the fall in serum calcium by releasing PTH from the chief cells
- PTH stimulates the resorption of calcium from bone,
- Causes activation of vitamin D (leads to calcium absorption from enterocytes)
- increased renal tubular reabsorption of calcium
- increases phosphate excretion
A rise in extracellular calcium detected by the CaSR has the opposite effect. Th receptor is turned on which inhibits the release of PTH
It leads to a reduction in the release of PTH and stimulates the release of calcitonin.
This combined effect helps decrease bone resorption and promotes calcium excretion in the kidneys.
Where is most of the calcium in the body found?
Bone
Intracellular calcium is divided into 3 categories, what are they?
Ionised (~ 50%) - metabolically active, or ‘ionised’, free pool of calcium.
Bound (~ 41%) - bound to albumin (90%) and globulin (10%).
Complexed (~ 9%) - forms complexes with phosphate and citrate.
What is the meaning of the term corrected calcium?
When serum calcium is adjusting for the albumin level.
Because a lot of calcium is bound to albumin so the albumin level is taken into account
List the 6 main causes of hypercalcemia
- Malignant hypercalcaemia
- Primary hyperparathyroidism
- Secondary hyperparathyroidism
- Tertiary hyperparathyroidism
- Thyrotoxicosis
- Hypervitaminosis D
- Milk alkali syndrome
What is Malignant hypercalcaemia?
- most common cause of hypercalcaemia in hospital
- Hypercalcaemia commonly occurs due to release of parathyroid related peptide (PTHrP), which mimics the action of PTH.
- Other mechanisms include osteolytic damage to bone or activation of vitamin D.
What is Primary hyperparathyroidism?
- most common cause of hypercalcaemia in the general population
- occurs due to excess release of PTH, which leads to bone resorption and excess calcium release
- commonly occurs secondary to a parathyroid adenoma or or by diffuse hyperplasia of the glands
- Other mechanisms include parathyroid hyperplasia and rarely parathyroid cancer. Primary hyperparathyroidism may be part of aMultiple endocrine neoplasia.
What is secondary hyperparathyroidism? What would the blood tests show regarding calcium?
When hypocalcaemia causes the hypertrophy of all parathyroids. This is to compensate and produce more calcium.
Occurs in chronic kidney disease or vitamin D deficiency
PTH levels are raised but calcium levels are low or normal, and PTH falls to normal after correction of the cause of hypocalcaemia where this is
What is tertiary hyperparathyroidism?
What would the blood tests show regarding calcium?
Autonomous PTH excess due to parathyroid hyperplasia in response to longstanding secondary hyperparathyroidism - seen in patients with chronic kidney disease.
Plasma calcium and phosphate are both raised, the latter often grossly so
How does Thyrotoxicosis cause hypercalcemia?
Elevated thyroid hormones can lead to thyroid hormone-mediated bone resorption. Causes mild hypercalcaemia
How does Hypervitaminosis D cause hypercalcaemia?
High concentrations of vitamin D lead to hypercalcaemia by increasing calcium absorption and bone resorption. This usually occurs due to inadvertent ingestion of excess amounts of vitamin D or continuing a high loading dose for too long.
Some conditions lead to excess endogenous production of activated vitamin D, which include:
Granulomatous disorders (e.g. sarcoidosis, tuberculosis) Cancers (e.g. lymphoma)
What is Milk alkali syndrome and how does it cause hypercalcaemia?
Milk alkali syndrome is due to the excess ingestion of milk or calcium containing compounds (e.g. calcium carbonate).
The full syndrome is characterised by:
Hypercalcaemia
Metabolic alkalosis
Acute kidney injury
Hypercalcaemia is compounded by metabolic alkalosis, which affects calcium excretion in the distal convoluted tubule of the nephron. In addition, the high calcium levels cause renal vessel vasoconstriction that causes renal impairment and further compounds calcium excretion.
Which drugs can cause hypercalcaemia?
Thiazide diuretics
Vitamin D analogues
Lithium administration (chronic)
Vitamin A
Where endocrine conditions cause hypercalcemia?
Thyrotoxicosis
Addison’s disease
Mild only
Name the genetic cause of hypercalcaemia. How is this condition inherited?
Familial hypocalciuric hypercalcaemia
autosomal dominant
What is the pathophysiology of Familial hypocalciuric hypercalcaemia?
mutation to calcium-sensing receptors (CaSR)
Parathyroid gland: CaSRs enable the parathyroid gland to sense changes to calcium levels and respond appropriately.
Kidneys: CaSRs have a number of complex functions that appear to increase calcium excretion in the urine when serum levels are raised.
causes a mildly elevated calcium with a PTH that is either mildly elevated or at the upper limit of normal.
What are the clinical features of hypercalcaemia?
Bones - fragility fractures, bone pain
Stones - renal calculi
Thrones - polyuria, constipation
Abdominal groans - abdominal pain, N&V, pancreatitis
Psychic moans - mood disturbance, depression, fatigue, psychosis
Fatigue Myalgia Mood changes Depression Fragility fracture Insomnia Polydipsia
Signs Dehydration (skin turgor, dry mucous membranes) Hypertension Cardiac arrhythmia (severe disease) Confusion (severe disease)
How is hypercalcaemia diagnosed?
diagnosis of hypercalcaemia is based on a serum corrected calcium > 2.6 mmol/L.
Parathyroid hormone - useful at differentiating between primary hyperparathyroidism and hypercalcaemia of malignancy
Elevated PTH (i.e. PTH-mediated): suggestive of primary hyperparathyroidism or tertiary hyperparathyroidism
Mid-to-upper normal PTH (suspected PTH-mediated): in the context of hypercalcaemia this is considered ‘inappropriately high’ and suggestive of hyperparathyroidism
Low or low-normal PTH (i.e. non-PTH mediated): suggestive of malignancy, which needs to be excluded. Hypervitaminosis D also poss
Which additional investigations are conducted for hypercalcaemia?
Routine bloods: FBC, U&E, LFT, CRP/ESR
Thyroid function test
Vitamin D levels
ACE (if sarcoid suspected)
Malignancy screen: protein electrophoresis, serum free light chains, tumour markers
Urine calcium levels (if FHH suspected)
General imaging: routine chest x-ray, consider CT chest abdomen pelvis if malignancy suspected
Parathyroid imaging: used if
primary hyperparathyroidism suspected. Neck ultrasound, parathyroid uptake scans (e.g. 99mTc MIBI) and MRI can all be used.
How is hypercalcaemia treated?
Mild (< 3 mmol/L) and asymptomatic/mild symptoms: increase oral fluids and avoid precipitants (e.g. thiazide diuretics, lithium, dehydration).
Moderate (3-3.5 mmol/L): acute rise requires inpatient admission for intravenous fluids. Chronically raised elevations may not require acute management depending on the aetiology and symptomatology.
Severe (>3.5 mmol/L): all patients require urgent admission to hospital and treatment. Treatment involves aggressive intravenous fluids and consideration of bisphosphonates and calcitonin, particularly if malignancy is suspected.
addition of a loop diuretic (e.g. furosemide) to fluids can be used to enhance urinary calcium excretion.
How do bisphosphonates help in treating hypercalcaemia?
inhibiting the action of osteoclasts - decreases break down of bone
they can take several days (2-4) before their action is noticed but they provide calcium-lowering effects over a prolonged period (2-4 weeks).
Which bisphosphonates are typically used in hypercalcaemia? In which condition are bisphosphonates contraindicated?
Pamidronate or zoledronic acid are typically used. They are potentially nephrotoxic and contraindicated in severe renal impairment.
Which drug can be used as an alternative to bisphosphonates in the treatment of hypercalcaemia?
denosumab, which is a monoclonal antibody that binds to RANK ligand and inhibits the action of osteoclasts.
Describe 4 additional treatments for hypercalcaemia?
Corticosteroids: may be used in hypervitaminosis D.
Surgery: able to provide a cure in primary hyperparathyroidism. Potential option in tertiary hyperparathyroidism
Cinacalcet: calcimimetic that mimics the action of calcium on calcium-sensing receptors. May be utilised in primary hyperparathyroidism if surgery has failed or not an option. Also used in secondary/tertiary hyperparathyroidism.
Dialysis: may be reserved for severe, refractory hypercalcaemia.
What is the serum calcium level concentration hypocalcaemia?
< 2.2 mmol/L.
What is the normal serum calcium concentration?
2.2-2.6 mmol/L - then this should be corrected for albumin
What is mild and what is saver hypocalcaemia?
Mild - corrected calcium ≥ 1.9 mmol/L
Severe - corrected calcium < 1.9 mmol/L
What are the 4 categories/ groups which categories the causes of for hypocalcaemia?
Hypocalcaemia with raised PTH
Hypocalcaemia with low PTH
Hypocalcaemia related to magnesium metabolism
Medication-induced hypocalcaemia
Describe the pathophysiology behind Hypocalcaemia related to magnesium metabolism
Hypomagnesaemia impairs the action of PTH leading to resistance.
This happen at quite low levels (< 0.4 mmol/L).
In more severe hypomagnesaemia it can cause a reduction in PTH secretion.
when assessing a patient with hypocalcaemia it is important to check and replace magnesium.
If severe hypomagnesaemia is present, calcium will not improve without normalisation of magnesium
Rarely, hypermagnesaemia (markedly raised levels e.g. > 2.5 mmol/L) can cause hypocalcaemia through suppression of PTH secretion
PPI induced can also cause Magnesium deficiency
Which medications can cause hypocalcaemia?
Bisphosphonates (bind calcium in bone and inhibit osteoclasts)
Calcium chelators (e.g. citrate used to inhibit coagulation in banked blood)
Denosumab (monoclonal antibody to RANK ligand)
Cinacalcet (calcimimetic that mimics the action of calcium on calcium-sensing receptors)
Describe the causes of Hypocalcaemia & raised PTH
- PTH is secreted in response to low calcium in an attempt to restore normal calcium levels
- Vitamin D deficiency
- Chronic kidney disease
(secondary
hyperparathyroidism)
Pseudohypoparathyroidism- When peripheral tissue is unresponsive to the effects of PTH due to an alteration in the PTH receptor. he condition presents in childhood
Extravascular deposition - sequestration of calciummcauses hypocalcaemia and a rise in PTH to normalise calcium
Causes:
Tumour lysis syndrome: release of intracellular phosphate which binds to plasma calcium
Rhabdomyolysis: similar mechanism to tumour lysis syndrome
Acute pancreatitis: free fatty acids released in the inflammation are thought to bind and cause precipitation of calcium
Osteoblastic metastases: deposition of calcium around metastatic sites. Usually seen in breast and prostate cancer.
Other causes -
Severe illness: hypocalcaemia thought to be due to low magnesium levels and PTH resistance
Blood transfusions: citrate in banked blood to prevent coagulation can bind to calcium and cause hypocalcaemia.
Describe the causes of Hypocalcaemia & low PTH
classically seen following thyroid surgery
Post-surgical hypocalcaemia can be divided into three types:
Transient: usually from disruption of blood supply or removal of 1-2 glands. May last days, weeks or months. Seen in 20% after surgery for thyroid cancer
Intermittent: recurrent episode of hypoparathyroidism and subsequent hypocalcaemia due to poor PTH reserve
Permanent: requires life-long treatment.
Hypoparathyroidism
commonly an autoimmune disorder resulting in immune-mediated destruction of the parathyroid glands. Also occurs due to autoantibodies that bind to the calcium-sensing receptors (CaSR), which decreases PTH secretion.
abnormal parathyroid gland development, as seen in DiGeorge syndrome, can result in hypocalcaemia.
How does Chronic kidney disease cause hypocalcaemia?
Reduced activation of vitamin D
Reduced renal absorption of calcium
Reduced renal excretion of phosphate
What are the signs and symptoms of hypocalcaemia?
Symptoms - (present at calcium concentrations < 1.9 mmol/L)
- Paraesthesia (numbness and tingling sensation, usually located peri-orally and in the fingers/toes)
Muscle cramps Wheezing Voice changes (laryngospasm) CNS disturbance (seizures, irritability, confusion) Chest pain (angina) Palpitations (arrhythmias)
Signs
- Trousseau’s sign: development of carpopedal spasm* following inflation of a blood pressure (BP) cuff above systolic BP
- Chvostek’s sign: tapping over the course of the facial nerve in the pre-auricular area causes muscle spasms (seen as twitching of the face, mouth or nose)
What is a Carpopedal spasm?
flexion at the wrist and metacarpophalangeal joints, extension of the interphalangeal joints and adduction of the thumb
How is hypocalcaemia diagnosed?
serum corrected calcium < 2.2 mmol/L.
Investigations for cause?
Bone profile Urea & electrolytes Vitamin D Parathyroid hormone Magnesium ECG a lipase or amylase in suspected acute pancreatitis or a uric acid level if tumour lysis syndrome is suspected
What is the difference between acute and chronic hypocalcaemia? What are the symptoms of acute and sever hypercalcemia.
Acute severe hypocalcaemia (< 1.9 mmol) is a medical emergency that requires urgent treatment and cardiac monitoring.
Can cause life-threatening arrhythmias and seizures
Which ECG changes are associated with hypocalcaemia?
prolonged QT interval and arrhythmias
How is Acute/ mild hypocalcaemia managed?
Mild hypocalcaemia (≥ 1.9 mmol/L)
- Oral calcium supplements
- Vitamin D replacement
If hypo Magnesium the cause then replacement -
- Intravenous: magnesium sulphate
- Oral: Magnesium glycerophosphate
OR Magnesium aspartate
How is Acute/ sever hypocalcaemia managed?
<1.9 with no symptoms
- Oral calcium supplements
- If due to severe vitamin D def, treat with high dose vit D
<1.9 with symptoms
- IV calcium gluconate
- High dose 1-alfacalcidol
How is chronic hypocalcaemia managed?
treatment of the underlying cause and management with vitamin D supplementation is usually sufficient.
