Calcium disorders

Question 1

Describe the normal physiology of calcium

Answer 1

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.

Question 2

Where is most of the calcium in the body found?

Answer 2

Bone

Question 3

Intracellular calcium is divided into 3 categories, what are they?

Answer 3

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.

Question 4

What is the meaning of the term corrected calcium?

Answer 4

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

Question 5

List the 6 main causes of hypercalcemia

Answer 5

• Malignant hypercalcaemia
• Primary hyperparathyroidism
• Secondary hyperparathyroidism
• Tertiary hyperparathyroidism
• Thyrotoxicosis
• Hypervitaminosis D
• Milk alkali syndrome

Question 6

What is Malignant hypercalcaemia?

Answer 6

• 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.

Question 7

What is Primary hyperparathyroidism?

Answer 7

• 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.

Question 8

What is secondary hyperparathyroidism? What would the blood tests show regarding calcium?

Answer 8

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

Question 9

What is tertiary hyperparathyroidism?

What would the blood tests show regarding calcium?

Answer 9

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

Question 10

How does Thyrotoxicosis cause hypercalcemia?

Answer 10

Elevated thyroid hormones can lead to thyroid hormone-mediated bone resorption. Causes mild hypercalcaemia

Question 11

How does Hypervitaminosis D cause hypercalcaemia?

Answer 11

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)

Question 12

What is Milk alkali syndrome and how does it cause hypercalcaemia?

Answer 12

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.

Question 13

Which drugs can cause hypercalcaemia?

Answer 13

Thiazide diuretics

Vitamin D analogues

Lithium administration (chronic)

Vitamin A

Question 14

Where endocrine conditions cause hypercalcemia?

Answer 14

Thyrotoxicosis
Addison’s disease

Mild only

Question 15

Name the genetic cause of hypercalcaemia. How is this condition inherited?

Answer 15

Familial hypocalciuric hypercalcaemia

autosomal dominant

Question 16

What is the pathophysiology of Familial hypocalciuric hypercalcaemia?

Answer 16

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.

Question 17

What are the clinical features of hypercalcaemia?

Answer 17

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)

Question 18

How is hypercalcaemia diagnosed?

Answer 18

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

Question 19

Which additional investigations are conducted for hypercalcaemia?

Answer 19

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.

Question 20

How is hypercalcaemia treated?

Answer 20

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.

Question 21

How do bisphosphonates help in treating hypercalcaemia?

Answer 21

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).

Question 22

Which bisphosphonates are typically used in hypercalcaemia? In which condition are bisphosphonates contraindicated?

Answer 22

Pamidronate or zoledronic acid are typically used. They are potentially nephrotoxic and contraindicated in severe renal impairment.

Question 23

Which drug can be used as an alternative to bisphosphonates in the treatment of hypercalcaemia?

Answer 23

denosumab, which is a monoclonal antibody that binds to RANK ligand and inhibits the action of osteoclasts.

Question 24

Describe 4 additional treatments for hypercalcaemia?

Answer 24

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.

Question 25

What is the serum calcium level concentration hypocalcaemia?

Answer 25

< 2.2 mmol/L.

Question 26

What is the normal serum calcium concentration?

Answer 26

2.2-2.6 mmol/L - then this should be corrected for albumin

Question 27

What is mild and what is saver hypocalcaemia?

Answer 27

Mild - corrected calcium ≥ 1.9 mmol/L | Severe - corrected calcium < 1.9 mmol/L

Question 28

What are the 4 categories/ groups which categories the causes of for hypocalcaemia?

Answer 28

Hypocalcaemia with raised PTH Hypocalcaemia with low PTH Hypocalcaemia related to magnesium metabolism Medication-induced hypocalcaemia

Question 29

Describe the pathophysiology behind Hypocalcaemia related to magnesium metabolism

Answer 29

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

Question 30

Which medications can cause hypocalcaemia?

Answer 30

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)

Question 31

Describe the causes of Hypocalcaemia & raised PTH

Answer 31

- 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.

Question 32

Describe the causes of Hypocalcaemia & low PTH

Answer 32

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.

Question 33

How does Chronic kidney disease cause hypocalcaemia?

Answer 33

Reduced activation of vitamin D Reduced renal absorption of calcium Reduced renal excretion of phosphate

Question 34

What are the signs and symptoms of hypocalcaemia?

Answer 34

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)

Question 35

What is a Carpopedal spasm?

Answer 35

flexion at the wrist and metacarpophalangeal joints, extension of the interphalangeal joints and adduction of the thumb

Question 36

How is hypocalcaemia diagnosed?

Answer 36

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 ```

Question 37

What is the difference between acute and chronic hypocalcaemia? What are the symptoms of acute and sever hypercalcemia.

Answer 37

Acute severe hypocalcaemia (< 1.9 mmol) is a medical emergency that requires urgent treatment and cardiac monitoring. Can cause life-threatening arrhythmias and seizures

Question 38

Which ECG changes are associated with hypocalcaemia?

Answer 38

prolonged QT interval and arrhythmias

Question 39

How is Acute/ mild hypocalcaemia managed?

Answer 39

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

Question 40

How is Acute/ sever hypocalcaemia managed?

Answer 40

<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

Question 41

How is chronic hypocalcaemia managed?

Answer 41

treatment of the underlying cause and management with vitamin D supplementation is usually sufficient.