Calcium Metabolism

Question 1

Calcium is a metal iron that is wide-spread in the body, what are the normal serum levels and where is the calcium?

Answer 1

Normal serum levels are 2.2-2.6M (biologically active, free ionised calcium is regulated at about 1-1.3M, with the rest bound to plasma proteins or complexed with citrate - most is stored in the skeleton.

Question 2

It is very important to regulate serum calcium as it has so many important functions, name a few.

Answer 2

Regulates heart rhythm, assists normal blood clotting (it is factor IV), intracellular signalling pathways etc.

Question 3

An adult human contains ~1000g of calcium, how much is in the bone, in what form and how does this change physiologically?

Answer 3

99% is sequestered in the form of hydroxyapatite crystals (Ca2+ + Pi) in bone. ~300-600mg of calcium are exchanged between the bone and extracellular fluid each day.

Question 4

The daily dietary requirement for calcium intake is 1000mg, how are regular levels maintained (briefly)?

Answer 4

Each day there is urinary loss of 175mg and a GI loss of 825mg. The skeleton helps to buffer the serum levels by releasing calcium phosphate into the interstitum / the uptake of these.

Question 5

Regulation of calcium levels is controlled by 3 hormones, what are they and how?

Answer 5

Parathyroid hormone stimulates bone reabsorption (release of Ca2+ into blood), reabsorption in kidney (and phosphate excretion) and hydroxylation of D3 to active vitamin D.
Active vitamin D increases interstitial absorption of dietary calcium, renal reabsorption and bone resorption.
Calcitonin (from C cells in thyroid), counteract effects of PTH.

Question 6

What is active vitamin D called?

Answer 6

Calcitriol.

Question 7

How are changes in the plasma concentration of calcium regulated?

Answer 7

Feedback - first with PTH.

Question 8

What are parathyroid glands made up of and where are they?

Answer 8

Parathyroid glands are usually found 2 per lobe on the back of the thyroid gland (functionally separate). It is made up of chief cells, which produce PTH, oxyphil cells (with more cytoplasm) and some adipose.

Question 9

PTH is a ___________ chained polypeptide hormone (prepro hormone cleaved twice, to form one that’s _____ amino acids long). There is no serum __________ protein and ___________ is regulated at a transcription and post-transcriptional level.

Answer 9

Straight
84
Binding
Synthesis

Question 10

PTH synthesis and secretion is regulated. What happens with low and high serum concentrations of calcium

Answer 10

Low serum calcium upregulates transcription and prolongs mRNA survival. The half life of PTH is only 4 minutes and it’s continually synthesised with little stored (chief cells degrade as well as synthesise. High serum levels of calcium down regulate transcription, and accelerates the cleavage of PTH. Ca2+ binds to a GPCR (q) to slow transcription and release.

Question 11

Parathyroid hormone may sometimes be cleaved in the chief cells, before release. Once it has been released, where is the PTH cleaved?

Answer 11

The liver.

Question 12

What are the target organs and physiological effects at them of parathyroid hormone?

Answer 12

Bone - increases resorption of calcium into the blood, Gut - activates vitamin D and hence increases trans cellular uptake of calcium, Kidney - decrease calcium loss in urine (and increase phosphate loss).

Question 13

What are the two primary functions of bone and which is more important?

Answer 13

Structural support and maintaining serum calcium concentrations, the latter of which is a priority. Disease of the bone affecting structural integrity can have consequences for serum calcium concentration and vice versa.

Question 14

Calcium phosphate crystals are found within collagen fibrils in the extracellular matrix of bone. Which cells are involved in the lay down/removal and how?

Answer 14

Osteoblasts are involved in deposition, making the collagen matrix which is mineralised by hydroxyapatite.
Osteoclasts are involved in resorption, producing an acid micro-environment, so the hydroxyapatite dissolves.

Question 15

Bone is dynamic. In 1-2 hours parathyroid can stimulate osteolysis, how specifically?

Answer 15

PTH induces osteoblastic cells to synthesise and secrete cytokines on their cell surface, which stimulates differentiation and activity in osteoclasts, protecting them from apoptosis and decreasing the osteoblasts activity (calcium and phosphate go into the extra cellular fluid).

Question 16

Where specifically does parathyroid hormone work in the kidney and how?

Answer 16

PTH increases calcium reabsorption in the thick ascending limb and distal convoluted tube, phosphate is removed from the circulation by inhibition of kidney reabsorption (preventative to calcium stone formation). There is also an impact on magnesium.

Question 17

The calcium receptor in chief cells of the parathyroid gland is also present and important elsewhere in the body, where?

Answer 17

In the TAL of the kidney, regulating calcium reabsorption.

Question 18

How and why does parathyroid hormone exert its effect on the gut?

Answer 18

Only 30% of the 1000mg/d is absorbed by paracellular uptake effective when the calcium concentration is not limited. This is significantly increased by vitamin D transcellular uptake - PTH stimulates the conversion to the active form, increasing calcium gut uptake.

Question 19

Calcitriol is the active form of vitamin D used by the body, where does the body get vitamin D from?

Answer 19

It can be made from cholesterol in the skin when exposed to sunlight (UV) or from dietary dairy (D2). Alternatively from foods that are fortified with D3 made by fungi and yeast. Both are equipotent in forming active vitamin D, calcitriol.

Question 20

How does the body go from vitamin D 2/3 to the active calcitriol?

Answer 20

2 step hydroxylation.
First at the liver into 25-hydroxyvitamin D (25 hydroxylase), which is a major circulating hormone. Then in the kidney, triggered by PTH, active 1,25-dihydroxyvitamin D / calcitriol is formed (1 alpha hydroxylase).

Question 21

Vitamin D3 is is lipid soluble so how must it travel in the blood and what are the consequences of its short half life?

Answer 21

It is bound to transcalciferin with only a small fraction free form. It doesn’t exist as it is for too long, but once converted into 25-hydroxyvitamin D, it can stay in the liver for around 2 weeks.

Question 22

The previtamin 25-hydroxyvitamin D is bound to a carrier small enough to be filtered by the glomerulus and enter the PCT, where it is converted by 1 alpha hydroxylase. After this, what is the half life of calcitriol?

Answer 22

A quarter of a day.

Question 23

Feedback is important in the production of calcitriol as it affects the very influential calcium concentration, how is it regulated?

Answer 23

Elevated serum calcium prevents C-1 hydroxylation and elevated PTH stimulates it.
Calcitriol works on the bone, gut and kidney - decreases urinary loss by stimulating kidney reabsorption.

Question 24

Where is calcitonin secreted?

Answer 24

From the thyroid, calcitonin is secreted by parafollicular cells / C cells.

Question 25

Calcitonin is rapid acting, so can have use clinically, treating hypercalcaemia. Does this mean it plays a large role in calcium regulation in the body?

Answer 25

No, a thyroidectomy doesn’t demonstrate a marked effect on serum calcium levels (unless parathyroid complications).

Question 26

Give a summary of the effects on the body of too much or little serum calcium.

Answer 26

Hypocalcaemia - hyperexcitability of neuromuscular junctions. Chronic hypercalcaemia - kidney stones, psychic groans, GI moans and aching bones.

Question 27

How is calcium involved in clotting and what stops blood clotting when it’s outside the body?

Answer 27

Calcium is factor IV in the clotting cascade. EDTA is in bottles when blood is taken and acts as a calcium chelator.
Citrate chelates calcium in blood bags, so anyone receiving massive blood transfusions will also require intravenous calcium.

Question 28

Hypercalcaemia repercussions are seen at levels >3mmol/L. Give 2 ways it is caused in a hospital setting.

Answer 28

Malignant osteolytic bone metastases (breast, thyroid, kidney, lung -prostate often causes osteoblastic metastases so no hypercalcaemia). Osteolytic metastases are painful.
Multiple myeloma with >90% of metastases found in vertebrae, ribs, proximal femur, proximal humerus and skull.
Hyperparathyroidism.

Question 29

Hyperparathyroidism may be primary, secondary or tertiary, explain.

Answer 29

Primary is when an adenoma develops in 1 out of 4 glands - secretes excessive hormone, causing serum calcium to rise and Pi to fall. Secondary has all 4 glands hyperplastic e.g. From vitamin D deficiency-dietary or chronic renal failure (failure of 25 hydroxylation)-calcium absorption low, so serum levels, so PTH rises.
Tertiary - long term secondary hyperparathyroidism, even if cause corrected, can’t reverse, so all levels are high.

Question 30

What happens in secondary hyperparathyroidism, once lots of parathyroid hormone is circulating?

Answer 30

Osteoclasts are activated, mobilising calcium from bone, leading to pain from osteomalacia or condition called renal dystrophy (give 1 alpha hydroxylase). Phosphate may be high, in the latter instance, if it can’t be excreted.

Question 31

What is the significance of alkaline phosphatase in cases of hyperparathyroidism?

Answer 31

It is released from bone with increased turnover.

Question 32

Malignant hypercalcaemia may produce PTHrp, what is this, give an example of what could release it and what would be the result?

Answer 32

Parathyroid hormone related peptide, which acts similarly but doesn’t affect 1 alpha hydroxylase or phosphate reabsorption. E.g. Squamous cell lung carcinoma.

Question 33

What are the symptoms of primary hyperparathyroidism?

Answer 33

As a result of hypercalcaemia: psychic moans, abdominal groans, kidney stones and aching bones, so tired/depressed, constipation/peptic ulcers/pancreatitis, polyuria, muscle/bone aches. Many are asymptomatic and their condition only comes to light with coincidental serum biochemistry tests.

Question 34

What are the symptoms of hypo and hypercalcaemia and the mechanisms by which they are caused?

Answer 34

Calcium raises the threshold for nerve membrane depolarisation and so action potential, meaning that hypercalcaemia results in suppression of neuronal activity, so lethargy, confusion and coma. Hypocalcaemia means excitable nerves, so tingling, muscle tetany and epilepsy.

Question 35

Symptoms of severe hypercalcaemia happen with serum calcium>3mmol/L, what are they?

Answer 35

Polyuria leading to dehydration, exacerbating other symptoms. Lethargy, weakness, confusion, coma and renal failure.

Question 36

What is the significance of dehydration from polyuria being a result of severe hypercalcaemia?

Answer 36

Rehydration is a mainstay of treatment. A coma of malignant hypercalcaemia is not necessarily a terminal event, because it can be treated by this.

Question 37

When does symptomatic hypocalcaemia most often occur and why?

Answer 37

Post-thyroidectomy, due to inadvertent removal or ischaemia. It may start within 6 hours.

Question 38

Symptoms of hypocalcaemia may present when the serum concentration of calcium gets below 2.1mmol/L. What are they (motor and sensory)? How can this quickly escalate?

Answer 38

Tingling around the mouth and fingers.
Tetany of muscles in the same areas, carpo-pedal spasm (flexors stronger at elbow and wrist). Chvostek’s sign is a mouth twitch following tapping a facial nerve.
Hypocalcaemia can be fatal, with laryngeal muscle tetany and so need quick treatment (IV Ca2+).

Question 39

What is the difference between osteoporosis and osteomalacia?

Answer 39

Osteoporosis is decreased bone density with a normal mineral : matrix ratio - degeneration of already constructed bone, resulting in brittle bones, prone to fracture.
Osteomalacia has a decreased mineral : matrix ratio, affecting bone building in children (Rickets) or mineralisation in adults, leading to soft bones, prone to bending.

Question 40

What are the conditions called when osteomalacia is due to dietary/environmental vitamin D deficiency in children and what about from chronic renal disease?

Answer 40

Rickets and renal osteodystrophy.

Question 41

What are the risk factors for osteoporosis?

Answer 41

Age, post-menopausal, low BMI, smoking, long term oral steroid use, heavy drinking and prolonged inactivity.

Question 42

What are the possible consequences of osteoporosis?

Answer 42

Hip or wrist fracture, as well as a vertebral crush fracture.