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Semester 2 - MEH > 17. PARATHYROID GLAND CALCIUM AND PHOSPHATE REGULATION > Flashcards

17. PARATHYROID GLAND CALCIUM AND PHOSPHATE REGULATION Flashcards

1
Q

What is the average mass of calcium in an adult and where is most of it stored?

A

1000g

- most stored as hydroxyapatite crystals in bone

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2
Q

How much calcium is exchanged between bone and the ECF each day?

A

~300-600 mg

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3
Q

What is the normal serum calcium levels?

A

2.2-2.6mM

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4
Q

What is the role of the skeleton?

A
  • structural support
  • major reserve of calcium
  • Helps to buffer serum levels
  • Releasing calcium phosphate into interstitium
  • Up taking calcium phosphate
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5
Q

Give the 3 states in which calcium can be found in the ECF and what are their percentages?

A
  • ionised Ca++ (47%)
  • Protein Bound Ca++ (47%)
  • Complexed Ca ( Pi, citrate etc) (6%)
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6
Q

Which form of Ca++ is biologically active and what is its serum concentration?

A

Ionised Ca++

- closely regulated to 1.0-1.3 mM

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7
Q

What are some of the functions of Ca++?

A
  • Appropriate levels of calcium required for nerve transmission at NMJ
  • Builds and maintains bones and teeth
  • Regulates heart rhythm
  • Helps regulate the passage of nutrients in & out of the cell walls
  • eases insomnia
  • Assists in normal blood clotting (factor IV)
  • Helps maintain proper nerve and muscle function
  • Lowers blood pressure
  • Reduces blood cholesterol levels
  • Important to normal kidney function
  • Needed for activity of some enzymes and some hormone receptor binding
  • Reduces the incidence of colon cancer
  • Important in intracellular signalling pathways

Calcium plays a critical role in many cellular processes, including hormone secretion, muscle contraction, nerve conduction, exocytosis, and the activation and inactivation of many enzymes. Ca2+ also serves as an intracellular second messenger by carrying information from the cell membrane into the interior of the cell

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8
Q

What is present in packets of blood used for transfusion? relevant to calcium

A

Citrate: chelates Ca++ to prevent coagulation

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9
Q

What should be given to a patient who has had massive blood transfusion?

A

Calcium - transfused blood contains citrate which chelates Ca++

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10
Q

What 3 hormones are involved in regulation of calcium?

A

Increase serum Ca++:

  • PTH
  • calcitriol (active form of Vitamin D)

Decreases serum Ca++:
- calcitonin

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11
Q

What are the 2 cell types in parathyroid gland and which produces PTH?

A
  • Chief cells which produce PTH (also degrade it)

- Oxyphil cells (unknown function) (old chief cell)

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12
Q

Describe the position of the thyroid and the parathyroid glands in the body

A

The thyroid gland is an organ made up of 2 loves found on either side of the trachea just below the larynx.
The loves are connected by a band of tissue called the isthmus.

On the dorsal surface of the thyroid gland you can find 4 circular masses of epithelial tissue which are the parathyroid glands.

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13
Q

Describe the histological appearance of different cells in parathyroid gland.

A

Chief cells: more abundant in younger age, prominent nucleus, little cytoplasm (which is usually paler staining)

Oxyphil cells: larger, less numerous in younger age, occur in clumps, smaller densely stained nuclei, strongly eosinophilic staining cytoplasm containing fine granules.

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14
Q

How is PTH transported in the blood?

A 
Travels free (soluble)
- no serum binding protein
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15
Q

Describe the features of the parathyroid hormone (PTH)

e.g storage, synthesis, degradation, transport

A
  • PTH is a straight chain polypeptide hormone.
  • It’s formed in chief cells of the parathyroid gland.
  • Straight chain polypeptide hormone- Pro-pre-hormone (115AA long), cleaved to 84AA
  • After processing, the mature hormone is packaged in the Golgi into secretory vesicles and secreted into blood by exocytosis.
  • The half life of PTH is short and is only 4 minutes which means that it’s been continuously synthesised but there’s little storage possible.
  • Chief cells will degrade the hormone and this degradation can be accelerated by by high serum calcium levels.
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16
Q

At what levels is synthesis of PTH regulated and what regulates it?

A

Both at transcriptional and post transcriptional levels

- controlled by serum calcium levels

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17
Q

How does low/high serum calcium levels affect PTH synthesis?

A

Low serum calcium:
• Low serum calcium up-regulates gene transcription
• low serum calcium prolongs survival of mRNA

High serum calcium
• High serum calcium down-regulates transcription

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18
Q

What is the half life of PTH and where is released PTH cleaved?

A

T ½ is 4 min and released PTH cleaved in liver

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19
Q

What type of receptor is the calcium receptor on chief cells?

A

Gαq GPCR.

  • phospholipase c (secondary messenger)
  • IP3 and DAG
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20
Q

How does high Ca++ reduce PTH synthesis/secretion?

A

Binds to Gαq GPCR

IP3 leads to release of Ca++ from intracellular store and leads to down regulation of PTH transcription (and secretion)

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21
Q

Explain the function and physiological effects of PTH

A

PTH is used to regulate serum calcium through its effects on the kidney, bone and intestines.

In bone PTH enhances the release of calcium, this is done by increasing the activity of osteoclasts but reducing the activity of osteoblasts. This causes an increase in the release of calcium and phosphate.

In the kidney PTH works by stimulating resorption of calcium from the kidney tubules to increase calcium levels whilst simultaneously inhibiting the resorption of phosphate back into the plasma so Increases the loss of phosphate from blood in urin.

In the intestines PTH inadvertently enhances the absorption of calcium by stimulating the conversion of vitamin D to calcitrol. . Calcitriol increases the rate of Ca2+ and phosphate absorption from food in the gastrointestinal
tract into the blood

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22
Q

How can PTH be regulated?

A

The secretion of PTH is based on a negative feedback mechanism. There are calcium receptors on the surface of parathyroid cells.

When there are high levels of calcium present these cause a reduction in the secretion of PTH but when there are low levels of calcium present it causes an increase in the secretion of PTH.

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23
Q

What is the effect on serum phosphate by PTH?

A

Bone resorption increases serum phosphate, but phosphate excretion in urine is increased
- so overall decrease

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24
Q

How does vitamin D affect absorption of calcium in the intestines?

A

Absorption is significantly increase by Vitamin D via a transcellular uptake

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25
Q

What are the two primary functions of the skeleton?

A

structural support and maintaining serum Ca2+ conc

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26
Q

How does bone alter the calcium concentrations and What effect do bone pathologies have on calcium?

A

• Calcium phosphate crystals found within collagen fibrils - Ca2+ + Pi = hydroxyapatite crystals
Bone deposition:-
• osteoblasts produce collagen matrix which is mineralized by hydroxyapatite
Bone reabsorption
• osteoclasts produce acid micro-environment hydroxyapatite dissolves

However pathologies in bone can affect the structural integrity of the skeleton which can affect the bones ability to store calcium. dissolves

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27
Q

What is typical intake of Ca++/day and what percentage of this is absorbed and by what process is it absorbed?

A

1000mg/day

- 30% absorbed by paracellular transport

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28
Q

Describe how PTH affects the bone

A
  • 1-2 hrs PTH stimulates osteolysis
  • PTH induces osteoblastic cells to synthesis and secrete cytokines on cell surface
  • Cytokines stimulate differentiation and activity in Osteoclasts and protect them from apoptosis
  • PTH decreases Osteoblasts activity exposing bony surface to Osteoclasts
  • Reabsorption of mineralized bone and release of Pi (inorganic phosphate) and Ca2+ into extracellular fluid
29
Q

Why is there a link between calcium and phosphate

A
  1. calcium and phosphate are the principal components of hydroxyapatite crystals [Ca10(PO4)6(OH)2)].
  2. they are regulated by the same hormones, primarily
    parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (calcitriol)and, to a lesser extent, the hormone calcitonin. These hormones act on three organ systems-the bone, the kidneys, and the gastrointestinal (GI) tract-to control the levels of these two ions in plasma. However, the actions of these hormones on calcium and phosphate are typically opposed in that a particular hormone may elevate the level of one ion while lowering that of the other.
30
Q

What is Vitamin D?

A

Vitamin D is a collective name for a group of hormones.
It’s in D can be obtained from food, sun exposure and supplements and is biologically inert. This means it has to undergo activation before it can be used.

31
Q

Describe calcitriol formation.

A
  • 7-dehydrocholesterol in the skin converted into cholecalciferol (VitD3) by sunlight
  • Cholecalciferol hydroxylated in the liver to form 25(OH)D
  • this is hydroxylated further in the kidney to form 1,25(OH)2D (calcitriol)
32
Q

What renal enzyme is responsible for production of calcitriol?

A

C-1 hydroxylase

33
Q

How is PTH involved in calcitriol production?

A

Promotes calcitriol production in the kidney

34
Q

What are the effects of calcitriol on Ca and PO4?

A

GI: increases absorption of both
Kidney: increases reabsorption of both
Bone: promotes action of PTH

35
Q

What type of transport of Ca++ does calcitriol promote in the gut?

A

Paracellular, transcellular and endo/exocytosis

36
Q

Which cells produce calcitonin?

A

Parafollicular cells, C cells or clear cells (same thing) in the thyroid

37
Q

What is calcitonin?

A

Calcitonin is a 32AA peptide hormone that’s secreted by the parafollicular cells in the thyroid gland.
It works to reduce blood calcium levels and aims to oppose the action of PTH.

38
Q

Explain the function of calcitonin in serum calcium maintenance

A

It has 2 mechanisms by which it works by:

  1. The inhibition of osteoclasts activity in bones, this reduces the breakdown of bone and the release of calcium and phosphate.
  2. Inhibition of renal tubular cell resorption of Ca2+ and phosphate, this allows them to be excreted in urine.

(DECREASES plasma calcium levels
DECREASES plasma phosphate levels)
MINOR ROLE IN HUMANS
If the thyroid gland is removed or destroyed the lack of
secretion of calcitonin has no apparent effect on calcium homeostasis. However, there is some suggestion that during pregnancy this hormone may serve to preserve the maternal skeleton.

39
Q

Compare feedback regulation of serum calcium when there’s an increase in plasma calcium and vice versa

A

An increase in plasma calcium will cause a decrease in PTH secretion.
This’ll affect the bone meaning that there’s a less calcium released from these structures, this is due to to a reduction in the activity of osteoclasts and an increase in the activity of osteoblasts.

In the kidney you get a reduction in the production of the active calcitriol and a reduction in calcium reabsorption from the urine.

This’ll result in less calcium being taken from the gut and over a fall in the plasma calcium concentration back to normal.

A decrease in plasma concentration causes an increase in the secretion of PTH.
This will act on the kidneys to cause an increase in the formation of the active calcitriol hormone, this’ll mean that more calcium is taken the gut. As well as this you’ll also get an increase in the calcium reabsorption in the kidneys.
PTH also acts on bone causing an increase in osteoclast activity and a decrease in osteoblasts activity.
Overall this’ll cause an increase in the plasma calcium level back to the norm.

40
Q

What is chronic hypercalcaemia?

A

Chronic hypercalcaemia refers to a high calcium level in the blood serum. It’s said to occur when the calcium levels are greater than 2.6mmol. It causes a suppression of neuronal activity.
Most cases are due to primary hyperparathyroidism or cancer.

41
Q

Give the symptoms associated with hypercalcaemia

A 
Symptoms associated include:
1. Renal calculi (kidney stones)
2. Kidney damage
3. Constipation
4. Dehydration
5. Tiredness
6. Depression
(Stones, moans, groans and bones)
42
Q

What are the effects of severe hypercalcaemia? How can it be treated?

A

Severe hypercalcaemia is when the concentration of calcium in the plasma is greater than 3.0mmol/L.

At high calcium levels the polyuria can lead to dehydration which then exacerbates the hypercalcemis.
This can lead to
• Lethargy
• Weakness
• Confusion
• Coma
• Renal failure

The main treatment encouraged is rehydration.

43
Q

What is hypocalcaemia? What are its causes?

A

Hypocalcaemia is low blood serum levels of calcium. It’s said to occur when the level is below 2.1mmol/L.
It causes excitable nerves.
Example causes for this condition include hypoparathyroidism and vitamin D deficiency.

44
Q

What are the symptoms of hypocalcaemia?

A 
Hypocalcaemia can result in hyper-excitability at the neuromuscular junction resulting in symptoms such as:
• Lower serum calcium, causes increase in Na+ entry into neurones, leading to depolarisation and increased likelihood of AP.
• pins and needles
• tetany (muscle spasms)
• paralysis
• convulsions
• death
• carpopedal spasm
45
Q

What medical procedure is hypocalcaemia most likely to develop from? When do symptoms of this condition usually develop?

A

Hypocalcaemia is most likely to be seen in post total-thyroidectomy patients (because of inadvertent
removal/ischaemia of parathyroid glands)

Symptoms can develop when serum calcium falls below 2.10 mmol/L and can start within 6 hrs of thyroidectomy

46
Q

Describe the role malignant bone metastasis can have on calcium levels

A

Malignant osteolytic bone metastasis can result in the wearing and breakdown of bone. It’s a major cause of hypercalcaemia.

There are certain common cancers that metastasise to the bone causing lytic lesions and hypercalcaemia:
Breast, lung, renal and thyroid

47
Q

Why does prostate cancer not lead to hypercalcaemia?

A
  • Prostate cancer is a common cause of bone metastasis.

* However, it causes osteoblastic metastasis that do not cause hypercalcemia

48
Q

Give the common sites for bone metastasis

A
  • Vertebrae,
  • Pelvis,
  • Proximal parts of the femur,
  • Ribs,
  • Proximal part of the humerus
  • Skull.
49
Q

What are the 2 main ways by which malignancy can

cause hypercalcaemia?

A
  1. Haematological malignancies (e.g. myeloma) and those that metastasize to bone produce local factors that act in a paracrine manner to activate osteoclasts
  2. Squamous tumours of the lung, head and neck produce a hormone, parathyroid hormone-related peptide (PTHrp) that acts at parathyroid hormone receptors.
50
Q

What are the pathological features seen in a patient with osteoclasts metastasis

A

You’ll see holes in the bone where there’s a been a destruction and wearing of the bone.

51
Q

When is parathyroid hormone related peptide (PTHrp) secreted pathologically?

A

Secreted by some tumour cells e.g. squamous tumours of the lung or head and neck

52
Q

How does PTHrp lead to hypercalcaemia?

A

it binds to parathyroid hormone receptors and mimics some effects of PTH leading to increased calcium release from bone, reduced renal calcium excretion and reduced renal phosphate reabsorption.

53
Q

Why is there no increase in calcitriol due to PTHrp?

A

PTHrp does not increase renal C-1 hydroxylase enzyme, which normally increases concentrations of 1, 25-dihydroxyvitamin D

54
Q

What are the normal physiological roles of PTHrp?

A
  • Tooth eruption (secreted by enamel epithelium to stimulates local bone resorption.
  • Mammary gland development
  • Lactation
  • Placental transfer of calcium
55
Q

What is hyperparathyroidism?

A

This is a condition that causes an increase in the levels of PTH in the blood serum.

56
Q

What is primary hyperparathyroidism?

A
  • One of the 4 parathyroid glands develops an adenoma and secretes excessive parathyroid hormone.
  • This causes serum calcium to rise and serum phosphate to fall
57
Q

What is secondary hyperparathyroidism?

A

All 4 parathyroid glands become hyperplastic
- commonly seen in vitamin D deficiency
• Vitamin D Deficiency means that their calcium absorption is low resulting in low serum calcium levels, that then causes PTH levels to rise

58
Q

What are 2 possible causes of vitamin D deficiency?

A
  • Vitamin D deficiency can be dietary/environmental

* or seen in chronic renal failure due to failure of the 25 hydroxylation of Vitamin D

59
Q

Give the symptoms of primary hyperparathyroidism

A
  • Stones – kidney stones. Also polyuria due to impaired sodium and water reabsorption
  • Moans – tired, exhausted, depressed
  • Groans – constipation, peptic ulcers, pancreatitis
  • Bones – bone and muscle aches
60
Q

What are the effects of hyper/hypocalcaemia on neuronal activity and what are the symptoms of each?

A
  • Hypercalcemia leads to supression of neuronal activity - lethargy, confusion, coma
  • Hypocalcemia leads to ‘excitable’ nerves - tingling, muscle tetany and even epilepsy
61
Q

What are the sensory and motor symptoms of hypocalcaemia?

A
  • Tingling around mouth and in fingers

* Tetany in the hands (and feet)

62
Q

Compare osteomalacia and osteoporosis

A

Osteoporosis is a condition in which the bones get weaker as you get older increasing the risk of bone breakage. You end up getting holes, gaps and spaces in the bones.

Osteomalacia on the other hand is the softening of the bones caused by impaired bone metabolism due to inadequate levels of available phosphate, calcium and vitamin D.

63
Q

Compare osteomalacia in children and in adults

A

In children this condition is known as rickets and can cause the bowing of bones during growth particularly in weight bearing limbs.

In adults osteomalacia causes bone pain, muscle weakness and may lead to deformity.

64
Q

Why would the measurement of PTHrP be useful?

A

The measurement of PTHrP can be of assistance in determining the cause of an otherwise unexplained hypercalcaemia.

65
Q

What are the cellular roles of calcium?

A 
• Neuromuscular excitability
• Coagulation
• Synaptic transmission
• Second messenger for hormones and
growth factors
• Regulation of gene transcription
• Coordination of Metabolic activity
• Bone formation
66
Q

What are the cellular roles of phosphate?

A
  • Structure of membrane phospholipids
  • Energy metabolism (e.g. ATP)
  • Protein phosphorylation
  • Genetic information (DNA/RNA)
  • Bone formation
67
Q

How does the control of plasma Ca2+ differ from the

regulation of Na+ and K+?

A

1) The extent Ca2+ absorption from the G.I. tract is hormonally controlled and depends on Ca2+ status of the body (K+ and Na+ homeostasis is maintained primarily by regulating urinary excretion……controlled output matches uncontrolled input)
2) Bone serves as a large Ca2+ reservoir that can be drawn on to maintain free plasma Ca2+ levels (Similar in house stores not available for K+ and Na+)

68
Q

What does alkaline phosphatase indicate on blood tests?

A
  • Enzyme present on osteoblasts and in plasma
  • Marker of bone turnover and increase in osteoblast activity
  • High plasma levels correlate with increased bone formation
69
Q

What is the overall effect of PTH on calcium and phosphate?

A

INCREASES plasma calcium levels

DECREASES plasma phosphate levels

Semester 2 - MEH (23 decks)

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