Parathyroid and calcium function

describe the physiological importance of calcium

-              99% of calcium resides in bone and teeth as hydroxyapatite crystals, providing structural integrity to skeleton and teeth

-              Extracellular calcium (0.1% of total calcium)

o   45% bound to plasma proteins eg albumin therefore not active

o   10% complexed with anions eg citrate, phosphate, sulfate

o   45% unbound – only active form

-              Intracellular calcium forms around 0.9% of total calcium

what are the require calcium concentrations around the body?

o   Serum is 8.8-10.4mg/dl

o   Interstitium/extracellular is ~6.0mg/dl

o   Intracellular is 0.4-4/0mg/dl

what is the role of calcium?

o   Bone growth and remodelling

o   Blood coagulation (enzyme co-factor)

o   Muscle contraction for sliding filament

o   Neuronal functioning

o   Exocytosis of hormones and neurotransmission

o   Intracellular signalling (second messenger)

how does calcium trigger insulin release?

-              High blood glucose

-              Glucose binds to beta cell

-              Glucose becomes metabolised

-              Glucose forms ATP via aerobic respiration from the mitochondria

-              This closes the ATP sensitive K+ channel which alters the membrane potential (depolarisation occurs)

-              This causes the voltage sensitive Ca2+ channel to open, causing a calcium influx

-              This causes secretion of insulin from the insulin secretory granules via the exocytosis of their granules from the beta cells

o   Release of insulin is highly dependent on glucose levels being above 20mM, which causes the influx of Ca2+ into the beta cells

what is the connection between calcium and PTH?

-              Serum Ca2+ is increased by parathyroid hormone (PTH) and vitamin D

what regulates calcium homeostasis?

PTH related peptide and calcitonin

descirbe the the structure of the parathyroid gland

-              Parathyroid glands are embedded in the posterior surface of the thyroid gland

o   Consists of 4 cluster of cells

§  Oxyphil cells where the function is unknown

Chief cells – produce PTH

what is the role of PTH?

polypeptide hormone which promotes INCREASED plasma Ca2+

what is the role of vitamin D3?

o   cholesterol derivative promotes INCREASED plasma Ca2+

§  Converted to it’s active form in the kidneys where PTH also plays a role in activating it  

what is the role of calcitonin?

polypeptide hormone, which fine tunes plasma Ca2+

what produces PTH?

parathyroid chief cells

how is PTH synthesised?

-              Synthesised from the precursor pre-pro-PTH (formed of 115 amino acids)

o   This precursor is cleaved to pro-PTH (90 amino acids)

o   PTH is biologically active and is 84 amino acids longs

-              PTH is synthesised continuously and is released from the parathyroid gland

how is PTH secreted?

-              PTH is secreted by exocytosis in response to reduced Ca2+ in plasma which is detected by calcium sensing receptors (CaSR) on the surface of chief cells

what causes inhibition of PTH?

-              PTH is inhibited by an increase in extracellular Ca2+

o   This would activate CaSR, which inhibits adenylate cyclase, leading to decreased cAMP, inhibiting the exocytosis of PTH

o   PTH is also inhibited by vitamin D via a secondary mechanism negative feedback

what happens when PTH binds to GPCR PTH-R?

o   When this is activated, it causes an increase in cAMP and release of Ca2+ from intracellular stores, leading to increased Ca2+

what happens to the bone, kidneys and small intestine when PTH binds to PTH-R?

§  In the bones PTH-R is present on osteoblasts (responsible for initial bone formation)

§  Then bone resorption occurs via cytokines from osteoblasts, resulting in an overall release of Ca2+ from bone

§  Overall, promotes bone resorption, increasing Ca2+ plasma levels

what does PTH inhibit in the kidney?

PO4 reabsorption

§  Normally, Ca2+ is in a complex with Phosphate

§  So, when there are reduced phosphate levels, more Ca2+ is available in the free form, thus increasing the plasma Ca2+ levels

what is the effect of PTH in the small intestine?

o   In the small intestine, PTH stimulates Ca2+ reabsorption via the activation of vitamin D

§  PTH stimulates renal 1a-hydroxylase (rate-limiting enzyme, which is essential in converting vitamin D into it’s active form) to convert 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol

§  This stimulates intestinal absorption of Ca2+

how is vitamin D synthesised?

-              Vitamin D is synthesised in the skin by keratinocytes from 7-dehdrocholesterol via the action of UV light

-              Can also be ingested from food

how is vitamin D metabolised?

-              Metabolised in the liver and kidney to activated from (1,25-dihydroxyvitamin D3)

-               Major site of regulation and synthesis in the kidney, controlled by PTH

what is the effect of vitamin D3 upon binding to it’s receptor?

-              Active D3 has a short half-life

o   Circulates bound to specific binding proteins

o   Binds to nuclear receptors, leading to an alteration of gene transcription so vitamin D can therefore be considered a transcription factor

what does increased vitamin D binding lead to?

§  Increased binding of vitamin D to it’s nuclear receptor in the cytosol leads to increased expression of Ca2+ transport proteins, increasing plasma Ca2+ levels  

o   This causes an increase in Ca2+ transport protein, causing an increase rate of Ca2+ absorption from the gut

o   This increases bone resorption and reduces Ca2+ loss at the kidney

why is vitamin D3 considered a steroid hormone?

o   This is because only 10% comes from the diet

what is calcitriol?

o   Calcitriol (most active form of vitamin D) is produced in the kidney and is released into the systemic circulation, where no duct is involved

o   Calcitriol then acts on a distant organ and circulates via blood, so is therefore considered a hormone

how can vitamin D deficiency occur?

-              Can occur due to a lack of sun

-              Dietary sources include fish, dairy and whole grains

Addition of chalk-calcium to food by UK law

what are C cells?

-              The thyroid gland is lined by epithelial cells, which are responsible for the secretion of thyroid hormones

-              C cells are responsible for the synthesis and secretion of calcitonin

what is calcitonin?

-              Calcitonin is a peptide hormone, which is released in response to increased Ca2+ in extracellular fluid (directly controlled by Ca2+ levels, no hypothalamus or pituitary involvement)

what is the effect of secretion of calcitonin?

-              Generally, opposes effects of PTH by inhibiting osteoclasts, protecting the bone and stimulating Ca2+ release from the kidneys

-              However, calcitonin in excess or when deficient is not too much of an issue because PTH and vitamin D are enough to regulate plasma Ca2+ levels

what is the physiological response to hypercalcaemia?

-              An increase in plasma Ca2+, causes decreased PTH secretion

o   This causes reduced mobilisation of bone by osteoclasts and increased action by osteoblasts

o   This also decreases renal Ca2+ absorption and reduces calcitriol synthesis

o   Decreased reabsorption of Ca2+ from small intestine

o   This causes an overall Ca2+ levels

what can hypocalcaemia be caused by?

o   Vitamin D deficiency – lack of UV or lack of dietary

o   Chronic renal failure – reduced hydroxylation of vitamin D

o   Pseudohypoparathyroidism – tissue resistance to PTH

o   Iatrogenic – damage of removed during thyroid surgery

o   Autoimmune disorders – auto-antibodies destroy tissue

what are the symptoms of hypocalcaemia?

o   Tetanic muscle contacts (laryngeal stridor – spasms)

o   Seizures

o   Neurological conditions such as depression

o   Cardiac effect – repolarisation is delayed with prolonged QT interval

o   Cataract due to protein accumulation (CA3(PO4)2)

o   Dry and flaky skins – brittle nails

o   Tetany in the hand

o   Osteoporosis (caused by hormonal changes, deficiency of Ca2+ or D3 or long-term uses of corticosteroid hormones)

what are rickets?

-              – severe lack of D3 and therefore calcium, which is common in malnourished children

what are the symptoms of hypercalcaemia?

o   Moans – depression of nervous system

o   Groans – abdominal pain/constipation

o   Stones – kidney stones via calcification

what can cause excess PTH?

tumour in the parathyroid gland

what occurs as a result of excess PTH?

o   Causes continuous bone resorption and Ca2+ absorption in kidney due to continuous release of PTH

o   More common in woman

o   Caused by adenoma