Endocrine control of calcium metabolism Flashcards
What is the most abundant metal in the human body?
Calcium
State 7 roles of calcium in the body.
Neuromuscular excitability Muscle Contraction Strength in bone Blood coagulation (factor IV) Intracellular 2nd messenger Intracellular co-enzyme Hormone/neurotransmitter stimulus-secretion coupling
Where is calcium mainly stored?
Bone: 99% is stored as hydroxyapatite crystals (calcium salt)
How is calcium present in the blood? What is the main component?
Unbound ionised Ca2+: 50%
Bound to plasma proteins: 45%
Tiny bit as soluble salts
Which form of calcium is bioactive?
Free unbound ionised calcium
What is the usual daily intake of calcium?
1000 mg
What happens to ingested calcium?
Most not needed: excreted in faeces
Some goes into blood: to bones or to be excreted from kidneys
What is the concentration of unbound ionised calcium in the blood?
1.25 mM
What 2 hormones raise plasma calcium concentration?
Parathyroid Hormone (PTH) Calcitriol (1,25-dihydroxycholecalciferol)
What hormone decreases plasma calcium concentration?
Calcitonin
Where is parathyroid hormone produced?
Parathyroid Glands (4 of them): produced in the follicular cells
Where is calcitonin produced?
Parafollicular cells on the outside of thyroid follicular cells
Where are calcium sensing receptors found?
Parathyroid cells
Kidney
GI tract
What is the primary effect of an activated calcium sensing receptor?
Activation of adenyl cyclase to change intracellular cAMP levels
Also works through Phospholipase C (PLC) as 2nd messenger systems
Describe the effects of parathyroid hormone on the kidneys.
Increases calcium reabsorption
Increases phosphate excretion
Describe the effects of PTH on bone.
Stimulates osteoclasts
Inhibits osteoblasts
Increases bone resorption
Describe the effects of PTH on the small intestines.
Stimulates 1 alpha hydroxylase (in the kidneys), which is involved in the production of calcitriol
This increases Ca2+ and phosphate absorption in the small intestine.
Actions of osteoblasts and osteoclasts
Osteoclasts: bone break down
Osteoblasts: bone build up
What are the overall effects of PTH?
Increase circulating Ca2+ levels
How does PTH increase calcium release from bone?
PTH binds to and inhibits osteoblasts.
PTH makes the osteoblasts produce osteoclast activating factors (e.g. RANKL) that bind to receptors on osteoclasts and stimulates more bone resorption, breaking bone down and freeing trapped Ca2+
(sacrifices bone mass to preserve circulating Ca2+ levels)
Why does PTH cause the kidney to increases calcium reabsorption and increases phosphate excretion?
Breaking down bone liberates calcium and phosphate
We don’t want high phosphate, just want high calcium
So increase phosphate excretion
What can stimulate PTH release?
Low plasma Ca2+ concentration
Catecholamines (via beta receptors)
Describe the negative feedback loops on PTH.
Increased plasma Ca2+ concentration and Calcitriol have a negative feedback effect on parathyroid glands to reduce PTH release
What is the precursor of calcitriol?
Cholecalciferol (VITAMIN D3)
Where does Cholecalciferol come from?
Diet Sun Light (UV B converts 7-dehydrocholesterol to cholecalciferol)
Describe the reactions that have to take place to convert the Cholecalciferol to calcitriol.
In the liver 25-hydroxylase converts it to 25-hydroxycalciferol
This is stored in the liver.
It then moves to the kidneys where 1 alpha hydroxylase converts 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (calcitriol)
Describe the effects of calcitriol.
Primary action in small intestine:
stimulates calcium and phosphate absorption
Bone: Promotes lying down of calcium and phosphate salts. Increases osteoblast activity
Kidneys: increases calcium and phosphate reabsorption
What regulates phosphate metabolism?
Fibroblast growth factor 23 (FGF 23)
What happens when phosphate levels rise too high?
FGF 23 is stimulated to reduce circulating phosphate levels
Major effect in kidney
What can inhibit phosphate reabsorption in the kidney? What does this result in?
PTH and FGF-23 via sodium phosphate co-transporter. More phosphate (and sodium) released in urine
What does calcitriol in the presence of high phosphate stimulate?
Release of FGF-23
FGF-23 has a negative feedback cycle which suppresses release of calcitriol
What stimulates calcitonin release?
High plasma calcium levels
Gastrin
Describe the effects of calcitonin.
Inhibits osteoclast activity (inhibits bone breakdown, decrease release of Ca2+ into blood)
Acts on Kidneys to increase sodium excretion and hence increase urinary excretion of phosphate and calcium.
Why is it difficult to remove calcium?
Calcitonin has a limited effect
List 3 endocrine causes of hypocalcaemia
Hypoparathyroidism (too little parathyroid hormone)
Pseudohypoparathyroidism
Vitamin D deficiency
List 2 clinical signs of hypocalcaemia
Tetany: More frequent neuromuscular spasms (Na+ enters cell more easily, more firing of nerves, more contraction)
Trousseau’s sign (main d’accoucheur)
Chvostek’s sign: twitch in lips and nose when ear is flicked
3 causes of Hypoparathyroidism
IDIOPATHIC: low circulating parathyroid hormone
HYPOMAGNESAEMIA: low circulating magnesium
(SUPPRESSION by raised plasma Ca2+ concentration)
What is pseudohypoparathyroidism and what is it also known as?
Target organ resistance to PTH
AKA: Allbright Heriditary Osteodystrophy
List 6 clinical signs of pseudohypoparathyroidism
Round face Short Low IQ Short 4th metacarpal Hypothyroidism Hypogonadism
What is the underlying cause of pseudohypoparathyroidism?
Defective Gs protein (needed to increase cAMP intracellularly in response to PTH receptor activation).
What does vitamin D deficiency cause in children and adults? What are the clinical features of these?
Children: rickets- bowing bones
Adults: osteomalacia- fractures
State 3 causes of hypercalcaemia.
Primary hyperparathyroidism
Tertiary hyperparathyroidism
Vitamin D Toxicosis
Describe the differences between primary, secondary and tertiary hyperparathyroidism.
Primary: caused by parathyroid adenoma producing excess PTH, increases circulating Ca2+, negative feedback loop doesn’t work
Secondary: caused by other reasons e.g. Kidney disease. prevents reabsorption of Ca2+, so unable to restore Ca2+ levels
Tertiary: often seen in people who’ve had secondary (initial chronic low plasma Ca2+ concentration): parathyroid gland is massively stimulated for a long time and so PTH production becomes autonomous and stops responding to negative feedback (leads to hypercalcaemia)
State 2 consequences of parathyroid hormone excess for the kidneys
Polyuria
Kidney stones
State 2 consequences of parathyroid hormone excess for the GI tract
Increased gastric acid
Duodenal ulcers
State 2 consequences of parathyroid hormone excess for the bone
Bone lesions
Bone rarefaction
Fractures
What is a distinctive clinical feature of primary hyperparathyroidism?
Clubbing of the fingers
Hypoparathyroidism:
Plasma Ca2+
Plasma PO4(3-)
PTH
Plasma Ca2+: Decreases
Plasma PO4(3-): Increases
PTH: Decreases
Pseudohypoparathyroidism:
Plasma Ca2+
Plasma PO4(3-)
PTH
Plasma Ca2+: Decreases
Plasma PO4(3-): Increases
PTH: Increases
Vitamin D deficiency:
Plasma Ca2+
Plasma PO4(3-)
PTH
Plasma Ca2+: Decreases
Plasma PO4(3-): Decreases
PTH: Increases
