51. Electrolytes & Fluid Balance 💦 Flashcards
Name the two main nuclei within which neurones of the neurohypophysis have their cell bodies.
Paraventricular Nucleus Supraoptic Nucleus
What two hormones are produced by the neurohypophysis?
Vasopressin Oxytocin
What is the principal action of vasopressin and how does it carry out this action?
Vasopressin’s main action is on the V2 receptors in the renal cortical and medullary collecting ducts It stimulates the synthesis and assembly of aquaporin 2, which then increases water reabsorption and has an antidiuretic effect
State some other actions of vasopressin.
Vasoconstriction Corticotrophin release Factor VIII and von Willebrand factor Central effects
What are the main actions of oxytocin?
It is a contractile molecule that binds to oxytocin receptors It causes contraction of the myometrium during parturition and is involved in milk ejection It also has central effects
What are the consequences of a lack of the neurohypophysial hormones?
Lack of Oxytocin – not clinically significant Lack of Vasopressin – Diabetes Insipidus
What are the two forms of diabetes insipidus?
Central (cranial) and Nephrogenic Diabetes Insipidus
What can cause central diabetes insipidus?
Damage to neurohypophysial system (injury, surgery, cerebral thrombosis, tumours, granulomatous infiltration) Idiopathic Familial (rare)
What can cause nephrogenic diabetes insipidus?
Familial (rare) Drugs e.g. lithium, dimethyl chlortetracycline (DMCT)
State some signs and symptoms of diabetes insipidus.
Polyuria Polydipsia Hypo-osmolar urine Dehydration Possible disruption of sleep Possible electrolyte imbalance
State another cause of polydipsia that isn’t diabetes.
Psychogenic polydipsia This is a central disturbance that increases the drive to drink
What test can be used to distinguish between normal, psychogenic polydipsia, central DI and nephrogenic DI? Describe the results you would expect.
Fluid deprivation test ï‚· Normals and psychogenic polydipsia will show a rise in urine osmolality ï‚· Central and nephrogenic diabetes insipidus will show little or no change in urine osmolality Fluid deprivation with administration of DDAVP (Desmopressin) ï‚· Central diabetes insipidus will show a rise in urine osmolality ï‚· Nephrogenic DI will still have a low urine osmolality (because of end-organ resistance)
Why is the urine osmolality of someone with psychogenic polydipsia lower (in the fluid deprivation test) than a normal subject?
Over time, the constant passage of large volumes of water through the kidneys will wash out the osmotic gradient that is necessary for AVP to exert its diuretic effect
Describe the normal change in urine osmolality as plasma osmolality increases.
Normally, urine osmolality will increase as plasma osmolality increases (in a graph of urine osmolality against plasma osmolality it will show a sigmoid shape) In DI, there is little change in urine osmolality as plasma osmolality increases
Describe changes in plasma vasopressin following administration of hypertonic saline in a normal subject, psychogenic polydipsia, central DI and nephrogenic DI.
Hypertonic saline will increase the plasma osmolality and hence will increase the vasopressin secretion in patients that have the capacity to produce vasopressin (normal, psychogenic polydipsia and nephrogenic DI) Patients with central DI can’t produce vasopressin at all so the hypertonic saline will show no change in plasma vasopressin
What is SIADH?
Syndrome of Inappropriate ADH = when the plasma vasopressin concentration is inappropriate for the existing plasma osmolality
State some signs of SIADH.
Decreased urine volume Increased urine osmolality
What is the main consequence of SIADH?
HYPONATRAEMIA
State some symptoms of SIADH that are caused by the hyponatraemia.
At relatively mild hyponatraemia = generalized weakness, poor mental function, nausea Severe hyponatraemia = confusion, coma, death
State some causes of SIADH.
Tumours (ectopic secretion) Neurohypophysial malfunction (e.g. meningitis, cerebrovascular disease) Thoracic disease (e.g. pneumonia) Endocrine disease (e.g. Addison’s) Physiological – it can happen under normal circumstances where AVP is release is stimulated by non-osmotic stimuli (e.g. hypovolaemia, pain, surgery) Drugs Idiopathic
How is SIADH treated?
Fluid Restriction Provide appropriate treatment when the cause is identified (e.g. surgery for a tumour) NOTE: if someone is hyponatraemic you need to deal with that as soon as possible – e.g. use drugs that prevent vasopressin action in the kidneys
What is the name given to exogenous vasopressin?
Argipressin
Where are V1 and V2 receptors found?
V1 ï‚· Vascular smooth muscle ï‚· Non-vascular smooth muscle ï‚· Anterior pituitary ï‚· Liver ï‚· Platelets ï‚·CNS V2 ï‚· Kidney ï‚· Endothelial cells
State the pharmacological actions of argipressin.
NATRIURESIS – this is one of the unexplained side-effects of having a large amount of vasopressin – it is V2 mediated and only happens when given at high doses PRESSOR ACTION – V1 mediated vasoconstriction – the coronary vessels are particularly sensitive to vasopressin (this can cause cardiac ischaemia and angina attacks) Contraction of vascular smooth muscle Increased ACTH secretion Increased factor VIII and vWF production
State two selective peptidergic vasopressin selective agonists.
V1 – Terlipressin V2 - Desmopressin
Compare the effects of argipressin and desmopressin.
Argipressin acts on V1 and V2 Argipressin is more effective in causing vasoconstriction via V1 receptors Desmopressin is more effective in the kidneys in causing water reabsorption via V2 receptors
State some clinical uses of Desmopressin.
Treatment of diabetes insipidus Treatment of nocturnal eneuresis Haemophilia (need V2 stimulation) NOTE: it is taken orally or nasally
State some unwanted effects of Desmopressin.
Nausea Headaches Abdominal pain Fluid retention and hyponatraemia
State two peptidergic V1 receptor agonists and their uses.
Terlipressin – used to treat oesophageal varices (it causes vasoconstriction) Felypressin – injected by dentists along with local anaesthetic (the vasoconstriction keeps the local anaesthetic at the site of injection for longer thus prolonging the action of the local anaesthetic)
State one treatment used for nephrogenic diabetes insipidus and its possible mechanism of action.
Thiazide Diuretics (e.g. bendroflumethiazide) This inhibits the Na+/Cl- pump in the DCT leading to a diuretic effect This leads to volume depletion resulting in a compensatory increase inNa+ reabsorption from the PCT This increases proximal water reabsorption so less water reaches the collecting duct This ultimately leads to reduced urine volume
What are vaptans?
Non-peptide vasopressin receptor antagonists Tolvaptan = V2 receptor antagonist It is used to treat hyponatraemia associated with SIADH and may be useful in treating congestive heart failure
State some drugs that increase or decrease vasopressin secretion.
Increase vasopressin secretion = nicotine Decrease vasopressin secretion = alcohol + glucocorticoids
What are diuretics?
Drugs that act on the renal tubule to promote excretion of Na+, Cl- and H2O
What percentage of filtered fluid is reabsorbed in the proximal tubule?
65-70%
How does water move into the epithelial cells from the lumen inthe proximal tubule?
Osmosis – it will follow the diffusion of Na+ into the cell
What important protein is present on the basolateral membrane of epithelial cells along most of the tubule and is responsible for maintaining the concentration gradient that allows sodium reabsorption?
Na+/K+ ATPase
What other force is present, within the interstitium, that helps draw water in from the tubule?
Oncotic pressure – proteins in the blood in the arterioles
Other than through the cell, what other route is there for the movement of ions and water?
Paracellular pathway
What are diuretics?
Drugs that act on the renal tubule to promote excretion of Na+, Cl- and H2O
What percentage of filtered fluid is reabsorbed in the proximal tubule?
65-70%
How does water move into the epithelial cells from the lumen inthe proximal tubule?
Osmosis – it will follow the diffusion of Na+ into the cell
What important protein is present on the basolateral membrane of epithelial cells along most of the tubule and is responsible for maintaining the concentration gradient that allows sodium reabsorption?
Na+/K+ ATPase
What other force is present, within the interstitium, that helps draw water in from the tubule?
Oncotic pressure – proteins in the blood in the arterioles
Other than through the cell, what other route is there for the movement of ions and water?
Paracellular pathway
What is this pathway dependent on?
Gap junctions
What two other molecules in the filtrate are reabsorbed in the proximal tubule and are coupled with Na+ reabsorption?
Glucose Amino acids
Explain how sodium exchange is linked to carbonic anhydrase?
HCO3- and H+ are filtered in the glomerulus They are then converted, by carbonic anhydrase, to H2O and CO2, which freely diffuse into the proximal tubule epithelial cell Inside the epithelial cell, carbonic anhydrase converts the H2O and CO2 to H+ and HCO3- HCO3- is then cotransported with Na+ into the interstitium H+ is exchanged for Na+ at the apical membrane via the Na+/H+ exchanger
How are exogenous agents removed in the kidneys?
Drugs are removed by transport proteins that pick up drugs as they pass through the kidneys and transport them into the lumen
Describe the permeability of the loop of Henle to water.
The descending limb is freely permeable to water but not to ions The ascending limb is impermeable to water but is permeable to ions
What is the main channel present on the apical membrane of theepithelial cells of the ascending limb of the loop of Henle?
Na+/K+/2Cl- cotransporter
What are the channels that are present on the basolateral membrane of the epithelial cells of the ascending limb of the loop of Henle?
Na+/K+ ATPase K+/Cl- cotransporte
Describe how the counter-current system is established.
The filtrate would travel down the loop of Henle and as it goes up the ascending limb (impermeable to water but permeable to ions), Na+ moves from the tubule to the interstitium thus making the interstitium hypertonic and the tubular fluid hypotonic. Then, more fluid will come down the descending limb (permeable to water) and the hypertonic interstitium will attract water and increase the reabsorption of water from the tubule into the interstitium This will increase the concentration of fluid reaching the ascending tubule where even more Na+ will be reabsorbed and move into the interstitium This occurs repetitively and you end up with a hypertonic interstitium and hypotonic tubular fluid leaving the loop of Henle This hypertonic interstitium is also responsible for increasing water reabsorption in the collecting duct (mediated by vasopressin)
What are the main channels on the apical membrane of epithelial cells of the distal tubule?
Na+/Cl- cotransporter Aldosterone dependent sodium channels
Which channels are found on the basolateral membrane of the epithelial cells of the distal tubule?
Na+/K+ ATPase K+/Cl- cotransporter
Which aquaporin molecules are found in epithelial cells of the distal tubule?
AQP2 – apical membrane AQP3/AQP4 – basolateral membrane
Which vasopressin receptors are present on collecting duct cells?
V2 receptors
Describe the effect of aldosterone on collecting duct cells.
Aldosterone stimulates the production of Na+ channels and the production of Na+/K+ ATPases
Describe the effect of vasopressin on collecting duct cells.
Vasopressin stimulates the production and assembly of AQP2 molecules thus increasing the ability of the collecting duct to reabsorb water
List the five groups of diuretics.
Osmotic Diuretics Carbonic Anhydrase Inhibitors Loop Diuretics Thiazide Diuretics Potassium Sparing Diuretics
Give an example of an osmotic diuretic.
Mannitol
Describe the mechanism of action of osmotic diuretics.
This is a pharmacologically inert chemical that can increase plasma and urine osmolarity It is filtered by the glomerulus but not reabsorbed Increasing the osmolarity of the filtrate means that less water leaves the lumen and is reabsorbed
What are osmotic diuretics used for?
They are mainly used for their effect in increasing plasma osmolarity –they draw out fluid from cells and tissues (e.g. in oedema)
Give an example of a carbonic anhydrase inhibitor
Acetazolamide
Describe the mechanism of action of carbonic anhydrase inhibitors.
Inhibition of carbonic anhydrase reduces HCO3- reabsorption into the blood It also reduces the amount of H+ available within epithelial cells to drive the Na+/H+ exchanger and allow Na+ reabsorption
Give an example of a loop diuretic.
Frusemide (furosemide)
How much fluid loss can loop diuretics cause?
15-20%
What is the target of loop diuretics?
Na+/K+/2Cl- cotransporter
Explain how loop diuretics exert their diuretic effect.
They block the triple transporter thus reducing the reabsorption of Na+ in the ascending tubule This increases the tubular fluid osmolarity thus reducing water reabsorption from the tubular fluid so the urine fluid volume increases
Explain why loop diuretics cause an increase in urinary excretionof Mg2+ and Ca2+.
Potassium recycling, under normal conditions, means that there is a certain amount of K+ in the tubular fluid that can maintain the positive lumen potential and drive other positively charged ions (Mg2+ and Ca2+) into the interstitium via the paracellular pathway Loop diuretics cause the loss of potassium recycling meaning that there is insufficient K+ in the lumen to drive the other positive ions through the paracellular pathway so you get increased urinary excretion of Mg2+ and Ca2+
Why do loop diuretics cause an increase in K+ loss?
Loop diuretics increase the concentration of Na+ in the tubular fluid that is reaching the distal tubule This means that there is increased Na+/K+ exchange is the distal tubule –> increased K+ loss
What is the main use of loop diuretics?
Oedema
What are the unwanted effects of loop diuretics?
Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis
Give an example of a thiazide diuretic.
Bendrofluazide (bendroflumethiazide)
Where do thiazide diuretics act and what do they act on?
They act in the distal tubule They bind to the Na+/Cl- cotransporter
How much fluid loss can thiazide diuretics cause?
5-10% fluid loss
What effect do thiazide diuretics have on Mg2+ and Ca2+?
Increase in Mg2+ and Ca2+ reabsorption (unknown mechanism)
What are the uses of thiazide diuretics?
Hypertension Heart failure Nephrogenic diabetes insipidus Idiopathic hypercalciuria
What are the unwanted effects of thiazide diuretics?
K+ loss – metabolic alkalosis Inhibits insulin secretion (bad in diabetes mellitus)
What effect do loop diuretics have on the macula densa cells?
Macula densa cells have the same Na+/K+/2Cl- cotransporter that is present in the ascending limb of the loop of Henle and is targeted by loop diuretics This means that loop diuretics prevent the entry of sodium into macula densa cells
Where are macula densa cells found?
At the top of the ascending limb of the loop of Henle The top of the ascending limb comes very close to the afferent arteriole
Explain the counter-productive effects of loop and thiazide diuretics on the renin-angiotensin system.
Given that they cause a loss of Na+ in the urine, loop and thiazide diuretics will eventually cause reduced Na+ in the blood meaning that less Na+ is filtered in the glomerulus and hence less Na+ will reach the macula densa cells A reduction in the Na+ reaching the macula densa is a stimulus for renin secretion This leads to aldosterone production, which promotes sodium reabsorption (hence counterproductive to the effects we are trying to achieve with diuretics)
What measure can be taken to prevent this from happening?
Give ACE inhibitors with the diuretics
What are the two classes of potassium sparing diuretic? Give an example of a drug that falls into each class.
Aldosterone receptors antagonist – spironolactone Inhibitors of aldosterone-sensitive sodium channels – amiloride
How much fluid loss can potassium-sparing diuretics cause?
5%
Describe the effects of potassium-sparing diuretics.
They reduce sodium reabsorption in the late distal tubule, which leads to increased tubular osmolarity This will result in reduced water reabsorption from the tubular fluid in the collecting duct They also lead to increased H+ retention (because of reduced Na+/H+ exchange)
What is the main use of amiloride?
It is given with K+ losing diuretics
What are the main uses of spironolactone?
Hypertension/heart failure Hyperaldosteronism
State some unwanted effects of K+ sparing diuretics.
Hyperkalaemia – metabolic acidosis Spironolactone (very non-specific action) – gynaecomastia, menstrual irregularities
State some unwanted effects of K+ sparing diuretics.
Hyperkalaemia – metabolic acidosis Spironolactone (very non-specific action) – gynaecomastia, menstrual irregularities
What are the main uses of spironolactone?
Hypertension/heart failure Hyperaldosteronism
What is the main use of amiloride?
It is given with K+ losing diuretics
Describe the effects of potassium-sparing diuretics.
They reduce sodium reabsorption in the late distal tubule, which leads to increased tubular osmolarity This will result in reduced water reabsorption from the tubular fluid in the collecting duct They also lead to increased H+ retention (because of reduced Na+/H+ exchange)
How much fluid loss can potassium-sparing diuretics cause?
5%
What are the two classes of potassium sparing diuretic? Give an example of a drug that falls into each class.
Aldosterone receptors antagonist – spironolactone Inhibitors of aldosterone-sensitive sodium channels – amiloride
What measure can be taken to prevent this from happening?
Give ACE inhibitors with the diuretics
Explain the counter-productive effects of loop and thiazide diuretics on the renin-angiotensin system.
Given that they cause a loss of Na+ in the urine, loop and thiazide diuretics will eventually cause reduced Na+ in the blood meaning that less Na+ is filtered in the glomerulus and hence less Na+ will reach the macula densa cells A reduction in the Na+ reaching the macula densa is a stimulus for renin secretion This leads to aldosterone production, which promotes sodium reabsorption (hence counterproductive to the effects we are trying to achieve with diuretics)
Where are macula densa cells found?
At the top of the ascending limb of the loop of Henle The top of the ascending limb comes very close to the afferent arteriole
What effect do loop diuretics have on the macula densa cells?
Macula densa cells have the same Na+/K+/2Cl- cotransporter that is present in the ascending limb of the loop of Henle and is targeted by loop diuretics This means that loop diuretics prevent the entry of sodium into macula densa cells
What are the unwanted effects of thiazide diuretics?
K+ loss – metabolic alkalosis Inhibits insulin secretion (bad in diabetes mellitus)
What are the uses of thiazide diuretics?
Hypertension Heart failure Nephrogenic diabetes insipidus Idiopathic hypercalciuria
What effect do thiazide diuretics have on Mg2+ and Ca2+?
Increase in Mg2+ and Ca2+ reabsorption (unknown mechanism)
How much fluid loss can thiazide diuretics cause?
5-10% fluid loss
Where do thiazide diuretics act and what do they act on?
They act in the distal tubule They bind to the Na+/Cl- cotransporter
Give an example of a thiazide diuretic.
Bendrofluazide (bendroflumethiazide)
What are the unwanted effects of loop diuretics?
Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis
What is the main use of loop diuretics?
Oedema
Why do loop diuretics cause an increase in K+ loss?
Loop diuretics increase the concentration of Na+ in the tubular fluid that is reaching the distal tubule This means that there is increased Na+/K+ exchange is the distal tubule –> increased K+ loss
Explain why loop diuretics cause an increase in urinary excretionof Mg2+ and Ca2+.
Potassium recycling, under normal conditions, means that there is a certain amount of K+ in the tubular fluid that can maintain the positive lumen potential and drive other positively charged ions (Mg2+ and Ca2+) into the interstitium via the paracellular pathway Loop diuretics cause the loss of potassium recycling meaning that there is insufficient K+ in the lumen to drive the other positive ions through the paracellular pathway so you get increased urinary excretion of Mg2+ and Ca2+
Explain how loop diuretics exert their diuretic effect.
They block the triple transporter thus reducing the reabsorption of Na+ in the ascending tubule This increases the tubular fluid osmolarity thus reducing water reabsorption from the tubular fluid so the urine fluid volume increases
What is the target of loop diuretics?
Na+/K+/2Cl- cotransporter
How much fluid loss can loop diuretics cause?
15-20%
Give an example of a loop diuretic.
Frusemide (furosemide)
Describe the mechanism of action of carbonic anhydrase inhibitors.
Inhibition of carbonic anhydrase reduces HCO3- reabsorption into the blood It also reduces the amount of H+ available within epithelial cells to drive the Na+/H+ exchanger and allow Na+ reabsorption
Give an example of a carbonic anhydrase inhibitor
Acetazolamide
What are osmotic diuretics used for?
They are mainly used for their effect in increasing plasma osmolarity –they draw out fluid from cells and tissues (e.g. in oedema)
Describe the mechanism of action of osmotic diuretics.
This is a pharmacologically inert chemical that can increase plasma and urine osmolarity It is filtered by the glomerulus but not reabsorbed Increasing the osmolarity of the filtrate means that less water leaves the lumen and is reabsorbed
Give an example of an osmotic diuretic.
Mannitol
List the five groups of diuretics.
Osmotic Diuretics Carbonic Anhydrase Inhibitors Loop Diuretics Thiazide Diuretics Potassium Sparing Diuretics
Describe the effect of vasopressin on collecting duct cells.
Vasopressin stimulates the production and assembly of AQP2 molecules thus increasing the ability of the collecting duct to reabsorb water
Describe the effect of aldosterone on collecting duct cells.
Aldosterone stimulates the production of Na+ channels and the production of Na+/K+ ATPases
Which vasopressin receptors are present on collecting duct cells?
V2 receptors
Which aquaporin molecules are found in epithelial cells of the distal tubule?
AQP2 – apical membrane AQP3/AQP4 – basolateral membrane
Which channels are found on the basolateral membrane of the epithelial cells of the distal tubule?
Na+/K+ ATPase K+/Cl- cotransporter
What are the main channels on the apical membrane of epithelial cells of the distal tubule?
Na+/Cl- cotransporter Aldosterone dependent sodium channels
Describe how the counter-current system is established.
The filtrate would travel down the loop of Henle and as it goes up the ascending limb (impermeable to water but permeable to ions), Na+ moves from the tubule to the interstitium thus making the interstitium hypertonic and the tubular fluid hypotonic. Then, more fluid will come down the descending limb (permeable to water) and the hypertonic interstitium will attract water and increase the reabsorption of water from the tubule into the interstitium This will increase the concentration of fluid reaching the ascending tubule where even more Na+ will be reabsorbed and move into the interstitium This occurs repetitively and you end up with a hypertonic interstitium and hypotonic tubular fluid leaving the loop of Henle This hypertonic interstitium is also responsible for increasing water reabsorption in the collecting duct (mediated by vasopressin)
What are the channels that are present on the basolateral membrane of the epithelial cells of the ascending limb of the loop of Henle?
Na+/K+ ATPase K+/Cl- cotransporte
What is the main channel present on the apical membrane of theepithelial cells of the ascending limb of the loop of Henle?
Na+/K+/2Cl- cotransporter
Describe the permeability of the loop of Henle to water.
The descending limb is freely permeable to water but not to ions The ascending limb is impermeable to water but is permeable to ions
How are exogenous agents removed in the kidneys?
Drugs are removed by transport proteins that pick up drugs as they pass through the kidneys and transport them into the lumen
Explain how sodium exchange is linked to carbonic anhydrase?
HCO3- and H+ are filtered in the glomerulus They are then converted, by carbonic anhydrase, to H2O and CO2, which freely diffuse into the proximal tubule epithelial cell Inside the epithelial cell, carbonic anhydrase converts the H2O and CO2 to H+ and HCO3- HCO3- is then cotransported with Na+ into the interstitium H+ is exchanged for Na+ at the apical membrane via the Na+/H+ exchanger
What two other molecules in the filtrate are reabsorbed in the proximal tubule and are coupled with Na+ reabsorption?
Glucose Amino acids
What is this pathway dependent on?
Gap junctions
What is the most important vitamin D metabolite?
1, 25-dihydroxycholecalciferol (calcitriol)
What is the principle effect of calcitriol?
Increase calcium, magnesium and phosphate absorption in the small intestines
What are the other effects of calcitriol?
Increased reabsorption of calcium and decreased phosphate reabsorption in the kidneys (via FGF23) Stimulates osteoclast formation from precursors Stimulates osteoblasts to make osteoclast-activating factors (OAFs e.g. RANKL)
What does vitamin D deficiency cause? State some symptoms.
Lack of bone mineralisation Softening of bone (can lead to bowing of the legs) Bone deformities Bone pain Severe proximal myopathy
What are the different names for vitamin D deficiency in children and adults?
Children – Rickets Adults – Osteomalacia
State some causes of vitamin D deficiency.
Inadequate dietary intake Lack of sunlight Receptor defects Renal failure Gastrointestinal malabsorptive states
Which step, in vitamin D metabolism, required UV light?
The conversion of 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3) requires UV light
Describe the two hydroxylation reactions in vitamin D metabolism.
Cholecalciferol is firstly hydroxylated to form 25-hydroxycholecalciferol in the Liver It then goes to the kidneys where it undergoes its next hydroxylation (by 1-hydroxylase) to form 1, 25-dihydroxycholecalciferol (calcitriol)
What can stimulate 1-hydroxylase in the kidneys?
Parathyroid Hormone (PTH)
How can lack of sunlight cause vitamin D deficiency?
It will mean that less 7-dehydrocholesterol is being converted to cholecalciferol
How can liver disease cause vitamin D deficiency?
The liver is where the first hydroxylation takes place and where 25-hydroxycholecalciferol is stored so liver disease can interfere with this step in vitamin D metabolism
How can renal failure cause vitamin D deficiency?
The second hydroxylation step takes place in the kidneys (via 1-alpha-hydroxylase) so renal failure can interfere with 1-alpha-hydroxylase activity
What is usually measured to gage the level of calcitriol? Whatcondition must be fulfilled for this to be a good measure of calcitriol?
25-hydroxycholecalciferol This is only a good measure in the case of normal renal function
Describe how you would diagnose vitamin D deficiency.
Plasma Calcium = LOW Plasma 25-hydroxycholecalciferol = LOW Plasma PTH = HIGH (secondary hyperparathyroidism stimulated by the hypocalcaemia) Plasma Phosphate = LOW Radiological findings e.g. widened osteoid seams
What would you expect the plasma phosphate level to be in someone with renal failure and why?
HIGH – because there is a decrease in plasma excretion via the kidneys
What would you expect the plasma calcium level to be in someone with renal failure and why?
LOW – because they are not producing as much calcitriol (due to renalfailure interfering with 1-alpha hydroxylase) so there is less calcium absorption in the small intestines
What are the consequences of hypocalcaemia caused by renal failure?
There is a decrease in bone mineralisation and an increase in bone resorption (because of an increase in PTH) leading to osteitis fibrosa cystica The imbalance in calcium and phosphate can also lead to the formation of salts that can be deposited in extra-skeletal tissue causing extra-skeletal calcification
What can vitamin D excess lead to?
Hypercalcaemia and hypercalciuria (due to increased intestinal absorption of calcium)
What can vitamin D excess result from?
Excessive treatment with active metabolites of vitamin D, as in patients with chronic renal failure Granulomatous disease – granulomatous tissue has 1-hydroxylase so it can be a source of ectopic calcitriol
What is Paget’s disease?
Very active (increased), localised but disorganised bone metabolism –usually slowly progressive. There is increased bone breakdown and bone formation.
What is Paget’s disease characterised by histologically?
Abnormal, large osteoclasts
State some symptoms of Paget’s disease.
Increased vascularity (warmth over affected bone) Increased osteoblast/osteoclast activity ï‚· Initially increased osteoclast activity ï‚· Followed by increased osteoblast activity (leading to thickening of deformed bone) Most commonly affected bones are: pelvis, femur, tibia, skull, and spine Increased incidence of fracture Bone pain
Describe how you would diagnose Paget’s disease.
Plasma calcium = NORMAL Plasma ALP (alkaline phosphatase) = HIGH Radiological findings: ï‚· Loss of trabecular (spongy) bone ï‚· Increased bone density ï‚· Deformity Radioisotope (technetium) scanning can be performed to indicate areas of involvement
What are the two components of bone in which 95% of the body’s calcium is stored?
Inorganic mineral component –65%  Stored as calcium hydroxyapatite crystals between the collagen fibrils Organic (osteoid) component –35%  Collagen fibres (95%)
What is the normal plasma calcium range?
2.2-2.6 mmol/L
State 2 hormones that increase plasma calcium concentration.
Calcitriol PTH
State a hormone that decreases plasma calcium concentration.
Calcitonin
What are the 2 direct effects of PTH?
Increased mobilisation of calcium in bone Increased calcium reabsorption in the kidneys and stimulation of 1a-hydroxylase
What are the 2 direct effects of calcitriol?
Increased calcium absorption from the small intestine Increased mobilisation of calcium in bone
What can stimulate PTH release?
Hypocalcaemia
State 4 signs of hypocalcaemia.
Parasthesia Arrhythmias Convulsions Tetany
What effect does hypocalcaemia have on excitable tissues?
It sensitises excitable tissue –> neuromuscular excitability
State 2 clinical signs of neuromuscular irritability due to hypocalcaemia.
Chvostek’s Sign  Tap the facial nerve just below the zygomatic arch  Positive = twitching of facial muscles Trousseau’s Sign  Pump the blood pressure cuff for several minutes  Induces carpopedal spasm
State 4 causes of hypocalcaemia.
Hypoparathyroidism (e.g. due to surgery) Vitamin D deficiency Pseudohypoparathyroidism Renal failure (impaired 1-alpha hydroxylase)
Describe the effect of hypercalcaemia on neuronal excitability.
It reduces neuronal excitability and you get atonal muscles
What are the main signs and symptoms of hypercalcaemia?
Stones, abdominal moans and psychic groans Stones – renal effects  Polyuria + polydipsia  Nephrocalcinosis = deposition of calcium in the kidneys (can cause renal colic) Abdominal moans – GI effects  Anorexia, nausea, constipation, pancreatitis, dyspepsia Psychic groans – CNS effects  Fatigue, depression, impaired concentration, altered mentation, coma
What are the 2 main causes of hypercalcaemia?
Primary Hyperparathyroidism (e.g. parathyroid adenoma) Malignancy (e.g. bone tumours/metastases –> increased bone turnover –> increased plasma calcium; tumours can also produce PTH-like peptide)
State 2 other causes of hypercalcaemia.
Conditions of increased bone turnover (e.g. hyperthyroidism, Paget’s) Vitamin D excess (rare)
Describe how you would differentiate between primary hyperparathyroidism and malignancy causing hypercalcaemia.
In primary hyperparathyroidism there is no negative feedback because the parathyroid adenoma will be producing PTH autonomously ï‚· Plasma Calcium = HIGH ï‚· PTH = HIGH In malignancy, the negative feedback will be intact as it is due to increased bone turnover due to bony metastases ï‚· Plasma Calcium = HIGH ï‚· PTH = LOW
Describe the treatment of vitamin D deficiency in the case of normal renal function.
Give 25-hydroxy vitamin D This can be in the form of: ï‚· Ergocalciferol = 25-hydroxy vitamin D2 ï‚· Cholecalciferol = 25-hydroxy vitamin D3
Describe the treatment of vitamin D deficiency in the case of renal failure.
Alfacalcidol = 1-hydroxycholecalciferol
What do osteocytes produce?
Type 1 collagen and other extracellular matrix components
What is RANK ligand?
An osteoclast-activating factor – it increases the activation of osteoclasts It stimulates the maturation of osteoclasts from osteoclast precursors If there are more mature osteoclasts, you get more bone resorption
Define osteoporosis.
Having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young healthy adults (usually referred to as a T-score of -2.5 or lower) BMD is measured using Dual Energy X-ray Absorptiometry (DEXA)
State some predisposing conditions for osteoporosis.
Post-menopausal oestrogen deficiency Age-related deficiency of bone homeostasis Hypogonadism in young men and women Endocrine conditions (e.g. Cushing’s syndrome, hyperthyroidism, primary hyperparathyroidism) Iatrogenic (e.g. prolonged use of glucocorticoids, heparin)
What are the benefits of oestrogen replacement to prevent osteoporosis in post-menopausal women?
It has an anti-resorptive effect in bone and, hence, prevents bone loss
What are some cautions and risks of oestrogen replacement?
In patients with a uterus (i.e. not had a hysterectomy), you must give additional progestogen to prevent endometrial hyperplasia and reduce the risk of endometrial carcinoma Risks: ï‚· Breast cancer ï‚· Venous thromboembolism
Name 2 selective oestrogen receptor modulators and their effects.
Selective oestrogen receptor ANTAGONISTS – Tamoxifen  Antagonises ERs in the breast  Oestrogenic activity in bone  But, oestrogenic activity in uterus, which limits its use in osteoporosis Selective oestrogen receptor AGONIST – Raloxifene  Oestrogenic in bone  Anti-oestrogenic in breast and uterus  But there is a risk of stroke and venous thromboembolism
What are the 1st, 2nd and 3rd line treatments for osteoporosis?
Bisphosphonates Denusomab Teriparatide
What are bisphonates analogues of?
Pyrophosphate
Give 2 examples of bisphosphonates.
Alendronate Sodium etidronate
Describe how bisphosphonates work.
They bind avidly to hydroxyapatite crystals in the bone and are ingested by osteoclasts They impair the ability of osteoclasts to resorb bone It also decreases the maturation of osteoclasts and promotes osteoclast apoptosis
State some uses of bisphosphonates.
Osteoporosis Malignancy – reduces bony pain Paget’s disease – reduces bony pain Severe hypercalcaemic emergency  I.V. saline to rehydrate  Then bisphosphonates
Describe the pharmacokinetics of bisphosphonates.
They are orally active but poorly absorbed Must be taken on an empty stomach Accumulates at the site of bone mineralisation and remains a part of the bone until it is resorbed
State 4 unwanted actions of bisphosphonates.
Oesophagitis Flu-like symptoms Osteonecrosis of the jaw (greatest risk in cancer patients receiving IV bisphosphonates) Atypical fractures (due to over-suppression of bone remodelling)
What is denusomab and how often does it need to be given?
It s a human monoclonal antibody It binds to RANKL and inhibits osteoclast formation and activity It is given subcutaneously every 6-12 months
What is teriparatide and how often does it need to be given?
Recombinant fragment of PTH Increases bone resorption and formation – but formation exceeds resorption Daily subcutaneous injections EXPENSIVE
What is strontium ranelate?
Not used anymore Stimulates bone formation and reduces bone resorption Increased risk of MI and thromboembolism
What are the three main functions of bones?
Mechanical – support and site for muscle attachment Protective Metabolic – reserve of calcium
What are the three main functions of bones?
Mechanical – support and site for muscle attachment Protective Metabolic – reserve of calcium
What are the two main components of bone and what are their relative proportions?
Inorganic (65%) – calcium hydroxyapatite (store of 99% of the body’s calcium, 85% of the phosphorous and 65% of Na and Mg) Organic (35%) – bone cells and protein matrix
What are the indications for bone biopsy?
Evaluate bone pain or tenderness Investigate abnormality seen on X-ray For bone tumour diagnosis To determine the cause of unexplained infection To evaluate therapy
What are the two types of bone biopsy?
Closed – needle – core biopsy with Jamshidi needle Open – for sclerotic or inaccessible lesions
What are the three types of bone cell?
Osteoblast – build bone by laying down osteoid Osteoclast – multinucleate cells of the macrophage family that resorb bone Osteocyte – osteoblast like cells
Where are osteocytes found?
Lacunae
What cytokine is important for stimulating the differentiation of osteoclast precursors into pre-osteoclasts?
M-CSF (this is produced by osteoblasts)
Which cells produce RANKL and what is its effect?
Pre-osteoblasts It stimulates the maturation of osteoclasts
What do mature osteoblasts produce that blocks the RANK/RANKL binding?
Osteoprotegrin
How are bones classified anatomically?
Flat Long Cuboid
What type of ossification leads to the formation of: a. Long Bones b. Flat Bones
a. Long bones Endochondral ossification b. Flat bones Intramembranous ossification
How else can bone be classified?
Trabecular (cancellous) or compact (cortical) Woven (immature) or lamellar (mature)
What is metabolic bone disease?
Disordered bone turnover due to imbalance of various chemicals in the body (vitamins, hormones, minerals etc.) Overall effect is reduced bone mass (osteopaenia) often resulting in fractures from little or no trauma
What are the three main categories of metabolic bone disease?
Related to endocrine abnormality (e.g. Vit D and PTH) Non-endocrine (e.g. age-related osteoporosis) Disuse osteopaenia
Describe the staining of calcified and uncalcified bone.
Calcified – green Uncalcified – orange
What are the primary causes of osteoporosis?
Age Post-menopause
What are the secondary causes of osteoporosis?
Drugs Systemic disease
Describe the histology of osteoporotic bone.
Weak trabecular bridging Holes and cysts
What is osteomalacia and what can it be caused by?
Condition of defective bone mineralisation that can be caused by: Vitamin D deficiency Phosphate deficiency (usually related to chronic renal disease)
What are the metabolic and endocrine consequences of vitamin D deficiency?
Secondary hyperparathyroidism –> increased bone resorption Hypocalcaemia – neuronal excitability causing muscle twitching, spasms, tingling and numbness
Describe the histology of osteomalacia.
No calcification of bone More uncalcified osteoid Bones are very bendy and cannot carry musculature very easily
What are the clinical consequences of osteomalacia?
Bone pain/tenderness Fracture (horizontal fractures at Looser’s zone at the neck of the femur are commonly seen) Proximal weakness Bone deformity
