51. Electrolytes & Fluid Balance 💦 Flashcards
(537 cards)
1
Q
A
2
Q
Name the two main nuclei within which neurones of the neurohypophysis have their cell bodies.
A
Paraventricular Nucleus Supraoptic Nucleus
3
Q
What two hormones are produced by the neurohypophysis?
A
Vasopressin Oxytocin
4
Q
What is the principal action of vasopressin and how does it carry out this action?
A
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
5
Q
State some other actions of vasopressin.
A
Vasoconstriction Corticotrophin release Factor VIII and von Willebrand factor Central effects
6
Q
What are the main actions of oxytocin?
A
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
7
Q
What are the consequences of a lack of the neurohypophysial hormones?
A
Lack of Oxytocin – not clinically significant Lack of Vasopressin – Diabetes Insipidus
8
Q
What are the two forms of diabetes insipidus?
A
Central (cranial) and Nephrogenic Diabetes Insipidus
9
Q
What can cause central diabetes insipidus?
A
Damage to neurohypophysial system (injury, surgery, cerebral thrombosis, tumours, granulomatous infiltration) Idiopathic Familial (rare)
10
Q
What can cause nephrogenic diabetes insipidus?
A
Familial (rare) Drugs e.g. lithium, dimethyl chlortetracycline (DMCT)
11
Q
State some signs and symptoms of diabetes insipidus.
A
Polyuria Polydipsia Hypo-osmolar urine Dehydration Possible disruption of sleep Possible electrolyte imbalance
12
Q
State another cause of polydipsia that isn’t diabetes.
A
Psychogenic polydipsia This is a central disturbance that increases the drive to drink
13
Q
What test can be used to distinguish between normal, psychogenic polydipsia, central DI and nephrogenic DI? Describe the results you would expect.
A
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)
14
Q
Why is the urine osmolality of someone with psychogenic polydipsia lower (in the fluid deprivation test) than a normal subject?
A
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
15
Q
Describe the normal change in urine osmolality as plasma osmolality increases.
A
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
16
Q
Describe changes in plasma vasopressin following administration of hypertonic saline in a normal subject, psychogenic polydipsia, central DI and nephrogenic DI.
A
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
17
Q
What is SIADH?
A
Syndrome of Inappropriate ADH = when the plasma vasopressin concentration is inappropriate for the existing plasma osmolality
18
Q
State some signs of SIADH.
A
Decreased urine volume Increased urine osmolality
19
Q
What is the main consequence of SIADH?
A
HYPONATRAEMIA
20
Q
State some symptoms of SIADH that are caused by the hyponatraemia.
A
At relatively mild hyponatraemia = generalized weakness, poor mental function, nausea Severe hyponatraemia = confusion, coma, death
21
Q
State some causes of SIADH.
A
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
22
Q
How is SIADH treated?
A
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
23
Q
What is the name given to exogenous vasopressin?
A
Argipressin
24
Q
Where are V1 and V2 receptors found?
A
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
25
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
26
State two selective peptidergic vasopressin selective agonists.
V1 – Terlipressin V2 - Desmopressin
27
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
28
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
29
State some unwanted effects of Desmopressin.
Nausea Headaches Abdominal pain Fluid retention and hyponatraemia
30
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)
31
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
32
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
33
State some drugs that increase or decrease vasopressin secretion.
Increase vasopressin secretion = nicotine Decrease vasopressin secretion = alcohol + glucocorticoids
34
What are diuretics?
Drugs that act on the renal tubule to promote excretion of Na+, Cl- and H2O
35
What percentage of filtered fluid is reabsorbed in the proximal tubule?
65-70%
36
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
37
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
38
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
39
Other than through the cell, what other route is there for the movement of ions and water?
Paracellular pathway
40
What are diuretics?
Drugs that act on the renal tubule to promote excretion of Na+, Cl- and H2O
41
What percentage of filtered fluid is reabsorbed in the proximal tubule?
65-70%
42
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
43
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
44
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
45
Other than through the cell, what other route is there for the movement of ions and water?
Paracellular pathway
46
What is this pathway dependent on?
Gap junctions
47
What two other molecules in the filtrate are reabsorbed in the proximal tubule and are coupled with Na+ reabsorption?
Glucose Amino acids
48
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
49
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
50
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
51
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
52
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
53
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)
54
What are the main channels on the apical membrane of epithelial cells of the distal tubule?
Na+/Cl- cotransporter Aldosterone dependent sodium channels
55
Which channels are found on the basolateral membrane of the epithelial cells of the distal tubule?
Na+/K+ ATPase K+/Cl- cotransporter
56
Which aquaporin molecules are found in epithelial cells of the distal tubule?
AQP2 – apical membrane AQP3/AQP4 – basolateral membrane
57
Which vasopressin receptors are present on collecting duct cells?
V2 receptors
58
Describe the effect of aldosterone on collecting duct cells.
Aldosterone stimulates the production of Na+ channels and the production of Na+/K+ ATPases
59
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
60
List the five groups of diuretics.
Osmotic Diuretics Carbonic Anhydrase Inhibitors Loop Diuretics Thiazide Diuretics Potassium Sparing Diuretics
61
Give an example of an osmotic diuretic.
Mannitol
62
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
63
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)
64
Give an example of a carbonic anhydrase inhibitor
Acetazolamide
65
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
66
Give an example of a loop diuretic.
Frusemide (furosemide)
67
How much fluid loss can loop diuretics cause?
15-20%
68
What is the target of loop diuretics?
Na+/K+/2Cl- cotransporter
69
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
70
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+
71
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
72
What is the main use of loop diuretics?
Oedema
73
What are the unwanted effects of loop diuretics?
Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis
74
Give an example of a thiazide diuretic.
Bendrofluazide (bendroflumethiazide)
75
Where do thiazide diuretics act and what do they act on?
They act in the distal tubule They bind to the Na+/Cl- cotransporter
76
How much fluid loss can thiazide diuretics cause?
5-10% fluid loss
77
What effect do thiazide diuretics have on Mg2+ and Ca2+?
Increase in Mg2+ and Ca2+ reabsorption (unknown mechanism)
78
What are the uses of thiazide diuretics?
Hypertension Heart failure Nephrogenic diabetes insipidus Idiopathic hypercalciuria
79
What are the unwanted effects of thiazide diuretics?
K+ loss – metabolic alkalosis Inhibits insulin secretion (bad in diabetes mellitus)
80
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
81
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
82
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)
83
What measure can be taken to prevent this from happening?
Give ACE inhibitors with the diuretics
84
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
85
How much fluid loss can potassium-sparing diuretics cause?
5%
86
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)
87
What is the main use of amiloride?
It is given with K+ losing diuretics
88
What are the main uses of spironolactone?
Hypertension/heart failure Hyperaldosteronism
89
State some unwanted effects of K+ sparing diuretics.
Hyperkalaemia – metabolic acidosis Spironolactone (very non-specific action) – gynaecomastia, menstrual irregularities
90
State some unwanted effects of K+ sparing diuretics.
Hyperkalaemia – metabolic acidosis Spironolactone (very non-specific action) – gynaecomastia, menstrual irregularities
91
What are the main uses of spironolactone?
Hypertension/heart failure Hyperaldosteronism
92
What is the main use of amiloride?
It is given with K+ losing diuretics
93
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)
94
How much fluid loss can potassium-sparing diuretics cause?
5%
95
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
96
What measure can be taken to prevent this from happening?
Give ACE inhibitors with the diuretics
97
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)
98
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
99
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
100
What are the unwanted effects of thiazide diuretics?
K+ loss – metabolic alkalosis Inhibits insulin secretion (bad in diabetes mellitus)
101
What are the uses of thiazide diuretics?
Hypertension Heart failure Nephrogenic diabetes insipidus Idiopathic hypercalciuria
102
What effect do thiazide diuretics have on Mg2+ and Ca2+?
Increase in Mg2+ and Ca2+ reabsorption (unknown mechanism)
103
How much fluid loss can thiazide diuretics cause?
5-10% fluid loss
104
Where do thiazide diuretics act and what do they act on?
They act in the distal tubule They bind to the Na+/Cl- cotransporter
105
Give an example of a thiazide diuretic.
Bendrofluazide (bendroflumethiazide)
106
What are the unwanted effects of loop diuretics?
Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis
107
What is the main use of loop diuretics?
Oedema
108
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
109
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+
110
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
111
What is the target of loop diuretics?
Na+/K+/2Cl- cotransporter
112
How much fluid loss can loop diuretics cause?
15-20%
113
Give an example of a loop diuretic.
Frusemide (furosemide)
114
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
115
Give an example of a carbonic anhydrase inhibitor
Acetazolamide
116
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)
117
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
118
Give an example of an osmotic diuretic.
Mannitol
119
List the five groups of diuretics.
Osmotic Diuretics Carbonic Anhydrase Inhibitors Loop Diuretics Thiazide Diuretics Potassium Sparing Diuretics
120
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
121
Describe the effect of aldosterone on collecting duct cells.
Aldosterone stimulates the production of Na+ channels and the production of Na+/K+ ATPases
122
Which vasopressin receptors are present on collecting duct cells?
V2 receptors
123
Which aquaporin molecules are found in epithelial cells of the distal tubule?
AQP2 – apical membrane AQP3/AQP4 – basolateral membrane
124
Which channels are found on the basolateral membrane of the epithelial cells of the distal tubule?
Na+/K+ ATPase K+/Cl- cotransporter
125
What are the main channels on the apical membrane of epithelial cells of the distal tubule?
Na+/Cl- cotransporter Aldosterone dependent sodium channels
126
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)
127
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
128
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
129
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
130
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
131
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
132
What two other molecules in the filtrate are reabsorbed in the proximal tubule and are coupled with Na+ reabsorption?
Glucose Amino acids
133
What is this pathway dependent on?
Gap junctions
134
What is the most important vitamin D metabolite?
1, 25-dihydroxycholecalciferol (calcitriol)
135
What is the principle effect of calcitriol?
Increase calcium, magnesium and phosphate absorption in the small intestines
136
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)
137
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
138
What are the different names for vitamin D deficiency in children and adults?
Children – Rickets Adults – Osteomalacia
139
State some causes of vitamin D deficiency.
Inadequate dietary intake Lack of sunlight Receptor defects Renal failure Gastrointestinal malabsorptive states
140
Which step, in vitamin D metabolism, required UV light?
The conversion of 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3) requires UV light
141
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)
142
What can stimulate 1-hydroxylase in the kidneys?
Parathyroid Hormone (PTH)
143
How can lack of sunlight cause vitamin D deficiency?
It will mean that less 7-dehydrocholesterol is being converted to cholecalciferol
144
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
145
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
146
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
147
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
148
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
149
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
150
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
151
What can vitamin D excess lead to?
Hypercalcaemia and hypercalciuria (due to increased intestinal absorption of calcium)
152
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
153
What is Paget’s disease?
Very active (increased), localised but disorganised bone metabolism –usually slowly progressive. There is increased bone breakdown and bone formation.
154
What is Paget’s disease characterised by histologically?
Abnormal, large osteoclasts
155
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
156
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
157
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%)
158
What is the normal plasma calcium range?
2.2-2.6 mmol/L
159
State 2 hormones that increase plasma calcium concentration.
Calcitriol PTH
160
State a hormone that decreases plasma calcium concentration.
Calcitonin
161
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
162
What are the 2 direct effects of calcitriol?
Increased calcium absorption from the small intestine Increased mobilisation of calcium in bone
163
What can stimulate PTH release?
Hypocalcaemia
164
State 4 signs of hypocalcaemia.
Parasthesia Arrhythmias Convulsions Tetany
165
What effect does hypocalcaemia have on excitable tissues?
It sensitises excitable tissue --\> neuromuscular excitability
166
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
167
State 4 causes of hypocalcaemia.
Hypoparathyroidism (e.g. due to surgery) Vitamin D deficiency Pseudohypoparathyroidism Renal failure (impaired 1-alpha hydroxylase)
168
Describe the effect of hypercalcaemia on neuronal excitability.
It reduces neuronal excitability and you get atonal muscles
169
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
170
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)
171
State 2 other causes of hypercalcaemia.
Conditions of increased bone turnover (e.g. hyperthyroidism, Paget’s) Vitamin D excess (rare)
172
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
173
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
174
Describe the treatment of vitamin D deficiency in the case of renal failure.
Alfacalcidol = 1-hydroxycholecalciferol
175
What do osteocytes produce?
Type 1 collagen and other extracellular matrix components
176
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
177
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)
178
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)
179
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
180
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
181
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
182
What are the 1st, 2nd and 3rd line treatments for osteoporosis?
Bisphosphonates Denusomab Teriparatide
183
What are bisphonates analogues of?
Pyrophosphate
184
Give 2 examples of bisphosphonates.
Alendronate Sodium etidronate
185
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
186
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
187
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
188
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)
189
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
190
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
191
What is strontium ranelate?
Not used anymore Stimulates bone formation and reduces bone resorption Increased risk of MI and thromboembolism
192
What are the three main functions of bones?
Mechanical – support and site for muscle attachment Protective Metabolic – reserve of calcium
193
What are the three main functions of bones?
Mechanical – support and site for muscle attachment Protective Metabolic – reserve of calcium
194
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
195
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
196
What are the two types of bone biopsy?
Closed – needle – core biopsy with Jamshidi needle Open – for sclerotic or inaccessible lesions
197
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
198
Where are osteocytes found?
Lacunae
199
What cytokine is important for stimulating the differentiation of osteoclast precursors into pre-osteoclasts?
M-CSF (this is produced by osteoblasts)
200
Which cells produce RANKL and what is its effect?
Pre-osteoblasts It stimulates the maturation of osteoclasts
201
What do mature osteoblasts produce that blocks the RANK/RANKL binding?
Osteoprotegrin
202
How are bones classified anatomically?
Flat Long Cuboid
203
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
204
How else can bone be classified?
Trabecular (cancellous) or compact (cortical) Woven (immature) or lamellar (mature)
205
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
206
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
207
Describe the staining of calcified and uncalcified bone.
Calcified – green Uncalcified – orange
208
What are the primary causes of osteoporosis?
Age Post-menopause
209
What are the secondary causes of osteoporosis?
Drugs Systemic disease
210
Describe the histology of osteoporotic bone.
Weak trabecular bridging Holes and cysts
211
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)
212
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
213
Describe the histology of osteomalacia.
No calcification of bone More uncalcified osteoid Bones are very bendy and cannot carry musculature very easily
214
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
215
What is used to investigate mineralisation?
Fluorescent tetracycline labelling
216
What are the consequences of hyperparathyroidism?
Hypercalcaemia (increased Ca2+ reabsorption) Hypophosphataemia (increased phosphate excretion in the urine) Osteitis fibrosa cystica (due to increased osteoclast activity)
217
List the four organs that are directly or indirectly affected by parathyroid hormone to control calcium metabolism.
Parathyroid glands Bones Kidneys Proximal small intestine
218
State some causes of primary hyperparathyroidism.
Parathyroid adenoma Chief cell hyperplasia
219
State some causes of secondary hyperparathyroidism.
Chronic renal insufficiency Vitamin D deficiency
220
What are the symptoms of hyperparathyroidism?
Stones, Bones, Abdominal Groans and Psychic Moans Stones – calcium oxalate renal stones Bones – osteitis fibrosa cystica Abdominal Groans – acute pancreatitis Psychic Moans – psychosis and depression
221
What is the most important investigation for hyperparathyroidism and what will it show in someone with hyperparathyroidism?
X-ray of the hand Subperiosteal bone erosions Brown cell tumours – small areas of resorption in the long bones of the fingers that are filled with osteoclasts
222
What are the five features of renal osteodystrophy?
Increased bone resorption (osteitis fibrosa cystica) Osteomalacia Osteoporosis Osteosclerosis Growth retardation
223
What are the consequences of renal osteodystrophy?
Hyperphosphataemia Hypocalcaemia as a result of a decrease in vitamin D metabolism Secondary hyperparathyroidism Metabolic acidosis Aluminium deposition
224
What is Paget’s disease?
Disorder of bone turnover (there is a lack of proper communication between the cells)
225
What are the three stages of Paget’s disease?
Osteolytic Osteolytic-osteosclerotic Quiescent osteosclerotic
226
Describe the histology of Paget’s disease.
Prominent reversal lines Masses of osteoclasts in the same site as osteoblasts
227
In which ethnicities is Paget’s disease rare?
Asian African
228
Which sites does Paget’s disease most commonly affect?
Skull Sternum Spine Humerus Pelvis Femur Tibia
229
List some clinical features of Paget’s disease.
Pain Microfractures Nerve compression Skull changes Deafness Haemodynamic changes Cardiac failure Hypercalcaemias Development of sarcoma in the area of involvement
230
What is a Haversian canal?
Channel that blood vessels run in within bone
231
What are Howship’s Lacunae?
Pits in the bone surface where osteoclasts are found (also called resorption bays)
232
Describe the classification of bone as cortical and cancellous.
Cortical ï‚· Long bones ï‚· 80% of skeleton ï‚· Appendicular skeleton ï‚·80-90% calcified ï‚· Mainly mechanical and protective role Cancellous ï‚· Vertebrae and pelvis ï‚· 20% of skeleton ï‚· Axial ï‚·15-25% calcified ï‚· Mainly metabolic ï‚· Large surface
233
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
234
What are the two types of bone biopsy?
Closed – needle – core biopsy with Jamshidi needle Open – for sclerotic or inaccessible lesions
235
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
236
Where are osteocytes found?
Lacunae
237
What cytokine is important for stimulating the differentiation of osteoclast precursors into pre-osteoclasts?
M-CSF (this is produced by osteoblasts)
238
Which cells produce RANKL and what is its effect?
Pre-osteoblasts It stimulates the maturation of osteoclasts
239
What are Howship’s Lacunae?
Pits in the bone surface where osteoclasts are found (also called resorption bays)
240
What is a Haversian canal?
Channel that blood vessels run in within bone
241
List some clinical features of Paget’s disease.
Pain Microfractures Nerve compression Skull changes Deafness Haemodynamic changes Cardiac failure Hypercalcaemias Development of sarcoma in the area of involvement
242
Which sites does Paget’s disease most commonly affect?
Skull Sternum Spine Humerus Pelvis Femur Tibia
243
In which ethnicities is Paget’s disease rare?
Asian African
244
Describe the histology of Paget’s disease.
Prominent reversal lines Masses of osteoclasts in the same site as osteoblasts
245
What are the three stages of Paget’s disease?
Osteolytic Osteolytic-osteosclerotic Quiescent osteosclerotic
246
What is Paget’s disease?
Disorder of bone turnover (there is a lack of proper communication between the cells)
247
What are the consequences of renal osteodystrophy?
Hyperphosphataemia Hypocalcaemia as a result of a decrease in vitamin D metabolism Secondary hyperparathyroidism Metabolic acidosis Aluminium deposition
248
What are the five features of renal osteodystrophy?
Increased bone resorption (osteitis fibrosa cystica) Osteomalacia Osteoporosis Osteosclerosis Growth retardation
249
What is the most important investigation for hyperparathyroidism and what will it show in someone with hyperparathyroidism?
X-ray of the hand Subperiosteal bone erosions Brown cell tumours – small areas of resorption in the long bones of the fingers that are filled with osteoclasts
250
What are the symptoms of hyperparathyroidism?
Stones, Bones, Abdominal Groans and Psychic Moans Stones – calcium oxalate renal stones Bones – osteitis fibrosa cystica Abdominal Groans – acute pancreatitis Psychic Moans – psychosis and depression
251
State some causes of secondary hyperparathyroidism.
Chronic renal insufficiency Vitamin D deficiency
252
State some causes of primary hyperparathyroidism.
Parathyroid adenoma Chief cell hyperplasia
253
List the four organs that are directly or indirectly affected by parathyroid hormone to control calcium metabolism.
Parathyroid glands Bones Kidneys Proximal small intestine
254
What are the consequences of hyperparathyroidism?
Hypercalcaemia (increased Ca2+ reabsorption) Hypophosphataemia (increased phosphate excretion in the urine) Osteitis fibrosa cystica (due to increased osteoclast activity)
255
What is used to investigate mineralisation?
Fluorescent tetracycline labelling
256
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
257
Describe the histology of osteomalacia.
No calcification of bone More uncalcified osteoid Bones are very bendy and cannot carry musculature very easily
258
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
259
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)
260
Describe the histology of osteoporotic bone.
Weak trabecular bridging Holes and cysts
261
What are the secondary causes of osteoporosis?
Drugs Systemic disease
262
What are the primary causes of osteoporosis?
Age Post-menopause
263
Describe the staining of calcified and uncalcified bone.
Calcified – green Uncalcified – orange
264
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
265
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
266
How else can bone be classified?
Trabecular (cancellous) or compact (cortical) Woven (immature) or lamellar (mature)
267
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
268
How are bones classified anatomically?
Flat Long Cuboid
269
What do mature osteoblasts produce that blocks the RANK/RANKL binding?
Osteoprotegrin
270
Describe the classification of bone as cortical and cancellous.
Cortical ï‚· Long bones ï‚· 80% of skeleton ï‚· Appendicular skeleton ï‚·80-90% calcified ï‚· Mainly mechanical and protective role Cancellous ï‚· Vertebrae and pelvis ï‚· 20% of skeleton ï‚· Axial ï‚·15-25% calcified ï‚· Mainly metabolic ï‚· Large surface
271
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
272
What are the two main radiographic signs?
Osteopenia Osteosclerosis
273
What is the lucency of the following scans proportional to: a. X rays b. Densitmetry c. CT scans d. MRI scans e. Radionucline bone scans
a. X rays Density b. Densitometry Density and attenuation c. CT scans Density and attenuation d. MRI scans Chemical and water content e. Radionuclide bone scans Bone turnover
274
What is the main difference between osteoporosis and osteomalacia?
Osteoporosis – decreased bone mass Osteomalacia – decreased bone mineralisation
275
Describe the microstructure in osteoporosis.
Normal Though there is an overall decreased quantity of bone
276
What are the features of osteomalacia?
Too little mineral – osteopenic and soft bone bends and deforms Too much osteoid – Looser’s zones If calcium remains low --\> secondary hyperparathyroidism
277
What are Looser’s zones? Where are they found?
Narrow lucency, perpendicular to the bone cortex Found in the pubic rami, proximal femur, scapular and lower ribs
278
What is a distinctive feature of osteomalacia that can be seen in an X-ray of the vertebrae?
Codfish vertebrae – biconcave loss of height
279
What radiographic feature is common to both osteomalacia andosteoporosis?
Osteopenia
280
What is the key difference between osteomalacia and rickets?
Rickets occurs before the growth plates have fused As the metaphysis grows most rapidly, it shows the most obvious changes
281
What are the radiographic features of rickets that are linked to the metaphysis?
Indistinct frayed metaphyseal margin Widened growth plate (no calcification taking place) Bowing of weight bearing bones
282
What is Rickety Rosary?
Enlargement of the anterior ribs
283
Describe how PTH, calcium and phosphate change in: a. Primary HPT b. Secondary HPT c. Tertiary HPT
a. Primary HPT PTH – high Calcium – high Phosphate – low b. Secondary HPT PTH – high Calcium – low Phosphate – normal or low c. Tertiary HPT PTH – high Calcium –high Phosphate – low
284
What are the main consequences of secondary HPT to bone?
Resorption and increased density
285
List 4 types of bone resorption.
Subperiosteal Subchondral Intracortical Brown tumours
286
What are the differences between slow and fast bone loss?
Slow – Involutional Osteoporosis  Bone has time to remodel  Bone loss occurs according to mechanical needs Fast – hyperparathyroidism/disuse osteoporosis  Bone loss is too rapid  Loss does not cater to mechanical needs
287
Describe the radiological features of renal osteodystrophy.
 Subperiosteal bone erosions  Brown tumours  Sclerosis – axial skeleton/vertebral end plates (rugby jersey spine)  Soft tissue calcification (arteries/cartilage)
288
What is metabolic bone disease?
A group of disease that cause a change in bone density and bone strength by increasing bone resorption, decreasing bone formation or altering bone structure
289
What are the five main metabolic bone disorders?
Primary Hyperparathyroidism Osteomalacia/Rickets Osteporosis Renal Osteodystrophy Paget’s Disease
290
What are the main components of bone strength?
Mass Material Microarchitecture Macroarchitectue
291
When is peak bone mass reached?
Around 25 years
292
When does bone mass begin to decline?
Around 40 years NOTE: in women, the decline in bone mass accelerates after menopause
293
How are microfractures repaired?
Bone remodelling
294
Briefly describe the bone remodelling cycle.
A microcrack crosses the canaliculi and severs the osteocyte processes, inducing osteocyte apoptosis This signals to the surface lining cells, which release factors to recruit cells from the blood and marrow to the remodelling compartment Osteoclasts are generated locally and resorb the matrix and the mitrocrack Then osteoblasts deposit new lamellar bone Osteoblasts that become trapped in the matrix become osteocytes
295
What is the normal range for serum calcium concentration?
2.15-2.56 mmol/L
296
Describe the distribution of calcium.
46% plasma protein bound (albumin) 47% free calcium 7% complexes (with phosphate or citrate)
297
What is the ‘corrected’ calcium level?
This compensates for changes in protein level (if proteins are high, itcompensates down) Corrected calcium = [Ca2+] + 0.02(45-[albumin])
298
Describe the effect of metabolic alkalosis on calcium distribution.
It makes more calcium bind to plasma proteins thus reducing the free calcium levels NOTE: venous stasis may elevate free calcium
299
What are the two main targets of PTH?
Kidneys Bone
300
Describe the effects of PTH in: a. Bone b. Kidneys
a. Bone Acute release of available calcium (not stored in hydroxyapatite crystal form) More chronically, increased osteoclast activity b. Kidneys Increased calcium reabsorption Increased phosphate excretion Increased stimulation of 1-alpha hydroxylase (thus increasing calcitriol production)
301
Where does the PTH-mediated increase in calcium reabsorption take place in the nephron?
DISTAL convoluted tubule
302
Where does the PTH-mediated increase in phosphate excretion take place in the nephron?
PROXIMAL convoluted tubule
303
How many amino acids make up PTH and which part of this is active?
84 Active: N1-34
304
What is PTH dependent on?
Magnesium
305
What is the half-life of PTH?
8 mins
306
What else can the PTH receptor be activated by other than PTH?
PTHrP (PTH related protein) This is produced by some tumours
307
What does the parathyroid gland use to monitor serum calcium?
Calcium-sensing receptors
308
Describe the relationship between PTH level and calcium in vivo.
Steep inverse sigmoid function NOTE: there is a minimum level of PTH release (it can’t get below this even in the case of hypercalcaemia)
309
What are the causes of primary hyperparathyroidism?
Parathyroid adenoma (80%) Parathyroid hyperplasia (20%) Parathyroid cancer Familial syndromes
310
What biochemical results are diagnostic of primary hyperparathyroidism?
Elevated total/ionised calcium With PTH levels frankly elevated or in the upper half of the normal range (negative feedback should drop PTH if there is hypercalcaemia)
311
What are the clinical features of primary hyperparathyroidism?
Stones, Bones, Abdominal Groans and Psychic Moans Stones – renal colic, nephrocalcinosis Bones – osteitis fibrosa cystica Abdominal moans – dyspepsia, pancreatitis, constipation Psychic groans – depression, impaired concentration NOTE: patients may also suffer fractures secondary to the bone resorption IMPORTANT NOTE: hypercalcaemia also causes diuresis (polyuria and polydipsia)
312
What is the main site of action of calcitriol and what effect does it have?
Small intestine – increases calcium and phosphate absorption
313
Describe the effects of calcitriol on bone and in the kidneys.
Facilitates PTH effect on the DCT in the kidneys (increased calcium reabsorption) Synergises with PTH in the bone to increase osteoclast activation/maturation
314
Which receptors/proteins are involved in mediating the effects of calcitriol on the intestines?
TRPV6 Calbindin
315
What parameter is used to determine whether a patient is vitamin D deficient?
Deficient \< 20 ng/M (50 nmol/L) Normal \> 30 ng/M (75 nmol/L)
316
What is Rickets?
Inadequate vitamin D activity leads to defective mineralisation of the cartilaginous growth plate (before a low calcium)
317
State some signs and symptoms of Rickets.
Symptoms: ï‚· Lack of play ï‚· Bone pain and tenderness (axial) ï‚· Muscle weakness (proximal) Sign: ï‚· Age dependent deformity ï‚· Myopathy ï‚· Hypotonia ï‚· Short stature ï‚· Tenderness on percussion
318
State some Vitamin D related causes of Rickets/Osteomalacia.
Dietary deficiency Malabsorptoin Drugs – e.g. enzyme inducers such as phenytoin Chronic renal failure Rare hereditary
319
For each of the following state whether it would be high, low ornormal in the serum of a Rickets patient: a. Calcium b. Phosphate c. Alkaline Phosphatase d. 25-OH cholecalciferol e. PTH f. URINE phosphate
a. Calcium Normal or Low b. Phosphate Normal or Low c. Alkaline Phosphatase High d.25-OH cholecalciferol Low e. PTH High f. URINE phosphate High
320
Other than PTH, what else can cause increased phosphate excretion?
FGF23
321
What effect does this factor have that is unlike PTH?
It inhibits 1 alpha-hydroxylase, thus inhibiting calcitriol production
322
Which cells produce this factor?
Osteoblast lineage cells
323
Other than Vitamin D deficiency, what else can cause Rickets/Osteomalacia?
Phosphate deficiency
324
State some phosphate-related conditions that cause Rickets/Osteomalacia.
X-linked Hypophosphataemic Rickets (mutation in Phex (this cleaves FGF23)) Autosomal Dominant Hypophosphataemia Rickets Oncogenic Osteomalacia (mesenchymal tumours can produce FGF23)
325
What can cause osteoporosis due to increased bone resorption and decreased bone formation?
Glucocorticoids
326
How does oestrogen deficiency lead to a decrease in bone mineral density?
It increases the number of bone remodelling units It causes an imbalance in bone remodelling with increased bone resorption compared to bone formation
327
Describe the biochemistry of someone with osteoporosis.
Everything should be normal if the cause is primary
328
What is the single best predictor of fracture risk?
BMD
329
What is used to measure BMD?
DEXA scans
330
Which bones are used when measuring BMD and why?
Vertebral bodies  Commonest fracture  Good measure of cancellous bone  It is a highly metabolically active bone so it is quick to respond to treatment Hip – second commonest fracture NOTE: fracture risk assessment tool (FRAX) uses hip BMD
331
Which chains make up type 1 collagen?
2 x alpha 1 1 x alpha 2
332
What can be used as a marker of bone formation that is linked tocollagen production?
Procollagen type 1 N-terminal propeptide (P1NP)
333
What can be used as a measure of bone resorption that is linked to collagen production?
C-terminal telopeptide (CTX) – serum N-terminal telopeptide (NTX) – urine 3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form a pyridinium ring linkage These can be measured
334
After how long do bone resorption markers fall?
4-6 weeks
335
What are the problems with cross-linking collagen, with regards to measurement of bone markers?
Reproducibility Positive association with age Need to correct for creatinine Diurnal variation in urine markers
336
What bone formation marker is commonly in use?
Alkaline Phosphatase
337
What is it used in the diagnosis and monitoring of?
Osteomalacia Paget’s Bone Metastases
338
What is P1NP being used for now?
Used as a predictor of response to anabolic treatments
339
What are the two forms of alkaline phosphatase?
Liver Bone
340
Which bone diseases will cause a rise in ALP?
Osteomalacia Bone metastases Also hyperparathyroidism and hyperthyroidism
341
How does alkaline phosphatase change with age?
Increases markedly during puberty reaching its highest levels Remains relatively constant following puberty (potential small rise after the age of 50)
342
What biochemical changes occur in renal osteodystrophy?
Increased serum phosphate Reduction in calcitriol
343
Describe the sequelae of renal osteodystrophy.
Secondary hyperparathyroidism This is unsuccessful and hypocalcaemia develops This leads to excessive stimulation of the parathyroid glands, leading to parathyroid hyperplasia The parathyroid cells begin to reduce expression of calcium-sensing receptors (CSR) and Vitamin D receptors (VDR) and become autonomous (tertiary) This causes hypercalcaemia
344
When is hypercalcemia usually found? - what accounts for most cases?
- relatively clinical problem that is often incidentally found on screening labs - hyperparathyroidism and malignancy account for 90% of cases
345
What occurs in primary HPT that causes hypercalcemia?
- increase bone resorption and usually small elevations in Ca
346
What occurs in malignancy that causes hypercalcemia?
- occurs with solid tumors and leukemias - Ca values are high - in nonmetastatic solid tumors secretion of PTHrP
347
What occurs in Milk-Alkali syndrome that causes hypercalcemia?
- high intake of milk or Ca carbonate (tums) - metabolic alkalosis stimulates Ca2+ reabsorption
348
What medications cause hypercalcemia?
- lithium (increased secretion of PTH) - Thiazide diuretics (lower urinary Ca2+ excretion) - thyroid hormone - estrogens and progesterones - Hypervit A and hypervit D (this increases calcitriol)
349
What is pseudohypercalcemia?
- elevation in total Ca2+, but not the ionized form: thyrotoxicosis, pheochromcytoma, adrenal insufficiency, islet cell tumors of the pancreas, and elevated platelet count (more bound Ca2+ but not true elevation of active Ca2+)
350
Manifestations of Hypercalcemia?
- bones, stones, abdominal pain and psychic overtones - bones: bone pain and muscle weakness - stones: nephrolithiasis: used to be most common presentation, will see high Ca on CMP - abdominal pain: constipation, nausea and anorexia - psychic: anxiety, depression and cognitive dysfunction - renal: polydipsia, and polyuria which will result in dehydration - CV: bradycardia, shortening of QT interval, and varying arrhythmias - CNS depression
351
Work up of calcium disorders?
- serum calcium level: will be artificially elevated if tourniquet left on too long or if pt is dehydrated - can be artificially increased by elevated albumin or decreased if albumin is decreased - normal: 8.2-10.2 mg/dL - ionized calcium: 50% of calcium in this form, changed by blood pH (look at arterial blood gas) - normal: 1.15-1.35 mg/dL
352
When will there be falsely elevated Ca in asymptomatic pt?
- when albumin levels are elevated - need to confirm elevated Ca2+ with 2 readings with albumin
353
What else will you see in hypercalcemic lab findings?
- phosphate usually is slightly decreased - ALP may be slightly increased because bone is getting turned over - need to rule out thyroid dysfunction - check PTH level and if that is normal check PTHrP
354
When would 24 hr urinary Ca excretion be low?
- in Milk-alkali sydrome, thiazide diuretic use and familial hypocalciruic hypercalcemia
355
Tx of hypercalcemia?
- depends on etiology - tx underlying etiology will correct hypercalcemia
356
Lab findings in primaray hyperparathyroidism?
- serum Ca will be high, elevated PTH is also present, high urine phosphate and low serum phosphate levels, ALP will be elevated, urine calcium will be high because hypercalcemia in blood overwhelms absorptive capacity of kidneys for calcium - increased urinary cAMP
357
What happens in a hypercalcemic crisis?
- saline diuresis: Ca2+ \> 14 mg/dL - pt is usually dehydrated - so hydrate the personto decrease Ca; infuse 250-500 ml/hr of saline to rehydrate - give IV synthetic calcitonin - give IV biphosphonates (stop leaching of bone): max effect in 2-4 days, zoledronic acid or pamidronate
358
Etiologies of primary HPT
- 80%: parathyroid adenoma (enlarged gland) - 15%: hyperplasia -
359
Presentation of a parathyroid carcinoma?
- rare:
360
2 criteria dx PT cancer?
- local invasion of contiguous structures - lymph node or metastatic spread
361
What is primary method of tx of parathyroid cancer?
- surgery - chemo and radiation not very helpful 3 outcomes: 1/3 cured at surgery, 1/3 recur and may be cured with reoperation, other 1/3: short, aggressive course - if not surgically tx: manage hypercalcemia
362
Presentation of primary HPT?
- hypercalcemia (asymptomatic) - PTH mediated bone resorption: decreased bone resorption: decreased bone mineral density, and increased risk of vertebral fractures - CV: HTN and left ventricular hypertrophy and diastolic dysfunction - often aren't a lot of physical findings unless malignancy is underlying cause -\> then you have to search for a tumor, metastases and nodes should be carried out
363
What is secondary HPT due to?
- maligancy: etiologies: multiple myeloma, lung, kidney, esophagus, head and neck, breast, skin and bladder cancers are some of the more common - work up: PTHrP - chronic to advanced renal disease: hypocalcemia/hyperphosphatemia, Cr/BUM elevated, PTH increased b/c of hypocalcemia
364
Levels of PTH and Ca in blood if primary HPT?
- blood PTH levels: 30-180 - blood calcium: 9-14
365
Levels of PTH and Ca in blood if malignancy?
- low blood PTH levels (less than 20) but PTHrP would be high - high blood calcium levels (11-14)
366
Work up of HPT
- intact PTH: normal - 10-50 pg/mL - serum creatinine: assess renal fxn - bone-specific alkaline phosphate: assess bone turnonver - calcitrol: Vit D metabolites- suppressed in hypercalcemia: normal 1.5 pmol/L
367
How do you measure bone density?
- DEXA-scan: dual energy x-ray absorption - most common, used to measure bone density of the femoral neck, lumbar spine and wrist
368
Management of primary HPT?
- pts with sx or progressive disease: surgical tx - general surgeons usually, although ENT also can do surgery
369
Preop localization for PHPT?
- use technetium-99m-sestamibi schintigraphy w/ SPECT imaging - ultrasonography - CT scan or MRI - used prior to minimally invasive parathyroidectomy - used if 1st surgery unsuccessful and need to do more extensive procedure or locate ectopic tissue
370
MIP?
-minimally invasive parathyroidectomy - must do preop imaging, limits the operative field to localize 2-4 cm incision, intraoperative PTH assay, 84-99% success rate based somewhat on surgeons experience - post surgical complication: hypocalcemia, vocal cord paralysis (recurrent laryngeal nerve)
371
Reoperation for PHPT
- 1st determine correct dx of PHPT - then may need to use localizing modalities again, aberrant location - need to do bilateral neck exploration to find causative gland(s)
372
Surgery indications in Asx pts?
- serum Ca2+: 1.0 mg/dL \> then normal - creatinine clearance
373
Asx pts - nonsurgical management?
- pts with only mild increase in Ca2+, pts who are unfit for surgery - pts who refuse surgery, and pts who are asx - avoid meds that make hypercalcemia worse - low Ca2+ diet: get rid of excessive Ca2+
374
Med management for Asx pts?
- bisphosphonates: IV - effects last for a week, pamidronate and zoledronate \* be aware of renal problems and jaw necrosis - calcimimetic: cinacalcet: activates Ca sensing receptor in PT gland inhibiting PTH secretion - used in pts with parathyroid carcinoma or those with secondary hyperparathyroidism - dialysis is a last resort
375
Bisphosphonates SE
- flu like sxs - ocular inflammation (uveitis) - hypocalcemia - hypophosphatemia - impaired renal fxn (nephrotic syndrome) - osteonecrosis of the jaw (more common in cancer pts) - nephrotoxic
376
Hypercalcemia of malignancy tx?
- tx underlying malignancy - use bisphophonates - calcitonin: SQ or IM, rapid antiresorptive agent - dialysis in Ca2+ free bath for pts in renal failure (secondary HPT)
377
Etiologies of hypocalcemia?
- hypoparathyroidism: usually from surgery for thyroid disease or for surgery for hyperparathyroidism, autoimmune - hypovitaminosis D - hyperphosphatemia: usually secondary to renal failure
378
Sxs of mild hypocalcemia?
- circumoral parethesias, hyperventilation - myalgias, muscle cramps - fatigue, hyperirritability, anxiety
379
Sxs of severe hypocalcemia?
- tetany/laryngospasm - seizures - myopathy - prolonged QT interval on EKG - papilledema, hypotension
380
what is trousseau's sign?
blood pressure cuff on arm -\> inflating cuff causes a tetanic spasm of wrist - this indicates hypocalcemia
381
Work up of hypocalcemia?
- decreased serum Ca2+ (need to check albumin levels, may need to use corrected form) - increased serum phosphate - 1, 25 (OH) 2D levels can be low - usually high PTH levels
382
Tx of hypocalcemia?
- Vit D and Ca supplement - Ca: 600-1200 mg elemental Ca - Thiazide diuretic: because increase Ca reabsorption - Calcitriol can be given as itincreases levels more rapidly - watch Ca2+ levels carefully as they can get hypercalcemic
383
Etiologies of hyperphosphotemia?
- marked tissue breakdown: sepsis, rhabdomyolysis - can induce hypocalcemia b/c Ca/phosphate precipitation in tissue - lactic acidosis/DKA - renal failure!!!! - hypoparathyroidism: also will have hypocalcemia - Vit D toxicity
384
Work up of hyperphosphatemia?
- serum phosphate: measured on whole blood, level usually inverse of Ca when abnormal values, normal: 2.5-4.5 mg/dL - CMP: check renal fxn, glucose - ABG for pH - urinalysis
385
Tx of hyperphosphatemia?
- acute: saline infusion to increase phosphate excretion, but can lower Ca2+ even more - hemodialysis Chronic: low phosphate diet: 900 mg a day, phosphate binders
386
Etiologies of hypophosphatemia?
- redistribution of phosphate from ECF into cells: admin of insulin in tx DKA, refeeding malnourished pts such as alcoholics and those with anorexia nervosa, acute respiratory alkalosis - decreasd intestinal absorption - increased urinary excretion
387
How does decreased intestinal absorption lead to hypophosphatemia?
- poor intake combined with chronic diarrhea or steatorrhea, Vit D deficiency, antacids w/ aluminum, or magnesium
388
How does increased urinary excretion lead to hypophosphatemia?
- primary and secondary hyperparathyroidism - primary renal phosphate wasting (rare) - osmotic diuresis (usually secondary to glucosuria)
389
Signs and sxs of hypophosphatemia?
- CNS: paresthesias, irritability, can progress to seizures and coma - CV: decreased contractility may lead to CHF - MS: proximal myopathy, dysphagia, may progress to rhabdomyolysis - lungs: decreased ventilation - releases PH04 from bone and with it Ca2+ resulting in hypercalcemia
390
Work up of hypophosphatemia?
- serum phosphate level - CMP - measure 24 hr urine phosphate excretion: low: DKA, refeeding, intestinal malabsorptio high: hyperparathyroidism, or renal tubular defect
391
Tx of hypophosphatemia?
- with DKA the phosphate will correct on its own - if phosphate is
392
What is usually the culprit of Vit D toxicity?
- usually due to those taking megadoses of Vit D - D is a fat soluble vitamin and in excess is stored in liver and adipose tissue
393
Main presenting sxs of Vit D toxicity?
- hypercalcemia - with hypophosphatemia - confusion (dehydrated), anorexia, and vomiting - extreme: muscle weakness and bone demineralization from being hypercalcemic - kidney stones
394
Work up of Vit D toxicity?
- Vit D level - hypercalcemia work up
395
Tx of Vit D toxicity?
- if not severe: IV saline - if more severe: glucocorticosteroids, IV bisphosphonates
396
Etiologies of Vit D deficiency
- elderly - winter months/houseboubd - northern climate - chronic renal disease - GI disease- malabsorption (celiac, gastric bypass, inflammatory bowel disease (crohns and ulcerative colitis) - liver failure - drugs: phenytoin, phenobarbitol, caracbomezepine, isoniazid, rifampin (TB), and prolonged glucocorticoid use
397
Presentation of Vit D deficiency?
- initially reduced absorption of Ca2+ and PO4- - leding to hypophosphotemia \> hypocalcemia - with persistent deficiency: hypocalcemia will result in HPT -\> phophoturia -\> demineralization of bone and w/o t it will manifest as osteomalacia/osteoporosis (adults), rickets (children) sxs: bone pain, muscle weakness: difficulty walking, and fractures
398
Work up of Vit D deficiency
- Vit D level - serum Ca2+ - phosphorus - PTH - ALP - electrolytes - BUN and creatinine
399
Tx of Vit D deficiency
- depending on how low level of serum vitamin D determines dosing of supplement - oral replacement of Vit D and not it's metabolites is recommended - there is an IM version in some countries: quite painful no added benefit - for those with malabsorption sometime metabolites are given or just sun is Rx
400
State some roles of calcium in the body.
Control of neuromuscular excitability (hypocalcaemia leads to hyperexcitability because Ca2+ normally blocks the Na+ channels) Muscle Contraction Strength in bone Blood clotting Intracellular second messenger
401
Where is calcium mainly stored?
Bone - 99% is stored as hydroxyapatite crystals in bone
402
How is calcium present in the blood? What is the main component?
Unbound ionised calcium - 50% Bound to plasma proteins - 45% Tiny bit as soluble salts
403
What is the usual daily intake of calcium?
1000 mg/day
404
What is the concentration of unbound ionised calcium in the blood?
1.25 Mm
405
What two hormones raise plasma calcium concentration?
Parathyroid Hormone Calcitriol (1,25-dihydroxycholecalciferol)
406
What hormone decreases plasma calcium concentration?
Calcitonin
407
Where is parathyroid hormone produced?
Parathyroid Glands (four of them) - produced in the follicular cells
408
Where is calcitonin produced?
Parafollicular cells in the thyroid gland
409
Describe the effects of parathyroid hormone on the kidneys.
Increases calcium reabsorption Increases phosphate excretion
410
Describe the effects of PTH on bone.
Stimulates osteoclasts Inhibits osteoblasts
411
Describe the effects of PTH on the small intestines.
PTH increases the activity of 1 alpha hydroxylase (in the kidneys), which is involved in the production of calcitriol, which increases calcium and phosphate absorption in the small intestine.
412
How does PTH increase calcium release from bone?
PTH has a direct effect in inhibiting osteoblasts. PTH makes the osteoblasts produce osteoclast activating factors (such as RANKL) that bind to receptors on osteoclasts and stimulates the break down of bone matrix to release calcium.
413
What can stimulate PTH release?
Low plasma calcium concentration Catecholamines (by binding to beta receptors)
414
Describe the negative feedback loops on PTH.
Increased plasma calcium concentration has a negative feedback effect on PTH Calcitriol also has a negative feedback effect
415
What is the precursor of calcitriol?
Cholecalciferol
416
Where does this precursor come from?
Diet Sun Light (UV B converts 7-dehydrocholesterol to cholecalciferol) NOTE: cholecalciferol is VITAMIN D3
417
Describe the reactions that have to take place to convert the precursor to calcitriol.
Cholecalciferol travels to the liver where 25-hydroxylase converts it to 25-hydroxycalciferol, which is then stored in the liver. It then moves to the kidneys where 1 alpha hydroxylase converts 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (calcitriol)
418
Describe the effects of calcitriol.
MAIN ACTION: stimulates calcium and phosphate absorption in the SMALL INTESTINE Minor effect on bone Kidneys - increases calcium reabsorption and increases phosphate excretion
419
How does calcitriol and PTH decrease phosphate reabsorption in the kidney?
They block the sodium/phosphate cotransporter Calcitriol does this via the action of FGF23 (fibroblast growth factor 23)
420
Describe the effects of calcitonin.
Calcitonin inhibits osteoclast activity Calcitonin also affects the KIDNEYS - increase sodium excretion and hence increase urinary excretion of phosphate and calcium.
421
State a physiological benefit of calcitonin.
During pregnancy women need a higher plasma calcium concentration (e.g. for milk), calcitonin protects the bone from break down.
422
State three causes of hypocalcaemia.
Hypoparathyroidism Pseudohypoparathyroidism Vitamin D Deficiency
423
What two signs are used to demonstrate hypocalcaemia?
Trousseau's Sign Chvostek's Sign These are both signs of tetany
424
What is pseudohypoparathyroidism and what are some clinical features?
Target organ resistance to PTH (also called Allbright Heriditary Osteodystrophy) Round face, short, low IQ, short 4th metacarpal, hypothyroidism, hypogonadism
425
What does vitamin D deficiency cause in children and adults?
Children - rickets Adults - osteomalacia
426
State three causes of hypercalcaemia.
Primary hyperparathyroidism Tertiary hyperparathyroidism Vitamin D Toxicosis
427
Describe the differences between primary, secondary and tertiary hyperparathyroidism.
Primary - caused by parathyroid adenoma producing huge amounts of PTH Secondary - caused by other reasons e.g. renal excretion of Ca2+ ions leading to compensatory increase in release of PTH (this causes low Ca2+ because it is being lost from the kidneys) Tertiary - initial chronic low plasma calcium 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)
428
State some consequences of parathyroid hormone excess.
Kidney stones (calcium deposits) Increased risk of fracture
429
What is a distinctive clinical feature of primary hyperparathyroidism?
Clubbing of the fingers
430
In what state is the iron in the haem group of haemoglobin?
Fe2+ (ferrous)
431
How much iron do you need per day to maintain the production of red blood cells?
20 mg/day
432
How can iron be lost under normal, non-pathological conditions?
Desquamation of cells in the skin and gut Bleeding (menstruation is one of the largest causes of loss of iron from the body in women)
433
How much iron does the human diet normally provide?
12-15 mg/day
434
State some natural foods that are high in iron.
Meat and fish Vegetables Whole grain cereal Chocolate
435
Which form of iron cannot be absorbed?
Fe3+ (ferric)
436
What effect does drinking tea have on iron absorption?
Cups of tea promotes the conversion of Fe2+ to Fe3+
437
Why do meat and fish eaters have an advantage over vegetarians in terms of iron absorption?
They will absorb iron in the haem form
438
State three systemic factors that increase iron absorption.
Iron deficiency Anaemia/hypoxia Pregnancy
439
Which channel, on the basement membrane of intestinal epithelial cells, allows movement of iron into the circulation?
Ferroportin
440
What is a key regulator of iron absorption that affects ferroportin?
Hepcidin
441
How is the level of hepcidin affected?
There are certain proteins (such as hepcidin) that have iron-responsive elements in their genes So iron is part of the complex that switches on hepcidin transcription
442
How is iron stored within cells?
In ferritin micelles
443
What transports iron in the circulation?
Transferrin
444
State three parameters that can be measured that involve transferrin?
Transferrin Transferrin Saturation Total Iron Binding Capacity (TIBC)
445
What is the normal transferrin saturation?
20-40%
446
Where is erythropoietin produced and what effect does it have?
Kidneys (stimulated by hypoxia) Increase in red blood cell precursors Red blood cell precursors will survive longer and the EPO will make them grow and differentiate to produce more progeny
447
What is anaemia of chronic disease?
Anaemia that is seen in patients with chronic disease
448
What typical signs of anaemia will these patients NOT have?
They will NOT be bleeding They will NOT be iron deficient, B12 deficient or folate deficient They will NOT have any bone marrow infiltration
449
State some laboratory signs of being ill.
Raised C-reactive protein (CRP) Raised Erythrocyte Sedimentation Rate (ESR) Raised Ferritin Raised Factor VIII Raised Fibrinogen Raised Immunoglobulins
450
State some causes of anaemia of chronic disease.
Chronic infections – e.g. TB/HIV Chronic inflammation – e.g. SLE, rheumatoid arthritis Malignancy Miscellaneous (e.g. cardiac failure)
451
What is the underlying cause of ACD?
ACD is due to the cytokine release that happens when someone is unwell The cytokines block utilisation of iron by red blood cells They also stop erythropoietin from increasing Stop iron flowing out of cells Increase production of ferritin Increased death of red cells
452
Give examples of cytokines involved in ACD.
TNF- Interleukins
453
State four broad causes of iron deficiency.
Bleeding Increased use (e.g. growth, pregnancy) Dietary deficiency (e.g. vegetarian) Malabsorption (e.g. Coeliac disease)
454
Under what conditions are full GI investigations performed?
Male Women over 40 Post-menopausal women Women with scanty menstrual loss
455
State some other investigations that can be performed.
Antibodies for coeliac disease Check for urinary blood loss
456
State three causes of a low MCV.
Iron deficiency Anaemia of chronic disease Thalassemia trait
457
How would you confirm thalassemia trait?
Haemoglobin electrophoresis
458
How does serum iron help distinguish between the three causes of microcytic anaemia?
Iron deficiency – LOW serum iron ACD – LOW serum iron
459
Describe the difference in ferritin levels in iron deficiency and anaemia of chronic disease.
Iron deficiency – LOW ACD – HIGH (because it is an acute phase protein)
460
Why is ferritin not always reliable?
Some people may have a chronic disease and be bleeding e.g. rheumatoid arthritis and a bleeding ulcer In this case the ferritin may appear normal You need to check the signs of infection/inflammation such as ESR and CRP to see if there is an underlying condition causing a rise in acute phase proteins
461
Describe the difference in transferrin in iron deficiency and ACD.
Iron deficiency – HIGH ACD – LOW/NORMAL
462
Describe the difference in transferrin saturation in iron deficiency and ACD.
Iron deficiency – LOW ACD – NORMAL
463
What is the diagnosis of a man of any age with a low ferritin?
Iron deficiency He needs upper and lower GI endoscopies to look for the source of the bleeding
464
State what you’d expect the following parameters to be in iron deficiency: a. Hb b. MCV c. Serum Iron d. Ferritin e. Transferrin f. Transferrin Saturation
a. Hb - LOW b. MCV - LOW c. Serum Iron - LOW d. Ferritin - LOW e. Transferrin - HIGH f. Transferrin Saturation - LOW
465
State what you’d expect the following parameters to be in anaemia of chronic disease: a. Hb b. MCV c. Serum Iron d. Ferritin e. Transferrin f. Transferrin Saturation
a.Hb - LOW b. MCV - LOW/NORMAL c. Serum Iron - LOW d. Ferritin - HIGH/NORMAL e. Transferrin - LOW/NORMAL f. Transferrin Saturation - NORMAL
466
State what you’d expect the following parameters to be in thalassemia trait: a. Hb b. MCV c. Serum Iron d. Ferritin e. Transferrin f. Transferrin Saturation
a.Hb - LOW b. MCV - LOW c. Serum Iron - NORMAL d. Ferritin - NORMAL e. Transferrin - NORMAL f. Transferrin Saturation - NORMAL
467
What is anaemia?
A reduction in the amount of haemoglobin in a given volume of blood below what would be expected in comparison with a healthy subject of the same age and gender
468
Other than a reduction in the absolute amount of haemoglobin in the blood stream, what else could cause anaemia?
An increase in the plasma volume can decrease the haemoglobin concentration
469
Why would this type of anaemia only be transient in a healthy individual?
The excess fluid would be excreted in a healthy individual
470
Broadly speaking, state four mechanisms of anaemia.
Reduced production of red blood cells/haemoglobin in the bone marrow Loss of blood from the body (haemorrhage) Reduced survival of red blood cells (haemolytic) Pooling of red blood cells in a very large spleen
471
For each type of anaemia, state whether they are usually hypochromic, normochromic or hyperchromic.
Microcytic – hypochromic Normocytic – normochromic Macrocytic - normochromic
472
State the common causes of microcytic anaemia.
Problem with Haem synthesis ï‚· Iron deficiency ï‚· Anaemic of chronic disease Problem with globin synthesis ï‚· Alpha thalassemia ï‚· Beta thalassemia
473
What mechanism usually causes macrocytic anaemia?
It usually results from abnormal haemopoiesis The cells fail to divide properly
474
What is megaloblastic erythropoiesis? Describe the appearance of a megaloblast.
Megaloblastic erythropoiesis refers to a delay in the maturation of the nucleus while the cytoplasm continued to mature and the cell continues to grow A megaloblast is an abnormal bone marrow erythroblast They are large and show nucleo-cytoplasmic dissociation
475
What is an alternative mechanism of macrocytosis?
You can get premature release of cells from the bone marrow Reticulocytes are about 20% larger than mature red cells so reticulocytosis would increase the MCV
476
State the two most common causes of megaloblastic anaemia.
B12 deficiency Folate deficiency
477
State some other common causes of macrocytic anaemia.
Drugs that interfere with DNA synthesis (e.g. chemotherapy) Liver disease Ethanol toxicity Recent major blood loss with adequate iron stores (if you’ve lost blood, the bone marrow will start spitting out reticulocytes to compensate) Haemolytic anaemia (reticulocytosis due to the loss of red cells)
478
State three mechanisms of normocytic normochromic anaemia.
Recent blood loss Failure to produce red blood cells Pooling of red blood cells in the spleen
479
State five causes of normocytic normochromic anaemia.
Peptic ulcer Oesophageal varices Trauma Failure of production of red blood cells ï‚· Early stages of iron deficiency and ACD ï‚· Renal failure ï‚· Bone marrow failure ï‚· Bone marrow infiltration Hypersplenism
480
Define haemolytic anaemia.
Anaemia resulting from shortened survival of red blood cells in the circulation
481
State two different classifications of haemolytic anaemia.
Haemolysis can be inherited (resulting from abnormalities of the cell membrane, haemoglobin or the enzymes in the red blood cell) It can be acquired usually resulting from extrinsic factors such as micro-organisms, chemicals or drugs Haemolytic anaemia can also be described as intravascular if there is very acute damage to the red cell It can also be classified as extravascular when the spleen removes defective red cells
482
State some inherited abnormalities that can cause haemolytic anaemia.
Abnormal red cell membrane Abnormal haemoglobin Defect in the glycolytic pathway Defect in the enzymes of the pentose shuttle
483
State some acquired abnormalities that cause haemolytic anaemia.
Damage to the red cell membrane Damage to the whole red cell Oxidant exposure
484
Explain how G6PD Deficiency can cause haemolytic anaemia.
G6PD is part of the pentose phosphate pathway This is the only source of reduced glutathione in red blood cells Because of the oxygen-carrying role of red blood cells, they are at constant risk of oxidant damage So people with G6PD deficiency are at risk of haemolytic anaemia in states of oxidative stress
485
When would you suspect haemolytic anaemia?
Otherwise unexplained anaemia that is normochromic and usually either normocytic or macrocytic Evidence of morphologically abnormal red cells Evidence of increased red blood cell turnover Evidence of increased bone marrow activity
486
What does the presence of fragments in the blood film suggest?
This suggests that red blood cells are being broken down within the circulation (in the small circulation)
487
What condition causes breakdown of red blood cells in small blood vessels?
Microangiopathic haemolytic anaemia
488
State some important signs of haemolytic anaemia.
Jaundice – because of the increased break down of red blood cells there is an increase in bilirubin The increase in bilirubin can also increase the risk of getting gallstones
489
State examples of inherited diseases causing haemolytic anaemia that have defects at the following sites: a. Membrane b. Haemoglobin c. Glycolytic Pathway d. Pentose Shunt
a. Membrane Hereditary spherocytosis b. Haemoglobin Sickle cell anaemia c. Glycolytic Pathway Pyruvate kinase deficiency d. Pentose Shunt G6PD deficiency
490
State examples of acquires disease causing haemolytic anaemia that have defects at the following sites: a. Membrane - immune b. Whole red cell - mechanical c. Whole red cell - oxidant d. Whole red cell - microbiological
a. Membrane – immune Autoimmune haemolytic anaemia b. Whole red cell –mechanical Microangiopathic haemolytic anaemia c. Whole red cell – oxidant Drugs and chemicals d. Whole red cell – microbiological Malaria
491
What is hereditary spherocytosis?
This is haemolytic anaemia or chronic compensated haemolysis resulting from an intrinsic inherited defect of the red cell membrane After entering the circulation, the cells lose membrane in the cell and become spherocytic
492
What are the features of red cells in hereditary spherocytosis?
They are LARGE and ROUND and have an increased MCHC
493
How does the bone marrow respond to the increased extravascular haemolysis in hereditary spherocytosis?
It increases the output of red cells leading to polychromasia and reticulocytosis
494
What is an effective treatment for hereditary spherocytosis?
Splenectomy
495
Why is a good diet important in patients with hereditary spherocytosis?
They have increased bone marrow activity and erythropoiesis so they need a supply of B12, folate and iron to keep producing red blood cells
496
Describe the pattern of inheritance of G6PD deficiency.
X linked recessive
497
What can G6PD deficiency cause?
Intermittent, severe intravascular haemolysis as a result of infection or exposure to an exogenous oxidant
498
What tends to appear in blood films during these episodes of severe intravascular haemolysis?
Irregularly contracted cells
499
What happens to the haemoglobin during these episodes?
It becomes denatured and forms round inclusions called Heinz bodies NOTE: you can get more than one Heinz body per cell unlike Howell-Jolly bodies
500
What causes acute haemolytic anaemia?
Results from the production of antibodies against red cell antigens This is very sudden and dramatic
501
Describe how acute haemolytic anaemia can lead to spherocytosis.
The immunoglobulin bound to the red cell is recognised by splenic macrophages, which remove parts of the cell membrane leading to spherocytosis
502
State two causes of spherocytosis.
Hereditary spherocytosis Autoimmune haemolytic anaemia
503
Describe the diagnosis of acute haemolytic anaemia.
Finding spherocytes Increased reticulocyte count Detecting immunoglobulin on the red cell surface Detecting antibodies to red cell antigens or other antibodies in the plasma
504
What is the treatment for acute haemolytic anaemia?
Corticosteroids or other immunosuppressive agents Splenectomy in severe cases
505
Which red blood cell parameters are increased in polycythaemia?
RBC Hct Hb
506
What is the term given to a condition where these parameters are increased but the absolute amount of haemoglobin is not increased?
Pseudopolycythaemia (or apparent polycythaemia) This is due to a decrease in plasma volume
507
State some causes of polycythaemia.
Blood doping Elevation of EPO when at altitude Tumour (renal or other tumour that can secrete high amounts of EPO) Abnormal function of bone marrow – it can result from inappropriately increased erythropoiesis that is independent of EPO, this is an intrinsic bone marrow disorder called polycythaemia vera It is a chronic myeloproliferative neoplasm
508
What are the consequences of polycythaemia?
Hyperviscosity of the blood This can lead to vascular obstruction
509
Define bone strength.
The ability of bone to resist fracture
510
What factors contribute to bone strength?
Density Structure
511
What method has been used for diagnosing osteoporosis and what are the limitations of this method?
DEXA scans This gives a reading of bone mineral density (BMD) but it doesn’t tell you anything about the bone structure
512
Describe the effects of oestrogen on osteoclasts.
Oestrogen stimulates apoptosis in osteoclasts
513
What are the two main divisions of bone composition?
Cell (10% of volume) Matrix (90%)
514
What are the two subsets of bone matrix and what falls undereach?
Organic – collagen, non-collagenous proteins, mucopolysaccharides Inorganic – hydroxyapatite crystals (calcium and phosphorus)
515
What are the four types of bone cells?
Osteoprogenitor cells Osteocytes Osteoblasts Osteoclasts
516
What is the role of osteoprogenitor cells?
These differentiate into the other types of bone cell
517
What is the role of osteocytes?
They are involved in bone homeostasis (they are found in the lacunae and have projections into the canaliculi)
518
How often does bone normally turnover?
120 days
519
Describe normal bone turnover.
The osteoclast will dissolve away the bone Preosteoblasts will move in and differentiate into osteoblasts In a healthy person, the osteoblasts will lay down more bone than the osteoclasts dissolved (so you don’t get any bone loss)
520
How is bone turnover different in an elderly person?
There is less apoptosis of osteoclasts and the resorption pits are very big and don’t get filled in by osteoblasts so you get loss of bone
521
What effect do bisphosphonates have on osteoblasts and osteoclasts?
Bisphosphonates encourage cell death in osteoclasts They damage their cytoskeleton so that the osteoblasts lose their RUFFLED BORDER, and without this they can’t function
522
What is a major problem with bisphosphonate use?
Atypical fractures
523
What causes this?
Bisphosphonates also have an effect on osteoblasts They reduce bone remodelling (which replaces old and damaged bone) so you get premature ageing of the bone Furthermore, microcracks form in the bones due to day-to-day use and if these microcracks are not filled in by bone remodelling they will eventually join up and cause stress fractures
524
What is the half-life of alendronate?
Around 10 years
525
What new drug has come onto the market that has a similar action to bisphosphonates but with a shorter half-life?
Denusomab (half-life = 6 months)
526
Describe the action of RANKL.
RANKL binds to RANK receptors on precursors to osteoclasts and promotes their maturation to osteoclasts
527
In a healthy person, what protein is responsible for regulating the bone remodelling process and how does it do this?
Osteoprotegrin It prevents the binding to RANKL to the RANK receptor (this is what denusomab also does)
528
State Wolff’s Law.
Bone remodels according to the stresses applied to it
529
At what age is peak bone mass reached?
30-40 years
530
State some other factors that contribute to bone mass
Genetics Nutrition Vitamin D Exercise
531
What are the five stages of fracture healing?
Haematoma Inflammation Soft Callous Hard Callous Remodelling
532
Which type of collagen is deposited in the soft callous?
Type 2 collagen
533
What prevents mineralisation in the soft callous?
Proteoglycans
534
What happens in stage 3 of fracture healing?
The soft callous is invaded by blood vessels Chondroblasts break down the calcified callous It is replaced by osteoid (type I collagen) produced by osteoblasts Osteoid calcifies to form woven bone
535
What happens in stage 4 of fracture healing?
Woven bone remodels to lamellar bone It is shaped relative to the load (Wolff’s law) Medullar canal reforms
536
Name four types of fracture
Spiral Oblique Comminuted Transverse
537
What type of fracture can occur in the bones of children due to their plasticity?
Greenstick fractures One cortex could break but the other cortex could bend but stay intact
