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3rd year medicine > Biochemistry > Flashcards

Biochemistry Flashcards

1
Q

What is the distribution of body calcium?

A

99% within the skeleton, of the 1% outside the skeleton, 2/3rds is found within the cell and only a relatively small proportion is found extracellularly.

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2
Q

What about further subdividing the extracellular calcium component?

A

About 40% is bound to plasma proteins (mainly albumin), about 10% is complexed with e.g. citrate and phosphate and about 50% exists in the free form/ ionised state. Importantly, it is the free calcium only which is physiologically active.

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3
Q

What is the normal range for total serum calcium?

A

2.15 - 2.60 mmol/l

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4
Q

Tell me about pH and calcium (that classic exam Q)i.e. why someone could present with symptoms of acute hypocalcaemia but when you measure their calcium it appears normal

A

pH e.g. in an acute panic attack -> hyperventilation -> breathes off CO2 -> pH of blood increases (respiratory alkalosis) -> this causes albumin (which is an important buffer for H+ ions) to release H+ ions in order to try and bring down the pH. This allows more binding sites for calcium to bind to albumin, so you get a fall in the free calcium but if you were to measure the total calcium it appears normal.

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5
Q

Other than pH what else can affect total vs free calcium?

A

Plasma protein concentration: venous stasis and posture.
Venous stasis (don’t want to apply the tourniquet too tightly when talking blood because you get fluid leaking across the capillaries which leads to an increased concentration of albumin which results in an increase in the total measured calcium).
Posture (ideally want to take a sample of blood for calcium measurement when a patient is lying flat).

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6
Q

Why might hospitalised patients have a low albumin?

A

Albumin is a negative acute phase reactant and will decrease in times of inflammation etc. Therefore, this can cause their total calcium measurement to be low (so we use the corrected calcium measurement (corrected for albumin concentration)).

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7
Q

What is the formula for corrected/adjusted calcium?

A

Corrected calcium = measured calcium + 0.02 (40-albumin)

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8
Q

Where is PTH produced?

A

Produced by the parathyroid chief cells in response to a fall in free ionised calcium

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9
Q

What are the actions of PTH?

A

Stimulates resorption of bone by increasing the number and activity of osteoclasts (requires normal levels of vit D)
In the kidney: increases renal tubular reabsorption of calcium, decreases renal tubular reabsorption of phosphate, promotes hydroxylation to active vitamin D which allows gut absorption of calcium. So the net effect is to increase calcium and decrease phosphate.

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10
Q

What is an important co-factor in the release of PTH?

A

Magnesium.
So if somebody is hypocalcaemic you should measure their magnesium and if the magnesium is low, this can explain why the patient is hypocalcaemic. Once you replace the Mg, PTH can increase and calcium can rise.

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11
Q

What is the key thing to remember when looking at PTH normality (comparing it to the normal range)?

A

PTH normality needs to be interpreted in the context of the calcium

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12
Q

What is the active form of vitamin D?

A

1,25 (OH)2 cholecalciferol

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13
Q

What is the net effect of vitamin D on both calcium and phosphate?

A

Active vitamin D increases the gut absorption of both calcium and phosphate

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14
Q

The enzyme in the kidney involved in the final step of synthesis of active vitamin D is 1 alpha hydroxylase. What is it stimulated by?

A

Low plasma phosphate
Increase PTH
Oestrogens, prolactin, growth hormone (don’t worry too much about these)

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15
Q

What is the most important investigation to perform when you are managing a patient with either hypocalcaemia or hypercalcaemia?

A

Measure their PTH

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16
Q

What is the net effect of calcitonin in calcium homeostasis is when is it mostly used?

A

It’s net effect is to decrease calcium and phosphate (is released in response to raised ionised calcium). It has a relatively minor role in calcium homeostasis, it used to be used to treat patients with a raised calcium but its main use now is as a tumour marker.

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17
Q

What is the most common cause of hypercalcaemia?

A

Primary hyperparathyroidism (85% of the time this is due to a single adenoma)

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18
Q

What blood test results would you expect to see with primary hyperparathyroidism?

A

The calcium will be high and PTH will either be in the normal range or it will be increased (because under normal circumstances if someone is hypercalcaemic you would expect the PTH to be low).

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19
Q

What are the main treatments for hypercalcaemia?

A

Rehydration- give fluids because patients are often polyuric
Bisphosphonates - e.g. alendronate to inhibit osteoclast activity
Steroids, especially in patients with malignancy

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20
Q

What is Di George syndrome?

A

A congenital form of hypoparathyroidism that presents in infancy (leading to hypocalcaemia)

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21
Q

What is the commonest cause of hypoparathyroidism?

A

Due to surgery

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22
Q

Remind me of the structure of the glomerulus

A

Plasma side of the glomerulus, fenestra between the endothelial cells, and acellular basement membrane and slit pores between the epithelial cells lining Bowman’s capsule.

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23
Q

What is one of the cardinal biochemical signs of renal failure?

A

The development of proteinuria/ albuminuria, reflecting the fact that the glomerulus is damaged (because normally albumin is almost entirely retained within the glomerulus)

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24
Q

Why is serum urea not a great marker of glomerular function?

A

The production rate to urea is not constant and depends on protein breakdown, and there is also some renal tubular reabsorption of urea.

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25
Q

Why is serum creatinine a much more suitable marker of glomerular function?

A

Creatinine comes from skeletal muscle breakdown which is non regulated and constant from day to day, so we all create a constant amount of creatinine every day. (The only problem with this is that muscle mass means that one person’s creatinine production rate might be different to that of another person’s).

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26
Q

What are the stages of acute kidney injury? (Note: the stages of AKI are based on how much the creatinine goes up from baseline)

A

Stage 1= 1.5-2.0 x increase in creatinine from baseline or >26 micromol/l increase in 48 hrs.
Stage 2 = 2.0-3.0 x increase in creatinine from baseline
Stage 3 = >3.0 x increase in creatinine from baseline or >1.5 x to >354 micromol/l

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27
Q

Why is it important to establish whether a patient is in the pre-renal uraemic phase of an AKI or whether they have gone into ATN (acute tubular necrosis)?

A

Because if you give the patient fluid at the point of pre-renal uraemia then you save the day. However, if you give fluids to a patient with ATN or don’t do anything to restrict their fluid intake, over a period of time the patient will develop fluid overload and die as a result (because the damaged kidneys are unable to excrete the excess fluid)

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28
Q

What is the best way to distinguish between pre-renal uraemia and ATN?

A

Measure the urine sodium
Urine sodium in pre-renal uraemia will be <20 (because of RAAS)
Urine sodium in ATN will be >20 (inability to produce renin/ respond to aldosterone).

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29
Q

What is Fanconi syndrome in simple terms?

A

Globular tubular defect

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30
Q

Why don’t we rely on vasopressin for our hour to hour regulation of water balance?

A

Vasopressin stimulates water-only reabsorption, resulting in a diluted composition of the blood. So if you simply switch on vasopressin every time you become slightly volume depleted you would dilute down the concentration of everything in your blood and in particular the plasma sodium concentration would drop.

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31
Q

What does vasopressin (ADH) do?

A

It acts on the kidney to increase water permeability by inserting 4 aquaporin channels into the collecting duct, leading to increased water reabsorption which then decreases the plasma osmolality and completes a negative feedback loop.

32
Q

Where does aldosterone exert its action in the nephron?

A

In the distal tubule (note: the distal tubule is for fine tuning/ homeostatic regulation).

33
Q

What are the stages of CKD?

A 
Stage 1= eGFR > 90
Stage 2 = eGFR 60-90
Stage 3a = eGFR 45-60
Stage 3b = eGFR 30-45
Stage 4 = eGFR 15-30
Stage 5 = eGFR < 15
Stages 1 and 2 only if also structural abnormalities or proteinuria
34
Q

What are the consequences of CKD?

A

Increased urea and creatinine (due to decreased GFR)
Hyperkalaemia (due to failure of Na+/K+ ATPase in the DCT and because there is no Na+ coming round the nephrons to exchange for K+)
Metabolic acidosis (failure of the Na+/H+ exchange)
Hyperphosphataemia (because phosphate is not cleared by the glomerulus)
Secondary hyperparathyroidism
Anaemia (reduction in EPO)
Increased cholesterol/ triglycerides (don’t worry about mechanism of this)

35
Q

What is the equation for osmolarity?

A

2[Na] + urea + glucose

36
Q

What is pseudohyponatriaemia?

A

When someone has got a large amount of non-water in their plasma (lots of lipid and protein). The concentration of sodium in the plasma water is still being regulated normally (e.g. by vasopressin and aldosterone) but there is less water per unit volume of plasma. So now even though the plasma (water) concentration of sodium might be 140mmol/L, the plasma (total) sodium concentration could be e.g. 119mmol/L.

37
Q

What is the management for SIADH?

A

Treat the underlying cause (e.g. chest infection), fluid restriction (because it is a water overload problem). Tolvaptan (V2 ADH receptor antagonist).

38
Q

Why is over-rapid correction of hyponatriaemia dangerous?

A

You can draw water out of the cells and cause rapid cerebral cellular dehydration, and this is what causes central pontine myelinosis (which is irreversible brain damage within the midbrain that leads to an untreatable vegetative state).

39
Q

What is cranial diabetes insipidus versus nephrogenic DI?

A

Cranial DI is when patients are not making enough vasopressin, and nephrogenic DI is when patients are unable to respond to it.

40
Q

What test is sometimes indicated in the diagnosis of diabetes insipidus?

A

The water deprivation test

41
Q

How do we distinguish between cranial and nephrogenic DI?

A

Give the patient a synthetic peptide called DDAVP / desmopressin which is a vasopressin analogue. Then measure their urine output every 30 mins for a couple of hours. If the urine them concentrates, this proves there was a deficiency of vasopressin (i.e. cranial DI), if the urine still doesn’t concentrate then it proves it was renal insufficiency

42
Q

Which form out of cranial / nephrogenic DI do most patients have and how can we treat it?

A

Most patients have the cranial form and desmopressin then becomes the treatment (nasal spray).

43
Q

Why do we often see acidosis going alongside hyperkalaemia?

A

In the DCT of the kidney each Na+ ion can either be exchanged for potassium or a hydrogen ion but not both. So essentially, hydrogen and potassium ‘compete’ for excretion. In acidosis you generate more H+ ions which need to excreted so there will be less capacity left for K+ ions to be excreted = hyperkalaemia

44
Q

What is refeeding syndrome?

A

It occurs in starved patients, if you suddenly give them large amounts of carbohydrate, it will cause a very acute rise in insulin which will drive potassium acutely into cells and cause an acute drop in potassium (as well as other ions include magnesium and phosphate).

45
Q

What are the characteristic ECG changes seen in hypokalaemia?

A

Low T wave, ST segment depression, wide QT interval and prominent U wave

46
Q

What characteristic ECG changes are seen in hyperkalaemia?

A

Tented T waves, prolonged PR interval, flattened P waves, widened QRS

47
Q

What are the treatments for hyperkalaemia?

A 
10mls 10% calcium gluconate (to protect the myocardium) 
Salbutamol 
Insulin and dextrose 
Calcium resonium 
Haemofiltration or dialysis
48
Q

What is the treatment of hypokalaemia?

A

You can give oral supplements, but Sando-K which is the strongest one only has 12mmol of potassium in it, so you would need to five a lot of it to have any chance of it having a significant effect. If you need to give IV potassium to correct a deficit because there is a risk of cardiac dysrhythmias then you need to be really careful.

49
Q

What are the phenotypic changes of GH (growth hormone) excess?

A

Facial changes (coarsening of features, enlargement of the jaw which tends to spread the teeth out), changes in the hand (rings which no longer fit) and changes in the feet (shoes no longer fitting). Changes are related to the underlying remodelling of cartilage and bone under the influence of GH and IGF1 production (which is stimulated by GH).

50
Q

Does GH influence height?

A

If the patient is pre-pubertal you will see changes in height, although most people present post-pubertally where GH excess doesn’t influence height.

51
Q

What are some of the physiological changes seen in GH excess?

A

Because you have an enlarging pituitary tumour, that often causes the suppression of other pituitary hormones, particularly susceptible in the early phases are suppression of LH and FSH so you tend to end up with irregular/ absent periods, loss of libido and loss of secondary sexual characteristics. Patients may also develop hypertension, glucose intolerance and hypercalciuria (doesn’t appear as hypercalciuria because it is simply excreted in the urine, but it puts these patients at increased risk of developing calcium containing renal stones)

52
Q

How do you diagnose GH excess?

A

Clinical
Biochemical confirmation: basal GH and IGF1 (better to measure IGF1 as it doesn’t have the same pulsatility or circadian rhythm as GH)
Ultimately to clinch the diagnosis need to do a suppression test using glucose: glucose tolerance testing (GTT)

53
Q

GH deficiency may cause short stature in children. Considering that nutritional factors and other psychosocial factors are more likely to be the cause of short stature in children than GH deficiency, which particular group of individuals is short stature due to GH deficiency more likely / more common?

A

Survivors of childhood cancer (who have had chemotherapy / whole body radiation).

54
Q

What can cause GH deficiency?

A

Destructive lesions within the pituitary e.g. tumours, surgery, irradiation, meningitis, head injury.

55
Q

How do you diagnose GH deficiency?

A

In children the key thing is to monitor growth and look for a reduced growth velocity over time.
Basal GH/ IGF1 levels - remember that IGF1 levels are potentially slightly better than measuring GH levels, but IGF1 levels are highly dependent on the stage of pubertal development so the reference ranges are very complicated).
Ultimately you can only clinch the diagnosis with a stimulation test.

56
Q

How does stimulation testing work in GH deficiency?

A

Stimulation tests: insulin, glucagon (children <5 years), arginine +/- GHRH, clonidine. Failure of two stimuli required ideally.
The gold standard is the insulin stress test but it has issues with insulin dose miscalculation and mismanaging the correction of severe hypoglycaemia. You can use glucagon stimulation testing (used in young children) which causes blood glucose to increase which leads to release of insulin naturally.

57
Q

What does the thyroid gland produce when it is stimulated by TSH?

A

Predominantly T4 but also some T3 thyroid hormone.

58
Q

Tell me more about the thyroid hormones

A

T3 is around 5 times as physiologically active as T4. T4 is secreted solely from the thyroid. T3- <20% secreted from the thyroid, majority from peripheral de-iodination of T4. The T3 made from T4 can either be active T3 or reverse T3 which is inactive.

59
Q

What are the 3 proteins which bind thyroid hormone?

A

Thyroid binding globulin (TBG)
Thyroid binding pre-albumin
Albumin
99.98% of T4 is bound and 99.7% of T3 is bound. Only the free unbound forms are physiologically active.

60
Q

What TFTs would you see in a patient with primary hypothyroidism?

A

An increase in TSH (trying to stimulate thyroid hormone production) and a low free T4. (Note that T3 isn’t particularly helpful in the diagnosis of hypothyroidism).

61
Q

What TFT results would you see in sub-clinical (compensated) primary hypothyroidism?

A

A fairly mild increase in TSH and a low normal free T4 (on the lower side of normal). Can think of this as mild thyroid failure.

62
Q

What is the treatment for hypothyroidism?

A

Thyroxine replacement

63
Q

What TFTs would you see in a patient with primary hyperthyroidism?

A

An increase in free T4 and free T3 leading to a negative feedback suppression of TSH (can be undetectable). So note we do tend to measure free T3 in the context of hyperthyroidism

64
Q

Give an example of a specific scenario in which you may want to use thyroxine replacement with the aim of suppressing TSH

A

In some patients with thyroid cancer, because the thyroid cancer will grow under the influence of TSH

65
Q

What are the causes of TSH suppression (other than negative feedback from T3 and T4)?

A 
Low TRH (suppression by free thyroid hormones or by a defect in the hypothalamus which could lower TRH)
IL-1 and TNF cytokines (they are probably part of the mechanism seen in non-thyroidal illness)
Somatostatin, glucocorticoids and dopamine
66
Q

Which drug can cause hypo and hyperthyroidism?

A

Amiodarone (it contains a large amount of iodine)

67
Q

What does the adrenal cortex produce and what does the adrenal medulla produce?

A

The adrenal medulla is associated with catecholamine production and the adrenal cortex is associated with the production of adrenal androgens, cortisol and aldosterone.

68
Q

Where in the adrenal gland do phaechromocytomas arise?

A

From the adrenal medulla

69
Q

What proteins bind cortisol?

A

Cortisol binding globulin (CBG) and albumin. 90% bound.
When we report cortisol levels we report total cortisol levels, so anything which very significantly influences CBG levels or albumin levels can give you a false impression of cortisol excess or deficiency. E.g. in pregnancy CBG levels rise substantially and as a consequence total cortisol levels rise substantially (but you re-establish a new equilibrium so that your free fraction remains the same so you don’t see any physiological effect of this, but if you’re not aware of this you might see the high total cortisol level and wonder whether they have got Cushing’s for example).

70
Q

What are the physiological effects of cortisol?

A 
Carbohydrate metabolism (insulin antagonist, promotes gluconeogenesis)- so its part of the response to maintain blood glucose levels. 
Protein catabolism (break down) 
Immunosuppressant- this is usually the desired effect when using steroids therapeutically 
‘Permissive action’- catecholamines, free water clearance (so you need some cortisol present for catecholamines to function properly and also to clear free water, which is part of the mechanism for the development of hyponatriaemia in cortisol deficiency).
71
Q

Tell me about CTRF and MSH etc.

A

CTRF acts on the anterior pituitary. The anterior pituitary produces ACTH (adrenocorticotrophic hormone) which stimulates the adrenal glands. But ACTH is produced as part of a much larger precursor molecule and the other two cleavage products are beta-endorphins and MSH (melanocyte stimulating hormone), so if you have got a clinical condition associated with elevated ACTH levels, you tend to see the development of pigmentation.

72
Q

Tell me about congenital adrenal hyperplasia’s.

A

Patients are cortisol deficient because they have got an enzyme defect on the pathway of cortisol metabolism.

73
Q

What is the most common cause of secondary adrenal insufficiency? (Note: secondary causes are where you have got impaired ACTH production)

A

Exogenous steroid use

74
Q

What are the consequences of adrenal insufficiency?

A

Hyponatriaemia and hyperkalaemia (due to the loss of mineralocorticoid production- aldosterone). Hypotension (you tend to lose volume so patients can have postural hypotension). Pigmentation (due to raised ACTH levels). Hypoglycaemia (more rarely) and other non-specific symptoms (very often people just feel lethargic and unwell).

75
Q

What is the laboratory investigation for adrenal insufficiency? And how does it work?

A

Dynamic synacthen stimulation test. Based on the measurement of serum cortisol before and after injection of synthetic ACTH (the active ingredient in a synacthen injection is tetracosactrin). Give 250 micrograms of synacthen IM. Normal: absolute rise >420nmol/L (incremental rise)

76
Q

Why might patients with Addison’s disease have an increase in urea?

A

Because they are volume depleted so they develop a pre-renal uraemia

77
Q

Do you see the electrolyte disturbances seen in primary adrenal failure in people with secondary adrenal failure?

A

No because the RAAS system is working in these cases

3rd year medicine (31 decks)

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