Assessing Endocrine Disorders Flashcards
Physiology
3 levels of endo system?
role of hypothalamus?
role of pituitary?
role of end organs for negative feedback?
what is top of pituitary?
below it? what does this contain?
on the sides?
what happens if optic chiasm compressed?
peptide hormone - charged and act where? come from?
steroid hormones - charge and act where? come from?
why wont one off blood test tell us much? what needs to be done instead? what is the principle behind this test?
The endocrine system is split into three levels:
• Primary – End organ
• Secondary – Pituitary
• Tertiary – Hypothalamus
In endocrine diseases, a person is either hyper-functioning, hypo-functioning or eu-functioning. The role of the hypothalamus is to integrate signals and convert them to chemical messengers. The chemical messenger can travel throughout the body via the blood. The signal is amplififed by the pituitary gland which contains enough hormones to be diluted and travel around the body. The hormones then act on their target organs. The end organs switch off the production of the central hormones, which is the principle of negative feedback.
The area around the pituitary gland is important, there is the hypothalamus at the top, with the optic chiasm and pituitary stalk below it. These structures may get compressed if there is a tumour. There is also the cavernous sinus just below, which contains various cranial nerves supplying the extra-ocular muscles. Therefore, any compressing of the optic chiasm can lead to double vision as well as loss of sight. The hypothalamus can only be seen in a saggital section. The pituitary fossa sits on top of the sphenoid sinus.
Hormones act at receptors which can be on the cell surface or nuclear:
• Peptide hormones
o are charged (on average negatively due to their side chains) and will act at surface receptors
o comes from the brain, pituitary or gut
• Steroid hormones
o are aliphatic (fat soluble) and so will act on nuclear receptors
o comes from the gonads or adrenals
Most hormone release is pulsatile and varies during the day. Thus, apart from the thyroid which has a long half life, doing a one-off blood test doesn’t tell us very much. Therefore, a dynamic test needs to be carried out.
The principle of a dynamic test is that although a one-off blood test doesn’t provide much information, a dynamic test can tell what the extremes of physiology are (E.g. if looking for deficiency, can be seen when a hormone should be highest or if looking for excess can be seen when hormone should be lowest), defining normality by looking at the extremes.
Tests
what is RIA? what is involved in the test? what happens in a test tube?
how do you measure binding? how do you measure amount of this?
how do you construct a curve?
what are the two types of assays used?
The principle of endocrine testing is based on the law of mass action. In old days they used radioactive tracers, but nowadays using coloured dyes. This is radioactive immunoassay (RIA). In the test there is a binding site, usually an antibody, and the hormone. If put into a test-tube, they form an equilibrium. In the test tube there will be hormone bound to the antibody, free hormones and antibodies.
To measure binding, there are radioactive tracer/colour markers bound to the hormone. To measure the amount of binding, the binding sites need to be full of the marker.
The first stage of measurement is constructing a curve. Known amounts of un-labelled hormone are added, which will displace some of the labeled hormone and thus there will be a drop in radioactivity. This can be used to construct a curve:
There are two types of assays that are used: total hormone assay and free hormone assay.
Total hormone assays are cheap and easy to do, but they have problems with regards to physiology (they are not always reflective of free hormone levels). This is because most hormones are bound to a binding protein in plasma (either specific or albumin), designed to protect the hormone from being broken down by enzymes before it reaches its target site.
In a total hormone assay, you would measure all of the triangles in the picture (sample) below to get an overall idea of how much hormone is in the sample. Hormones that are bound to proteins are not biologically active, they are being stored. Only free hormone is biologically active and can activate receptors on cells. This is measured by using a free hormone assay.
A free hormone assay is representative of the active hormone fraction, and is not binding protein dependent. However, free hormone assays are complex and expensive. Binding proteins and the hormones bound to them need to be removed, which is difficult as this could remove hormones or join hormones to more proteins. For this reason, free hormone assays are only used for thyroid hormone testing.
Thryoid
what causes release of TSH and what does this act on? what is released? which is more active?
Thyrotrophin releasing hormone (TRH) causes release of TSH, which acts on thyroid gland to release triiodothyronine and thyroxine (tetraiiodothyronine). T3 is the more active, and can be activated from T4 by being converted to T3 using deiodinases. T4 provides negative feedback, as it acts as an intravascular store of thyroid hormone. When a cell requires T3, it expresses deidonase which converts T4 to T3.
Thyroid Investigation
how can over production be tested?
how can under production be tested?
how can thyroiditis be tested?
what is a technesium scan and how is it used? what will we expect with a technesium scan?
• Over-production can be investigated using:
o Thyroid function test
o Autoantibodies (as most hyperthyroidism is caused by autoimmune reaction)
o Technesium scanning (tells the type)
• Underproduction can be investigated using:
o Thyroid function test
o Autoantibodies
• Thyroiditis (irritation of thyroid gland) can be investigated using:
o Thyroid function
o ESR (erythrocyte sedimentation rate)
o Technesium scanning
A technesium scan is used because technesium is taken up into the thyroid gland in the same way iodine is. This can be used to show if the thyroid gland is taking up iodine to tell if the cells are over-active or not.
In thyrotoxicosis the gland is biologically overactive, but in thyroiditis we have a destructive process, something destroying the gland making it leaky. Thus, the gland leaks its stores into the circulation, but biologically the thyroid is functioning fine. A technesium scan would be negative as the gland will not be taking up technesium as it is stunned/being destroyed.
Thyroid Function Tests
how long is the half life? how long does it take for levels to stabilise? what does this mean for testings?
T3 and T4 levels are always looked at first when diagnosing using TFTs.
As the half life of thyroid hormones is about 10 days, levels take around 6 weeks to stabilise. Therefore, TFTs cannot be carried out more frequently than once every 6 weeks.
Adrenals and Cortisol
how does cortisol affect plasma glucose levels?
fat stores?
muslces?
BP? how?
other two effects
Cortisol has it’s own diurnal rhythm, and has multiple effects on the body:
• Increases plaslma glucose levels
o Inc. gluconeogenesis
o Dec. glucose utilisation
o Increases glycogenesis
o Inc. glycogen storage
• Increases lipolysis (but usually insulin takes over, resulting in lipogenesis)
o Provides energy
• Proteins are catabolised
o Releasing amino acids, fed into gluconeogenic pathway (reason for red skin stretch marks)
• Na+ and H2O retention
o Maintains BP
• Anti-inf lammatory
• Increased gastric acid production (getting ready to possibly eat harmful food)
The Investigation of Cushing’s Disease is in Three Stages
what are the three stages?
what does low dose prove? why?
what does high dose prove? how?
• Screening
o Test urinary free cortisol
o Check diurnal rhythm
• Confirmation of the Diagnosis
o Do a low dose dexamethasone suppression test
• Differentiation of the Cause
o High dose dexamethasone suppression test
- if pituitary, cortisol falls; if ectopic or adrenal, it doesn’t
o Plasma ACTH
o Localisation (by using radiology)
Cortisol is released according to a circadian rhythm, and is highest in the early hours of the morning. In someone with high cortisol, levels will be high over the whole day.
Dexamethasone testing is used to see:
• the effect of ACTH
• if the body is producing too much cortisol
• what the source of the ACTH may be
Dexamethasone is a synthetic glucocorticosteroid, mimicking cortisol and therefore it inhibits ACTH production via negative feedback. It is given in a low dose and high dose.
Dexamethasone Suppression Test
3 diagnoses after low dose?
after high dose if cortisol go down - what
if doesnt, what are two diagnoses?
how do you differentiate?
First a low dose of 0.5mg of dexamethasone is given (6 hourly, 48 hours). In a normal person, there should be complete suppression of ACTH. If there is no decrease, then it could be one of the following:
• Cushing’s Disease – In which case it is a pituitary adenoma
• Adrenal Tumour – May be benign or malignant
• Ectopic ACTH production – May be benign or malignant
Then a high dosage of 2mg of Dexamethasone is given (6 hourly for 48hrs). This should suppress cortisol in pituitary dependent Cushing’s (i.e. Cushing’s disease) to less than 50% of the baseline. If the high dexamethasone dosage doesn’t suppress cortisol, it is due to
• Ectopic ACTH secreting tumour (ACTH is being released unregulated from the tumour, causing stimulation of cortisol release)
o In this case ACTH will be high
• Adrenal neoplasia releasing cortisol
o In this case ACTH will be low
• For the first result, the person has high cortisol that hasn’t decreased in the low dexamethasone test. ACTH is also high. When given high dexamethasone, cortisol level falls below 50% of the baseline (145 is less than 50% of 750). This means it is a pituitary cause, and therefore it is Cushing’s disease.
• In the second result, the person doesn’t have true Cushing’s as cortisol hasn’t fallen below 50% of the baseline (i.e. 750 is not half of 800). By using the differential diagnosis it cannot be said there is an ectopic source as ACTH is low; this means there is an adrenal tumour producing cortisol, resulting in negative feedback (hence low ACTH).
• The final result does have true Cushing’s as it hasn’t fallen below 50%, and ACTH is raised so person has an ectopic source of ACTH.
Localisation
how to see tumour?
if no tumour, what do you do? what does this tell us?
how do you test adrenal function locally?
how to you test for ectopic sources?
- Pituitary tumours can be seen using MRI scanning
- If no tumour is present, inferior petrosal sinus sampling (IPSS) can be used. This is when a catheter is placed into pituitary veins that drain into the inferior petrosal sinus, and comparing the amount of ACTH there with the amount in the periphery. This can tell if the source of ACTH is in the brain or ectopic.
- Adrenal function can be looked at with a CT or MRI scan.
- Ectopic sources can be looked at using an octreotide scan (type of nuclear medicine) or by ACTH sampling where blood is tested in the body to see where the ACTH is coming from.
Low Cortisol Levels
how do you test for hypo-activity?
short test? used to diagnose what?
long test? used to diagnose what? how?
Hypo-activity of cortisol can be diagnosed using the Synacthen test (Synacthen is synthetic ACTH).
A short synacthen test (250mcg) is where synacthen is given and ACTH levels are monitored in the following hour. This can be used to diagnose primary adrenal failure.
A long synacthen test (1mg) can be used to diagnose pituitary disease (secondary adrenal failure). For the first hour the levels would be low because in pituitary disease the adrenals would be shrunken. The dose given in the long synacthen test, is so large that over 24hrs there is some adrenal growth.
If at the end of first hour there is no response but on the second day there is, it suggests the gland isn’t working as the pituitary gland isn’t telling it what to do.
Insulin Tolerance
who wouldnt you do this with?
The better test however is the insulin tolerance test (wouldn’t give in elderly, epileptics or people with ischemic heart disease, instead use glucagon). Here the same parameters would be used as the synacthen test (low dose, then high dose).
Oral Glucose Tolerance Test
how can this be used to diagnose gh issues?
what happens with anoerxics?
- In normal individuals, GH levels fall following oral glucose and one of the samples during the test should have undetectable GH levels.
- Failure of suppression or a paradoxical rise in GH suggests acromegaly. Hence OGTT can be used to diagnose acromegaly.
- Anorexics starve themselves, resulting in liver dysfunction and thus they cannot produce IGF-1. When given a glucose load, GH falls, but as they haven’t got enough IGF-1, GH doesn’t fall below the target level, but it also doesn’t paradoxically rise.
Summary
Diseases are due to too much hormone or too little hormone. Hormone levels vary physiologically and hence testing needs to be dynamic:
• If the hormone is too high, suppress it (dexamethasone)
• If the hormone is too low, stimulate it (synacthen)
