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BIOL31571 > Lecture 12 - HPA axis disorders > Flashcards

Lecture 12 - HPA axis disorders Flashcards

1
Q

Hyperactivity of the HPA axis

A

Cushing’s syndrome

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2
Q

Hypoactivity of the HPA axis

A

Hypopituitarism

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3
Q

Hypopituitarism: what is it, what is it caused by, what clinical features are there, how is it diagnosed, and how is it treated?

A

Underactivity of the pituitary gland

  • Post-partum haemorrhage
  • Severe head trauma
  • Non-secreting pituitary tumours
  • Coma
  • Pale
  • Increased insulin sensitivity leading to * hypoglycaemia (may lead to coma)

Low cortisol and low/undetectable ACTH

Give hydrocortisone two or three times daily to replace the cortisol levels

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4
Q

Cushing’s syndrome: what is it, what may it be caused by, are the tumours adenomas or carcinomas, what hormones do they cause overproduction of, and how many cases are these attributed to?

A

The overproduction of cortisol

Tumours (either adenomas or carcinomas):
* Pituitary - ACTH - 70%
* Ectopic - ACTH-related peptides - 13%
* Ectopic - CRH - 1/1,250,000
* Adrenal - cortisol - 17%

Other causes:
* Synthetic glucocorticoids
* Immune suppression in transplantation
* Alcohol – pseudo-Cushings

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5
Q

Cushing’s syndrome: what are the steps of its diagnosis?

A
  1. Measurement of circulating Hormone Levels
  2. Low dose & high dose dexamethasone suppression test
  3. CRH stimulation test
  4. Petrosal sinus sampling
  5. CT or MR imaging of the Pituitary
  6. Detection of Metabolic Effects of Excess Hormone (e.g. hyperglycaemia)
  7. Serum Potassium
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6
Q

Pituitary tumours causing Cushing’s disease: what is the molecular mechanism behind it?

A

The pituitary causes secretion of high levels of ACTH, stimulating high levels of cortisol

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7
Q

Ectopic tumours causing Cushing’s disease: what are the types, what are they caused by, what are the molecular mechanisms behind them, how do those with this condition present, and how serious is it?

A
  • Ectopic ACTH-related peptide tumours - lung, thymus, pancreas tumours, result in high levels of ACTH/ACTH-containing peptide secretion, stimulating high levels of cortisol
  • Ectopic - CRH tumour - 1/1,250,000
  • Classical Cushing’s Syndrome signs
  • May present with electrolyte disturbances -hypokalaemia, etc
  • Infections - immune suppression

An ectopic tumour can progress very rapidly and the patient can die very soon after presentation - in benign tumours this it is a little less serious

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8
Q

Adrenal tumours causing Cushing’s disease: what is the molecular mechanism behind it?

A

Overproduction of cortisol

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9
Q

Synthetic glucocorticoids: what are they, what are some examples, and why may they cause Cushing’s disease?

A

Steroids that may be used in treatments for conditions such as asthma, arthritis, and immune suppression in transplantation

  • Prednisolone
  • Dexamethasone
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10
Q

Alcohol: how may it cause Cushing’s disease?

A

May cause a pseudo-Cushing

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11
Q

Why may ectopic ACTH syndrome result in pigmentation?

A

αMSH, a product of ACTH acts on melanocortin 1 receptor (MC1R/MC5R) in the skin to cause pigmentation - if tumours secrete high concentrations of ACTH or its precursors then these will act at the MC1R to cause pigmentation in some patients

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12
Q

Measurement of circulating hormones: what hormones are measured, how are they measured, and what other substances may be measured?

A
  • Cortisol (ie analyse diurnal rhythm)
  • ACTH
  • ACTH precursors
  • Measurement of urinary metabolites of hormones (cortisol, other adrenal steroids, etc)

Measurement of plasma ACTH - with two-site antibody-based ELISA

Cortisol (levels affected by stress, meals, and pulsatile release) - measure salivary levels or immunoassay based on a single antibody:
* Can use mass spec
* During day-200-550nmol/l
* At midnight less than 50nmol/l - optimal to use here for diagnosis, pituitary tumour would continue to produce cortisol

Measurement of urinary metabolites of hormones e.g. cortisol, and other adrenal steroids - affected by incomplete collection of urine

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13
Q

Why can’t you measure CRH for use in diagnosis?

A

CRH moves directly from the hypothalamus to the pituitary - no chance to test for levels without great invasion

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14
Q

Adrenal tumours: what are the expected levels of circulating hormones?

A

ACTH low
Cortisol high

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15
Q

Pituitary tumours: what are the levels of circulating hormones?

A

ACTH high
Cortisol high

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16
Q

Ectopic tumours: what are the levels of circulating hormones?

A

K⁺ often low

17
Q

Low dose dexamethasone suppression test: what is dexamethasone, what is this test used for, what happens when it is administered, why, what is the procedure of administration, and what is the expected result?

A

Synthetic form of cortisol

Determine excessive ACTH function suggesting a tumour

  • Normal pituitary suppressed - negative feedback, ACTH production is inhibited
  • Tumour pituitary partially resistant - negative feedback essentially ignored and secretion continues

Test:
* 0.5 mg dexamethasone every 6h for 48h
* Measure ACTH and cortisol at 0h and 48h

Result:
* Normal response: ACTH suppressed to <5ng/L, cortisol suppressed to <50nmol/L
* Cushing’s syndrome (any cause) - Cortisol remains >50nmol/L

18
Q

High dose dexamethasone suppression test: what is it, why is it used, what happens when it is administered, why, what is the procedure of administration, what is the expected result, and are there any issues in this method?

A

HDDST

Distinguish between pituitary and ectopic tumours

Suppresses pituitary gland - negative feedback

Test:
* 2mg dexamethasone every 6h for 48h
* Measure ACTH and cortisol at 0h and 48h

Result:
* Pituitary tumour - ACTH suppressed to 50% basal, cortisol suppressed to 50% basal
* Ectopic tumour - No suppression

Problems:
* 10% false negative - ie Pituitary tumours fail to suppress
* 10% false positive - ie. Suppression in ectopic tumours

19
Q

Test to stimulate ACTH: what are they used for, what do they test, what is the administration process, what are the results, and what are the problems in diagnosis?

A

To distinguish between pituitary and ectopic tumours

CRH test

Test:
* Collect baseline samples
* Give 100µg CRH iv
* Measure ACTH (& cortisol)

Results:
* Pituitary tumour - exaggerated or normal response
* Ectopic tumour - normal response
* Adrenal tumour - normal response

Problems:
* 10-15% of pituitary tumours fail to respond (false negative)
* Some ectopic tumours do respond to CRH

20
Q

IPSS: what is it, when is it used, what is the process, and are there any issues with it?

A

Inferior Petrosal Sinus Sampling

Helpful in cases where the ACTH source is in doubt - petrosal sinuses should have high ACTH levels if the tumour is in the pituitary gland, periphery should have high ACTH if the tumour is ectopic

  • Catheterise the petrosal sinuses draining the right and left sides of the pituitary
  • Give CRH into the peripheral vein & take blood samples

Disadvantage of IPSS:
* must be done in a specialised centre with appropriate technical expertise
* Requires precise and reliable ACTH assay
* Can cause mortality or morbidity

21
Q

Use of imaging techniques in diagnosing Cushing’s disease: do they differ in different tumours and what are the problems of imaging techniques?

A

Pituitary tumours:
* Plain radiology - can reveal large pituitary tumours (10-20%)
* High-resolution CT scanning - reveals ~50%
microadenomas
* MRI - pituitary adenomas

Problems:
* Imaging may not identify a pituitary microadenoma
* 12-27% false positive
* 20-30% false negative - ie pituitary adenomas are not visible

Adrenal tumours:
* High-resolution CT scanning will reveal tumour

Ectopic Tumours
* High-resolution CT scanning - may pin point ectopic tumours on a whole body scan

Problems: Imaging may not identify a tumour causing Ectopic ACTH

22
Q

Detection of metabolic effects of excess
hormone

A

Hyperglycaemia, etc

23
Q

Serum potassium: when should it be measured and what are the negatives of this test?

A

Expected that potassium would be low in patients with ectopic ACTH syndrome

  • 30% false negative - ie potassium normal in ectopics
  • 10% false positive - ie potassium low in patients with pituitary tumours
24
Q

Pathway to the diagnosis of Cushing’s syndrome

A

1) Is it Cushing’s syndrome?
* Establish hypercortisolism in two 24h urine cortisol samples (may need LDDST)

2) Is it an adrenal tumour?
* Differentiate adrenal tumour by measuring ACTH and Cortisol at 4pm (may need HDDST)

3) If ACTH-dependent IPSS:
* Discover ACTH source

4) Use imaging techniques to find tumours

25
Q

Cushing’s syndrome: treatment

A

Adrenal Tumour - surgery to remove adrenal tumour

Pituitary Tumour - removal of pituitary tumour, irradiation, or treatment with metyrapone which blocks cortisol synthesis
Bilateral adrenalectomy.

Ectopic ACTH Syndrome:
* Aggressive tumours - chemotherapy
* Benign tumours - metyrapone to block excess cortisol production
* NOT generally removed by surgery

BIOL31571 (17 decks)

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