Hypoadrenal Disorders Flashcards

1
Q

How many carbon atoms does cholesterol have?

A

27

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2
Q

What determines which steroid hormones the different parts of the adrenal gland produce?

A

The combination of enzymes present in the different parts of the adrenal gland - hydroxylation in different positions of the cholesterol molecule gives different products

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3
Q

Which enzyme converts cholesterol to pregnenolone?

A

P450SCC = cholesterol side-chain cleavage enzyme

NOTE: Pregnenolone is the precursor for all the different steroid synthesis pathways (i.e. there is pregnenlone at the start of all of them)

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4
Q

The pituitary gland produces ACTH in response to what?

A

Stress → stimulates cortisol synthesis

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5
Q

Which enzyme converts corticosterone to aldosterone?

A

Aldosterone synthase (includes 18-hydroxylase)

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6
Q

State three causes of adrenocortical failure.

A

Adrenal glands destroyed

  • Tuberculous Addison’s disease - TB (bacterial infection) commonest cause worldwide
  • Autoimmune Addison’s disease - autoimmune disease commonest cause in UK

Congenital adrenal hyperplasia = disruption in the steroid synthesis pathway due to enzyme mutations → deficiency in functioning enzymes

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7
Q

State some consequences of adrenocortical failure.

A

In adrenocortical failure (Addison’s disease), you have a cortisol AND aldosterone deficiency

  • Fall in blood pressure
  • Loss of salt in the urine → hyponatraemia
  • Increased plasma potassium → hyperkalaemia
    • The above three consequences are all due to aldosterone deficiency
    • Reduced Na+ reabsorption via Na+/K+ pump and hence reduced water reabsorption to increase blood volume
  • Fall in glucose due to glucocorticoid deficiency
    • Cortisol acts to increase blood glucose levels for use by the body in times of stress
  • High ACTH resulting in increased pigmentation
  • Vitiligo
  • Eventual death due to severe hypotension

NOTE:

  • Sex steroids (mainly testosterone and precursors) no longer produced in adrenal cortex too as a result of adrenocortical failure
  • However, sex steroids can also be produced (from scratch) by gonads,
  • Therefore, this lack of production by the adrenal cortex doesn’t cause much of a problem
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8
Q

Why does Addison’s cause skin pigmentation?

A
  • The lack of cortisol stimulates the production of huge amounts of ACTH
    • Lack of negative feedback on ACTH production by cortisol
    • Due to the fact that cortisol levels are low, more and more ACTH is released to try and stimuate the adrenal cortex to produce cortisol
  • POMC (pro-opiomelanocortin) is a pro-hormone - synthesisd in the anterior pituitary
  • POMC is then broken down to form ACTH and MSH and endorphins and enkephalins and other peptides
  • High ACTH = high POMC = high MSH
    • MSH (melanocyte-stimulating hormone) causes skin pigmentaion

NOTE:

  • Endorphins = hormones naturally produced in response to pain
  • Enkephalins = peptide released by CNS neurones and adrenal medulla which acts to reduce/control pain
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9
Q

Why do Addison’s patients get vitiligo?

A

Vitiligo is an autoimmune disease where you have antibodies attacking the melanocytes → white patches on skin (loss of pigment)

Autoimmune diseases tend to go hand-in-hand

  • Probably due to the fact that there is already a fundamental problem in immune regulation, so when onea autoimmune disease develops, it is more likely another will develop too
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10
Q

State some tests for Addison’s disease.

A

You could measure:

  • 9am cortisol = low in Addison’s (but should be high in normal person)
    • Typical results in Addison’s = 100
  • ACTH = high in Addison’s (but should be low in normal person)
    • Normal range: 270-900

Then you could do a short synacthen test:

  • Inject 250µg synthetic ACTH (synacthen) intramuscularly
  • Measure cortisol response
    • If they have functioning adrenals, they should start to produce cortisol
    • However in Addison’s their cortiol levels would not increase regardless
    • Typical results in Addison’s (cortisol at 9:30am) = 150
    • Normal range: > 600
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11
Q

What is the most common cause of congenital adrenal hyperplasia (CAH)?

A

21-hydroxylase deficiency

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12
Q

What are the two degrees of CAH?

A

Complete enzyme deficiency

Partial enzyme deficiency

NOTE: Differences in the mutation of the gene determines whether the enzyme is completely non-functional (i.e. complete deficiency) OR the mutation allows lowe-level production of the functioning enzyme (i.e. partial deficiency)

  • Mutation in the site determining active site structure could mean enzyme is non-functional
  • Mutation is site recognised by TF could reduce rate of transcription and protein synthesis, resulting in lower amounts of functional enzyme
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13
Q

Which hormones are absent in complete 21-hydroxylase deficiency?

A

Cortisol

Aldosterone

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14
Q

Why are foetuses with CAH normally fine in utero?

A

In utero, the foetus will have maternal cortisol and aldosterone so don’t need to rely on their own endogenous production.

NOTE: These steroid hormones found in the mother’s blood circulation can cross the placenta to supply the foetus

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15
Q

What effect does 21-hydroxylase deficiency have on sex steroid synthesis?

A

It funnels the precursors towards the steroid synthesis pathway so you get an increase in adrenal sex steroids production

  • Mainly testosterone (and androgens). will be in excess the adrenal cortex can’t produce oestradiol - doesn’t have the aromatase enzyme required

NOTE:

  • Due to lack of cortisol, ACTH levels will be high to try and stimulate cortisol production in the adrenal cortex
  • However, because the pathway for cortisol synthesis will be blocked due to 21-hydroxylase deficiency, the sex steroid synthesis pathway will be stimulated instead
    • NOTE:
      • ACTH stimulates both cortisol and adrenal sex steroid production pathways, but cortisol is the main
      • However, if one pathway is blocked, then the other pathway will be stimulated in excess
  • Leads to excess sex steroid synthesis
  • This could be the reason for the adrenal hyperplasia - increase in proliferation of the sex steroid producing cells (mainly in zona reticularis)
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16
Q

What will happen to a baby with complete 21-hydroxylase deficiency after they are born?

A
  • They will have a salt losing Addisonian crisis due to the lack of aldosterone.
  • Addisonian crisis = acute adrenal insufficiency (i.e. suddenly have a major lack of hormones as all this time they were receiving their mother’s)
  • Addisonian crisis leads to dangerous symptoms like hypovolaemic shock (severe salt loss → severe hypotension → shock)
    • Shock = where tissue perfusion is insufficient to meet metabolic demand
  • Therefore a neonate with complete 21-hydroxylase deficiency can only survive less than 24 hours
17
Q

What are the two main features of 21-hydroxylase deficiency?

A
  • Hypotension
    • Due to lack of aldosterone
  • Virilisation → female babies will be born with ambiguous genitalia
    • Due to excessive androgen (testosterone) production

NOTE: Androgen = male sex hormone

18
Q

Describe the presentation of partial 21-hydroxylase deficiency.

A
  • They may present much later because they don’t have a salt losing Addisonian crisis
    • They still have enough aldosterone to prevent this
  • They will present once they start to see the effects of the excess adrenal sex steroids (mainly androgens like testosterone)
    • Hirsutism and virilisation in females
      • Hirsutism = excessive amounts of male-pattern hair growth in females
      • Virilisation during childhood just means developing male physical characteristics (e.g. muscle bulk, deep voice, hirsutism)
    • Precocious (earlier than normal) puberty in females
19
Q

Describe and explain the presentation and explanation of complete 11-hydroxylase deficiency.

A
  • With 11-beta hydroxylase deficiency there will be a build up of They will have high levels of 11-deoxycorticosterone
  • 11-deoxycorticosterone has mineralocorticoid effects (behaves like alosterone)
  • Therefore, they will have similar effects to having high aldosterone → HYPERTENSION and HYPOKALAEMIA
  • There will still be some funnelling of precursors towards the sex steroid synthesis pathway so the child will also be
    • NOTE: As virisation means masculanisation, boys may be missed because they tend to look normal
20
Q

Describe and explain the presentation of 17-hydroxylase deficiency.

A

They will have high levels of mineralocorticoids: aldosterone (and 11-deoxycorticosterone - precursor for aldosterone synthesis)

  • This is because the synthesis pathways for the other adrenocortical hormones are blocked
  • High aldosterone → hypertension and hypokalaemia

Cortisol deficiency → borderline hypoglycaemia

  • Because cortisol acts to increase blood glucose levels
  • NOTE: They will also have a lot of infections because you need cortisol to cope with the stress of infections

Sex steroid deficiency → absence of secondary sexual characteristics, problems with puberty (i.e. becoming capable of reproduction)