Lecture 17: Steroid abnormalities

Question 1

What do you look at in Glucocorticoid deficiency (cortisol)

Answer 1

• Hyponatraemia
• Hypoglycaemia
• Hypotensin

Question 2

What do you look for in mineralcorticoid deficiency (aldosterone)

Answer 2

Also

• Hyponatraemia
• Hypotension

As well as

• Metabolic Acidosis (inc. H⁺)
• hyperkalaemia

Question 3

Defining feature of glucocorticoid vs mineralcorticoi deficiency?

Answer 3

Both have hypotension and hyponatraemia.

But Glucocorticoid deficiency also has Hypoglycaemia

And Mineralcorticoid deficiency has Hyperkalaemia (inc K⁺) and metabolic acidosis

These symptoms are caused by differen things/systems so combined has a larger negative effect

Question 4

What’s the mechanism of sy mptoms fromGlucocorticoid deficiency (cortisol)

Remember Cortisol acts to increase body glucose levels?

Answer 4

Hyponatraemia (decr. Na⁺) due to dilutional effect not SALT LOSS

• Unable to excrete a water load (reduced GFR) cortisol is important for vascular, no cortisol → vessels collapse and tissues (eg kidneys) aren’t perfused.
  Low Na+ can be due to not being able to remove the free water in their body, retain water
• Loss of cortisol inhibition of ADH: ADH stops you peeing, GC usually a negative feedback to this, but if gone we retain all our fluid and don’t pee much

Hypoglycaemia (low Glucose)

• Reduced Hepatic gluconeogenesis

Hypotension

• Loss of cortisol effects on vascular tone

Question 5

Whats the mechanism of symptoms from mineralcorticoid deficiency?

Remember Aldosterone acts on the DCT of the nephron; Reabsorbs Na⁺, excretes K⁺ and H⁺

Answer 5

Hyponatraemia

• Urine Na+ loss and water (intravascular fluid) loss, and secondary ADH/vasopression secretion once ECF drops by 10%
• Na+ main ion in ECF but H₂O always follows so your ECF volume changes.
• Therefore aldosterone deficiency loses salt and water, when you turn on ADH/vasopressin to maintain BP by retaining water (better to have dilute volume then no volume at all)
• so its Na+ loss plus the ADH activation that causes the hyponatraemia

Hyperkalaemia

• Reduced renal K+ excretion

Metabolic Acidosis

• Reduced renal H⁺ excretion

Question 6

Draw a diagram on what stimulates Aldosterone (mineralcorticoid) and what this leads to?

Answer 6

..

Question 7

Causes of Adrenal Failure (no glucacorticoid or mineralcorticoid)

Answer 7

Divide into

1. Primary (adrenal Gland)
2. Secondary/Teritary (pituitary/hypothalamus)

You need to think about the feedback loops (draw this out)

These feedback loops failing can lead you to get a good tan!

Question 8

What is the reasoning behind her tanned skin and white patches of depigmentation

Answer 8

White areas of skin are called vitiligo; autoimmune disease which destroys melanocytes in skin and you get ares of depigmentation.

The Tan is from Primary** Adrenal Failure

• ACTH is a product of POMC (proopiomelanocortin)
• POMC cleavage → 1 ACTH and 3 MSH (melanocyte stimulating hormone)
  
  • ACTH also contains an extra aMSH

Therefore if cortisol is deficient → no negative feedback loops → increased CRF (hypothalamus) → increased ACTH and MSH → tan skin

Question 9

Where do you see the pidmentation that occurs from primary adrenal failure

Answer 9

Occurs generally, but especially…

• skin flextures
• Buccal mucosa (mouth)
• old scars
• freckles
• nails

ACTH is therefore regulated by CORTISOL (independent of mineralcorticoid axis)

Question 10

What do you need to think about with an obese child, and what key observations should be made?

Answer 10

Is this an input/output (exogenous) obesity, or something endocrine/pathological endogenous?

Key Observations:

• Change in appearance overtime
• Growth Pattern (in kids)
• Other features suggestive of pathalogical issue

Question 11

What can change in appearence tell us for obese patient?

Answer 11

Look at old photos to see a pattern of change

Simple Obesity: becomes apparent by 3-4 yrs of age with progressive worsening

Sudden weight increase often pathalogical

Childhood Glucocorticoid Excess: generalised obesity

Adult Glucocorticoid excess: leads to truncal obesity

Question 12

What can Growth Patterns tell us for obese patient?

Answer 12

• Simple obesity drives growth
  
  • fat kids are taller than you would expect from their genetic potential (mum/dad heights)
  • Enter puberty earlier but end up at a height similar to parents
• Glucocorticoid Excess causes profound growth failure and a crossing of percentiles downwards

A SHORT fat kid is more likely to have an underlying cause for their obesity until proven otherwise!

Question 13

What are other features/symptoms of glucocorticoid exess?

Answer 13

• Moon face due to obesity
• Thinning skin
  
  • violaceous striae RED strecth marks not white
  • facial plethora face ‘glows’ red
  • bruising
• Androgen excess as ACTH produces androgens as well as GCs
  
  • hirsutism excess hair
  • amenorrhea/irreg. period
• Myopathy
  
  • proximal weakness
• Glucose intolerance
  
  • diabetes mellitus
• Hypertension
• Osteoporossis

Question 14

Pregnenolone → progesterone → aldosterone → cortisol → androgens

Answer 14

So if you make lots and lots of cortisol you also make lots of male hormones,

Question 15

Cushing Disease vs Cushing Syndrome

Answer 15

Cushings Disease: tumour in adrenal gland

Cushings Syndrome: generalised excess of glucacorticoids

Question 16

Why would the K+ and renin be low in an obese girl with GC excess (Cushings Syndrome).

Answer 16

• Too much aldosterone → retaining too much Na+ → turn off renin by the feedback loop*
• And excess aldosterone means you excrete heaps of K+.*

BUT she has a glucocorticoid excess not mineral corticoid?!?

• Cortisol binds to the MC receptor with equal affinity, but is usually metabolised too rapidly to cortisone to have an activating effect
• With excess cortisol states Mineralcorticoid effects are seen; overrides kidneys ability to degrade

Question 17

Where is the cause of the Cushings?

Answer 17

Primary (cushings disease): in the adrenal gland (primary functional adrenal tumour)

Secondary: ACTH secreting tumour

• pituitary (cushings)
• Ectopic (lung, gut etc making ACTH)

Exogenous Glucocorticoid

Tumours easily removed and symptoms reverse!!

Question 18

Partial LOF in the glucocorticoid receptor will cause

(complete LOF you would die)

Answer 18

The GC receptor in the brain now requires lots more cortisol to bind to it to have an effect. (and to turn off the normal negative feedback loop)

1. Your going to make lots of ACTH
2. This ACTh makes the adrenal glands get much bigger
3. Increased Cortisol production to turn the process off
4. But the Cortisol level is going to overwhelm the MC receptor on the kidneys → Hypertension (from incr Na+ reabsorb), hypokalaemia and alkolosis

These are Secondary Mineralcorticoid Effects

​Also get Hyperandrogenism from driving adrenal glands so hard (hirustism, amenorrhea)

Fatigue and tiredness due to low cortisol

Question 19

Loss of Function of the Mineralcorticoid will cause

Answer 19

Pseudohypoaldosteronism

• High aldosterone and renal levels (to try restore negative feedback)
• Reduced ECF due to fluid loss via salt
• High serum K+ and low Na+

Question 20

If you get and ACTH receptor LOF mutation

Answer 20

Low Cortisol (and Androgen) levels as not formed

Small non functioning Zona Reticularis and Fasciculata

Severe cortisol deficiency from birth:

• Hypotensin
• Low Na+
• Hypoglycaemia

Question 21

Guthrie Card (day 7): came back positive for 17 OH progesterone; markedly elevated

If no testis at birth, be cautious, could be a girl in disguise!!

Answer 21

17 OH progesterone is a metabolite of the adrenal gland, suggesting a defect in the adrenal gland, so this kid can’t make aldosterone/cortisol properly.

Check the Karyotype: 46XX

USS shows a normal uterus (no Sertoli Cells) ; therefore baby didn’t have haematuria but normal uterine withdrawal bleed (baby period) tat came out urogenital sinus, as they come out of being in excess estrogen with mum

Question 22

This is due to a defect in cortisol synthesis with a defective enzyme

~95% from 21 hydroxylase Deficiency

Answer 22

Low cortisol → high ACTh with secondary stimulation of the adrenal cortex, excess production of adrenal precursors and adrenal hyperplasia (grows) and hyperfuncitoning

affects both pathways so low cortisol and aldosterone

Question 23

Answer 23

Dark indicate high ACTH (is that due to defective cortisol??)

Is this early Puberty? Look at Gonad size; this is the 1^st thing to develop in puberty so if not affected (<3mls) we know the androgens making the big penis are from somewhere else.

Sex Steroid androgens only come from 2 places

1. Adrenal Glands: so HAS to be this (tall, big phallus, hair)
2. Gonads

Super high BP and Low K+

Question 24

Whats the growth danger in being exposed to excess androgens

Answer 24

Kids have accelerated growth, in higher growth percentiles then you would expect from parents height.

But although sex steroids make you grow faster, it causes faster maturation/fusion of your bones earlier.

Look at the Patients hand epiphysis to see bone growth to see when this accelerated maturation will occur

Question 25

WHat could this be

Answer 25

1. PRecocious Puberty (but testis are <4ml)
2. Primary Adrenal Pathology
   
   • COngenital adrenal hyperplasia** more likely bc dark so making too much ACTH
   • Functional adrenal Neoplasm

Question 26

Answer 26

Congenital Adrenal Hyperplasia: due to 11 hydroxylase (21 hydroxylase main cause)

Therefore leads to a massive increase in deoxycortico steroid, which acts on the MC → excess aldosterone → hypertension and low K+, leading to low renin

Also low cortisol → increase of ACTH as compensation → excess androgens → virilisation

Question 27

Manage of this

Answer 27

1. Glucocorticoid Therapy to suppress ACTH
2. Inhibition of central precocious puberty (as already been turned off by 10-11yrs bone age)
3. Treat hypertension

Question 28

Glucocorticoid excess in infancy (CUshing Syndrome)

Answer 28

Endogenous:
adrenal adenoma/carcinoma,
multinodular adrenal hyperplasia
ACTH producing pituitary microadenoma (cushing disease)
Ectopic ACTH syndrome
Ovarian Tumour

Exogenous

Question 29

Normal COrtisol levels are?

IF they are low but the patient has cushings??

Answer 29

Normal Cortisol >200 nmol/l unstressed and >400 stressed

If super low, but sshowing symptoms of excess GC/cushings, then they are getting exogenous → turning ACTH off → low levels of Cortisol produced

When source removed, no cortisol so they get reeeeeally sick

Question 30

Baby was actually taking Dermol; a very important GC cream

Answer 30

Steroid creams can cross the skin and be absorped systemically by the skin anywhere

Some of these creams can bind to the androgen receptor

Question 31

Commonest cause of Cushing Syndrome in adults and children is _______?

Answer 31

Endogenous steroid exposure.

Steroid creams are absorped systemically through the skin and a common cause of this problem.

Question 32

She has low Na+, high K+ and Urea

_{Remember that a “low” number is either<strong> less of substrate</strong> or <strong>excess fluid (</strong>diluting substrate)}

A high pH, low HCO₃ and low CO₂

Answer 32

Urea: indirect measure of how kidney is functioning (produced in liver and excreted)
High urea → kidneys aren’t functioning well

_​A high pH, low HCO₃ and low CO_{2<span> → <strong>Compensated metabolic acidosis</strong></span>}

So she has hyponatraemia, hyperkalaemia, hypoglycaemia, intravascular volume depletion and metabolic acidosis

she likely has a combined glucocorticoid and mineralcorticoid deficiency