Lecture 22: Steroid abnormalities Flashcards
Case
31 year old woman, one year history of increasing tiredness, presents collapsed and rowsy following a mild “flu”
High pulse rate, low BP, afebrile, TANNED appearance and conspicous freckles
Low Glucose, low Na, K+
Low Co2 and low HCO3
Hyponatreamia (low Na+)
Hyperkalaemia (high K+)
Hypoglycaemia (low glucose)
Metabolic acidosis (increased H+)
Intraveascular volume depletion
Likely combined glucocorticoid and mineralocorticoid deficiency
Aldosterone and cortiosol deficiency cause a _low sodium concentratio_n and hypotension
_Mineralocorticoid deficiency (aldoster_one) causes high potassium
Aldosterone and cortiosol deficiency cause ______ and _______
Aldosterone and cortiosol deficiency cause a low sodium concentration and hypotension
Mineralocorticoid deficiency (aldosterone) causes_______
Mineralocorticoid deficiency (aldosterone) causes high potassium
________deficiency causes high potassium
Mineralocorticoid deficiency (aldosterone) causes high potassium
_______and _______deficiency cause a low sodium concentration and hypotension
Aldosterone and cortiosol deficiency cause a low sodium concentration and hypotension
What are the mechanism of consequences due to glucocorticoid deficiency
1) Hyponatraemia (Low Na+)
- Unable to excrete a water load (reduced glomerular filtration rate)
- Loss of cortisol i_nhibition of antidiuretic hormone (ADH)_
2) Hypoglycaemia
-Reduced hepatic gluconeogensis (decreased glucose)
3) Hypotension
-Loss of cortisol effects on vascular tone
Describe the mechanism of mineralocorticoid action on…
1) Hyponatraemia
2) Hyperkalaemia
3) Metabolic acidosis
e. g. aldosterone
- Mainly regulates sodium
Hyponatraemia (decreased Na+)
-Urine Na+ loss with intravascular volume contraction (vasocontriction) and secondary ADH/vasopressin secretion
Hyperkalaemia (increased K+)
-Reduced renal K+ excretion due to lack of aldosterone
Metabolic acidosis
-Reduced renal H+ excretion (increased H+)
Dehydration means _____-
Loss of SALT AND WATER
How is aldosterone formed?
JGA produces renin which converts Angiotensiogen to Angiotensin I
AT1 is converted to AT2 by ACE
AGT2 acts on the adrenal cortex zona glomerulosa (with K+ and ACTH) and Aldosterone is produced
Aldosterone causes Increase in Na+ and H20 and therefore increase in intravascular volume
Angiotensin II acts on the ____________________ (with K+ and ACTH) and Aldosterone is produced
AGT2 acts on the adrenal cortex zona glomerulosa (with K+ and ACTH) and Aldosterone is produced
What are the 2 groups of causes of adrenal failure?
1) Primary (adrenal gland)
2) Secondary/tertiary (pituitary/hypothalamus)
What is ACTH?
Adrenocorticotropic hormone
ACTH is made in the pituitary gland and travels through the bloodstream to the adrenal glands. It stimulates the adrenals to release cortisol, a key factor in many functions in the body’s metabolism of fats, carbohydrates, sodium, potassium, and protein as well as blood pressure.
Describe the hypothalamic-pituitary-adrenal axis
Hypothalamus releases corticotropin-releasing hormone
Anterior Pituitary releases Adrenocorticotropic hormone
Adrenal cortex releases Cortisol
Cortisol has a negative feedback on the pituitary and the hypothalamus
If someone has a tan (but hasn’t been in the sun), what can it be an indicator of?
Primary Adrenal Failure
How can a tan be an indicator of primary adrenal failure?
- PAF = Increased ACTH
- MSH (melanocyte stimulating hormone)- causes pigmentation
- Some POMC cleavage products form 3MSH
- ACTH contains a-MSH and is also a peptide product of POMC
- Therefore Increased POMC and Increased ACTH produces Increased MSH -> Pgimentation
- Increased POMC and Increased ACTH occurs with a lack of feedback inhibition (i.e. decreased cortisol) in primary adrenal failure
- Some of POMC cleavage products are 3 MSH (Malanoycyte Stimulating Hormones)
- ACTH is a peptide product of POMC
- ACTH contains a-MSH
- Therefore Increased POMC and Increased ACTH produces Increased MSH -> Pgimentation
- Increased POMC and Increased ACTH occurs with a lack of feedback inhibition (i.e. decreased cortisol) in primary adrenal failure
Where can increased pigmentation be observed in primary adrenal insufficiency?
Pigmentation occurs generally, but is more apparent in …
1) Skin flexures (e.g. hand creases)
2) Buccal mucosa (mouth)
3) Old scars
4) freckles
5) Nails
ACTH is regulated by cortisol (i.e. is independent of mineralocorticoid axis)
ACTH is regulated by _________(i.e. is independent of __________________axis)
ACTH is regulated by cortisol (i.e. is independent of mineralocorticoid axis- like aldosterone)
What should you look for (key observations) in children with increasing obesity to determine if its…
1) Simple obesity
vs
2) Glucocorticoid excess
Is this an input/output problem simle/exogenous obestiy?
1) Change in appearance over time
- Check old photos to look for patterns of change
- Simple obesity becomes apparent usually by 3-4 years of age, with progressive worsening
- Childhood glucocorticoid excess leads to generalised obesity whilst Adult glucocorticoid excess leads to truncal obesity
2) Growth pattern
-
Simple obesity drives growth
- Fat kids are taller than you would expect from their genetic potential (parents heights)
- However they enter puberty earlier and end up a height similar to their parents
- Glucocorticoid excess causes profound growth failure and corssing of percentiles downwards
3) Other features suggestive of pathological causes
- Moon face
- Thinning skin (Bruising, stretch marks)
- Androgen excess (e.g. hirsutism, amenorrhoea)
- Myopathy (e.g. proximal weakness)
- Glucose intolerance (diabetes)
- Hypertension
- Osteoporosis
*
If a child is ________________, they often have an underlying cause for their obesity until proven otherwise
Short and fat
What are Other features suggestive of pathological causes (not just simple obesity)
- Moon face
- Thinning skin (Bruising, stretch marks)
- Androgen excess (e.g. hirsutism, amenorrhoea)
- Myopathy (e.g. proximal weakness)
- Glucose intolerance (diabetes)
- Hypertension
- Osteoporosis
What are the differences in growth pattern between simple obesity and pathologically-based obesity?
Growth pattern
- Simple obesity drives growth
- Fat kids are taller than you would expect from their genetic potential (parents heights)
- However they enter puberty earlier and end up a height similar to their parents
- Glucocorticoid excess causes profound growth failure and corssing of percentiles downwards
What are the Change in appearance over time between simple obesity and pathologically-based obesity?
- Check old photos to look for patterns of change
- Simple obesity becomes apparent usually by 3-4 years of age, with progressive worsening
- Childhood glucocorticoid excess leads to generalised obesity whilst Adult glucocorticoid excess leads to truncal obesity
Patient comes in (child)
Symptoms:
Facial plethora
Facila and trunkal hair
Moon face
Violceaous striae over trunk and abdomen
Tests:
Increased urinary free cortisol
Low K+
Low renin (suggest everything is turned off)
What is the issue here?
Diagnose: Glucocorticoid excess and probably adrogen excess:
CUSHINGS SYNDROME
due to one of these….
1) Primaryfrunctional adrenal tumour
2) ACTH secreting tumour
3) Exogenous glucocorticoid
Cortisol can bind to mineralocorticoid receptor and glucocorticoid receptor with equal affinity. When it does happen, cortisol has no mineralocorticoid effects because it is metabolised straight away. But with excess, you get aldosterone effects. = hence low K+
What is Facial plethora?
Redness of face due to i_ncreased level of blood volume_ or increased blood flow. Basically, the term plethora is used for redness due to increased blood volume, so when it occurs on face, it is known as facial plethora
What is another word for….Stretch marks
Violaceous striae
What is the word for….Redness in face due to increased blood to the face?
Facial plethora
Describe Receptors and Ligand affinity of cortisol to different receptors and its effects
Cortisol binds to the mineralocorticoid receptor and glucocorticoid receptor with equal affinity
Cortisol usually has no mineralocorticoid (MC) effects as it is metabolised rapidly to cortisone before it can bind and activate the MC receptor. (renal 11B hydroxysteroid dehydrogenase type 2)
However with excess cortisol states however mineralocorticoid effects are observed. (e.g. low potassium and hypertension)
What do you get if you have partial loss of function (resistence) of glucocorticoid receptor in various organs?
(if all is lost- you die)
Cortisol won’t bind as well = Glucocorticoid resistance
If the brain doesn’t think there is enough cortisol, it will produce more ACTH which causes the _adrenal glands to get bigge_r and then produce more cortisol.
If there’s too much cortisol, it can bind to the mineralocorticoid receptor, so the patient may go into hypertension and low potassium. and alkalosis
By product of cortisol is androgen so you might get hirutism as well and fatigue (cortisol insensitivity)
What is a by-product of high cortisol?
Increased androgen- hirutism, amenorrhoea
and/or fatigue (cortisol insensitivity)
What are some symptoms of high mineralocorticoid?
hypertension and low potassium and alkalosis
What symptoms do you see when there is _loss of function (resistence) of the mineralocorticoid recepto_r?
Look like aldosterone deficiency (but if you measure aldosterone, it’ll be high) = Mineralocorticoid resistance (pseudohypoaldosteronism)
1) High aldosterone and renin levels
2) Depleted extracellular fluid space
3) High serum K+ and low Na+ concentrations
If someone has ACTH receptor mutation and therefore loses its function, what would you observe?
Adrenal crisis- low BP and often die.
Small nonfunctioning zona reticularis and fasciculata
Severe cortisol deficiency from birth
- Hypotension
- Low Na+
- Hypoglycaemia
What is the function of Aldosterone?
The most important physiological effect of aldosterone is s_timulation of sodium resorption_ and potassium secretion by principal cells of the late distal tubule and collecting duct
What is ADH?
Vasopressin, also named antidiuretic hormone (ADH)
causes the kidneys to reabsorb solute-free water
What is Cushing Syndrome
A pituitary gland tumor (pituitary adenoma). A noncancerous (benign) tumor of the pituitary gland, located at the base of the brain, secretes an excess amount of ACTH, which in turn stimulates the adrenal glands to make more cortisol.
