Pathophysiology of the Adrenal Cortex Flashcards
What enzymes does the zona glomerulosa lack as well as contain that allow it to synthesize aldosterone?
Lacks: 17-alpha hydroxylase -> cannot convert progesterones to 17-OH-progesterone precursors of cortisol and androgens
Contains: Aldosterone synthase
Is DHEA an active hormone?
No receptor is found for it, it has very little intrinsic activity (weak androgen)
However, it can be converted to more potent androgens via peripheral aromatase
How are cortisol and aldosterone transported in the blood?
Cortisool - 90% is bound to cortisol binding globulin / transcortin
Aldosterone - 50% bound to albumin, 20% to transcortin
What are two tests for daily cortisol secretion? What is the control which must be done with one of them?
- 24 hour urine free cortisol - creatinine is also measured to ensure adequate sample
- Salivary free cortisol - better / easier to get in children
When are stimulation vs suppression tests used and what drug is used for the stimulation test of the adrenal cortex?
Stimulation - used if hormone deficiency is suspected
Suppression - used if hormone excess is suspected (see if it’s suppressable)
Cosyntropin - ACTH analog which can be used for adrenal stimulation test (especially for Addison’s disease)
Tell me if cosyntropin will stimulate adrenal cortex in the following situations:
- Primary adrenal insufficiency
- Secondary adrenal insufficiency - recent onset
- Secondary adrenal insufficiency - longstanding
- Primary adrenal insufficiency
- > no, cortex is not responsive to ACTH - Secondary adrenal insufficiency - recent onset
- > yes, cortex is ready to receive ACTH stimulation - Secondary adrenal insufficiency - longstanding
- > no, cortical atrophy is likely to have occurred
What is the insulin-induced hypoglycemia test used for? How does it work?
Used for testing for secondary adrenal insufficiency
-> insulin dropping your blood sugar to below 40 mg/dL should naturally trigger release of growth hormone and ACTH (so cortisol can raise your blood sugar)
How do you differentiate between secondary and tertiary adrenal insufficiency?
CRH stimulation test
Tertiary -> ACTH release will be stimulated
Secondary -> ACTH release will not be stimulated
What is considered the “screening” test for Cushing’s syndrome or states of hypercortisolemia?
Overnight dexamethasone suppression test
-> levels at 8am the next morning should be low
What is the utility of low vs high dose dexamethasone suppression test in diagnosis of Cushing’s syndromes?
Low dose -> can make definitive diagnosis of Cushing’s syndrome of any time, as cortisol will not be suppressed.
High dose -> cortisol WILL be suppressed in Cushing’s disease (pituitary adenoma) but will NOT be suppressed in ectopic ACTH secretion
What is the most common cause of ectopic ACTH secreting tumor?
Small cell lung cancers
Can also occur in other neuroendocrine tumors, i.e. medullary thyroid carcinoma, pancreatic carcinoid tumors
What is the most common electrolyte imbalance seen in Cushing’s syndrome? Why? What other metabolic disease commonly occurs?
Hypokalemic metabolic alkalosis
- > high cortisol levels stimulate aldosterone receptor (11B hydroxy steroid DH can’t keep up)
- > aldosterone stimulates H+/K+ ATPase on alpha-intercalated cells
Diabetes mellitus Type 2 also occurs
-> hyperglycemia from cortisol
What is Nelson syndrome?
As background, refractory Cushing’s disease (ACTH-secreting pituitary adenoma) often has to be treated via bilateral adrenalectomy.
Nelson syndrome is when the Cushing’s disease adenoma enlarges and causes increased ACTH secretion (loss of negative feedback).
-> causes hyperpigmentation, bitemporal hemianopsia, and headaches
What are the most specific symptoms of Cushing’s syndromes?
- Central obesity
- Purpura, ecchymoses, striae -> connective tissue thinning
- Muscle atrophy / proximal myopathy -> for gluconeogenesis
- Hirsutism -> effect of ACTH on zona reticularis
What is Cushing’s syndrome vs Cushing disease?
Cushing’s syndrome -> ANY cause of increased circulating glucocorticoids (includes exogenous)
Cushing disease -> Pituitary adenoma secreting ACTH
How will the response to CRH stimulation test differ between Cushing’s disease and ectopic ACTH production?
Cushing’s disease - hyper-responds to exogenously administered CRH by increasing ACTH production massively
Ectopic ACTH (i.e. small cell carcinoma) -> minimal responds to CRH, they work autonomously
What is the test should be done after diagnosis of a Cushing syndrome via a dexamethasone suppression test?
Plasma ACTH levels
If ACTH is low -> primary adrenal adenoma / hyperplasia / carcinoma
If ACTH is high -> Cushing’s disease or ectopic ACTH secretion
What should be done if adrenal tumor or Cushing’s disease is diagnosed?
Adrenal tumor -> CT scan to visual adrenal glands, and surgical resection of tumor
Cushing’s disease -> MRI of theh pituitary, and transsphenoidal tumor resection
What is Addison’s disease?
PRIMARY adrenal insufficiency
contrast this to Cushing’s disease which is secondary adrenal hyperplasia basically
What is the definition of adrenal insufficiency? How do you differentiate primary for secondary clinically?
Deficiency in cortisol secretion (no other hormones matter, though they may be deficient)
Primary - ACTH levels will be high, and will not respond to cosyntropin or insulin-induced hypoglycemia
Secondary - ACTH levels will be low, cortex will respond to cosyntropin so long as the gland has not atrophied yetl
What symptoms are specific to Addison’s disease vs secondary adrenal insufficiency?
- Hyperpigmentation- Overproduction ACTH due to lack of negative feedback from primary issue
- Salt craving and hyperkalemia - Addison’s disease only, as zona glomerulosa will also not be working. In secondary, zona glomerulosa is intact and functioning normal (does not require ACTH)
Where are the top places to get hyperpigmentation in Addison disease, and why does this hyperpigmentation happen?
Buccal mucosa / lips, and gums
Can occur anywhere on body
Due to increased MSH, a byproduct of ACTH production from POMC
What are other common symptoms of all adrenal insufficiency?
Fatigue, weakness, hypotension, weight loss (lack of cortisol), GI disturbances
What are the top two causes of Addison’s disease?
- Autoimmune destruction (of adrenal gland)-> most common in Western world
- Tuberculosis -> most common in developing world
What are some other causes of Addison’s disease?
- Adrenal hemorrhage -> Waterhouse-Friderichsen syndrome
- Congenital adrenal hyperplasias
- X-linked adrenoleukodystrophy (look for in males, peroxisomal problem of VLCFA buildup)
Others are low yield or intuitive
What is the treatment of primary vs secondary adrenal insufficiency? What will renin levels be in each condition pretreatment (this is really a hint).
Primary - administration of a glucocorticoid + mineralocorticoid. Renin levels high pre-treatment.
Secondary - administration of a glucocorticoid only (aldosterone okay). Renin levels normal.
How does cortisol cause hypertension?
- Activation of aldosterone receptor
2. High cortisol increases sensitivity of peripheral vessels to catecholamines via upregulation of alpha1 receptors
What is functional / relative adrenal insufficiency?
Subnormal cortisol production / secretion during acute, severe illness (should lose diurnal pattern and increase 5-10 fold).
What hormone is the chief regulator of ACTH biofeedback? How does this explain congenital adrenal hyperplasia?
Cortisol. In situations where cortisol is low, ACTH levels will be increased, causing massive overproduction of mineralocorticoids and androgens.
What is the metyrapone stimulation test? What is normal / abnormal.
Test blocking the last step of cortisol synthesis -> 11-deoxycortisol to cortisol.
Normal: decreased cortisol and compensatory increase in ACTH + 11-deoxycortisol.
Primary adrenal insufficiency: ACTH is increased but 11-deoxycortisol is still low after test.
Secondary / Tertiary adrenal insufficiency: both ACTH / 11-deoxycortisol remain low after the test.
Why should you taper steroids? Will aldosterone be affected in the resulting condition?
Primary adrenal insufficiency may occur to abrupt withdrawal of steroids, due to cortical atrophy. Need to taper.
Aldosterone will not be affected -> loss of ACTH stimulation does not cause atrophy.
What is the most common cause of congenital adrenal hyperplasia? What accumulates / what is decreased in it?
21-hydroxylase deficiency, enzyme which catalyzes the conversion of 17-OH-progesterone and progesterone to aldosterone and cortisol precursors.
Accumulates: DHEA / androstenedione (androgens) + 17-OH progesterone
Decreased: Cortisol / aldosterone
What are the symptoms of classical 21-hydroxylase deficiency?
Presents in infancy:
Lack of aldosterone: Hyponatremia, hyperkalemia
Lack of cortisol: Hypotension (salt-wasting type)
Excess androgen:
Females - clitoral enlargement / ambiguous genitalia = female pseudohermaphroditism
What are the symptoms of non-classical 21-hydroxylase deficiency?
Less severe form, presents in childhood due to excess androgens:
Females - hirsutism with menstrual irregularities
Males - precocious puberty
In the classical form of 21-hydroxylase deficiency, is salt-wasting always present? Why or why not?
Not always -> only minimal aldosterone needs to be produced (relative to cortisol) to have normal functioning.
Virilization at birth will always happen in the classical form, however.
What is the second most common cause of CAH, and what accumulates / is underproduced?
11-beta-hydroxylase deficiency
-> similar to metyrapone testing
11-deoxycortisol accumulates -> decreased cortisol synthesis
11-deoxycorticosterone accumulates (precursor to aldosterone), but is actually a mineralocorticoid
Some level of excess androgen is also present due to shunting away from cortisol pathway
What are the clinical features of 11-beta-hydroxylase deficiency? Will renin levels be up or down?
Androgen excess -> similar to 21 hydroxylase deficiency, females have virilization at birth
11-deoxycorticosterone -> actually potentially activates mineralocorticoid receptor -> causes hypertension with hypokalemia, low renin levels.
What accumulates or is decreased in 17a-hydroxylase deficiency? Will aldosterone be increased?
Inability to make 17-OH-progesterones, so all is shunted into mineralocorticoid pathway
Accumulates: 11-deoxycorticosterone, mineralocorticoid. Aldosterone not increased because aldosterone synthase under control of angiotensin II
Decreased: cortisol / androgens
What are the clinical features of 17a-hydroxylase deficiency in males and females?
Increased 11-DOC -> hypertension with hypokalemia
Females: Normal genitalia at birth, but primary amenorrhea (lack of sex hormones for puberty)
Males: Normal testes but undescended, ambiguous external genitalia (lack of androgens, but testes present due to SRY)
What test is run at newborn screening to check for congenital adrenal hyperplasia? How will they be changed in the three major conditions?
17-hydroxyprogesterone levels
21-hydroxylase: increased
11beta-hydroxylase: increased
17alpha-hydroxylase: decreased
What are the presenting symptoms of aldosterone synthase deficiency? Why is this different than the other conditions?
Failure to thrive, Na+ wasting, hypotension, hyponatremia, and hyperkalemia
In this cause, lack of aldosterone matters since there isn’t ACTH stimulating 17,20 desmolase since cortisol levels will be normal -> 11-DOC will not accumulate enough to compensate for loss of aldosterone.
