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Screening = people who have hypertenson and hypokalemia, those you have been using anti-hypertensives that do not work

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Two adrenal glands on top on kidneys. Two big layers (medulla & cortex).

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Medulla: catecholamines are being produced here.
Cortex:
- Glomerulosa = producing mineralocorticoids (aldosterone)
- Fasciculata = producing glucocorticoids (cortisol)
- Reticularis = producing androgens

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Zona glomerulosa = is missing the enzyme CYP17 and because of that  you have the production of aldosterone
Zona fasciculata = has CYP17 so it can make cortisol
Zona recticulus = has co-factor SULT2A1 and because of this it can produced androstenedione (precursor for testosterone & estradiol).

*if an enzyme is missing/presence you have a particular hormone produced

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Normal HPA axis:
- glucocorticoid production by adrenal is under control of the hypothalamic & pituitary axis. CRH (corticotrophin releasing hormone) is secreted by several stimuli (ex. stress). This stimulates the pituitary to release ACTH (adrenocorticotrophin releasing hormone) which goes to the adrenal to stimulate the release of cortisol (which then has a negative feedback)

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Disorders resulting from adrenal insufficiency 

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Disorders resulting from adrenal insufficiency 

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ADDISON'S DISEASE (PRIMARY)
SECONDARY & TERTIARY ADRENAL INSUFFICIENCY

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Disorders resulting from adrenal overproduction

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Disorders resulting from adrenal overproduction

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Primary Hyperaldosteronism
HyperCortisolism (CUSHING'S DISEASE & SYNDROME)

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= primary insufficiency, rare (3-4 in a million), female predominance. Its main cause is autoimmune. You have increase CRH and ACTH but, because of the atrophic adrenal you do not produce enough cortisol. Specific signs are hyperpigmentation, weight loss, hypotension, muscle weakness, fatigue and psychic complaints (depression).

*excess ACTH, missing cortisol and missing aldosterone

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*low ACTH, low cortisol, normal aldosterone

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Hyperpigmentation = constant secretion of ACTH (pro-hormone which gets split in to corticotrophin and melanocyte stimulating hormone). The second goes and binds to the melano-receptor in the skin and causes the production melanin --> tanned. (cannot get it in the eye, but yes in the eye-lid).
Gums and back of the elbow have more melano-receptors

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similar signs and symptoms but NO HYPERPIGMENTATION, NO HYPOTENSION AND SALT HUNGER (so no aldosterone effect). Your adrenals are still working so you are still producing the hormones. You usually do not have auto-immune problems (vitiligo), because they auto-immune is not usually the cause

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Testing for anti-bodies against 21-hydroxylase is not as accurate and reliable. If it is positive you have the whole diagnosis, but you might be missing things. If you suspect the auto-immune pathology, then you will test it.

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Synachten Test = you give synthetic ACTH to see if the cortisol levels rise. If they do not then it is primary.

Test electrolytes in blood and urine (hyponatremia and hyperkalemia)

CT/MRI to see atrophy of glands or lesions in hypothalamus/pituitary

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Hydrocortisone drug (3x day at meals). Women need more DHEA & oral mineralocorticoids.

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Insulin tolerance test = induce hypoglycaemia, so that you expect a rise of cortisol. You test the HPA axis.

Metyrapone test = through tablets you block CYP11B1 and thus the conversion between 11-deozycortisol and cortisol, so cortisol goes down, stress is initiated, HPA axis is tested.

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Hydrocortisone drug (3x day at meals). Women need more DHEA

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primary = there are a lot of causes, main one is tumor (aldosterone secreting adenoma or bilateral adrenal hyperplasia) or you can have a genetic defect of your CYP11B2.
secondary = does not have to do with adrenal glands, but due to renal artery stenosis --> more renin and angiotensin II

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muscle weakness and you get proximal myopathy (due to hypokalemia) and increased respiratory rate. Sodium retention causing hypertension and damage to kidneys, heart and, when severe, also retina. Nocturia is also a sign (pee more than 3 times at night/more than usual).

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Plasma aldosterone renin ratio = will be elevated (renin is low)
Confirmation test = 1) saline infusion test: infuse saline and blood pressure goes up and nornally you produce less renin and aldosterone. if the level of aldosterone stays high than confirmed. 2) 24-hr urine: aldosterone being more than 10ug over 24hr and you look at potassium (low)

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Once confirmed, you still need to do CT/MRI and AVS (adrenal vein sampling).
Normal or unilateral. You trust the vein sampling more than CT/MRI because there could be hypertrophy but not hyper-secretion.

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If patient has bilateral, you go for medication (adrenal hyperplasia - you give spironolactone, amiloride, which blocks the MR receptor is used for the bilateral ). If unilateral and you have a young patient, then you do surgery. If patient if older than 40 then also AVS and potential surgery.

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Pheochromocytoma = tumor involving Chromaffin cells of sympathetic system. Leads to reactions of three hormones which results in cardiovascular problems (norepinephrine, epinephrine and dopamine). located 90% time in adrenal and 10% elsewhere. Cardiovascular problems leads to headache, palpitations and sweating

*important because you want the symptoms under control

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Circadian rhythm = it decreases while you sleep and before you wake up in increases so you can be ready to start your day.
Medications (hydrocortisone dosages) used to mimic the circadian rhythm of the body (taken with meals).
if you want to measure it for diagnosis, it is important to measure it at the peak.

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Cortisol = secreted in response to ACTH, part of the stress response. Once it is produced and released it stimulates the release of glucose and lipids from the body.
aldosterone = major mineralocorticoid, it is synthesised after angiotensin II. Effect on kidney = active in collecting duct, involved in sodium reabsorption and potassium excretion.

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Aldosterone promotes the production of the ENaC channel and the Na/K ATPase. Up-regulates the transcript of the gene that encodes for the channel

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Often with adrenal insufficiency you get hyponatremia because you have a lack of aldosterone.

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Most important hormone

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important in flight/fight response = it blocks all processes that are unnecessary for that reaction

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Disease = too much cortisol in the blood due to pituitary tumor secreting too much ACTH
Syndrome = due to adrenal problems, too much cortisol

Causes of Disease:
ACTH-dependent = pituitary adenoma or ectopic ACTH syndrome
Causes of Syndrome
ACTH independent = adrenal adenoma, adrenal carcinoma, or bilateral macro-nodular hyperplasia
Exogenous = due to medication

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High dose Desmopressin supression test

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if it is due to medication, then you stop hydrocortisone. If you have pituitary adenoma, resect it. If it is ectopic you give somatostatin analogues to lower ACTH production. If you have adrenal adenoma or hyperplasia you can do surgery, but you have to give life-long cortisol.

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Why cortisol impact glucose levels = it stimulates the liver to produce more glucose and it stimulates insulin resistance leading to hyperglycaemia. Design is made to have the increase only for a short-term (for energy to act during flight/fight response), however, it causes a chronic increase of blood sugar levels --> diabetes & obesity.

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A lot of doctors prescribed cortisol (last resort). You have to be careful because it has a lot of contra-indication (diabetes, compromised immune-system etc) and its systemic relevance. You do not want to prescribe it unless you have no other option. For example, some young patients develop osteoporosis when using cortisol. There is now research trying to see if you can modulate the immune response.

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Primary vs. Secondary = primary is a direct cause (adrenal gland not working, atrophic) whilst secondary is indirect cause due to other problems within axis (problem with pituitary). In primary you also have shortage of mineralocorticoids, whilst with secondary doesn't (making it milder). Tertiary is when you have a problem with your hypothalamus (tumor/lesion/infarct in that area and can also be caused by drug withdrawal)

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Acute deficiency of glucocorticoid & mineralocorticoids. Can be caused by trauma, wrong medication or sudden stop of prednisone and infection (tuberculosis). You get lower consciousness, nausea and vomiting, severe hypotension, fever, stomach ache and muscle ache. Lab tests = if it shows low glucose levels and increased potassium levels, it is a crisis.
Treatment = hydrocortisone and glucose (+ antibiotics if it is an infection). You have to treat it if not the patient will die.

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Measuring norepinephrine & epinephrine in blood or nor-metanephrine (finds levels more easily). You can find this latter one in the urine as well.

*Better to test normetanephrine and metanephrine (metabolites that are more stable in blood, better to create a diagnosis)

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Adrenalectomy (remove the adrenal gland)

curative

pre-treatment

10 % pheochromocytoma → malignant

Medication

α-blockers

Calcium antagonists

nitroprusside, nitroglycerine

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Cortisol in urine is not attached so it is the active form. Therefore, the test is more accurate.

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--> on measuring cortisol in urine, serum and saliva

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https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/8546