Adrenals

Question 1

Features of cortisol producing adenoma

Answer 1

• Signs of Cushing’s syndrome
• Positive dexamethasone suppression test (non-suppresion due to autonomous secretion of cortisol from tumour)
• Low or undetectable ACTH
• May also have hyperlipidaemia, hyperglycaemia
• Typically a homogenous mass on CT, <3cm

Question 2

Features of an adrenal carcinoma

Answer 2

• Symptoms from mass effect e.g. abdominal pain
• Elevated dehydropiandrosteone sulfate (DHES) level
• Usually >12cm by the time they are found, ?90% >6cm at presentation, heterogenous mass, irregular contour

(Typically ineffective steroid producers due to decreases expression of steroidogenic enzymes)

Question 3

Features of adrenal metastases

Answer 3

• History of breast, lung, renal cell, multiple myeloma, lymphoma
• Hyperpigmentation of skin and mucous membranes, hypotension
• Hyponatraemia, hypoglycaemia
• Heterogenous, irregular mass of variable size (often <3cm)

Question 4

Features of phaeochromocytoma

Answer 4

• Severe, episodic hypertension, palpitations, pallor, tremor, retinopathy, fever
• Syndromes A/W phaeo - neurofibromatosis, von Hippel-Lindau, MEN II
• Biochemical tests:
  
  • Fractionated plasma metanephrines
  • Confirmed by 24 hour urine total metanephrines and fractionated catecholamines
  • Plasma catecholamines >2000, +/- urinary metanephrines >1.6 diagnostic for phaeo
  • Heterogenous mass, cystic areas common, vascular, bright heterogenous signal intensity on T2-weighted MRI

Question 5

Features of Conn’s syndrome (aldosterone producing adenoma)

Answer 5

• Hypertension, muscle cramps/weakness, cardiac arrhytmias
• Hypokalaemia, High PAC/PRA ratio
• Confirmation:
  
  • Plasma aldosterone concentration on unrestricted salt diet
  • Saline infusion test
• Venous adrenal sampling confirms adrenal mass is the source of aldosterone excess
• Speckled appearance, well encapsulated, looks benign, average size is 1-2cm

Question 6

Acid base disturbance in Cushing’s Syndrome

Answer 6

• Hypochloraemic metabolic alkalosis

Question 7

Adrenal steroids and where they are produced in the adrenals

Answer 7

1. Glucocorticoids - zona fasciculata
2. Androgens - zona reticulata
3. Aldosterone - zona glomerulosa

Question 8

Mechanism of action of ACTH (corticotropin)

Answer 8

• Binds specific ell surface receptos - melanocortin 2 receptor (MC2R) - upregulates expression of these receptors → increases steroidogenic response to further ACTH stimulation
• Activates adenyl cyclase → increases cyclic AMP → stimulates cAMP dependent protein kinase & phosphorylation of proteins
• FGD → Familial glucocorticoid deficiency → failure of MC2R to activate in response to ACTH, severe cortisol deficiency, normal mineralocorticoids, high plasma ACTH

Question 9

Substrate for steroid hormone synthesis:

Answer 9

• Cholesterol - mainly LDL
• Cells of the adrenal cortex can either take up cholesterol from the cirulation of synthesis cholesterol de novo from acetate

Question 10

Brief overview of mineralocorticoid synthesis

Answer 10

• Activation of RAAS → angiotensin II (stimulant for mineralocorticoid synthesis), also hyperkalaemia, ACTH (acutely)
• Cholesterol → progresterone → (multiple enzymatic reactions) → aldosterone

Question 11

Brief overview of cortisol synthesis in adrenals:

Answer 11

• Stimulated by ACTH (in turn stimulated by stress and circadian rhythm)
• Cholesterol → progesterone → multiple ezymatic reactions → cortisol
• 4 distinct cytochrome P450 enzymes in cortisol production from cholesterol

Question 12

Brief overview of adrenal androgen synthesis:

Answer 12

• Zona reticulata
• From cholesterol → DHEA and DHEAS (most abundunt products of the adrenal glands)

Question 13

Overview of congenital adrenal hyperplasia:

Answer 13

• 95% cases due to 21-hydroxylase deficiency, AR inheritance, CYP21A2 gene
• Enzyme responsible for cortisol and aldosterone production pathway → deficiency → ACTH stimulation and products shunted down the androgen synthesis pathway → excess androgen production

Presentation

• Often diagnosed by screening in infancy (high 17-hydroxyprogesterone - normal substrate for 21-hydroxylase)
• Atypical genitalia in 46XX females - cliteromegaly, labial fusion, urogenital sinus, 46 XY often have normal appearing genitalia
• If undiagnosed at birth can present in adrenal crisis within 1st month of life
• Children → risk of bone age advanement, early puberty, premature epiphyseal closure, short stature in adulthood
• Nonclassic CAH - less severe form of the disorder, 20-50% 21-hydroxylase enzyme activity. More prevalent. Generally do not have salt wasting (mineralocorticoid deficiency), features of androgen excess and can be indistinguishable from features of PCOS

Question 14

Causes of adrenal insufficiency:

Answer 14

1. Addison’s disease (autoimmune adrenalitis)
2. Infectious adrenalitis
   
   1. TB
   2. Disseminated fungal infections e.g. histoplasmosis
   3. HIV
   4. Syphilis
3. Haemorrhagic infarction
   
   1. Adrenal haemorrhage secondary to bacterial infection esp. meningococcemia (Waterhouse-Friderichsen syndrome)
   2. HIT → bilateral adrenal haemorrhage
4. Metastatic disease - lung, breast, melanoma, stomach, colon
5. Drugs - ketoconazole, fluconazole (inhibit cortisol biosynthesis), enzyme inducers - phenytoin, rifampicin

Question 15

Causes of primary hyperaldosteronism:

Answer 15

• Conn’s syndrome (aldosterone secreting adenoma) - 70%
  
  • Benign, usually 3rd-6th decade
• Adrenal hyperplasia
  
  • Common, usually older than Conn’s, no difference between sees
• Adrenal carcinoma
  
  • Rare, 5th-7th decade, more common in females, tumour >4cm

Question 16

Screening thhresholds for primary hyperaldosteronism

Answer 16

1. HTN ≥ 160/100
2. Resistant to optimally dose conventional anti-hypertensives (≥3_
3. Low K+ and HTN (though hypokalaemia itself an uncommon finding in hyperaldosteronism)
4. Family history of young onset HTN (<40 years)
5. Known adrenal nodule/adenoma

Question 17

Screening test for primary hyperaldosteronism:

Answer 17

• Renin-aldosterone ratio > 30.5 → should go onto confirmatory testing
  
  • Before test stop spironolactone/amiloride etc., correct potassium deficit. Generally don’t need to stop other antihypertensives though they do interfere with result to some degree

Question 18

Confirmatory testing for primary hyperaldosteronism

Answer 18

• Saline suppression test
  
  • Baseline aldosterone, renin, potassium (want K to be in normal range - hyperkalaemia will stimulate aldosterone secretion)
  • 2000ml NaCl over 4 hours IV - generally remain seated for entire procedure
  • Measure aldosterone and potassium after. Aldosterone >280 confirms diagnosis
  • Stop antihypertensives before - 2-4 weeks washout period depending on drug
• Once confirmed - CT Abdomen
• If adrenal nodule and <35 years with lateralising focus for PA on CT Abdo → refer for sugery
• If >40 with adrenal nodule or no lateralising focus on CT abdomen → adrenal vein sampling (synacthen infused peripherally and aldosterone and cortisol measured from both sides)
• Generally don’t go down this route if surgery is not going to be a viable option for the patient

Question 19

Notes on apparent mineralocorticoid excess

Answer 19

• Cortisol and aldosterone bind mineralocorticoid receptors with a similar affinity
• Action of cortisol at these receptors normally limited by conversion of cortisol → cortisone by 11-beta-hydroxysteroid
  
  • AME = genetic defect in 11-beta-hydroxysteroid
  • 11-beta hydroxysteroid also inhibited by excess liqorice ingestion and triazole antifungals
• Leads to a clinical picture similar to primary hyperaldosteronism but with low aldosterone levels

Question 20

Principles of diagnosis adrenal insufficiency:

Answer 20

• Screening test - morning cortisol (suspect if low - also note need higher levels in acute illness to be reassured hypocortisolism is not present)
• Higher-dose ACTH stimulation test (250 microgram) - measure serum ACTH and cortisol, then 30 minutes after administration
• Other stimulation tests:
  
  • Insulin induced hypoglycaemia test - cortisol would normally go up in response to hypoglycaemia
  • Glucagon stimulated secretion of cortisol also - probably low sensitivity

Question 21

Principles of treating adrenal crisis:

Answer 21

• Correct hypocortisolaemia - no gold standard, generally 100mg hydrocortisone as a stat followed by 200mg/day as 50mg QID boluses
• Correct haemodynamic instability - fluid resuscitation
• Consider underlying cause - if known Addison’s disease - infection, MI, trauma, intentional, emotional stress

Question 22

When to suspect hypocortisolism

Answer 22

• Any patient with known pituitary/adrenal disease
• Any patient with previous exposure to exogenous steroids
• Any patient with unexplained haemodynamic instability
• Any patient with unexplained electrolyte disturbances

Question 23

Approach to adrenal incidentlomas

Answer 23

• 6% population - probability increases with age, abdominal CT frequency 4%
• 75% - non functioning adenomas
  
  • If hormonally active cortisol secreting most common
• Liklihood of malignancy increases with size particularly >4cm. If <3cm risk very low and generally don’t recommend surveillance imaging
• In most patients would check plasma metanephrines for phaeochromocytoma (yield low), and assessment of cortisol with dexametasone suppression test, if hypertensive renin/aldosterone. Generally don’t measure androgens unless clinical concern re virilisation.
• One-off assessment appropriate - does not need repeating

Question 24

Principles of steroid replacement in adrenal insufficiency

Answer 24

• Hydrocortisone - 20mg/day, 10 in AM, then 5mg BD
• Usually will end up requiring mineralocorticoid replacement also - fludrocortisone 100mcg/day
• Generally don’t replace androgens
  
  • In men - testosterone will serve that function
  • In women can consider DHEA if significantly low mood despite optimal fludrocortisone/cortisol replacement

Secondary adrenal insufficiency

• When ACTH deficiency is the cause of cortisol deficiency - only need to replace cortisol, no mineralocorticoid replacement required as RAAS will stimulate mineralocorticoid secretion.
• In ACTH deficiency → need to assess other pituitary hormones
• Replacement of thyroid without replacement of cortisol can precipitate adrenal crisis

Question 25

Clinical features of Addison's disease (exam findings):

Answer 25

* Cachexia * Pigmentation in the palmar creases, elbows, gums, and buccal mucosa, genitals and in scars * Vitiligo (commonly associated with autoimmune adrenal failure) * BP - postural hypotension

Question 26

Labaratory diagnosis of hypercortisolism:

Answer 26

* Don't test if known exogenous glucocorticoid use * Urinary corticsol excretion, or dexamethason suppression test (1mg dexamethasone pre-bed with cortisol measurement at 8AM)

Question 27

Tests to determine ACTH-dependent from ACTH-independent hypercortisolism:

Answer 27

* ACTH level - if high = ACTH dependent disease

Question 28

Investigations for ACTH independent Cushing's syndrome:

Answer 28

* CT Abdomen - looking for adrenal mass * If unilateral lesion → adrenalectomy * If bilateral lesions → needs adrenal venous sampling to guide surgery

Question 29

Causes of ACTH dependent Cushing's syndrome

Answer 29

**ACTH Dependent** * Cushing's disease (65-70%) - pituitary adenoma (mostly microadenomas) * Ectopic secretion of ACTH by non-pituitary tumours (10-15%) - typically nueuroendocrine tumours or lung, pancreas, thymus - small cell carcinomas of lung probably most common * Ectopic secretion of CRH by nonhypothalamic tumours → pituitary hypersecretion of ACTH (\<1%)

Question 30

Causes of ACTH-independent Cushing's syndrome

Answer 30

* Iatrogenic * Adrenocortical adenomas and carcinomas (18-20%) *

Question 31

Biochemical tests that help distinguish ACTH secreting pituitary adenoma from ectopic ACTH secretion

Answer 31

* Corticotropin-releasing hormone stimulation test → +ACTH response suggests Cushing's disease * High dose dexamethasone suppression test (8mg) - principle is that ACTH secreting pituitary adenomas are partially resistant to negative feedback from glucocorticoids whereas ectopic ACTH secreting tumours are completely resistant → if a pituitary adenoma is the cause cortisol may be suppressed after high dose dexamethasone * Desmopressin stimulation test → similar to CRH test, desmopressin stimulates aCTH release from a pituitary adenoma, ectopic secreting tumours rarely respond (not recommended for use in countries where CRH is available)

Question 32

Investigations to determine cause of suspected ectopic ACTH secretion in ACTH dependent hypercortisolism

Answer 32

* Chest imaging as first line - most ACTH secreting tumours found there

Question 33

Clinical exam findings in Cushing's syndrome

Answer 33

* Hands - increased skinfold thickness on backs of hands * Moon-like facies, central obesity, bruising, extensive pigmentation (ACTH), test for proximal myopathy, buffalo hump (fat deposition over the interscapular area) * Plethora of face, acne, hirsutism, telangiectasias, periorbital oedema * Visual fields, examine fundi for optic atrophy, papilloedema, hypertensive or diabetic changes * Striae * Palpate for adrenal masses, hepatomegaly (fat deposition or adrenal carcinoma deposits) * Lower limb oedema * Hypertension * Glycosuria on urinalysis