Adrenal Physiology and Disorders Flashcards
How much do the adrenal glands weigh in a healthy adult?
4g
Where are corticosteroids synthesised?
In the adrenal cortex from cholesterol
What regulates cortisol and androgen production?
Hormones produced by the hypothalamus and pituitary gland
What regulates aldosterone?
Renin-angiotensin system and plasma potassium
What are the precursors of cortisol, which is produced in the adrenal cortex?
Corticotropin-releasing hormone (CRH) produced by the hypothalamus, adrenocorticotropic hormone (ACTH) produced in the anterior pituitary
What is the renin-angiotensin system activated in response to?
Decreased blood pressure = leads to production of angiotensin II which causes direct (vasoconstriction) and indirect (aldosterone) methods of BP elevation
What is the action of corticosteroids?
Bind intracellular receptors = receptor/ligand complex binds DNA to affect transcription
What are the six classes of corticosteroids?
Glucocorticoids, mineralocorticoids, progestin, oestrogen, androgen, vitamin D
What are some of the actions of cortisol?
Increases CO, BP, renal flow and GFR
Increases blood sugar, lipolysis and proteolysis
Central redistribution of fat, mood lability, euphoria/psychosis, decreased libido
How does cortisol affect the immune system?
Decreased capillary dilation/permeability, leucocyte migration, macrophage activity and inflammatory cytokine production
How does cortisol accelerate osteoporosis?
Decreases serum calcium wound healing and collagen formation
What are the three main clinical uses of corticosteroids?
Suppress inflammation, suppress immune system, replacement treatment
What are some conditions treated by corticosteroids?
Asthma, anaphylaxis, rheumatoid arthritis, ulcerative colitis, Crohn’s disease, malignancy
Where are the mineralocorticoid receptors for aldosterone located?
Kidneys, salivary glands, gut, sweat glands
What are the effects of aldosterone acting on mineralocorticoid receptors?
Na+/K+ balance = K+/H+ excretion, increases Na+ reabsorption
Blood pressure regulation, regulation of extracellular volume
What is adrenal insufficiency?
Inadequate adrenocortical function
What are some causes of primary adrenal insufficiency?
Addison’s disease, congenital adrenal hyperplasia, adrenal TB, malignancy
What are some causes of secondary adrenal insufficiency?
Due to lack of ACTH stimulation = excess exogenous steroid, pituitary/hypothalamic disorders
What is Addison’s disease?
Autoimmune destruction of adrenal cortex = most common cause of primary insufficiency, >90% destroyed before symptomatic, autoantibody positive in 70%
What are some other autoimmune conditions associated with Addison’s disease?
Type 1 diabetes, autoimmune thyroid disease, pernicious anaemia
What are some symptoms of Addison’s disease?
Anorexia, weight loss, fatigue/lethargy, dizziness and low BP, abdominal pain, vomiting, diarrhoea, skin pigmentation (due to increased ACTH)
How is adrenal insufficiency diagnosed?
Low Na+, high K+, hypoglycaemia, very high ACTH, very high renin, low aldosterone, short synacthen test
How is a short synacthen test carried out?
Measure plasma cortisol before and 30mins after IV/IM ACTH injection = normal baseline is >250nmol/L, normal post-ACTH is >550nmol/L
How is adrenal insufficiency treated?
Hydrocortisone as cortisol replacement, fludrocortisone as aldosterone replacement, educate patients on sick day rules and wearing identification
What are some features of hydrocortisone therapy as adrenal insufficiency treatment?
Given via IV if unwell, usually 15-30mg daily in divided doses, try to mimic diurnal rhythm
What must be monitored when giving fludrocortisone as part of treatment for adrenal insufficiency?
Blood pressure and potassium
How does hydrocortisone dose change when a patient with adrenal insufficiency is unwell but managing their illness at home?
Dose is doubled until they have recovered
What is the most common cause of secondary adrenal insufficiency?
Exogenous steroid use (iatrogenic) = often high dose prednisolone, dexamethasone or inhaled corticosteroid
What are the features of secondary adrenal insufficiency?
Similar to Addison’s except pale skin (no raised ACTH) and aldosterone production intact
Treat with hydrocortisone replacement
What is Cushing’s syndrome?
Excess cortisol secretion = high mortality, rare, more common in women, aged 20-40
What are the symptoms of Cushing’s syndrome?
Easy bruising, facial plethora, striae, proximal myopathy
What are the ACTH dependent causes of Cushing’s syndrome?
Pituitary adenoma (68%, Cushing’s disease), ectopic ACTH (12%, carcinoid), ectopic CRH (<1%)
What are the ACTH independent causes of Cushing’s syndrome?
Adrenal adenoma (10%), adrenal carcinoma (8%), nodular hyperplasia (1%)
How is cortisol excess established in Cushing’s syndrome?
Overnight dexamethasone suppression test, 24hr urinary free cortisol, late night salivary cortisol
What is another test that can be used to diagnose Cushing’s syndrome?
Low dose dexamethasone suppression test
What causes iatrogenic Cushing’s syndrome?
Prolonged high dose steroid therapy = usually oral therapy, can occur with high dose inhaled steroids or steroid injections
What are some features of iatrogenic Cushing’s syndrome?
Chronic suppression of pituitary ACTH production, adrenal atrophy, most common cause of cortisol excess (negative feedback to anterior pituitary)
What are some implications of iatrogenic Cushing’s syndrome?
Unable to respond to stress, need extra doses when ill, cannot stop suddenly, gradual withdrawl of steroid therapy if >4-6 weeks
What causes primary aldosteronism?
Autonomous production of aldosterone independent of its regulators (ang II/K+) = commonest cause of secondary hypertension
What are the cardiovascular actions of aldosterone?
Increases sympathetic outflow, increases cardiac collagen, cytokines and ROS synthesis, sodium retention, altered endothelial function (increases pressor responses)
What are the features of primary aldosteronism?
Significant hypertension, hypokalaemia (30%), alkalosis
What are the subtypes of primary aldosteronism?
Adrenal adenoma = Conn’s syndrome, 30% of cases
Bilateral adrenal adenoma = most common cause (60%)
Rare causes = genetic mutations, unilateral hyperplasia
What can K+ channel mutations cause?
Adenomas and hereditary hypertension = mutations lead to loss of ion selectivity (Na+ entry and depolarisation)
What is the function of the KCNJ5 channel?
Rectifying selective channel which maintains the membrane hyperpolarisation = somatic mutations identified at two key sites
How is aldosterone excess confirmed in primary aldosteronism?
Measure plasma aldosterone and renin and express as ratio (ARR)
What should be done is the ARR is raised in a patient with suspected primary aldosteronism?
If ARR raised (assay dependent) then investigate further with saline suppression test
What result of a saline suppression test confirms the diagnosis of primary aldosteronism?
Failure of plasma aldosterone to suppress by >50% with 2L saline
How is the subtype of primary aldosteronism conformed?
Adrenal CT for adenoma, sometimes adrenal vein sampling to confirm adenoma is source of aldosterone excess
How is bilateral adrenal hyperplasia treated?
MR antagonists (e.g spironolactone, eplerenone)
What is the main treatment for primary aldosteronism?
Surgery = unilateral laparoscopic adrenalectomy, only if adrenal adenoma and excess confirmed by vein sampling
How effective is surgery as a treatment for primary aldosteronism?
Cure for hypokalaemia, cures 30-70% of hypertension
What is congenital adrenal hyperplasia?
Rare conditions associated with enzyme defects in the steroid pathway = most common is 21 alpha hydroxylase deficiency (autosomal recessive)
What are the variants of 21 alpha hydroxylase deficiency associated with congenital adrenal hyperplasia?
Classical = salt-wasting, simple virilising Non-classical = hyperandrogenaemia
How is congenital adrenal hyperplasia diagnosed?
Basal (or stimulated) 17-OH progesterone
What is the classical presentation of congenital adrenal hyperplasia?
Males = adrenal insufficiency (often at 2-3 weeks), poor weight gain Females = genital ambiguity
What are some non-classical features of congenital adrenal hyperplasia?
Hirsute, acne, oligomenorrhoea, precocious puberty, infertility or sub-fertility
How is congenital adrenal hyperplasia treated in children?
Timely recognition, glucocorticoid replacement, mineralocorticoid replacement in some, surgical correction, achieve maximal growth potential
How is congenital adrenal hyperplasia treated in adults?
Control androgen excess, restore fertility, avoid steroid over-replacement
What are the clues that someone has a phaeochromocytoma?
Labile hypertension, postural hypotension, paroxysmal sweating, pallor, sweating, tachycardia
What are phaeochromocytomas?
Rare tumours = phaeochromocytomas when in adrenal medulla, paragangliomas when extra-adrenal (sympathetic chain)
Why are phaeochromocytomas brown?
Chromaffin cells reduce chrome salts to metal chromium resulting in a brown colour reaction
What are some features of phaeochromocytomas?
Potentially fatal, high rate of post-mortem diagnosis, insidious onset, incidental finding, family tracing, <0.1-1% of hypertensive cases in secondary care
What are the differentials of phaeochromocytomas?
Angina, anxiety, carcinoid, thyrotoxicosis, insulinoma, menopause, arrhythmias, migraine, drug toxicity, alcohol withdrawl, pregnancy, hypoglycaemia, mastocytosis, autonomic neuropathy, factitious
What is the classic triad of symptoms for phaeochromocytomas?
Occur in up to 90% = hypertension (50% paroxysmal), headache, sweating
What are other symptoms of phaeochromocytomas?
Palpitations, breathlessness, constipation, anxiety, weight loss, flushing (rare)
What are some signs of phaeochromocytomas?
Hypertension, postural hypotension (50%), pallor, bradycardia, tachycardia, pyrexia
What are some signs of complications caused by a phaeochromocytoma?
LV failure, myocardial necrosis, stroke, shock, paralytic ileus of bowel
What are some biochemical abnormalities associated with phaeochromocytomas?
Hyperglycaemia (adrenaline-secreting tumour), may have low K+, raised Hb concentration, mild hypercalcaemia, lactic acidosis (in absence of shock)
Who should be investigated for phaeochromocytomas?
Family members with syndromes, resistant hypertension, age <50 with hypertension, classic symptoms, hypertension with hyperglycaemia
How is catecholamine excess confirmed in phaeochromocytomas?
Urine 2x24hr catecholamines or metanephrins, plasma at time of symtpoms
How is the source of catecholamine excess confirmed in phaeochromocytomas?
MRI of abdomen/body, MIBG, PET scan
How are phaechromocytomas treated?
Full alpha and beta blockade, fluid and/or blood replacement, chemotherapy if malignant (radio-labelled MIBG), laparoscopic surgery
How are alpha and beta blockades used to treat phaeochromocytomas?
Alpha blockade before beta blockade, phenoxybenzamine (alpha blocker), propanolol, atenolol or metoprolol (beta blockers)
What kind of laparoscopic surgery is done for phaeochromocytomas?
Total excision of lesion when possible, surgical tumour de-bulking also done
What are some extra elements of treatment for phaeochromocytomas?
Long term follow up, genetic testing, family tracing and investigation
What are some clinical syndromes associated with phaechromocytomas?
MEN2, Von-Hipple Lindau syndrome, succinate dehydrogenase syndrome, neurofibromatosis, tuberose sclerosis
What are the pitfalls of phaeochromocytoma diagnosis?
Catecholamines are also raised in heart failure, episodic catecholamine secretion so levels in plasma and urine may be normal
