03: Clinical Lectures 2 Flashcards
Classify the steroid hormones according to their main physiological effects and the endocrine gland cell types that secrete them.
MINERALCORTICOIDS (zona medullarosa) = ALDOSTERONE
*salt balance = water balance
GLUCOCORTICOIDS (zona fasciculata) = CORTISOL
*energy balance
SEX STEROIDS (zona reticularis) = TESTOSTERONE * sex
MEDULLA (extension of sympathetic system) = Norepinephrine and epinephrine
*stress response
Outline schematically the main pathways and cellular compartments involved in the synthesis of steroid hormones; and indicate the main agents and points of control.
CHOLESTEROL
=> PROGESTERONE
- > CORTICOSTERONE > ALDOSTERONE
- > CORTISOL
(21-hydroxylase)
CHOLESTEROL
=> PROGESTERONE + DHEA => ANDROSTENEDIONE
> ESTRONE
> ANDROSTENEDIONE > TESTOSTERONE > estradiol
> DHT
- different enzymes found in different adrenal zones in order to make different enzymes
e. g. aldosterone enzymes found in zona glomerulosa
Outline diagrammatically the structure of the (compound) adrenal gland, indicating its zonation, vascularisation and innervation.
thoracic splanchnic nerve
The adrenal medulla is driven by the sympathetic nervous system via preganglionic fibers originating in the thoracic spinal cord, from vertebrae T5–T11
Justify the view that the adrenal cortex is essential for survival of the individual while the adrenal medulla is not.
Adrenal cortex produces hormones that controls sex (androgens, estrogens), salt balance in the blood (aldosterone), and sugar balance (cortisol). The adrenal medulla produces hormones involved in the fight-or-flight response (catecholamines, or adrenaline type hormones such as epinephrine and norepinephrine).
Describe the normal circadian basal rhythm in plasma total cortisol concentration & levels in pathology
high @ morning, lowest at midnight, ACTH mirrors levels
very high ACTH plasma = ectopic ACTH
very low ACTH = non-ACTH-dependent = adrenal gland
CUSHINGS (pituitary) = overlap between ectopic ACTH therefore ACTH measurement not enough to dx
Define the terms: plasma protein bound cortisol; plasma free cortisol.
95% of plasma cortisol bound to CORTISOL BINDING GLOBULIN
bind to receptors found in all nucleated cells
State the likely effect upon the plasma glucose concentration of administering cortisol to a normal subject; and list the target sites and processes underlying that effect.
Under stressful conditions, cortisol provides the body with glucose by tapping into protein stores via gluconeogenesis in the liver
Discuss the clinical features and biochemical diagnosis of the hyperfunction syndromes of the adrenal cortex and medulla (Cushing’s syndrome)
causes:
1º HYPERALDOSTERONISM:
*unilateral adenoma, bilaeral hyperplasoa
- CUSHINGS: adrenal gland = XS cortisol androgens
- tissue breakdown, sodium retention, insulin antagonism = DM, immune system suppression
=> central obesity, HT, glucose intolerance, Hirsutism, Striae
• ACTH-dependent = pit. tumour (cushing’s disease), ectopic ACTH secretion (lung carcinoid) = ⇧ACTH = XS cortisol.
or CRH secreting tumour = ⇧ACTH
• ACTH-independent = adrenal tumour (adenoma/carcinoma); corticosteroid therapy = 1º issue @ adrenal gland level
1) SCREENING: overnight dex test + 24hr free cortisol in urine
2) 24hr free urine cortisol rpt. + low dose dex test
3) ACTH monitoring @ morning-midnight
4) High dose dex test (pit or not pit.)
5) MRI sella, CT adrenal, BIPSS, CT chest
> Sx of tumour
ADRENAL HORMONE SYNTH INHIB (Ketoconazole etc.)
Destroy adrenocortical cells (Mitotane)
RT
Bilateral adrenalectomy
Describe the clinical features, diagnosis and management of adrenal hypofunction (Addison’s disease).
causes: adrenal dysgenesis, adrenal destruction, impaired steroidogenesis
1º ADRENAL INSUFFICIENCY
- Addison’s: AuImm, Invasion, Infiltration, Iatrogenic, Infarction
- +ve adrenal autoantibodies, lymphocytic infiltrate
- no cortisol prod > ⇧CRH (hypothal) > ⇧ACTH & ⇧MSH (due to common POMC precursor) = PIGMENTATION
- Decreased BV = postural hypotension
ADRENAL ENZYME DEFECTS
- congenital adrenal hyperplasia (21-hydroxylase deficiency)
• Low Na High K
• CORTISOL LEVELS CHECK
• SYNACTHEN TEST + BASAL ACTH: basline cortisol and ACT > synthetic ACTH (tetracosactrin) > measure over time,
= 450nmol+ over normal
= 1º adrenal insufficiency = no response
= 2º adrenal insufficiency = no CRH thus trophic diminished = stunted cortisol production
• followed by PLASMA ACTH measurements
• followed by Adrenal Antibodies + other autoimmune antibodies monitoring
+ long chain fatty acids (men) for adrenoleukodystrophy
> STEROIDS (if too unwell for SYNACTHEN)
daily: GLUCOCORTICOID (steroids) in divided doses to mimic diurnal variation (HC)
Mineralocorticoid replacement (fludrocortisone) which bind to ALDOSTERONE receptors; monitored for dose adjustment
Discuss the importance of glucocorticoids in acute stress (guidelines for the management of patients on replacement steroids).
- HYPOADRENAL PATIENTS / REPLACEMENT STEROIDS require doubling steroid doses in order to react to stresses
- Patients receiving long-term treatment and take exogenous steroids: endogenous steroid prod affected thus replacement steroids required.
- minor short lived illness or stress = 2x
- major illness/operation = 100mg HC iv
- patient education to safetynet, partners and carers taught to inject IM HC w/ sever vom and diarrhoea
Outline inborn errors of the adrenal glands (congenital adrenal hyperplasia).
21-hydroxylase defect = aldosterone and cortisol def.
*salt and glucose balance disruption
- excessive adrenal androgen production
- hyperplasia d/t nil cortisol to negative feedback ACTH and CRH = continuous adrenal cortex stimulation
Screening tests for Cushings
24hr urinary free cortisol = 14-135nmol/24hr (normal)
Overnight Dex. suppression test = <50nmol/l @ 0900 (normal)
- normal: cortisol drops
- Pituitary dependent = drops after some time (day 4) d/t high dose eliciting neg feedback
- Ectopic ACTH = cortisol levels remain high and not suppressed,
Discuss the clinical features and biochemical diagnosis of the hyperfunction syndromes of the adrenal cortex and medulla (Conn’s syndrome)
Xs ALDOSTERONE d/t adenoma or bilateral hyperplasia: normally stimulated by Angio.II (powerful vasoconstrictor) = water retention and HT
d/t
ALDOSTERONE-PRODUCING TUMOUR = renal tubules ⇧water retention etc. = ⇩renin = ⇩Angio.II =
⇧aldosterone:renin ratio
1) measure aldosterone:renin ratio, ratio >20 1º hyperaldosteronism
2) plasma renin activity (PRA) & plasma aldosterone concentration (PAC)
3) 24hr urine aldosterone w/ salt loading
4) CT adrenal, plasma 18-hydroxycorticosterone
5) adrenal venous sampling
Discuss the clinical features and biochemical diagnosis of the hyperfunction syndromes of the adrenal cortex and medulla (Phaeochromocytoma)
PHEOCROMOCYTOMA: neuroendocrine tumour in adrenal medulla = XS catecholmaines
= ⇧HR = ⇧CO = ⇧BP
= Diabetogenic d/t adrenergic effect on glucose metabolism
- HT (especially young HT) & paroxysmal attacks: headache, sweating, palpitations, tremor, pallor, anxiety,
- TUMOUR-ASSOCIATED
- HYPERGLYCAEMIC; fight or flight stress.
- MEN II (multiple endocrine neoplasia): phaecrom.
- Von Hippel-Landau
- MEN III
1) 24hr urine for metanephrines & plasma metanephrines
2) discontinue any contributing medications
3) Adrenal CT/MRI
4) Radionecleotide scan: selective uptake and localisation of lesion
+genetic testing w/ family hx > tumour evaluation (expression studies)
> Sx risk of crisis release of hormone release
thus
• alpha-adrenergic blockade > THEN beta blocker (lols)
Adrenal Mass Dx Algorithm
1) endocrine workup: free metanephrine plasma/urine, dex test, ALD:PRA
= Sx if functional and secretory
2) CT or MRI (non-functional, need to id malignant or benign)
3) surveillance or surgery
Congenital adrenal Hyperplasia
21-hydroxylase def.
Xs of precursors and shunted pathway to TESTOSTERONE
*lack of cortisol = no neg feedback = ⇧ACTH = adrenal hyperplasia
- neonatal salt loss crisis
- ambiguous genitalia (girls)
- hirsutism (women)
Calcium distirbution & adjustment
dietary calcium forms salts and thus majorly excreted
BONE calcium reservoir
PLASMA calcium: 45% of plasma calcium is free/ionised and bio active
* total calcium needs to be adjusted
* albumin levels; binds to calcium thus dictate active calcium levels
- 2.20-2.6mmol/l
- ADJUST BY 0.1mmol/L FOR EACH 5G/L reduction in albumin from 40g/l
e.g. albumin of 30g/l = 0.2mmol INCREASE d/t to LOSS in albumin = above normal range
Parathyroid Glands
CHIEF CELLS: PTH
OXYPHIL CELLS: larger and less abundant;
*calcium-sensing receptors indicate and dictate PTH levels depending on plasma calcium