Endocrine disorders Flashcards
How does the hypothalamic pituitary thyroid axis work?
Negative feedback system
Controlled by negative feedback from the thyroid gland, which it stimulates
Parvocellular cells in hypothalamic nuclei synthesis and release hormone TRH
TRH released from axon terminals of the neurons at base of hypothalamus,
diffuses into portal vein, carries it to pituitary, binds on thyrotropes in ant pituitary
TSH produced by thyrotropes
TSH then released into general circulation stimulates thyroid gland to increase production of T4 and T3
T3 is biologically active form, most of initial thyroid hormone is produced as T4. Conversion in peripheral target tissues from T4 to T3 activates it
T4/T3 rises, negative feedback, inhibits production of TRH and TSH
What is hypothyroidism?
Too little thyroid hormone
T3/T4 low
Lethargy, weight gain
What is hyperthyroidism?
Too much thyroid hormone
T3/T4 levels high
What is primary hypothyroidism caused by?
Primary, thyroid gland malfunctioning
T3/4 not produced, negative feedback is reduced, low levels of inhibition of hypothalamus and pituitary
both hypo and pituitary produce TRH and TSH at high levels
TRH and TSH raised.
Low T3/T4, High TSH.
What is secondary hypothyroidism caused by?
Secondary hypothyroidism , disorder in pituitary or hypothalamus
Failure of stimulation of thyroid gland, low T3/T4
Low T3/4 and Low TSH
What is primary hyperthyroidism caused by?
Primary - Thyroid gland overactive so T3/4 high
Gives negative feedback on hypothalamus and pituitary
More inhibition of them so TSH levels are low
T3/T4 high, TSH low
What is secondary hyperthyroidism caused by?
Secondary, over production due to a change higher up.
High T3/T4
High TSH levels e.g if it was a pituitary adenoma which was overproducing TSH, thyroid gland would be overstimulated – high T3/4.
The high TSH is causing the high T3/4
What three zones is the adrenal cortex divided into/.
Zona glomerulosa secretes mineralocorticoids
Zona fasciculata secretes gluco-corticoids
Zona reticularis secretes adrenal androgens
blood flow is from outer surface of cortex to inner medulla
Adrenal steroids all synthesised from cholesterol branch into different biochemical pathways
Mineralocorticoids (aldosterone)
Glucocorticoids (cortisol)
Adrenal androgens
What does adrenal hyperfunction cause?
Excess cortisol (Cushing’s syndrome)
Excess aldosterone ( Conn’s syndrome )
What happens in adrenal insufficiency?
Hypercortisolism
Lack of aldosterone and cortisol (Addison’s)
What is aldosterone secretion activated by?
What is the RAAS system activated by?
Activated by
- RAAS
- Increased plasma [K+]
RAAS is activated by:
- Reduced renal perfusion e.g due to decreased blood pressure
- Increased sympathetic activity
body thinks blood volume has fallen
Describe the RAAS pathway
Some cells lining distal tubule form macula densa, sense presence of salt in tubular fluid
Communicate with juxtaglomerular cells on afferent arterial as it enters bowman’s capsule
RAAS activation increases secretion of renin from juxtaglomerular cells
Renin secreted into plasma, enzymatically cleaves angiotensinogen (synthesised by liver)
Into angiotensin 1, then converted to angiotensin 2 by ACE (found in lungs)
Angiotensin 2 is active hormonal form
Stimulates third by receptors in brain, vasoconstriction of blood vessels to increase BP and increases aldosterone secretion in adrenal cortex
What increases RAAS activity?
Decrease in perfusion pressure, less perfusion of renal tubules, falls below autoregulation threshold – reduced filtration – reduced fluid delivery to distal tubule
Hence reduced salt in the distal tubule (NaCl), which activates macula densa cells that signal to juxtaglomerular cell
Decrease in perfusion pressure can also result in increased sympathetic activity, which can directly activate the secretion of renin from juxtaglomerular cells
How does increased plasma potassium and therefore increased aldosterone secretion increase blood volume?
Increased plasma potassium
Increased aldosterone secretion
Increases sodium reabsorption from kidney tubules, increasing sodium in ECF
Sodium brings water with it - increased sodium reabsorption = increased water reabsorption
Net effect = increase in total amount of sodium with corresponding increase in water = increase in ECFV - maintians blood volume
What can be useful in diagnosis of primary hyperaldosteronism?
Plasma aldosterone / renin ratio
Source of excess aldosterone is adrenal e.g aldosterone secreting adenoma
Can be primary or secondary.
Primary – adrenal cortex producing too much aldosterone, often due to a tumour.
Secondary – overactivation of RAAS, driving adrenal gland to produce more aldosterone rather than overactivity of the gland itself
In either case there is excess of aldosterone in circulation.
What is the effect of excess aldosterone on RAAS activation?
Aldosterone will be stimulating the distal nephron to reabsorb sodium, sodium reabsorption high.
Water reabsorbed with it, increasing ECFV, increasing blood volume, which increases blood pressure.
Hypertension is a consequence of hyperaldosteronism.
Potassium secretion into the distal nephron will be increased by excess aldosterone. Hypokalaemia.
How is hyperaldosteronism diagnosed?
Measure plasma aldosterone and see if they’ve above the range
Test more useful is to measure both plasma aldosterone and plasma renin activity, then take ratio of these numbers
Aldosterone to renin ratio
What is primary aldosteronism?
Tumour overproducing aldosterone
Aldosterone high in circulation, blood volume and pressure high
Signals that usually increase RAAS activity are low.
Consequently there should be little activation of RAAS at its root
Expect plasma renin levels to be low
So high aldosterone + low renin = primary hyperaldosteronism
What is secondary hyperaldosteronism?
e.g Renal artery stenosis, blockage in renal artery so one kidney is under perfused. Significant decrease in perfusion of a kidney, activating signals that activate RAAS
Increase in renin secretion
Renin increases angiotensin and ultimately aldosterone
High levels of aldosterone due to being driven by increased renin production by adrenal cortex is working fine
Ratio of aldosterone to renin will be different here compared to primary
Both renin and aldosterone high = secondary hyperaldosteronism
What is the metabolic effects of cortisol?
Preserves plasma glucose - essential for brain:
By promoting insulin resistance in skeletal muscle so glucose isn’t used by muscles
Promotes lipolysis, breakdown of stored triglycerides into three fatty acids, used as alternative fuel instead of glucose
Promotes gluconeogenesis by stimulating synthesis of glucose by the liver from non-carbohydrate substrates
Can also include amino acids derived from proteolysis of muscle proteins
Net result is to maintain plasma glucose and enables you to survive in extreme starvation
What is the consequence of excess cortisol in the absence of physiological stress?
Clinical signs and symptoms
Insulin resistance in muscle leads to hyperglycaemia and increased gluconeogenesis
Increase in plasma glucose will lead to increase in insulin, plasma glucose not being taken up into muscle due to cortisol induced insulin resistance
Plasma glucose increases, increases insulin production, insulin promotes lipogenesis.
Excess glucose will be funnelled into lipogenesis, and newly synthesised lipids will be stored as fat.
- increased adiposity, around trunk and thinning of arms and legs due to muscle wasting
- hyperglycaemia and hypertension
Describe the HPA axis
Hypothalamus secretes CRH, carried via portal vein to pituitary
Stimulates pituitary cells to release ACTH
ACTH stimulates adrenal cortex to produce cortisol and adrenal androgens
And to a certain extent aldosterone secretion
Cortisol rises, binds to hypothalamus and ant. pituitary, inhibits release of CRH and ACTH
Why do cortisol levels fluctuate during the day?
Driven by circadian rhythms
Plasma cortisol peaks in morning, fluctuations during day, lowest around mightnight
So difficult to measure and assess actual level of cortisol and if it is appropriate or not
Circulating cortisol hs negative feedback of ADH (vasopressin), ADH rises in absence of cortisol
What is Cushing’s syndrome and it’s most common cause?
Elevated cortisol, most common reason is iatrogenic (result of medical therapy)
Exogenous glucocorticoids activate cortisol receptor
High doses will shut down HPA, strong inhibition but not from cortisol synthesised by the adrenal cortex but from exogenous glucocorticoids – stops CRH and ACTH production
Adrenal cortex atrophies with lack of ACTH , stops producing cortisol and androgens
Several days may be required for adrenal cortex to become responsive to ACTH again
- hence slow withdrawal from glucocorticoid therapy needed
What is Cushing’s DISEASE due to?
ACTH-secreting pituitary adenoma
ACTH is pumped out at higher levels than normal, raising adrenal production of cortisol and androgens.
Negative feedback loop still intact but everything is set at a higher level
Because there are more ACTH secreting cells in the anterior pituitary, there is more ACTH, and hence more cortisol
More negative feedback from cortisol, but the pituitary due to adenoma is at a higher set point.
Net result is high ACTH levels.
What else can cause Cushing’s syndrome other than iatrogenic cause
Ectopic ACTH source
Tumour somewhere else synthesising ACTH
Or could be primary, hypofunction of adrenal cortex itself, like adrenal adenoma leading to high cortisol secretion
Adrenal is stimulated by source of ACTH, producing higher level of cortisol and androgens
In circulation and provide negative feedback to HPA
Inhibiting release of CRH and ACTH
ACTH from pituitary will be low due to negative feedback, but it doesn’t matter as the source of circulating ACTH is not from pituitary but is ectopic.
- Feed back loop bypassed in Syndrome
How can you measure cortisol levels if they fluctuate?
Measure when you expect it to be high in morning and when you expect it to be low at night, compare results.
Collect 24hr urinary sample and measure urinary cortisol, compare to reference
Dexamethasone suppression test, synthetic glucocorticoid, activates cortisol receptors in hypothalamus and pituitary
- if feedback loop intact (Cushing’s disease) then dexa suppresses cortisol via suppressing ACTH - if healthy you would have high cortisol in morning, but this will be suppressed
- someone with cushing’s disease/syndrome due to ectopic ACTH, dexa not suppressed
Repeat dexa test with high dose for 4 nights, measure morning cortisol following morning
Why does dexamethasone at low or high dose have no effect is Cushing’s syndrome is due to ecotpic ACTH?
If source is ectopic ACTH, dexamethasone is inhibiting hypothalamus and anterior pituitary but the anterior pituitary is not the source of ACTH
Anterior pituitary produces little or no ACTH due to negative feedback
ACTH coming from ectopic source, stimulating cortisol secretion.
Dexamethasone at low or high dose has no effect on cortisol production because production is not stimulated by the HPA axis anyhow
NO EFFECT of dexamethasone test in ECTOPIC ACTH
distinguishes between disease and syndrome
What effect does high dose dexa have on primary cushing’s syndrome?
Due to adrenal gland
Adrenal produces lots of cortisol
Increased negative feedback to anterior pituitary
low plasma ACTH levels
Why does low dose dexa not have much effect in Cushing’s disease?
Suppression on second or third day, not first day in people with Cushing’s disease because the feedback loop is still intact
Single low dose dexamethasone the feedback loop is set at a high level so extra inhibition doesn’t have much effect
Bigger dose of the glucocorticoid, turn up amplitude of negative feedback, you get some suppression of cortisol if source is from anterior pituitary
How do you diagnose which type of Cushing’s syndrome person has with plasma ACTH?
Cushing’s disease
- Plasma ACTH is high as pituitary adenoma pumps out more ACTH than normal
- Therefore low dose dexa gives no suppression of cortisol
- Prolonged high dose gives suppression
Primary Hypercortisolism, Cushing’s syndrome, due to adrenal tumour
- No suppression with DEXA at any dose as it is not driven by ACTH, cortisol is not ACTH dependent
- Plasma ACTH is low due to negative feedback
Secondary hypercortisolism due to Ectopic ACTH source
- No suppression with any level of Dexa
- ACTH plasma is very high, from ectopic source
What is primary adrenal insufficiency?
Lack of adrenal steroids
Primary, problem within adrenal gland itself
- Addison’s disease – commonly caused by autoimmune disease that leads to destruction of adrenal cortex
- Insufficient cortisol and aldosterone
What is secondary adrenal insufficiency caused by?
Pituitary or hypothalamic disease
Insufficiency cortisol as adrenal gland is still functioning and mineralocorticoids under control of RAAS
Lack of cortisol, lack of negative feedback on HPA axis - increase in CRH, ACTH and VP/ADH
What are the clinical features of addison’s?
Hypotension
Plasma [Na+]: normal to low, lack of aldosterone causes less Na+ and water reabsorption – volume depletion. Plasma Na+ to be low as in absence of negative feedback there is increased ADH (which promotes pure water reabsorption) - has effect of diluting electrolytes in ECF.
Plasma [K+]: normal to high, hyperkalaemia. Depends on stage of disease, not seen in most patients. Aldosterone promotes K+ excretion (works against hyperkalaemia), in the absence of it plasma K+ can rise.
High ACTH – if primary disorder, failure of adrenal gland itself. Lack of negative feedback interpreted by HPA axis as not enough adrenal steroids, so causes high ACTH production.
Elevated plasma renin – due to lack of aldosterone and potential volume depletion, activation of RAAS.
What symptoms do patients with addison’s disease show?
Anorexia
Weakness, fatigue
Hyperpigmentation – in places not exposed to sun like elbow, due to high ACTH levels due to absence of negative feedback. ACTH cross reacts with melanocortin receptors, stimulating melanocytes at high concentrations.
Gastrointestinal symptoms
Hypotension – lack of cortisol and aldosterone
Salt cravings
Muscle or joint pain
Postural dizziness
What is the hallmark of Addison’s disease?
How can it be diagnosed?
High ACTH, low cortisol
Dynamic test: assess ability of adrenal cortex to produce cortisol in response to ACTH
- if primary, failure in adrenal cortex, ACTH stimulation won’t help, ACTH already high due to lack off negative feedback
- if secondary, lack of ACTH from pituitary, adrenal cortex will response
Descibe the ACTH stimulation test
short and long synacthen test
Short synacthen test
- Measure baseline cortisol (9am) and 30 min after 250ug synacthen (synthetic ACTH)
- Adrenal insufficiency is excluded by an increase in cortisol of >200nmol/L and/or a 30 min value >550 - excluding primary. If it is secondary, adrenal cortex should be capable of responding to ACTH.
Long synacthen test
- Adrenal cortex shuts down in absence of stimulation by ACTH – time needed to regain responsiveness as adrenal cortex atrophies, so long synacthen test is used
- 3-day stimulation with synacthen
- In secondary (but not primary) adrenal insufficiency cortisol increases by >200nmol/l
- Long test not often necessary since ACTH assay can distinguish
