Endocrine disorders

Question 1

How does the hypothalamic pituitary thyroid axis work?

Answer 1

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

Question 2

What is hypothyroidism?

Answer 2

Too little thyroid hormone

T3/T4 low

Lethargy, weight gain

Question 3

What is hyperthyroidism?

Answer 3

Too much thyroid hormone

T3/T4 levels high

Question 4

What is primary hypothyroidism caused by?

Answer 4

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.

Question 5

What is secondary hypothyroidism caused by?

Answer 5

Secondary hypothyroidism , disorder in pituitary or hypothalamus

Failure of stimulation of thyroid gland, low T3/T4

Low T3/4 and Low TSH

Question 6

What is primary hyperthyroidism caused by?

Answer 6

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

Question 7

What is secondary hyperthyroidism caused by?

Answer 7

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

Question 8

What three zones is the adrenal cortex divided into/.

Answer 8

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

Question 9

Adrenal steroids all synthesised from cholesterol branch into different biochemical pathways

Answer 9

Mineralocorticoids (aldosterone)

Glucocorticoids (cortisol)

Adrenal androgens

Question 10

What does adrenal hyperfunction cause?

Answer 10

Excess cortisol (Cushing’s syndrome)

Excess aldosterone ( Conn’s syndrome )

Question 11

What happens in adrenal insufficiency?

Answer 11

Hypercortisolism

Lack of aldosterone and cortisol (Addison’s)

Question 12

What is aldosterone secretion activated by?

What is the RAAS system activated by?

Answer 12

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

Question 13

Describe the RAAS pathway

Answer 13

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

Question 14

What increases RAAS activity?

Answer 14

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

Question 15

How does increased plasma potassium and therefore increased aldosterone secretion increase blood volume?

Answer 15

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

Question 16

What can be useful in diagnosis of primary hyperaldosteronism?

Answer 16

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.

Question 17

What is the effect of excess aldosterone on RAAS activation?

Answer 17

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.

Question 18

How is hyperaldosteronism diagnosed?

Answer 18

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

Question 19

What is primary aldosteronism?

Answer 19

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

Question 20

What is secondary hyperaldosteronism?

Answer 20

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

Question 21

What is the metabolic effects of cortisol?

Answer 21

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

Question 22

What is the consequence of excess cortisol in the absence of physiological stress?

Clinical signs and symptoms

Answer 22

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

Question 23

Describe the HPA axis

Answer 23

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

Question 24

Why do cortisol levels fluctuate during the day?

Answer 24

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

Question 25

What is Cushing’s syndrome and it’s most common cause?

Answer 25

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

Question 26

What is Cushing’s DISEASE due to?

Answer 26

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.

Question 27

What else can cause Cushing’s syndrome other than iatrogenic cause

Answer 27

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

Question 28

How can you measure cortisol levels if they fluctuate?

Answer 28

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

Question 29

Why does dexamethasone at low or high dose have no effect is Cushing’s syndrome is due to ecotpic ACTH?

Answer 29

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

Question 30

What effect does high dose dexa have on primary cushing’s syndrome?

Answer 30

Due to adrenal gland

Adrenal produces lots of cortisol

Increased negative feedback to anterior pituitary

low plasma ACTH levels

Question 31

Why does low dose dexa not have much effect in Cushing’s disease?

Answer 31

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

Question 32

How do you diagnose which type of Cushing’s syndrome person has with plasma ACTH?

Answer 32

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

Question 33

What is primary adrenal insufficiency?

Answer 33

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

Question 34

What is secondary adrenal insufficiency caused by?

Answer 34

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

Question 35

What are the clinical features of addison’s?

Answer 35

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.

Question 36

What symptoms do patients with addison’s disease show?

Answer 36

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

Question 37

What is the hallmark of Addison’s disease?

How can it be diagnosed?

Answer 37

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

Question 38

Descibe the ACTH stimulation test

short and long synacthen test

Answer 38

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