Endocrine disorders

Question 1

How can we measure hormone levels to see if they are appropriate?

Answer 1

1. Compare with reference range

2. Always interpret with respect to controlling variable

Question 2

What is the function of the thyroid gland

Answer 2

Thyroid gland produces thyroid hormones T3 + T4.
T3=triiodothyronine(more active form)
T4=thyroxine(majority)

T4 -> T3, activated by deiodinase enzymes in peripheral tissue

Question 3

What is the function of Thyroid hormone ?

Answer 3

1. Normal growth + development
   - Congenital hypothyroidism = developmental problems

2.Upregulates metabolism
Can ↑ metabolic rate , heat production, ATP production, metabolism = ↑ glucose release

Question 4

What are the two main categories of thyroid disorders ?

Answer 4

Underproduction = Hypothyroidism 
Overproduction = Hyperthyroidism

Question 5

What is the Hypothalamic-Pituitary-Thyroid control of the thyroid gland?

Answer 5

Negative feedback loop

In the hypothalamus there are neurosecretory cells located in specific nuclei called parvocellular neuron in specific thalamic nuclei synthesise + release thyrotropin releasing hormone (TRH)

These neurons have short axons and terminate on the capillary bed at the base of the hypothalamus where they release TRH into local capillaries.
These collect in the pituitary portal vein which carries TRH to the anterior pituitary gland which activates thyrotrophs (TSH/thyrotropin-synthesising cells). Thyrotropin/TSH travels in circulation, binds to receptors on thyroid gland = ↑ T4 and T3 release
Peripheral tissues: T4 -> T3 (active)

Question 6

What are the aspects which can result in thyroid disorders?

Answer 6

Thyroid gland problem = ↑/↓ thyroid hormone production = Primary problem

Pituitary problem can affect thyroid gland =Secondary problem

Hypothalamic disease

Question 7

How can primary hypo/hyper thyroidism be diagnosed ?

Answer 7

Primary disorders are more common

• Measure T3/T4
• Measure circulating TSH in blood

Primary hypothyroidism: ↓ T3/T4 = ↑ TSH
Secondary hypothyroidism: ↓ TSH = ↓ T3/T4
Primary hyperthyroidism: ↑ T3/T4 = ↓ TSH
Secondary hyperthyroidism: ↑ TSH = ↑ T3/T4

Question 8

What is Hashimoto’s Disease?

Answer 8

Hashimoto’s Disease = Autoimmune condition - Antibodies target + destroy thyroid tissue = ↓ T3+T4 production = primary hypothyroidism (dysfunction of thyroid gland itself)

Question 9

What is Grave’s Disease?

Answer 9

Grave’s Disease = Autoimmune condition - Antibodies bind to TSH Rs on thyroid gland cells + stimulate them = ↑ production of T3/T4 = primary hyperthyroidism (dysfunction of thyroid gland itself)

Question 10

Describe the structure of adrenal glands

Answer 10

Adrenal glands are on top of kidneys

Adrenal gland - outer cortex, inner medulla.

Cortex is divided into 3 zones :

• Zona glomerulosa (outer) - Mineralocorticoids (aldosterone)
• Zona fasciculata (middle) - Glucocorticoids (cortisol)
• Zona reticularis (Inner) - Adrenal androgens

Blood flows from the outer cortex layer to inner medulla = pattern of steroid synthesis (from cholesterol). Its due to the carrying of the precursors

Question 11

What are the adrenal steroids?

Answer 11

Mineralocorticoids (aldosterone)
Glucocorticoids (cortisol)
Adrenal androgens (DHEA, DHEAS)

Question 12

What are the 2 types of adrenocortical disorders ?

Answer 12

Adrenal hyperfunction:

• Excess cortisol = Cushing’s syndrome
• Excess aldosterone e.g. Conn’s syndrome - adrenal adenoma

Adrenal insufficiency:

• Hypocortisolism
• Addison’s = ↓ aldosterone + cortisol

Question 13

What is primary hyperaldosteronism ?

Answer 13

Conn’s syndrome (primary hyperaldosteronism):

• Adrenal cortex producing excess aldosterone.
• Dysfunction in adrenal cortex = primary hyperaldosteronism
• May be due to adrenal tumour

Question 14

What is secondary hyperaldosteronism ?

Answer 14

Overactivation of RAAS causes adrenal gland overproduction of aldosterone
Not overactivity of adrenal gland, but due to another reason

Question 15

What are the hormone levels in Primary Hypothyroidism?

Answer 15

↓ thyroid hormone (T4+T3)
↑ TSH
due to - fb on ant. pituitary gland

Question 16

What are the hormone levels in Primary Hyperthyroidism?

Answer 16

↑ thyroid hormone (T4+T3)
↓ TSH
due to - fb on ant. pituitary gland

Question 17

What is Secondary Hypothyroidism/Hyperthyroidism?

What is Tertiary Hypothyroidism/Hyperthyroidism?

Answer 17

Secondary Hypothyroidism/Hyperthyroidism = Ant. Pituitary causes excess/insufficient production of thyroid hormone
Tertiary Hypothyroidism/Hyperthyroidism = Hypothalamus causes excess/insufficient production of thyroid hormone

Question 18

What are the hormone levels in Secondary Hypothyroidism?

Answer 18

↓ TSH
↓ thyroid hormone (T4/T3)

e.g. hypopituitarism = pituitary underproduces TSH = understimulates thyroid gland = underproduction of thyroid hormone

Low TSH production causes low thyroid hormone production

Question 19

What are the hormone levels in Secondary Hyperthyroidism?

Answer 19

↑ TSH
↑ thyroid hormone (T4/T3)

= pituitary adenoma overproduces TSH = overstimulates thyroid gland = overproduction of thyroid hormone

High TSH production causes high thyroid hormone production

Question 20

Cortisol excess, Cushing’s syndrome may be ……….

Answer 20

Primary

Secondary

Question 21

What is the effect of RAAS (aldosterone)?

Answer 21

Aldosterone increases Na+ reabsorption from renal tubule = increases Na+ in ECF, bringing water with it by osmosis

Increased Na+ reabsorption = Increased reabsorption of water

Net effect: not increased Na+ conc. in ECF but Increased ECF volume bc increased amount of sodium + corresponding increased amount of water in ECF = no change in conc.

Then Starling’s principles of capillary exchange distribute the increased ECF volume b/w intravascular (plasma) + interstitial compartment to maintain blood volume.

RAAS maintains blood volume by increasing amount of Na+ and thereby increasing amount of water, which follows Na+ osmotically

Question 22

RAAS is activated by factors associated with ………….

Answer 22

a fall in blood volume:

• reduced perfusion
• increased sympathetic activity

RAAS monitors blood volume NOT plasma Na+ conc.

Question 23

Hyperaldosteronism causes hyper………….

Answer 23

Aldosterone = ↑ Na+ reabsorption + ↑ water reabsorption = ↑ ECF volume = ↑ blood volume = ↑ bp = hypertension

Hyperaldosteronism causes hypertension

Question 24

Hyperaldosteronism and K+ secretion?

Answer 24

Excess aldosterone causes ↑ K+ secretion in distal nephron = hypokalaemia

Question 25

How to diagnose hyperaldosteronism?

Answer 25

-Measure plasma aldosterone against reference range + measure plasma renin activity + take ratio aldosterone:renin

Primary hyperaldosteronism = dysfunction of adrenal cortex e.g. tumour overproducing aldosterone = ↑ aldosterone = ↑ blood vol. + ↑ bp = ↓ RAAS activity = ↓ juxtaglomerular apparatus = ↓ renin

Primary hyperaldosteronism = ↑ plasma aldosterone, ↓ plasma renin

Secondary hyperaldosteronism = renal artery stenosis = 1 kidney is underperfused = ↓ perfusion pressure, ↓ Na+Cl- delivery to distal tubule = activate RAAS = ↑ renin secretion = ↑ ang II = ↑ aldosterone
-Secondary hyperaldosteronism = functional adrenal cortex, but ↑ renin secretion causes ↑ aldosterone secretion

Secondary hyperaldosteronism = ↑ plasma aldosterone, ↑ plasma renin

Question 26

Aldosterone excess -

Cortisol excess -

Answer 26

Aldosterone excess - Conn’s syndrome (primary hyperaldosteronism)
Cortisol excess - Cushing’s syndrome (primary/secondary)

Question 27

Main functions of cortisol

Answer 27

-Cortisol = immunosuppressant
-Cortisol - maintains bp (CVS). lack of cortisol = vasodilation. Excess cortisol = hypertension (high bp)
-Cortisol - metabolic effects:
Cortisol preserves plasma glucose - promotes insulin resistance in skeletal muscle = muscles don’t use up glucose.
Cortisol also promotes lipolysis = breakdown of stored triglycerides into free fatty acids = muscle uses fats instead of glucose = spares glucose for the brain
Cortisol promotes gluconeogenesis = liver synthesises glucose from non-carb sources (aa’s)
Net result = maintain plasma glucose to survive starvation for 30days wo fatal hypoglycaemia

Question 28

Excess cortisol in the absence of physiological stress = counterproductive.
How?

Answer 28

-Muscle insulin resistance = hyperglycaemia
-Increased gluconeogenesis = hyperglycaemia
-Increased plasma glucose = increased insulin
-Plasma glucose is not taken up by muscle bc of cortisol-induced insulin resistance so plasma glucose rises, stimulating insulin production = insulin promotes lipogenesis = excess glucose goes to lipogenesis once glycogen stores are full.
newly-synthesised lipids are stored as fat

Question 29

Clinical signs + symptoms of Cushing’s disease

Answer 29

• Increased central adiposity
• Muscle Wasting (Thinning) of arms + legs
• Hyperglycaemia
• Hypertension

Question 30

Normal daily Cortisol fluctuation

Answer 30

Normal daily Cortisol fluctuation = high in morning, low at midnight

Question 31

Cushing’s syndrome =

Answer 31

Cushing’s syndrome = ↑ cortisol

Question 32

Most common cause of Cushing’s syndrome is …………..

Answer 32

Most common cause of Cushing’s syndrome is iatrogenic
Iatrogenic = as a consequence of medical therapy
Most cases of Cushing’s syndrome are due to glucocorticoid therapy

Question 33

What is the second most common cause of Cushing’s syndrome?

Answer 33

ACTH-secreting pituitary adenoma
benign tumour
= called Cushing’s disease
Tumour secretes high ACTH = high adrenal production of cortisol + adrenal androgens

more acth-secreting cells in ant pituitary = high ACTH = high cortisol = high -fb
-fb still intact, but at higher levels

Question 34

What is Cushing’s disease?

Answer 34

Cushing’s disease = Cushing’s syndrome due to benign anterior pituitary tumour

Question 35

2 other causes of Cushing’s syndrome

Answer 35

• Ectopic ACTH production - e.g. from tumour elsewhere = high cortisol secretion
• Hyperfunction of adrenal cortex - adrenal adenoma - primary = high cortisol secretion

Question 36

Ectopic ACTH

Answer 36

Ectopic ACTH stimulates adrenal cortex = high cortisol + adrenal androgen production
-fb to HPA axis = inhibit CRH + ACTH release
low ACTH from pituitary. but doesn’t matter bc source of circulating ACTH is ectopic - tumour somewhere else is releasing ACTH, which stimulates adrenal cortex

Bypasses -fb loop bc source of ACTH is not from HPA axis

slide 17

Question 37

Which test is used to diagnose Cushing’s syndrome?

Answer 37

Dexamethasone suppression test

Dexamethasone = synthetic glucocorticoid = activates cortisol Rs in hypothalamus and pituitary

In intact feedback loop, dexamethasone suppresses cortisol by suppressing ACTH.
In healthy person, give dexamethasone dose late the previous night + measure baseline cortisol in the morning, when cortisol is normally high, but in this case, cortisol is suppressed

Do the same test in someone with Cushing’s syndrome (Cushing’s disease/Ectopic ACTH)= dexamethasone dose won’t suppress morning cortisol - morning cortisol is still high. Single low-dose dexamethasone = fb loop set at high level so extra inhibition doesn’t have much effect.
Then repeat dexamethasone test with high dose. Repeat dexamethasone dose every night for 4 nights + measure morning cortisol for each of the 4 following days. With high dose dexamethasone, you get suppression on 2nd/3rd day but not 1st day in patients w Cushing’s disease. bc fb loop is still intact.
High-dose glucocorticoid = increase amplitude of -fb = some suppression of cortisol if source is from anterior pituitary

But If source is ectopic ACTH, dexamethasone will inhibit hypothal + ant pit but ant pit isn’t the source of ACTH anyway. Ant pit is producing no ACTH bc there is so much ectopic ACTH stimulating cortisol secretion. -fb from stimulated cortisol shuts down ant pit = ant pit ACTH is v. low but lots of ACTH from tumour elsewhere. so dexamethasone at both low dose/high dose won’t have effect on cortisol production bc cortisol production isn’t stimulated by HPA axis in this case, but from ectopic source.

Primary hypercortisolism/Cushing’s syndrome - due to adrenal cortex hyperfunction - producing more cortisol = increased -fb to anterior pituitary = low ACTH

Question 38

What is Primary adrenal insufficiency?

Answer 38

Primary adrenal insufficiency = problem in adrenal gland itself.
-Addison’s disease - e.g. destruction of adrenal cortex = adrenal failure = insufficient cortisol, aldosterone, adrenal androgens

Question 39

What is Secondary adrenal insufficiency?

Answer 39

-Pituitary/Hypothalamic disease = Insufficient cortisol. Adrenal gland is still functioning and mineralocorticoids (aldosterone) are under the control of RAAS.
Lack of cortisol = lack of -fb on HPA axis = increased CRH, increased ACTH, increased ADH/VP.

Osmolarity stimulates ADH secretion.
ADH secretion will still be regulated by plasma osmolarity but when high cortisol+CRH, it will do so at higher levels = increased ADH conc. in adrenal insufficiency

Question 40

Clinical features of Addison’s disease

Answer 40

-Anorexia
-Weakness
-Fatigue
-GI symptoms - nausea, vomiting
-Low bp (hypotension) - lack of cortisol+lack of aldosterone
-Hyperpigmentation - due to high ACTH that occur in absence of -fb. prolonged high ACTH cross-reacts with melanocortin R, stimulating melanocytes.
-Low plasma [Na+]. In the absence of -fb, we get increased CRH + ACTH + ADH. ADH promotes water reabsorption = dilutes electrolytes in ECF = hyponatraemia
-High plasma [K+] - aldosterone promotes K+ excretion = aldosterone counters hyperkalaemia.
Vomiting promotes hypokalaemia
-High ACTH bc primary endocrine disorder. lack of -fb is interpreted by HPA axis as insufficient adrenal steroids = high ACTH production
-Elevated plasma renin due to lack of aldosterone + vol. depletion (activation of RAAS)

Question 41

What is the hallmark of Addison’s disease?

Answer 41

High ACTH, Low cortisol

Question 42

How do we make differential diagnosis in Addison’s disease?

Answer 42

Dynamic test - assess ability of adrenal cortex to produce cortisol in response to ACTH.

• If secondary (lack of ACTH from pituitary) = adrenal can respond, but lacks stimulation from ACTH
• If primary (failure in adrenal cortec) = ACTH stimulation doesn’t help but is already high due to lack of -fb

Question 43

ACTH stimulation test of endocrine function - synacthen test

Answer 43

Inject synthetic ACTH + assess whether this causes elevated cortisol

Short synacthen test = measure cortisol early in morning (8/9am) to establish baseline value, then give synacthen injection + monitor cortisol at 30mins after + 60mins after. Expect significant rise in cortisol = not primary adrenal insufficiency

If Secondary adrenal insufficiency, adrenal cortex can still respond to ACTH. But if prolonged low ACTH (lack of adrenal stimulation by ACTH) = adrenal gland atrophies + takes some days to regain ability to respond + synthesise + release cortisol. Use Long Synacthen test. Extend over 3-day period - track cortisol in response to synthetic ACTH stimulation. If Secondary adrenal insufficiency, then cortisol will increase.