Endocrine disorders Flashcards
How can we measure hormone levels to see if they are appropriate?
- Compare with reference range
2. Always interpret with respect to controlling variable
What is the function of the thyroid gland
Thyroid gland produces thyroid hormones T3 + T4.
T3=triiodothyronine(more active form)
T4=thyroxine(majority)
T4 -> T3, activated by deiodinase enzymes in peripheral tissue
What is the function of Thyroid hormone ?
- Normal growth + development
- Congenital hypothyroidism = developmental problems
2.Upregulates metabolism
Can ↑ metabolic rate , heat production, ATP production, metabolism = ↑ glucose release
What are the two main categories of thyroid disorders ?
Underproduction = Hypothyroidism Overproduction = Hyperthyroidism
What is the Hypothalamic-Pituitary-Thyroid control of the thyroid gland?
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)
What are the aspects which can result in thyroid disorders?
Thyroid gland problem = ↑/↓ thyroid hormone production = Primary problem
Pituitary problem can affect thyroid gland =Secondary problem
Hypothalamic disease
How can primary hypo/hyper thyroidism be diagnosed ?
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
What is Hashimoto’s Disease?
Hashimoto’s Disease = Autoimmune condition - Antibodies target + destroy thyroid tissue = ↓ T3+T4 production = primary hypothyroidism (dysfunction of thyroid gland itself)
What is Grave’s Disease?
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)
Describe the structure of adrenal glands
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
What are the adrenal steroids?
Mineralocorticoids (aldosterone) Glucocorticoids (cortisol) Adrenal androgens (DHEA, DHEAS)
What are the 2 types of adrenocortical disorders ?
Adrenal hyperfunction:
- Excess cortisol = Cushing’s syndrome
- Excess aldosterone e.g. Conn’s syndrome - adrenal adenoma
Adrenal insufficiency:
- Hypocortisolism
- Addison’s = ↓ aldosterone + cortisol
What is primary hyperaldosteronism ?
Conn’s syndrome (primary hyperaldosteronism):
- Adrenal cortex producing excess aldosterone.
- Dysfunction in adrenal cortex = primary hyperaldosteronism
- May be due to adrenal tumour
What is secondary hyperaldosteronism ?
Overactivation of RAAS causes adrenal gland overproduction of aldosterone
Not overactivity of adrenal gland, but due to another reason
What are the hormone levels in Primary Hypothyroidism?
↓ thyroid hormone (T4+T3)
↑ TSH
due to - fb on ant. pituitary gland
What are the hormone levels in Primary Hyperthyroidism?
↑ thyroid hormone (T4+T3)
↓ TSH
due to - fb on ant. pituitary gland
What is Secondary Hypothyroidism/Hyperthyroidism?
What is Tertiary Hypothyroidism/Hyperthyroidism?
Secondary Hypothyroidism/Hyperthyroidism = Ant. Pituitary causes excess/insufficient production of thyroid hormone
Tertiary Hypothyroidism/Hyperthyroidism = Hypothalamus causes excess/insufficient production of thyroid hormone
What are the hormone levels in Secondary Hypothyroidism?
↓ 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
What are the hormone levels in Secondary Hyperthyroidism?
↑ TSH
↑ thyroid hormone (T4/T3)
= pituitary adenoma overproduces TSH = overstimulates thyroid gland = overproduction of thyroid hormone
High TSH production causes high thyroid hormone production
Cortisol excess, Cushing’s syndrome may be ……….
Primary
Secondary
What is the effect of RAAS (aldosterone)?
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
RAAS is activated by factors associated with ………….
a fall in blood volume:
- reduced perfusion
- increased sympathetic activity
RAAS monitors blood volume NOT plasma Na+ conc.
Hyperaldosteronism causes hyper………….
Aldosterone = ↑ Na+ reabsorption + ↑ water reabsorption = ↑ ECF volume = ↑ blood volume = ↑ bp = hypertension
Hyperaldosteronism causes hypertension
Hyperaldosteronism and K+ secretion?
Excess aldosterone causes ↑ K+ secretion in distal nephron = hypokalaemia
How to diagnose hyperaldosteronism?
-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
Aldosterone excess -
Cortisol excess -
Aldosterone excess - Conn’s syndrome (primary hyperaldosteronism)
Cortisol excess - Cushing’s syndrome (primary/secondary)
Main functions of cortisol
-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
Excess cortisol in the absence of physiological stress = counterproductive.
How?
-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
Clinical signs + symptoms of Cushing’s disease
- Increased central adiposity
- Muscle Wasting (Thinning) of arms + legs
- Hyperglycaemia
- Hypertension
Normal daily Cortisol fluctuation
Normal daily Cortisol fluctuation = high in morning, low at midnight
Cushing’s syndrome =
Cushing’s syndrome = ↑ cortisol
Most common cause of Cushing’s syndrome is …………..
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
What is the second most common cause of Cushing’s syndrome?
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
What is Cushing’s disease?
Cushing’s disease = Cushing’s syndrome due to benign anterior pituitary tumour
2 other causes of Cushing’s syndrome
- Ectopic ACTH production - e.g. from tumour elsewhere = high cortisol secretion
- Hyperfunction of adrenal cortex - adrenal adenoma - primary = high cortisol secretion
Ectopic ACTH
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
Which test is used to diagnose Cushing’s syndrome?
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
What is Primary adrenal insufficiency?
Primary adrenal insufficiency = problem in adrenal gland itself.
-Addison’s disease - e.g. destruction of adrenal cortex = adrenal failure = insufficient cortisol, aldosterone, adrenal androgens
What is Secondary adrenal insufficiency?
-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
Clinical features of Addison’s disease
-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)
What is the hallmark of Addison’s disease?
High ACTH, Low cortisol
How do we make differential diagnosis in Addison’s disease?
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
ACTH stimulation test of endocrine function - synacthen test
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.
