Endocrine disorders Flashcards
Clinical endocrinology consists of:
Measuring hormone levels to see if they are too high/too low and attempting to correct it by replacing deficit or correcting excess
Dynamic function tests where you stimulate or inhibit an endocrine tissue to see if it is still capable of producing (or suppressing) hormone output
What are thyroid hormone levels under the control of?
hypothalamic-pituitary-thyroid axis
-negative feedback control at hypothalamus and pituitary levels
What controls the synthesis and release of thyroid hormone?
What is the main hormone secreted by thyroid?
TSH
T4
What is the main biologically active thyroid hormone?
Thyroid hormones in the circulation
T3
-mostly formed from the peripheral conversion of T4
bound to protein carrier molecules
Function of thyroid hormones
Essential for normal growth and development
Increase basal metabolic rate (BMR) and affect many metabolic processes
How are thyroid hormones synthesised?
How do thyroid hormones exhibit their effects?
Synthesised in thyroid via series of enzyme catalysed reactions, beginning with uptake of iodine into gland
Their effects are mediated via activation of nuclear receptor
Disorders of Thyroid Function
Primary hyper/hypothyroidism
Secondary hyper/hypothyroidism
Describe the levels of hormones in hypothyroidism and hyperthyroidism (primary and secondary)
primary hyper/hypothism - dysfunction of the thyroid gland
secondary hyper/hypothyroidism - problem with the pituitary or hypothalamus (tertiary)
What is hyperthyroidism?
What is hypothyroidism?
excessive production of thyroid hormones (thyrotoxicosis)
deficient production of thyroid hormones
Clinical features of hyperthyroidism
Weight loss, heat intolerance, palpitations, goitre, eye changes (Graves)
In extreme: thyroid storm
Causes of hyperthyroidism
· Graves’ Disease (most common cause of hyperthyroidism)
>due to stimulatory thyroid stimulating hormone (TSH) receptor antibodies
· Toxic multinodular goitre
· Toxic adenoma
· Secondary: excess TSH production (rare)
Clinical features of hypothyroidism
- Weight gain, cold intolerance, lack of energy, goitre (from excess TSH due to -ve feedback)
- Congenital- developmental abnormalities (e.g. learning difficulties and mental retardation)
Causes of hypothyroidism
· Autoimmune thyroiditis (Hashimoto’s)
>thyroid peroxidase antibodies (anti-TPO)
· Iodine deficiency
· Toxic adenoma
· Secondary- lack of TSH
Hashimoto’s disease/autoimmune thyroiditis
In Hashimoto’s disease antibodies are produced against thyroid peroxidase which is one of the essential enzymes in the synthesis of thyroid hormone. By blocking this enzyme in effect, you block thyroid hormone synthesis.
Structure of the adrenal gland
The adrenal gland contains an outer cortex which produces steroids, and an inner medulla which produces catecholamines.
Adrenal cortex structure
Divided into three zones:
- Outer zona glomerulosa→produces mineralocorticoids (aldosterone)
- Middle zona fasciculata→produces glucocorticoids (cortisol)
- Inner zona reticularis→produces adrenal androgens
Adrenal steroids
Mineralocorticoids (aldosterone)
Glucocorticoids (cortisol)
Adrenal androgens
What are all of the adrenal steroids produced from?
CHOLESTEROL
-there are various enzymatic modifications of cholesterol which can result in the production of either adrenal androgens, mineralocorticoids or glucocorticoids.
Actions of mineralocorticoids (aldosterone)
Salt and water balance in order to maintain plasma volume and therefore maintenance of blood pressure over the long term
Action of glucocorticoids (cortisol)
Many functions; metabolism and immune function
Stress increases glucocorticoid release, but minimal levels essential for normal function
Cardiovascular system: low cortisol → low blood pressure
Disorders of adrenocortical function
Excess cortisol (Cushing’s syndrome)
Excess aldosterone (e.g. Conn’s syndrome)
Adrenal insufficiency
Hypocortisolism
Lack of aldosterone and cortisol (Addison’s)
Adrenocortical excess
Aldosterone excess
Conn’s syndrome (primary hyperaldosteronism)
Cortisol excess
Cushing’s syndrome (may be primary or secondary)
Control of aldosterone secretion
Activated by
- RAAS
- Increased plasma [K+]
RAAS is activated by
- Reduced renal perfusion
- Increased sympathetic activity
Both interpreted as a fall in blood volume
What are the androgens produced in the adrenal cortex considered?
weak androgens
Give an overview of cortisol actions
GLUCOSE-CONSERVING
- promotes insulin resistance in skeletal muscle and therefore muscle can’t take up glucose
- promotes gluconeogenesis in the liver
- promotes lipolysis of stored fats into free fatty acids to be used as a source of energy by muscle instead of glucose
Effects of cortisol in a modern setting where there aren’t stresses
Effects of cortisol will:
- raise blood glucose and cause hyperglycaemia
- hyperglycaemia will stimulate increased insulin production
- increased insulin is going to then promote lipogenesis (fat deposition)
What are the androgens produced in the adrenal cortex considered?
weak androgens
What controls the synthesis and release of cortisol?
The synthesis and release of cortisol is regulated by the hypothalamic-pituitary-adrenal axis (CRH, ACTH).
What controls the synthesis and release of aldosterone?
Aldosterone is controlled by the renin-angiotensin-aldosterone system (RAAS).
Most common cause of Cushing’s syndrome is iatrogenic
Exogenous glucocorticoids activate cortisol receptor
At high doses will shut down HPA
Adrenal cortex atrophies with lack of ACTH stimulation
Several days may be required for adrenal to become responsive to ACTH again
Cortisol levels throughout the day
Cortisol is subject to circadian rhythms and its levels fluctuate over a 24-hour cycle. Cortisol levels rise during the early hours of the morning and peaking early morning, and then falling throughout the day, dropping to their lowest levels around midnight.
ACTH receptor
GPCR
-via cAMP stimulates cholesterol uptake and synthesis
Conn’s syndrome
a disorder of the adrenal glands caused by the excessive production of aldosterone (primary hyperaldosteronism)
Cushing’s syndrome
hyper-secretion of cortisol from the adrenal cortex due to a disturbance in the negative loop feedback
Causes of Cushing’s syndrome
Exogenous Steroid Use
Pituitary Adenoma
Ectopic ACTH Secreting Tumour
Cushing’s syndrome: Exogenous Steroid use
When taking exogenous glucocorticoids, the high cortisol levels leads to strong negative feedback of both the hypothalamus and anterior pituitary. CRH from the hypothalamus, ACTH from the anterior pituitary and cortisol from the adrenal glands would all be reduced as the negative feedback system would be working normally. This is because the adrenal gland is not the source of the excess cortisol.
Cushing’s syndrome: Pituitary Adenoma
An adenoma on the anterior pituitary means the mass of ACTH secreting cells is increased. There is still negative feedback taking place, however at a higher set point. The negative feedback loop is still intact, but the larger number of cells secreting ACTH means there is more ACTH and more cortisol. This is known as Cushing’s Disease.
Cushing’s syndrome: Ectopic ACTH
It is possible that the source of excess ACTH is not the pituitary gland itself, but because of a tumour somewhere else in the body that happens to secrete ACTH.
How to find out source of excess cortisol in Cushing’s syndrome
Dexamethasone Suppression Test
Dexamethasone
synthetic glucocorticoid which will mimic cortisol and bind to glucocorticoid receptors
Action of dexamethasone in normal people
low doses of dexamethasone will normally suppress ACTH secretion via negative feedback and subsequently suppress plasma cortisol
How does dexamethasone suppression test work?
In Cushing’s Disease, a low dose of dexamethasone fails to suppress ACTH secretion. This is because the negative feedback set point has been raised due to the excess mass of cells producing ACTH.
> however, a higher dose of dexamethasone will suppress ACTH secretion and subsequently cortisol secretion in Cushing’s disease
If the higher dose of dexamethasone does not suppress cortisol, then it is not Cushing’s disease and you have to measure ACTH levels:
- if ACTH levels are low, source of cortisol secretion is an adrenal tumour
- if ACTH levels are high, source of cortisol secretion is an ectopic ACTH secreting tumour, as no amount of dexamethasone is going to suppress cortisol production as the excess cortisol production is unrelated to the hypothalamus or pituitary
Addison’s disease
Primary Adrenocortical Insufficiency
- loss of cortisol, aldosterone and androgen production
- typically autoimmune
-HIGH ACTH levels
Secondary adrenocortical insufficiency
Results from any disorder of the hypothalamus or pituitary that impairs ACTH release:
- head trauma, tumour, surgery
- abrupt steroid withdrawal
How do we test for adrenal insufficiency?
Short Synacthen Test (synthetic ACTH)
- measure baseline cortisol (9am) and 30min after inject 250ug synacthen IM
- adrenal insufficiency excluded by an increase in cortisol of >200nmol/L and/or a 30min value of >550