Lab Investigation of Endocrine Disorders Flashcards
Describe the hypothalamic-pituitary-thyroid axis
Circulating TH levels under negative feedback control at hypothalamic and pituitary levels
What controls TH release?
Synthesis and release of TH controlled by TSH
Outline the HPT axis
- TRH synthesised + released from hypothalamus
- TRH released into pituitary portal circulation, acts on
anterior Pituitary to release thyrotropin / TSH - TSH released into general circulation, stimulates TH
(T3/T4) production by thyroid gland
Describe the abundance of both T3 and T4
T4 main hormone secreted by thyroid, T3 is more biologically active – mostly formed by peripheral conversion from T4
What are the actions of T3 and T4 in circulation?
Circulating levels of T3 & T4 act to inhibit the source of the hormones at the pituitary and hypothalamus ∴
↑T3 and T4 = ↓TRH and TSH (negative feedback)
Lack of inhibition is excitation of TSH and TRH
What is the significance of thyroid hormones?
Essential for normal growth and development
What is the effect of thyroid hormones on metabolism?
Increase basal metabolic rate (BMR) and affect many metabolic processes
How are thyroid hormones produced?
Synthesized in thyroid via series of enzyme catalysed reactions, beginning with uptake of iodine into gland
How are the effects of thyroid hormone mediated?
Effects are mediated via activation of nuclear receptor
How are thyroid hormones transported in circulation?
Thyroid hormones in circulation are mostly bound to protein carriers (ie. thyroglobulin)
Describe the longevity of T3 and T4
T4 has 6-7 days half life
T3 has v short half life
Outline the terminology of thyroid function disorders
Euthyroid (normal range)
Hypothyroid (below)
Hyperthyroid (above)
What is meant by primary thyroid disorders?
Primary hyper/hypothyroidism: dysfunction is in thyroid gland
What is secondary thyroid dysfunctions?
Secondary: problem is with pituitary or hypothalamus (tertiary)
What is hyperthyroidism?
Excessive production of thyroid hormones (thyrotoxicosis)
How does hyperthyroidism effect metabolism?
Increased metabolic rate: Weight loss, heat intolerance, palpitations, goitre, eye changes (Graves)
In extreme: thyroid storm - treated with beta blockers and then the underlying cause
What is goitre?
Swelling in neck due to enlarged thyroid gland
many causes, excess thyroid is one
Outline the causes of hyperthyroidism
- Graves disease (most common)
Due to stimulatory TSH-R antibodies (act as agonist) - Toxic multinodular goiter
- Toxic adenoma
- Secondary: excess TSH production (rare)
What is hypothyroidism?
Deficient production of thyroid hormones
Describe the clinical features of hypothyroidism?
Weight gain
Cold intolerance,
Lack of energy
Goitre (due to lack of -ve feedback = inc. TSH)
Congenital - developmental abnormalities
Describe the investigations of hypothyroidism
Raised TSH, reduced fT4 = primary
Reduction in TSH and T4 suggests secondary (hypopituitarism)
What are the causes of hypothyroidism?
- Autoimmune thyroiditis (Hashimoto’s)
Thyroid peroxidase antibodies (anti-TPO)- block enzyme = no thyroid hormone synthesis
- Iodine deficiency
- Toxic adenoma
- Secondary – lack of TSH
Describe the blood flow in the adrenal cortex
Blood flows from outer cortex to inner medulla
Describe how the structure of adrenal glands effects its products
Outer cortex produces adrenal steroids
Inner medulla produces adrenaline
What hormones
Layer-specific enzymes; steroid synthesis in one layer can inhibit different enzymes in subsequent layers
Results in functional zonation of cortex with different hormones made in each layer
Outline the different hormones produced in each layer
Zona glomerulosa - mineralocorticosteroids (aldosterone)
Zona fasciculata - glucocorticoids (cortisol)
Zona reticularis - adrenal androgens
What is the precursor of steroids?
All adrenal steroids share a similar biochemical synthesis pathway starting with cholesterol
How does steroid synthesis occur
Various enzymatic modifications of cholesterol result in production of adrenal androgens, mineralocorticoid production of aldosterone or glucocorticoid production of cortisol
What is a significant steroidogenesis pathology associated with congenital adrenal hyperplasia
CYP21A is the gene for 21-hydroxylase. It’s deficiency is the major cause of congenital adrenal hyperplasia
What is the major role of aldosterone?
Mineralocorticoids (aldosterone)
Salt and water balance in order to maintain plasma volume by balancing ECFV via Na+ retention - maintenance of BP long term
How does aldosterone maintain BP?
Increased Na+ reabsorption from distal tubule
Starling’s forces then distribute inc. ECFV to Plasma and ICF
How does salt effect water balance?
Net loss of salt ⇒ equivalent amount of water lost with it = net loss in volume, ∴ plasma volume
What are the functions of cortisol?
Glucocorticoids (cortisol): metabolism and immune function
What induces glucocorticoid cortisol release?
Stress increases release, but minimal levels essential for normal function
Describe the effects of cortisol on the cardiovascular system
(low cortisol = low BP)
Normal regulation of BP via counterbalancing NO in endothelial cells of blood vessels to prevent vasodilation in order to lower BP
How does cortisol effect glucose metabolism?
Cortisol known as glucose sparing
Promotes insulin resistance in skeletal muscles (blocks GLUT4) allowing more glucose in circulation
Muscles use oxidative factors instead
Which metabolic processes are promoted by cortisol?
Cortisol promotes glucose production in liver via gluconeogenesis (from a.a.)
(in)directly promotes lipolysis of stored fats into free fatty acids - muscles use FFA instead
Why is the glucose sparing effect of cortisol not needed as often in modern day diet?
Increased [glucose] in circulation = hyperglycemia which stimulates insulin production which in turn promotes lipogenesis
What are the effects of excess cortisol glucose sparing?
Excess cortisol indirectly leads to wasting appearance of arms and legs but thicker in trunk and face
How is cortisol production regulated?
Synthesis and release regulated by hypothalamic-pituitary-adrenal axis (CRH, ACTH)
What controls aldosterone release?
Controlled by RAAS
What mediates adrenal androgen release?
ACTH (not gonadotropins)
Why is measuring glucocorticoids difficult?
Measuring glucocorticoid isn’t straightforward as levels fluctuate due to circadian rhythms
Which hormones are involved in the cortisol HPA axis?
Corticotropin-releasing hormone (CRH)
Adrenocorticotropic hormone (ACTH)
Describe the role of the ACTH receptor
ACTH receptor: G-protein coupled, via cAMP stimulates cholesterol uptake and steroid synthesis
Why is a cortisol reading not a reliable source of diagnosis?
Cortisol secretion fluctuates in a circadian rhythm, which means a random plasma cortisol reading cannot exclude abnormality, unless way outside of normal range
Outline the syndromes of a hyperfunctioning adrenal cortex
Aldosterone excess
- Conn’s syndrome
Cortisol excess
- Cushing’s syndrome
What causes Cushings syndrome?
The feedback loop is disturbed
collective term for a number of disorders with reason of excess varying
What is a common cause of excess cortisol in Cushings?
Rule out glucocorticoid therapy (medication / analogs) as this may be causing excess levels
How does glucocorticoid medication lead to excess cortisol?
Will lead to reduced ACTH and CRH due to -ve feedback
Cortisol from adrenal gland will also be reduced - feedback system is intact but exogenous glucocorticoids cause excess
What is a less common reason for cushings?
Excess cortisol may also be due to a tumour elsewhere in the body secreting ACTH
Other possibilities for Cushing’s ie. primary adrenal hyperplasia etc.
What is Cushings disease?
Adenoma anterior pituitary tumour may cause increased ACTH secretion causing excess cortisol
Secondary as adrenal gland not cause of problem
What are the effects of a pituitary adenoma in cushings?
High cortisol leads to strong -ve feedback of both hypothalamus and ant. Pituitary
However no. of ACTH secreting cells increases so -ve feedback now acting at a higher set point in adenoma tumour
What is the purpose of a dexamethasone suppression test?
Allows us to distinguish between Cushing’s possibilities
What is dexamethasone?
Dexamethasone: synthetic exogenous steroid that binds to glucocorticoid receptors like cortisol
What is the effect of low dose dexamethasone?
Low doses will normally suppress ACTH secretion via negative feedback
What are the results of a dexamethasone suppression test in a Cushings patient?
Low dose fails to suppress ACTH secretion with pituitary disease (Cushing’s)
Higher dose will suppress ACTH secretion in Cushing’s
What does no suppression in a dexamethasone test suggest?
No suppression with low or high dose: suggests ectopic source of ACTH e.g., tumour elsewhere
What is primary adrenocortical insufficiency?
Primary adrenocortical failure – Addison’s disease typically autoimmune; adrenal cortex stops functioning
Addison’s - progressive disease, leads to hypotension eventually
What is secondary adrenaocortical failure?
Secondary – impaired ACTH release
What causes secondary adrenocortical failure?
Head trauma, tumour, surgery
Abrupt steroid withdrawal
Why can adrenocortical failure lead to adrenal failure?
Adrenal failure, in extreme due to cortisol and aldosterone lack in Addison’s as its an attack on the adrenal cortex
If primary, signs are also due to ACTH excess.
What deficiencies cause Addisons disease?
Loss of:
- Cortisol
- Androgens
- Aldosterone
(primary adrenal failure)
What are the causes of primary adrenal failure?
usually autoimmune
What is the role of a dynamic test of adrenal function?
Assess ability of adrenal to produce cortisol in response to ACTH
Outline a short synacthen test
Short synacthen test (synthetic ACTH)
Measure baseline cortisol (9am) and 30 min after 250 µg synacthen (synthetic ACTH) i.m.
Describe results of a short synacthen test
Adrenal insufficiency excluded by increased cortisol of
>200 nmol/L and/or a 30 min value >550
Cortisol levels don’t increase as expected
Outline a long synacthen test
3-day stimulation with i.m. synacthen
Adrenal cortex ‘shuts down’ in absence of stimulation by ACTH – time needed to regain responsiveness
Long test not often necessary since ACTH assay can distinguish
Describe results of a long synacthen test
In secondary (but not primary) adrenal insufficiency cortisol increases by >200 nmol/L over baseline
