Clinical Biochemistry: Laboratory Investigation of Endocrine Disorders Flashcards
Describe the hypothalamic-pituitary-thyroid (HPT)-axis
- Thyroid releasing hormone (TRH) produced and secreted by hypothalamus
- TRH enters pituitary portal circulation where it binds to anterior pituitary gland
- This causes anterior pituitary to produce and secrete Thyroid stimulating hormone (TSH)
- TSH enters systemic circulation and eventually binds to thyroid gland
- This causes thyroid gland to produce and secrete thyroid hormone (T3 and T4) into systemic circulation
Which one out of the 2 thyroid hormones is the one that is mostly secreted by thyroid gland?
- T4 main hormone secreted by thyroid
- T3 is more biologically active
How is T3 formed?
- Mostly formed by peripheral conversion from T4
What controls circulating thyroid hormone levels?
- Circulating thyroid hormone levels under negative feedback control at hypothalamic and pituitary levels
- Effects are mediated via activation of nuclear receptor
What are the main functions of thyroid hormones?
- Essential for normal growth and development
- Increase basal metabolic rate (BMR) and affect many metabolic processes in adults
What controls the activity of thyroid hormones?
- Enzymes in the peripheral target tissue that convert T4 into more biologically active T3
How much of the thyroid hormone in circulation is bound?
Compare the total serum concentrations of T4 and T3
- Most of the thyroid hormones (T3 and T4) within circulation are bound to protein carrier molecules e.g. thyroglobulin
- Higher total serum concentration of T4 compared to T3
Does T3 or T4 have a longer half-life?
- T4 has a longer half-life than T3
State some of the terminology used in disorders of thyroid function
- Euthyroid (TH levels within normal range)
- Hypothyroid (TH levels below normal range)
- Hyperthyroid (TH levels above normal range)
What is the difference between primary and secondary thyroid disorders?
- Primary thyroid disorder: dysfunction is in thyroid gland
- Secondary thyroid disorder: Problem is with pituitary or hypothalamus (can be classified as tertiary)
What is hyperthyroidism?
- Excessive production of thyroid hormones leading to thyrotoxicosis
What are the clinical features of hyperthyroidsim?
- Weight loss
- Heat intolerance
- Palpitations
- Goitre - swelling of the thyroid gland that causes a lump in the neck
- Eye changes (Graves’ disease)
What might hyperthyroidism develop into if left untreated?
- Thyroid storm: During thyroid storm an individual’s heart rate, blood pressure, and body temperature can soar to dangerously high levels
What are some of the causes of hyperthyroidism?
- Graves’ disease (most common) - Due to stimulatory TSH-R antibodies which act as agonists to TSH receptor on thyroid gland
- Toxic multinodular goiter
- Toxic adenoma
- Secondary hyperthyroidism (rare) can be caused by excess TSH production
What is hypothyroidism?
- Deficient production of thyroid hormones
What are the clinical features of hypothroidism?
- Weight gain
- Cold intolerance
- Lack of energy
- Goitre - due to lack of negative feedback resulting in more TSH production
- Congenital - developmental abnormalities
What are some biochemical signs of hypothyroidism?
- Raised TSH, reduced T4 - indicates primary hypothyroidism
- Reduction in TSH and T4 - indicates secondary hypothyroidism (hypopituitarism)
What are some causes of hypothyroidism?
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Autoimmune thyroiditis (Hashimoto’s disease)
- Thyroid peroxidase antibodies (anti-TPO) which block thyroid peroxidase enzyme leading to inhibition of thyroid hormone synthesis
- Iodine deficiency
- Toxic adenoma
- Secondary hypothyroidism caused by lack of TSH
Use the following information to produce a diagnosis for this patient
A 48 year-old woman presented to her GP with palpitations, weight loss and heat intolerance. A serum sample gave the following results:
- Free T4 31 pmol/L (11-23)
- Free T3 12 pmol/L (3-8.8)
- TSH 0.08 mU/L (0.5-4.0)
- Patient has high free T3 and T4
- Also has low TSH
- This suggests woman has Primary hyperthyroidism
Use the following information to produce a diagnosis for this patient
A 70 year old man complained of tiredness and weight gain. His heart rate was 55 beats/min. Thyroid function tests were carried out:
- Free T4 10 pmol/L (11-23)
- TSH 18.4 mU/L (0.5-4.0)
- Patient has slightly low free T4
- Also has extremely high TSH level
- This suggest patient has primary hypothyroidism
Give a brief description of the adrenal glands
- An adrenal gland sits on top of both kidneys
- Each adrenal gland has an outer cortex and an inner medulla
- Adrenal cortex produces adrenal steroids and the medulla produces adrenaline
The adrenal cortex is divided into 3 zones, what are these 3 zones?
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
How does blood flow through the adrenal cortex?
- Blood flows from the outer cortex (Zona glomerulosa) to the inner cortex (Zona reticularis)
What does the fact that each zone of the adrenal cortex contains its own enzymes mean for the adrenal cortex?
- It means that in essence each zone of the adrenal cortex act as their own little adrenal cortex (functional zonation)
- Also means that steroid synthesis in one layer can inhibit different enzymes in subsequent layers
What steroid hormones are produced by each layer of the adrenal cortex?
- Zona glomerulosa - Mineralocorticoids
- Zona fasciculata - Glucocorticoids (cortosol)
- Zona reticularis - Adrenal androgens
Briefly explain the process of adrenal steroid synthesis
- All adrenal steroid synthesis starts off with the original substrate being cholesterol
- However, there are different enzymatic modifications of cholesterol that result in either adrenal androgens, mineralocorticoids or glucocorticoids being formed as the end product.
What are the functions of the different adrenal steroids?
-
Mineralocorticoids (Aldosterone): Controls salt and water balance in order to maintain plasma volume
- Does this by increasing Na+ reabsorption in distal tubule of kidney
- Leads to maintenance of blood pressure over the long term
-
Glucocorticoids (Cortisol): Metabolism and immune functions
- Stress increases release, but minimal levels essential for normal function
- Adrenal androgens: So called ‘weak androgens’
Explain some specific functions of cortisol
-
Cortisol and CVS
- Esential for maintainence of blood pressure
- Low cortisol = low blood prerssure
- High cortisol = high blood pressure
- Controls blood presssure by counteracting effects of NO in endothelial cells of blood vessels thus preventing too much vasodilation
-
Cortisol and Glucose metabolism
- Promotes insulin resistance in skeletal muscle blocking GLUT 4 receptors
- This allows glucose to be taken up by other organs such as the brain
- Also promotes gluconeogenesis (synthesis of glucose from amino acids) in the liver
- Promotes liposis of stored fats into free fatty acids allowing skeletal muscle to use free fatty acids for energy instead of glucose
- ALL OF THESE INCREASE GLUCOSE LEVELS
What condition can the effects of cortisol on glucose mtabolism cause and what might this lead to?
- May cause hyperglycaemia (high blood glucose)
- Hyperglycaemia will result in increased insulin production
- This along with increased insulin resistance as a result of cortisol will cause insulin to stimulate lipogenesis (production of fat from glucose)
What controls adrenal steroid secretion?
- Cortisol (glucocortocoids): Synthesis and release regulated by hypothalamic-pituitary-adrenal axis (CRH, ACTH)
- Aldosterone (mineralocorticoids): Controlled by RAAS
- Adrenal androgens: Synthesis and release also controlled by HPA-axis (mainly ACTH, Adrenocorticotropic hormone, and NOT gonadotropins)
What controls cortisol and androgen levels within the body?
- Cortisol and androgen levels controlled by circadian rhythms and stress
- Cortisol levels rise in early morning and slowly fall throughout day until they reach lowest levels at midnight
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What conditions can be caused by hyper-function of the adrenal cortex?
- Aldosterone excess - Conn’s syndrome
- Cortisol excess - Cushing’s syndrome
What symptoms would you expect to be present due to aldosterone excess - Conn’s syndrome?
- Hypokalaemia
- Hypertension
Why doesn’t excess aldosterone lead to hypernatremia?
- Because although aldosterone does promote Na+ reabsorption into distal tubule this would also cause water to be reabsorped so thre wouldn’t be a change in Na+ concentration
What may cause Cushing’s syndrome - excess cortisol?
-
Exogenous glucocorticoids
- Patient may be receiving cortisol as part of a treatment plan which may result in them developing Cushing’s syndrome
-
ACTH secreting pituitary tumour
- Adenoma in anterior pituitary secreting ACTH which reults in excessive cortisol production
- This is secondary hypercortisolism as problem is with anterior pituitary and not adrenal gland
How is the negative feedback of the HPA-axis affected by exogenous glucocorticoids?
- Exogenous glucocorticoids will cause greater amount of negative feedback on hypothalamus and anterior pituitary
- This results in less endogenous glucocorticoids (cortisol) being produced by the adrenal cortex
- Negative feedback isn’t affected in this case problem is just that exogenous cortisol causes levels of overall cortisol to be too high
How is the negative feedback of the HPA-axis affected by an ACTH secreting pituitary tumour?
- Anterior pituitary tumour results in increased ACTH
- This leads to increased production of cortisol from adrenal cortex
- High circulating cortisol leads to negative feedback on anterior pituitary and hypothalamus
- However, because of anterior pituitary tumour mass of cells in anterior pituitary is increased
- This means that although negative feedback is happening there is still more ACTH being produced by the anterior pituitary than if the same amount of negative feedback was happening in a normal situation
What is the difference between Cushing’s syndrome and Cushing’s disease?
- Cushing’s syndrome is just when excess cortisol is produced by the adrenal glands
- Cushing’s disease is when increased cortisol is caused specifically by a ACTH secreting anterior pituitary tumour
What is the Dexamethasone suppression test?
- It is a test used to assess adrenal gland function by measuring how cortisol levels change in response to an injection of dexamethasone
Explain how the Dexamethasone suppression test works
- Dexamethasone is a synthetic glucocorticoid and so will bind to glucorticoid receptors just like cortisol
- Low doses will normally supress ACTH secretion via negative feedback and so will suppress cortisol secretion
- In the case of Cushing’s disease however, low dose of dexamethasone won’t result in suppression of ACTH and by extension cortisol
- A higher dose will supress ACTH secretion in Cushing’s disease
- If there’s no supresssion of ACTH secretion with low or high dose of dexamethasone it suggests ectopic source of ACTH (e.g., tumour elsewhere
What are the different types of adrenocortical insufficiency?
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Primary adrenocortical failure – Addison’s disease (typically autoimmune)
- Results in loss of aldosterone, cortisol and androgen production
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Secondary adrenocortical failure - impaired ACTH release, may be due to:
- Head trauma, tumour, surgery
- Abrupt steroid withdrawal
What are the effects of low Cortisol, Aldosterone and androgen levels due to Addison’s disease?
- High CRH and ACTH - due to lack of negative feedback on pituitary and hypothalamus as low cortisol
- Hypotension
Describe some other dynamic tests of adrenal functional
-
Short synacthen (synthetic ACTH) test
- Measure baseline cortisol (9am) and 30 min after 250 µg synacthen i.m.
- Primary adrenal insufficiency is excluded by an increase in cortisol of >200 nmol/L and/or a 30 min value >550
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Long synacthen test
- Adrenal cortex ‘shuts down’ in absence of stimulation by ACTH – time needed to regain responsiveness
- 3-day stimulation with i.m. synacthen
- In secondary (but not primary) adrenal insufficiency cortisol increases by >200 nmol/L over baseline
Use the following information to provide a diagnosis for this patient and then state what alternate test could be done
A 51 year old woman was admitted to hospital with a history of weight loss and lethargy. She reported that she felt dizzy when she stood up.
Biochemical tests revealed that she was hyponatraemic and she was given i.v. saline.
A synacthen test was carried out with the following results:
- Baseline cortisol: 342 nmol/L (ref. range 150-650)
- 30 min post synacthen: 419 nmol/L
- 30 min post synacthen cortisol level is still quite low which suggests patient may have primary adrenal insufficiency - Addison’s disease
- Alternate test would be to measure ACTH level - if high would indicate primary adrenal insufficiency
