Clinical Biochemistry: Laboratory Investigation of Endocrine Disorders Flashcards

1
Q

Describe the hypothalamic-pituitary-thyroid (HPT)-axis

A
  • 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
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2
Q

Which one out of the 2 thyroid hormones is the one that is mostly secreted by thyroid gland?

A
  • T4 main hormone secreted by thyroid
  • T3 is more biologically active
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3
Q

How is T3 formed?

A
  • Mostly formed by peripheral conversion from T4
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4
Q

What controls circulating thyroid hormone levels?

A
  • Circulating thyroid hormone levels under negative feedback control at hypothalamic and pituitary levels
  • Effects are mediated via activation of nuclear receptor
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5
Q

What are the main functions of thyroid hormones?

A
  • Essential for normal growth and development
  • Increase basal metabolic rate (BMR) and affect many metabolic processes in adults
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6
Q

What controls the activity of thyroid hormones?

A
  • Enzymes in the peripheral target tissue that convert T4 into more biologically active T3
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7
Q

How much of the thyroid hormone in circulation is bound?

Compare the total serum concentrations of T4 and T3

A
  • 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
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8
Q

Does T3 or T4 have a longer half-life?

A
  • T4 has a longer half-life than T3
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9
Q

State some of the terminology used in disorders of thyroid function

A
  • Euthyroid (TH levels within normal range)
  • Hypothyroid (TH levels below normal range)
  • Hyperthyroid (TH levels above normal range)
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10
Q

What is the difference between primary and secondary thyroid disorders?

A
  • Primary thyroid disorder: dysfunction is in thyroid gland
  • Secondary thyroid disorder: Problem is with pituitary or hypothalamus (can be classified as tertiary)
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11
Q

What is hyperthyroidism?

A
  • Excessive production of thyroid hormones leading to thyrotoxicosis
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12
Q

What are the clinical features of hyperthyroidsim?

A
  • Weight loss
  • Heat intolerance
  • Palpitations
  • Goitre - swelling of the thyroid gland that causes a lump in the neck
  • Eye changes (Graves’ disease)
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13
Q

What might hyperthyroidism develop into if left untreated?

A
  • Thyroid storm: During thyroid storm an individual’s heart rate, blood pressure, and body temperature can soar to dangerously high levels
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14
Q

What are some of the causes of hyperthyroidism?

A
  • 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
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15
Q

What is hypothyroidism?

A
  • Deficient production of thyroid hormones
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16
Q

What are the clinical features of hypothroidism?

A
  • Weight gain
  • Cold intolerance
  • Lack of energy
  • Goitre - due to lack of negative feedback resulting in more TSH production
  • Congenital - developmental abnormalities
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17
Q

What are some biochemical signs of hypothyroidism?

A
  • Raised TSH, reduced T4 - indicates primary hypothyroidism
  • Reduction in TSH and T4 - indicates secondary hypothyroidism (hypopituitarism)
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18
Q

What are some causes of hypothyroidism?

A
  • 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
19
Q

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)
A
  • Patient has high free T3 and T4
  • Also has low TSH
  • This suggests woman has Primary hyperthyroidism
20
Q

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)
A
  • Patient has slightly low free T4
  • Also has extremely high TSH level
  • This suggest patient has primary hypothyroidism
21
Q

Give a brief description of the adrenal glands

A
  • 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
22
Q

The adrenal cortex is divided into 3 zones, what are these 3 zones?

A
  • Zona glomerulosa
  • Zona fasciculata
  • Zona reticularis
23
Q

How does blood flow through the adrenal cortex?

A
  • Blood flows from the outer cortex (Zona glomerulosa) to the inner cortex (Zona reticularis)
24
Q

What does the fact that each zone of the adrenal cortex contains its own enzymes mean for the adrenal cortex?

A
  • 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
25
Q

What steroid hormones are produced by each layer of the adrenal cortex?

A
  • Zona glomerulosa - Mineralocorticoids
  • Zona fasciculata - Glucocorticoids (cortosol)
  • Zona reticularis - Adrenal androgens
26
Q

Briefly explain the process of adrenal steroid synthesis

A
  • 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.
27
Q

What are the functions of the different adrenal steroids?

A
  • 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’
28
Q

Explain some specific functions of cortisol

A
  • 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
29
Q

What condition can the effects of cortisol on glucose mtabolism cause and what might this lead to?

A
  • 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)
30
Q

What controls adrenal steroid secretion?

A
  • 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)
31
Q

What controls cortisol and androgen levels within the body?

A
  • 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
    *
32
Q

What conditions can be caused by hyper-function of the adrenal cortex?

A
  • Aldosterone excess - Conn’s syndrome
  • Cortisol excess - Cushing’s syndrome
33
Q

What symptoms would you expect to be present due to aldosterone excess - Conn’s syndrome?

A
  • Hypokalaemia
  • Hypertension
34
Q

Why doesn’t excess aldosterone lead to hypernatremia?

A
  • 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
35
Q

What may cause Cushing’s syndrome - excess cortisol?

A
  • 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
36
Q

How is the negative feedback of the HPA-axis affected by exogenous glucocorticoids?

A
  • 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
37
Q

How is the negative feedback of the HPA-axis affected by an ACTH secreting pituitary tumour?

A
  • 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
38
Q

What is the difference between Cushing’s syndrome and Cushing’s disease?

A
  • 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
39
Q

What is the Dexamethasone suppression test?

A
  • It is a test used to assess adrenal gland function by measuring how cortisol levels change in response to an injection of dexamethasone
40
Q

Explain how the Dexamethasone suppression test works

A
  • 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
41
Q

What are the different types of adrenocortical insufficiency?

A
  • Primary adrenocortical failure – Addison’s disease (typically autoimmune)
    • Results in loss of aldosterone, cortisol and androgen production
  • Secondary adrenocortical failure - impaired ACTH release, may be due to:
    • Head trauma, tumour, surgery
    • Abrupt steroid withdrawal
42
Q

What are the effects of low Cortisol, Aldosterone and androgen levels due to Addison’s disease?

A
  • High CRH and ACTH - due to lack of negative feedback on pituitary and hypothalamus as low cortisol
  • Hypotension
43
Q

Describe some other dynamic tests of adrenal functional

A
  • 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
  • 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
44
Q

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
A
  • 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