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Clinical Biochemistry > Lab Investigation of Endocrine Disorders > Flashcards

Lab Investigation of Endocrine Disorders Flashcards

1
Q

Describe the hypothalamic-pituitary-thyroid axis

A

Circulating TH levels under negative feedback control at hypothalamic and pituitary levels

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2
Q

What controls TH release?

A

Synthesis and release of TH controlled by TSH

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3
Q

Outline the HPT axis

A
  1. TRH synthesised + released from hypothalamus
  2. TRH released into pituitary portal circulation, acts on
    anterior Pituitary to release thyrotropin / TSH
  3. TSH released into general circulation, stimulates TH
    (T3/T4) production by thyroid gland
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4
Q

Describe the abundance of both T3 and T4

A

T4 main hormone secreted by thyroid, T3 is more biologically active – mostly formed by peripheral conversion from T4

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5
Q

What are the actions of T3 and T4 in circulation?

A

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

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6
Q

What is the significance of thyroid hormones?

A

Essential for normal growth and development

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7
Q

What is the effect of thyroid hormones on metabolism?

A

Increase basal metabolic rate (BMR) and affect many metabolic processes

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8
Q

How are thyroid hormones produced?

A

Synthesized in thyroid via series of enzyme catalysed reactions, beginning with uptake of iodine into gland

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9
Q

How are the effects of thyroid hormone mediated?

A

Effects are mediated via activation of nuclear receptor

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10
Q

How are thyroid hormones transported in circulation?

A

Thyroid hormones in circulation are mostly bound to protein carriers (ie. thyroglobulin)

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11
Q

Describe the longevity of T3 and T4

A

T4 has 6-7 days half life

T3 has v short half life

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12
Q

Outline the terminology of thyroid function disorders

A

Euthyroid (normal range)
Hypothyroid (below)
Hyperthyroid (above)

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13
Q

What is meant by primary thyroid disorders?

A

Primary hyper/hypothyroidism: dysfunction is in thyroid gland

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14
Q

What is secondary thyroid dysfunctions?

A

Secondary: problem is with pituitary or hypothalamus (tertiary)

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15
Q

What is hyperthyroidism?

A

Excessive production of thyroid hormones (thyrotoxicosis)

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16
Q

How does hyperthyroidism effect metabolism?

A

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

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17
Q

What is goitre?

A

Swelling in neck due to enlarged thyroid gland

many causes, excess thyroid is one

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18
Q

Outline the causes of hyperthyroidism

A
  • Graves disease (most common)
    Due to stimulatory TSH-R antibodies (act as agonist)
  • Toxic multinodular goiter
  • Toxic adenoma
  • Secondary: excess TSH production (rare)
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19
Q

What is hypothyroidism?

A

Deficient production of thyroid hormones

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20
Q

Describe the clinical features of hypothyroidism?

A

Weight gain
Cold intolerance,
Lack of energy
Goitre (due to lack of -ve feedback = inc. TSH)

Congenital - developmental abnormalities

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21
Q

Describe the investigations of hypothyroidism

A

Raised TSH, reduced fT4 = primary

Reduction in TSH and T4 suggests secondary (hypopituitarism)

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22
Q

What are the causes of hypothyroidism?

A
  • Autoimmune thyroiditis (Hashimoto’s)
    Thyroid peroxidase antibodies (anti-TPO)
    • block enzyme = no thyroid hormone synthesis
  • Iodine deficiency
  • Toxic adenoma
  • Secondary – lack of TSH
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23
Q

Describe the blood flow in the adrenal cortex

A

Blood flows from outer cortex to inner medulla

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24
Q

Describe how the structure of adrenal glands effects its products

A

Outer cortex produces adrenal steroids

Inner medulla produces adrenaline

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25
Q

What hormones

A

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

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26
Q

Outline the different hormones produced in each layer

A

Zona glomerulosa - mineralocorticosteroids (aldosterone)

Zona fasciculata - glucocorticoids (cortisol)

Zona reticularis - adrenal androgens

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27
Q

What is the precursor of steroids?

A

All adrenal steroids share a similar biochemical synthesis pathway starting with cholesterol

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28
Q

How does steroid synthesis occur

A

Various enzymatic modifications of cholesterol result in production of adrenal androgens, mineralocorticoid production of aldosterone or glucocorticoid production of cortisol

29
Q

What is a significant steroidogenesis pathology associated with congenital adrenal hyperplasia

A

CYP21A is the gene for 21-hydroxylase. It’s deficiency is the major cause of congenital adrenal hyperplasia

30
Q

What is the major role of aldosterone?

A

Mineralocorticoids (aldosterone)

Salt and water balance in order to maintain plasma volume by balancing ECFV via Na+ retention - maintenance of BP long term

31
Q

How does aldosterone maintain BP?

A

Increased Na+ reabsorption from distal tubule

Starling’s forces then distribute inc. ECFV to Plasma and ICF

32
Q

How does salt effect water balance?

A

Net loss of salt ⇒ equivalent amount of water lost with it = net loss in volume, ∴ plasma volume

33
Q

What are the functions of cortisol?

A

Glucocorticoids (cortisol): metabolism and immune function

34
Q

What induces glucocorticoid cortisol release?

A

Stress increases release, but minimal levels essential for normal function

35
Q

Describe the effects of cortisol on the cardiovascular system

A

(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

36
Q

How does cortisol effect glucose metabolism?

A

Cortisol known as glucose sparing

Promotes insulin resistance in skeletal muscles (blocks GLUT4) allowing more glucose in circulation

Muscles use oxidative factors instead

37
Q

Which metabolic processes are promoted by cortisol?

A

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

38
Q

Why is the glucose sparing effect of cortisol not needed as often in modern day diet?

A

Increased [glucose] in circulation = hyperglycemia which stimulates insulin production which in turn promotes lipogenesis

39
Q

What are the effects of excess cortisol glucose sparing?

A

Excess cortisol indirectly leads to wasting appearance of arms and legs but thicker in trunk and face

40
Q

How is cortisol production regulated?

A

Synthesis and release regulated by hypothalamic-pituitary-adrenal axis (CRH, ACTH)

41
Q

What controls aldosterone release?

A

Controlled by RAAS

42
Q

What mediates adrenal androgen release?

A

ACTH (not gonadotropins)

43
Q

Why is measuring glucocorticoids difficult?

A

Measuring glucocorticoid isn’t straightforward as levels fluctuate due to circadian rhythms

44
Q

Which hormones are involved in the cortisol HPA axis?

A

Corticotropin-releasing hormone (CRH)

Adrenocorticotropic hormone (ACTH)

45
Q

Describe the role of the ACTH receptor

A

ACTH receptor: G-protein coupled, via cAMP stimulates cholesterol uptake and steroid synthesis

46
Q

Why is a cortisol reading not a reliable source of diagnosis?

A

Cortisol secretion fluctuates in a circadian rhythm, which means a random plasma cortisol reading cannot exclude abnormality, unless way outside of normal range

47
Q

Outline the syndromes of a hyperfunctioning adrenal cortex

A

Aldosterone excess
- Conn’s syndrome

Cortisol excess
- Cushing’s syndrome

48
Q

What causes Cushings syndrome?

A

The feedback loop is disturbed

collective term for a number of disorders with reason of excess varying

49
Q

What is a common cause of excess cortisol in Cushings?

A

Rule out glucocorticoid therapy (medication / analogs) as this may be causing excess levels

50
Q

How does glucocorticoid medication lead to excess cortisol?

A

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

51
Q

What is a less common reason for cushings?

A

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.

52
Q

What is Cushings disease?

A

Adenoma anterior pituitary tumour may cause increased ACTH secretion causing excess cortisol

Secondary as adrenal gland not cause of problem

53
Q

What are the effects of a pituitary adenoma in cushings?

A

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

54
Q

What is the purpose of a dexamethasone suppression test?

A

Allows us to distinguish between Cushing’s possibilities

55
Q

What is dexamethasone?

A

Dexamethasone: synthetic exogenous steroid that binds to glucocorticoid receptors like cortisol

56
Q

What is the effect of low dose dexamethasone?

A

Low doses will normally suppress ACTH secretion via negative feedback

57
Q

What are the results of a dexamethasone suppression test in a Cushings patient?

A

Low dose fails to suppress ACTH secretion with pituitary disease (Cushing’s)

Higher dose will suppress ACTH secretion in Cushing’s

58
Q

What does no suppression in a dexamethasone test suggest?

A

No suppression with low or high dose: suggests ectopic source of ACTH e.g., tumour elsewhere

59
Q

What is primary adrenocortical insufficiency?

A

Primary adrenocortical failure – Addison’s disease typically autoimmune; adrenal cortex stops functioning

Addison’s - progressive disease, leads to hypotension eventually

60
Q

What is secondary adrenaocortical failure?

A

Secondary – impaired ACTH release

61
Q

What causes secondary adrenocortical failure?

A

Head trauma, tumour, surgery

Abrupt steroid withdrawal

62
Q

Why can adrenocortical failure lead to adrenal failure?

A

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.

63
Q

What deficiencies cause Addisons disease?

A

Loss of:

  • Cortisol
  • Androgens
  • Aldosterone

(primary adrenal failure)

64
Q

What are the causes of primary adrenal failure?

A

usually autoimmune

65
Q

What is the role of a dynamic test of adrenal function?

A

Assess ability of adrenal to produce cortisol in response to ACTH

66
Q

Outline a short synacthen test

A

Short synacthen test (synthetic ACTH)

Measure baseline cortisol (9am) and 30 min after 250 µg synacthen (synthetic ACTH) i.m.

67
Q

Describe results of a short synacthen test

A

Adrenal insufficiency excluded by increased cortisol of
>200 nmol/L and/or a 30 min value >550

Cortisol levels don’t increase as expected

68
Q

Outline a long synacthen test

A

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

69
Q

Describe results of a long synacthen test

A

In secondary (but not primary) adrenal insufficiency cortisol increases by >200 nmol/L over baseline

Clinical Biochemistry (7 decks)

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