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Molecular basis of disease > Endocrine disorders > Flashcards

Endocrine disorders Flashcards

1
Q

Clinical endocrinology consists of:

A

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

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2
Q

What are thyroid hormone levels under the control of?

A

hypothalamic-pituitary-thyroid axis

-negative feedback control at hypothalamus and pituitary levels

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3
Q

What controls the synthesis and release of thyroid hormone?

What is the main hormone secreted by thyroid?

A

TSH

T4

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4
Q

What is the main biologically active thyroid hormone?

Thyroid hormones in the circulation

A

T3
-mostly formed from the peripheral conversion of T4

bound to protein carrier molecules

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5
Q

Function of thyroid hormones

A

Essential for normal growth and development

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

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6
Q

How are thyroid hormones synthesised?

How do thyroid hormones exhibit their effects?

A

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

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7
Q

Disorders of Thyroid Function

A

Primary hyper/hypothyroidism

Secondary hyper/hypothyroidism

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8
Q

Describe the levels of hormones in hypothyroidism and hyperthyroidism (primary and secondary)

A

primary hyper/hypothism - dysfunction of the thyroid gland

secondary hyper/hypothyroidism - problem with the pituitary or hypothalamus (tertiary)

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9
Q

What is hyperthyroidism?

What is hypothyroidism?

A

excessive production of thyroid hormones (thyrotoxicosis)

deficient production of thyroid hormones

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10
Q

Clinical features of hyperthyroidism

A

Weight loss, heat intolerance, palpitations, goitre, eye changes (Graves)

In extreme: thyroid storm

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11
Q

Causes of hyperthyroidism

A

· 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)

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12
Q

Clinical features of hypothyroidism

A
  • 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)
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13
Q

Causes of hypothyroidism

A

· Autoimmune thyroiditis (Hashimoto’s)
>thyroid peroxidase antibodies (anti-TPO)

· Iodine deficiency
· Toxic adenoma
· Secondary- lack of TSH

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14
Q

Hashimoto’s disease/autoimmune thyroiditis

A

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.

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15
Q

Structure of the adrenal gland

A

The adrenal gland contains an outer cortex which produces steroids, and an inner medulla which produces catecholamines.

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16
Q

Adrenal cortex structure

A

Divided into three zones:

  • Outer zona glomerulosa→produces mineralocorticoids (aldosterone)
  • Middle zona fasciculata→produces glucocorticoids (cortisol)
  • Inner zona reticularis→produces adrenal androgens
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17
Q

Adrenal steroids

A

Mineralocorticoids (aldosterone)
Glucocorticoids (cortisol)
Adrenal androgens

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18
Q

What are all of the adrenal steroids produced from?

A

CHOLESTEROL
-there are various enzymatic modifications of cholesterol which can result in the production of either adrenal androgens, mineralocorticoids or glucocorticoids.

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19
Q

Actions of mineralocorticoids (aldosterone)

A

Salt and water balance in order to maintain plasma volume and therefore maintenance of blood pressure over the long term

20
Q

Action of glucocorticoids (cortisol)

A

Many functions; metabolism and immune function

Stress increases glucocorticoid release, but minimal levels essential for normal function

Cardiovascular system: low cortisol → low blood pressure

21
Q

Disorders of adrenocortical function

A

Excess cortisol (Cushing’s syndrome)
Excess aldosterone (e.g. Conn’s syndrome)
Adrenal insufficiency
Hypocortisolism
Lack of aldosterone and cortisol (Addison’s)

22
Q

Adrenocortical excess

A

Aldosterone excess
Conn’s syndrome (primary hyperaldosteronism)
Cortisol excess
Cushing’s syndrome (may be primary or secondary)

23
Q

Control of aldosterone secretion

A

Activated by

  • RAAS
  • Increased plasma [K+]

RAAS is activated by
- Reduced renal perfusion
- Increased sympathetic activity
Both interpreted as a fall in blood volume

24
Q

What are the androgens produced in the adrenal cortex considered?

A

weak androgens

25
Q

Give an overview of cortisol actions

A

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
26
Q

Effects of cortisol in a modern setting where there aren’t stresses

A

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)
27
Q

What are the androgens produced in the adrenal cortex considered?

A

weak androgens

28
Q

What controls the synthesis and release of cortisol?

A

The synthesis and release of cortisol is regulated by the hypothalamic-pituitary-adrenal axis (CRH, ACTH).

29
Q

What controls the synthesis and release of aldosterone?

A

Aldosterone is controlled by the renin-angiotensin-aldosterone system (RAAS).

30
Q

Most common cause of Cushing’s syndrome is iatrogenic

A

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

31
Q

Cortisol levels throughout the day

A

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.

32
Q

ACTH receptor

A

GPCR

-via cAMP stimulates cholesterol uptake and synthesis

33
Q

Conn’s syndrome

A

a disorder of the adrenal glands caused by the excessive production of aldosterone (primary hyperaldosteronism)

34
Q

Cushing’s syndrome

A

hyper-secretion of cortisol from the adrenal cortex due to a disturbance in the negative loop feedback

35
Q

Causes of Cushing’s syndrome

A

Exogenous Steroid Use

Pituitary Adenoma

Ectopic ACTH Secreting Tumour

36
Q

Cushing’s syndrome: Exogenous Steroid use

A

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.

37
Q

Cushing’s syndrome: Pituitary Adenoma

A

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.

38
Q

Cushing’s syndrome: Ectopic ACTH

A

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.

39
Q

How to find out source of excess cortisol in Cushing’s syndrome

A

Dexamethasone Suppression Test

40
Q

Dexamethasone

A

synthetic glucocorticoid which will mimic cortisol and bind to glucocorticoid receptors

41
Q

Action of dexamethasone in normal people

A

low doses of dexamethasone will normally suppress ACTH secretion via negative feedback and subsequently suppress plasma cortisol

42
Q

How does dexamethasone suppression test work?

A

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
43
Q

Addison’s disease

A

Primary Adrenocortical Insufficiency

  • loss of cortisol, aldosterone and androgen production
  • typically autoimmune

-HIGH ACTH levels

44
Q

Secondary adrenocortical insufficiency

A

Results from any disorder of the hypothalamus or pituitary that impairs ACTH release:

  • head trauma, tumour, surgery
  • abrupt steroid withdrawal
45
Q

How do we test for adrenal insufficiency?

A

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

Molecular basis of disease (31 decks)

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