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Phase 2 3. Endocrinology > PBL 4 - Adrenal insufficiency > Flashcards

PBL 4 - Adrenal insufficiency Flashcards

1
Q

Where are the adrenal glands found?

A

situated above the kidneys, each about 4-6cm in length. It lies at the level of the 12th rib.

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2
Q

Describe the blood flow of the adrenal glands

A

The blood supply reaches the outer surface of the gland before entering and supplying each layer (centripetal flow)

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3
Q

Describe the histology of the adrenal glands

A

The adrenal glands consist of the outer cortex and inner medulla.

The cortex forms about 90% of its mass, and is split into 3 zones:
o zona glomerulosa
o zona fasciculata
o zona reticularis.

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4
Q

Describe the zona glomerulusa

A

produces mineralocorticoids e.g. Aldosterone which is important in the balances of
electrolytes (K+ and Na+) and the maintenance of water. The cells of this region form small, dense
clusters

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5
Q

Describe the zona fasciculata

A

produces glucocorticoids due to their effects on glucose metabolism e.g. Cortisol
which is regulated by ACTH. This region takes up most of the cortical region (75%). The cells contain
more lipids and appear foamy and pale. They are arranged to form individual cords composed of stacks
of cells. Adjacent cords are separated by fenestrated capillaries.

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6
Q

Describe the zona reticularis

A

produces androgens, DHEA that is also regulated by ACTH. This is an important
source of androgens in women. The endocrine cells of this region form a folded, branching network and
fenestrated capillaries that wrap around cells

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7
Q

Describe the adrenal medulla

A

Catecholamine production, 80% adrenaline & 20% noradrenaline. Stimuli from the
hypothalamus, medulla and pons activate preganglionic cholinergic nerves that stimulate the release of
adrenaline and smaller amounts of noradrenaline from the chromaffin cells. All synthetic steps take place
in the cytoplasm except the conversion of dopamine to norepinephrine, which occurs in the secretory
granules. Epinephrine is taken up into the secretory granules for storage and release.

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8
Q

Describe the blood supply of the adrenal arteries

A

Each gland is supplied by the superior, middle and inferior suprarenal
arteries
 The blood reaches the outer surface of the gland before entering and
supplying each layer (centrepetal blood flow).
 At the centre, it flows into the medullary vein.
 The medullary veins emerge from the hilum of each gland before
forming the suprarenal veins, which join the inferior vena cava on the
right side and the left renal vein on the left

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9
Q

Describe the innervation of the adrenal glands

A

Rich nerve supply derived from the coeliac plexus and the thoracic
splanchnic nerves.
 The nerves supply the chromaffin cells of the adrenal medulla.

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10
Q

Where are androgens unable to be formed?

A

The enzyme 17α-hydroxylase (CYP 17) is not present in the outer layer of the cortex and, thus, cortisol
and androgens cannot be formed in this layer.

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11
Q

Why can no aldosterone can be synthesized by cells below the outer glomerulosa layer?

A

Steroids and their metabolic by-products are released into the adrenal circulation and inhibit critical
enzymes in subsequent layers through which the blood flows.

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12
Q

What do high cortisol concentrations reaching the adrenal medulla stimulate?

A

the synthesis of phenylethanolamine-

N-methyltransferase which catalyzes the conversion of norepinephrine to epinephrine

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13
Q

What are the adrenal androgens?

A

DHEA and Androstenedione

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14
Q

Where are adrenal androgens synthesised?

A

Produced in ZR - regulated by ACTH

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15
Q

What are the Glucocorticoids?

A

Cortisol or Corticosterone

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16
Q

What is the importance of the adrenal androgens?

A

Important source of androgens in women

testosterone from the testes is much more active (in men

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17
Q

Where are glucocorticoids produces?

A

Produced in ZF - regulated by ACTH

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18
Q

What is the importance of glucocorticoids?

A

Carbohydrate Regulation

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19
Q

What are the mineralocorticoids?

A

Aldosterone or Deoxycorticosterone

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20
Q

Where are the mineralcorticoids produced?

A

Produced by ZG - regulated by RAAS

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21
Q

What is the importance of the mineralcorticoids?

A

Sodium/BP homeostasis

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22
Q

What are steroid hormones synthesised from?

A

cholesterol

all generated by the
enzymatic modification of the cholesterol nucleus

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23
Q

Where is cholesterol obtained from?

A

either obtained from the diet or synthesized from
acetate by a CoA reductase enzyme.

o Approximately 300 mg cholesterol is absorbed from the diet
each day
o About 600 mg synthesized from acetate.

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24
Q

How is cholesterol transported?

A

Cholesterol is insoluble in aqueous solutions and its transport from
the main site of synthesis, the liver, requires apoproteins to form a
lipoprotein complex

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25
Q

How does cholesterol reach the adrenal glands?

A

In the adrenal cortex, about 80% of cholesterol required for steroid synthesis is captured by receptors which bind low-density lipoproteins

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26
Q

What other way can the adrenal glands obtain cholesterol?

A

synthesized from acetate within the adrenal cells by the normal biochemical route. The cholesterol can be stored as esters in lipid droplets or utilized directly`

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27
Q

Why does cholesterol need to be transferred into the mitochondria?

A
  • cholesterol is converted to pregnenolone by cytochrome P450 (found - inner mitochondrial membrane)
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28
Q

How is cholesterol transferred into the mitochondria?

A

translocated there
=rate-limiting step

Carried out by Steroidogenic Acute Regulatory Protein (StAR)

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29
Q

What happens to pregnenolone?

A

Shuttles to smooth endoplasmic reticulum and converted to progesterone or to 17α-hydroxypregnenolone.

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30
Q

What happens to progesterone?

A

Through subsequent hydroxylations, progesterone can be converted to corticosterone (another
glucocorticoid that is only released in small amounts in the human) and then aldosterone

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31
Q

What happens to 17α-hydroxypregnenolone?

A

can be converted to androgens and cortisol

32
Q

Describe the regulation of cortisol

A

Cortisol will suppress its own production via negative feedback of the hypothalamus and anterior pituitary
gland.

33
Q

How is cortisol produced?

A

In response to ACTH, the zona fasciculata release cortisol and corticosterone.

34
Q

What type of receprot is the ACTH receptor?

A

G-protein coupled receptor.

35
Q

What actions occur on ACTH receptor activation?

A

it causes an increase in cAMP and activation of PKA and Ca2+ influx.
 There is subsequent rapid cholesterol delivery to the mitochondria.
 Genes for steroidogenic enzymes are turned on (enzymes that process cholesterols into their end
products) → ultimately results in increased cortisol/androgen production.

36
Q

What are the metabolic functions of cortisol?

A

o Stimulates gluconeogenesis in the liver - glucose is synthesised from non-hexose substrates
such as amino acids and lipids.
o Stimulation of lipolysis in adipose tissue.
o Glycogenesis - cortisol aims to store away glucose produced via gluconeogenesis as glycogen in
periods of stress.
o Opposes insulin - increases blood glucose

37
Q

What are the immunosuppresive functions of cortisol?

A

o Decreases lymphoid tissue volume and activity (↓ antibodies & lymphocytes)
o They show anti-inflammatory effects by inhibiting WBCs

38
Q

What are the systemic effects of cortisol?

A

o Increased appetite
o Increased bone resorption.
o Increased breakdown of skeletal muscle protein.
o Decreased Vitamin D3 and therefore decreased calcium reabsorption
o Promotes the effects of adrenaline → increased vascular tone and BP.

39
Q

What is aldosterone?

A

is a mineralocorticoid that is regulated by the RAAS that causes Na+ retention and K+
excretion.

40
Q

Where does aldosterone bind?

A

Acts on mineralocorticoid receptors (MR) in the principal cells of the distal tubule and collecting duct.
Since aldosterone is a steroid, the MR receptors are found in the cytosol.

41
Q

What are the main functions of aldosterone?

A

o causes the up regulation of basolateral Na+/K+ pumps.
o upregulates the number of ENaC transporters in the apical membrane, increasing permeability to
Na+

42
Q

What competes with aldosterone for binding at mineralocorticoid receptors?

A

cortisol

Aldosterone however has a higher affinity for MR than Cortisol. Although, cortisol is at a much higher
concentration in the blood than Aldosterone.

43
Q

Where are cortisol receptors found?

A

Receptors for glucocorticoids (GRs) are usually intracellular and unlike thyroid hormones they usually
exist in the cytoplasm, not the nucleus
 These are displaced when cortisol diffuses across the cell membrane, and binds to these receptors in
target cells.
 Subsequent phosphorylation of the receptors facilitates translocation of the hormone-receptor complex
into the nucleus where it forms a homo- or heterodimer with another hormone-receptor complex.

44
Q

What happens on receptor binding of cortisol?

A

The zinc fingers in the DNA-binding domain of the dimerized receptors interact with specific grooves of
the DNA helix containing a consensus sequence.
 The site of receptor binding on the DNA is known as the hormone response element (HRE) - in this case
the glucocorticoid response element (GRE).
 In association with other transcription factors, the GRs stimulate or suppress gene transcription that is
usually initiated down-stream of the GRE.
 The structural similarities of the DNA-binding domain of glucocorticoid, oestrogen, androgen and
progesterone receptors are such that they can all bind to the same hormone response element.
 Additionally, cortisol has equal affinity for the aldosterone receptor in the kidney tubules but its rapid
inactivation to cortisone in these cells normally prevents binding.

45
Q

Outline the functional relationships between the hypothalamus, the anterior pituitary and the adrenal
cortex (HPA-axis)

A

 The hypothalamus release CRH in response to illness, stress and time of day (early morning). It acts on
the anterior pituitary which then produces ACTH. This hormone acts on the adrenal cortex to produce
cortisol.
 Cortisol is released in a Circadian rhythm (24 hour clock), being highest during the mornings.
 ACTH is a long peptide which is cleaved off from a precursor molecule, POMC

46
Q

What tests are used to investigate adrenal insufficiency?

A
  • biochemistry
  • short synacthen test
  • acth levels
  • renin/aldosterone levels
  • adrenal autoantibodies
47
Q

What is Addison’s disease?

A

autoimmune destruction of the

entire adrenal cortex due to atrophy.

48
Q

What is the most common antigen in Addison’s disease?

A

21 HYDROXYLASE

49
Q

What aspect of adrenal cortex function is affected in addison’s disease?

A

↓ in ALL productions of the cortex

  • Mineralocorticoids,
  • Glucocorticoids
  • Androgens.

↓ in Cortisol levels, which results in ↑ CRH & ACTH
production

50
Q

How does hyperpigmentation in Addisons occur?

A

ACTH acts on melanocytes

51
Q

What are the clinical features of Addison’s disease?

A

 Anorexia, Weight Loss
 Fatigue/Lethargy
 Dizziness - Postural Hypotension (due to mineralocorticoid deficiency)
 Abdominal Pain, Diarrhoea, Vomiting
 Skin Pigmentation - due to ↑ ACTH
 Dehydration - mineralocorticoid deficiency

52
Q

How is Addison’s disease managed?

A
  • Glucocorticoid replacement

- Mineralcorticoid replacement

53
Q

What are the causes of primary adrenal insufficiency

A
  • Primary Adrenal Insufficiency - failure of the Adrenal Cortex.
  • Addison’s Disease - chronic adrenal insufficiency (most common cause of primary insufficiency)
  • Congenital adrenal hyperplasia - Insufficiency leads to decreased production of steroid hormones (glucocorticoids, mineralocorticoids,
    androgens) .
54
Q

Secondary Adrenal Insufficiency

A

 Lack of ACTH production and stimulation of the adrenal gland, which can be caused by
 Excess exogenous steroid (iatrogenic)
 Pituitary/hypothalamic disorders.
 Glucocorticoids are affected, however mineralocorticoid production (aldosterone) remains intact.

55
Q

How is hydrocortisone used as a cortisol replacement?

A

o Metabolised to cortisol. Most physiological way of replacing cortisol
o If unwell, give intravenously first
o Then 15-30mg oral tablets daily in divided doses (for long-term maintenance)
o Try to mimic diurnal rhythm
 Highest levels in the morning, therefore give higher dose in the morning

56
Q

How is fludocortisone used as an aldosterone replacement?

A

Careful monitoring of BP and plasma potassium to determine the adequacy of replacement

57
Q

What are the side effects of steroid therapy?

A

Long term therapy with synthetis or natural steroids can mimic endogenous Cushing Syndrome
 NB: inhaled steroids rarely cause Cushing’s but topical steroids can if they are strong (will be absorbed
from the skin)

58
Q

What is hyperadrenalism?

A

Cushing’s syndrome is caused by a chronic inappropriate elevation of free circulating cortisol.

59
Q

What are the two types of Cushing’s

A
  • ACTH dependent

- ACTH independent

60
Q

Describe ACTH dependent Cushing’s

A

↑ ACTH and therefore ↑ Cortisol

Pituitary adenoma, ectopic non-pituitary causes, ectopic CRH

61
Q

Describe ACTH independent Cushing’s

A
  • ↓ Cortisol

Long-term glucocorticoid administration
Adrenal adenoma, adrenal carcinoma, nodular hyperplasia

62
Q

How can Cushing’s occur?

A

caused by high exogenous or endogenous cortisol levels

63
Q

Describe the exogenous cause of Cushing’s

A

Iatrogenic from excess exogenous glucocorticoids (most common cause)

64
Q

Describe the Endogenous cause of Cushing’s

A

o ACTH dependent (80%): This can be caused by a pituitary adenoma which secretes ACTH
(Cushing’s disease) or ACTH secreted from an ectopic source (eg. from a small cell carcinoma).
o ACTH independent: Excess cortisol secreted from an adrenal carcinoma, a benign adenoma or
adrenal nodular hyperplasia
o Rarer causes: CRH secreting tumour

65
Q

What tests cant be used to diagnose Cushing’s

A

 Establish cortisol excess
 Dexamethasone suppression test
 24-hour urinary free cortisol
 Late night salivary cortisol

66
Q

What is the Late night salivary cortisol test and why is it used?

A

Elevated cortisol between 11:00 p.m. and midnight appears to be the earliest detectable abnormality in many patients with
Cushing’s as cortisol secretion is usually very low at this time

67
Q

What is the dexamethasone suppression test?

A

 serum cortisol is measured before midnight, 1mg of dexamethasone is then given at
midnight and then the serum cortisol is rechecked at 8am.
 In a patient without Cushing’s syndrome, the high dose of steroid given in this test will
cause negative feedback to the hypothalamus and pituitary to reduce production of CRH
and ACTH and therefore cortisol secretion.
 In Cushing’s syndrome, cortisol secretion is autonomous and therefore does not respond
to feedback loops. This means that the cortisol level will remain high.

68
Q

Why is ACTH tested in Cushing’s?

A

Used to work out where the problem lies: in

the hypothalamus, the pituitary, the adrenals or an ectopic site.

69
Q

What is the likely cause if ACTH is undetectable in Cushing’s?

A

most likely to be a problem with the adrenals as cortisol is feeding back to inhibit ACTH secretion.

70
Q

What is the likely cause if ACTH is normal or high in Cushing’s?

A

could either be due to a pituitary tumour or an ectopic source.

71
Q

What other investigation should be used to determine the cause of Cushing’s?

A
  • An MRI of the pituitary
  • inferior petrosal sinus sampling (IPSS)
  • CT or
    MRI of the neck, thorax and abdomen
72
Q

How is Cushing’s managed?

A

= treating cause

Iatrogenic Cause: If the patient is receiving exogenous steroids, stop medications if possible or reduce
the dosage
 Cushing’s disease - a pituitary tumour.
o can be managed surgically by trans-sphenoidal removal.
o Radiotherapy is often used in children.
o If the source cannot be localised then a bilateral adrenalectomy can be performed to prevent
high cortisol secretion and then the patient will need exogenous cortisol replacement

 Adrenal Tumor - adrenalectomy is usually successful for an adenoma, this is followed by radiotherapy for
carcinoma
 Ectopic ACTH - surgery if the tumour has not spread

73
Q

What is Primary Aldosteronism?

A

disorder of the adrenal cortex characterised by excess aldosterone
production leading to Na+ retention, K+ loss and the combination of hypokalaemia and hypertension.
This is due to either a single adrenal adenoma (Conn’s Syndrome) or bilateral adrenal nodules.

It is the commonest secondary cause of hypertension.

74
Q

What are the clinical features of primary aldosteronism?

A

Significant hypertension
Hypokalaemia (in up to 50%)
Alkalosis

75
Q

How is primary aldosteronism

A 
 Blood biochemistry
 Plasma aldosterone elevated (that are not surpassed with IV 0.9% saline load or fludrocortisone
administration 
 Plasma renin concentration suppressed 
 Hypokalaemia
 Urinary Potassium Loss >30mmoL/day
 Adrenal CT scan
76
Q

What is the management of primary aldosteronism?

A

 Surgical
o Unilateral laparoscopic adrenalectomy, only if there is an adrenal adenoma
o It cures hypokalaemia and cures hypertension in 30-70% of cases
 Medical
o MR antagonists (spironolactone)
o Or Amiloride (blocks Na+ reabsorption by acting on ENaC)

Phase 2 3. Endocrinology (25 decks)

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