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BRS2 Endocrinology > Adrenal Disorders > Flashcards

Adrenal Disorders Flashcards

1
Q

What are the adrenal glands?

A

2 triangular endocrine glands which are situated superiorly on the surface of the kidney, it is divided into two sections: Adrenal cortex and medulla.

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2
Q

List the 3 zones of the adrenal cortex from superficial to deep and what each zone secretes.

A

Zona glomerulosa: Produces and mineralocorticoids secretes (aldosterone).

Zona fasciculata: Produces
and secretes glucocorticoids (cortisol); in addition to small proportions of androgens.

Zona reticularis: Produces and secretes androgens and oestrogens, as well as smaller proportions of corticosteroids.

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3
Q

What are the names of the cells in the adrenal medulla and what do they secrete?

A

Chromaffin cells which secrete catecholamines into the systemic circulation in response to stress.

Adrenaline (80%)
Noradrenaline (20%)

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4
Q

What is the precursor molecule for steroidogenesis?

A

Cholesterol is a precursor substrate used to synthesise corticosteroids:
Mineralocorticoids (Aldosterone)
Glucocorticoids (Cortisol)
Sex steroids (Androgens and oestrogen)

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5
Q

List the enzymes for which angiotensin-II exerts an activator effect on.

A 
Side chain cleavage
3- beta hydroxy-steroid-dehydrogenase
21 hydroxylase
11 hydroxylase 
18 hydroxylases
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6
Q

What enzyme cleaves cholesterol into pregnenolone and what reaction follows?

A

p450scc enzyme

Pregnenolone > Progesterone (3 beta-hydroxysteroid dehydrogenase)

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7
Q

What is the physiological purpose of aldosterone?

A

Stimulates potassium excretion in the urine. Promotes sodium reabsorption in the kidneys.
By promoting the renal reabsorption of sodium, aldosterone also increases water retention, exerting a direct effect on blood pressure control.

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8
Q

Outline the synthesis of aldosterone after progesterone is formed from pregnenolone.

A

Stage I - 21-hydroxylase catalyses the hydroxylation of C21 converting progesterone into 11-deoxycorticosterone.
Progesterone > 11- deoxycorticsterone

Stage II - 11-hydroxylase hydroxylates C11, converting 11-deoxycorticosterone into corticosterone.
11-deoxycorticosterone > Corticosterone

Stage III - 18-hydroxylase hydroxylates C18, converting corticosterone into aldosterone
Corticosterone > Aldosterone

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9
Q

Name the hormone produced by the adrenal gland that is associated with the normal stress response.

A

Cortisol

(Cortisol is synthesised from cholesterol, the synthesis of cortisol in the zona fasciculata is stimulated by the anterior lobe of the pituitary gland with ACTH; ACTH production is stimulated by corticotrophin release by hypothalamic parvocellular neurones.
Cortisol has a diurnal rhythm, reaching a serum peak at 9:00am.)

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10
Q

List the metabolic effects of cortisol

A

Stimulates peripheral protein catabolism; hepatic gluconeogenesis; enhances effects of glucagon and catecholamines; stimulates glycogenolysis; fat lipolysis of adipose tissue makes tissues less responsive to insulin (susceptibility to developing diabetes): Overall effect: INCREASES BLOOD GLUCOSE CONCENTRATION

Alternative effects: Mineralcorticoid, renal, CVD effects. Cortisol has the ability to bind onto mineralocorticoid receptors, therefore, behaving as aldosterone assisting with water and Na+ ion retention.

Pharmacological effects of cortisol: Anti-inflammatory action, immunosuppressive action, anti-allergic action.

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11
Q

What type of receptors do aldosterone and cortisol bind to respectively?

A

Aldosterone binds to mineralocorticoid receptors.

Cortisol binds to glucocorticoid and mineralocorticoid receptors equally.

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12
Q

Compare the concentration of cortisol and aldosterone in the blood.

A

The concentration of cortisol in the blood is approximately 1000 times greater than that of aldosterone; however, cortisol binding in inhibited.

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13
Q

What substance do the kidneys secrete to convert bioactive cortisol into cortisone and why?

A

Kidneys secrete IIB-hydroxysteroid dehydrogenase 2, converting bioactive cortisol to cortisone; constantly removing cortisol to reduce interference with mineralocorticoid receptors.

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14
Q

What is Cushing’s disease?

A

Cushing’s disease is a condition resulting from excess amounts of cortisol secretion from the adrenal cortex, primarily caused by adrenal adenomas or overstimulation by ACTH from pituitary tumours.

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15
Q

What is the commonest cause of Cushing’s syndrome?

A

Oral consumption of steroids is a common causation of Cushing’s syndrome.

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16
Q

List the causes of Cushing’s, separate the ACTH dependent and independent.

A

ACTH dependent:
Pituitary adenoma
Ectopic ACTH secretion from lung cancer

ACTH independent:
Adrenal adenoma/carcinoma
Increased ingestion of steroids by mouth

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17
Q

What are the symptoms of Cushing’s disease?

A

Weight gain (Centripetal obesity).
Reddening of the face and neck. Thick skin, fat pads (Buffalo humps), moon face, red striae and pendulous abdomen.
Excess growth of body and facial hair
Hypertension and hyperglycaemia (Impaired glucose tolerance > Diabetes)
Osteoporosis
Proximal myopathy (muscle weakness due to catabolic effects of cortisol)
Mental changes (depression).

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18
Q

List and explain the 4 investigations that can be done to find out if a patient has Cushing’s.

A

1) 24-hour urine collection for urinary free cortisol: Cortisol level >50mg/24 hours.
2) Blood diurnal cortisol levels (Highest at 9am and lowest at midnight). N.B: It is difficult to distinguish whether a patient has Cushing’s syndrome at 9am considering cortisol is at a maximum serum level. A loss of diurnal rhythm is a feature of Cushing’s.
3) Late night salivary cortisol: Should be first-line test in any patient with suspected Cushing’s Syndrome. Samples are collected by saturating a collection swab with saliva or passively drooling into a collection tube between 23:00 and midnight. Positive results should be confirmed with dexamethasone suppression or 24-hour urinary free cortisol.
4) Low dose dexamethasone test: 0.5mg; 6 hourly for 48 hours. Dexamethasone is an artificial steroid concerned with eliciting a suppressive effect on ACTH production, down-regulating the production of cortisol. Patients with Cushing’s will demonstrate

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19
Q

Hypersecretion of cortisol within the adrenal cortex can be inhibited using what?

A

11-beta hydroxylase inhibitors (Enzyme is used to convert 11- deoxycorticosterone > corticosterone and 11-deoxycortisol > Cortisol)

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20
Q

Give an example of an 11-beta hydroxylase inhibitor and explain its mechanism.

A

Metyrapone
Metyrapone inhibits 11-beta hydroxylase within the zona fasciculata and zona reticularis, arresting cortisol synthesis at the 11- deoxycortisol stage.
11-deoxycortisol has no negative feedback effect on the hypothalamus and pituitary gland.

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21
Q

List the unwanted actions of metyrapone and explain how they can happen.

A

Deoxycorticosterone accumulates within the zona glomerulosa > aldosterone-like effects (Mineralocorticoid activity) > Salt retention and HYPERTENSION.

Using metyrapone can lead to increased adrenal androgen production (Hirsutism in women).

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22
Q

List the uses of metyrapone.

A

Control of Cushing’s syndrome prior to surgery.

  • adjust dose (oral) according to cortisol (aim for mean serum cortisol 150-300 nmol/L)
  • improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc.)

Control of Cushing’s symptoms after radiotherapy (which is usually slow to take effect).

23
Q

What is ketoconazole?

A

An antifungal agent (withdrawn in 2013 due to risk of hepatotoxicity-p450 poison). Liver damage can arise with ketoconazole use.

24
Q

Explain how ketoconazole can be used in the treatment of Cushing’s syndrome

A

At higher concentrations it inhibits steroidogenesis > Off- label use in Cushing’s syndrome.
Inhibition of 17-alpha hydroxylase > Inhibits cortisol production. It is an orally active drug that can be prescribed post-operatively.

25
Q

What is the treatment for an ACTH-secreting pituitary tumour?

A

Transsphenoidal hypophysectomy (Pituitary surgery) > First line therapy is the resection of the causative pituitary adenoma.

26
Q

What it is the treatment for a bilateral adrenal adenoma?

A

Bilateral adrenalectomy > Provides a cure for all endogenous hypercortisolism by removing hyperplastic autonomous adrenal nodules. N.B. Results in adrenal insufficiency, thus needing lifelong corticosteroid replacement.

27
Q

What is the treatment for a unilateral adrenal carcinoma/adenoma (ACTH-independent)?

A

Unilateral adrenalectomy for adrenal mass > Complete resection of the adrenal gland cures hypercortisolism in all patients without high risk of long-term adrenal insufficiency.

28
Q

What is Addison’s disease?

A

Primary adrenal insufficiency that is characterised by a disorder that causes a decreased production in adrenocortical hormones (cortisol and aldosterone) as a result to destruction to the adrenal cortex or due to disruption in hormone synthesis.

29
Q

What is the commonest cause of Primary adrenal failure (Addison’s disease) worldwide?

A

TB of the adrenal gland

However autoimmune diseases are the primary cause of adrenal insufficiency within the UK.

30
Q

List the symptoms of Addison’s disease.

A 
Hyponatremia
Hyperkalaemia
Hypotension 
Hypoglycaemia and fatigue 
Hyperpigmentation 
Weight loss
31
Q

Why do patients with Addison’s disease have a good tan?

A

Due to the inadequate secretion of cortisol by the zona fasciculata there is a loss of negative feedback exerted on the APG. This increases ACTH synthesis from corticotrophs as a compensatory mechanism. Pro-opio-melanocortin (POMC) is a large precursor protein that is cleaved to form a number of small peptides including ACTH, MSH, endorphins and enkephalins. Thus, there is a pathologically elevated level of MSH and ACTH leading to increased pigmentation.

32
Q

List the 3 causes of adrenocortical failure.

A

TB Addison’s Disease
Autoimmune Addison’s Disease
Congenital adrenal hyperplasia

33
Q

Explain how you can test a patient if you want to confirm whether or not they have primary adrenal failure.

A

9am cortisol is low (Due to the diurnal rhythms exhibited by cortisol secretion, 9am cortisol levels are at a peak); 100 (270-900) nM

ACTH - High (Loss of negative feedback exerted onto the pituitary gland)

Short synACTHen test: Administer 250ug synacthen intramuscular and measure the subsequent cortisol response. In patients with adrenal hypofunction, there is reduced cortisol secretion unresponsive to ACTH stimulation, thus the cortisol response is absent – minimal change.

Test result: Serum cortisol post synACTH injection 150 nM (>600nM in normal patient) > Indicative of adrenocortical failure.

34
Q

Why can’t you use aldosterone for treatment of a patient with adrenal failure and what should you use instead and why?

A

Half-life of aldosterone is too short for once daily administration.

Give fludrocortisone (50-100 mcg daily) → Fl doesn’t exist in natural steroids, so its presence slows metabolism substantially. Fludrocortisone binds to both mineralocorticoid and glucocorticoid receptors + increases half-life (3.5 hours), exerting effects for 18h.

35
Q

Why not use oral hydrocortisone as part of the treatment for primary adrenal failure and what should be used instead and why?

A

Oral hydrocortisone has a short half-life, thus presenting harmful late peaks if administered more than once daily (Thrice daily) → Consider using a longer lasting version.

Prednisolone (1,2-dehydrocortisone) should be used instead as it has a longer half-life and is more potent than cortisol (2.3x the binding affinity that cortisol).

36
Q

What is the dose range in which prednisolone should be administered daily?

A

2-4mg once daily (we need more research to define the correct dose for each patient).
This would be an equivalent dose of 15-25 mg hydrocortisone daily.

37
Q

Outline the treatment plan for a patient with adrenal failure.

A

Prednisolone (2-4mg daily)
AND
Fludrocortisone 50-100 mcg daily

38
Q

What is the commonest cause of congenital adrenal hyperplasia?

A

21-hydroxylase deficiency

can be complete or partial

39
Q

Which hormones will be totally absent in complete 21-hydroxylase deficiency?

A

Aldosterone and cortisol

40
Q

How long can you survive with complete 21-hydroxylase deficiency?

A

Less than 24 hours

41
Q

Which hormones will be in excess in complete 21-hydroxylase deficiency?

A

Sex steroids and testosterone

42
Q

Classical CAH describes an absolute lack of 21-hydroxylase which is typically identified soon after childbirth as the lack of cortisol and aldosterone results in what?

A

A salt-losing crisis (hyponatraemia, hypotension and dehydration).

43
Q

How would you be able to identify if a female new-born may have CAH?

A

Female new-borns may also have abnormal external genitalia (virilised by adrenal testosterone)
Survival is low (less than 24 hours) > Administer immediate glucocorticoid

44
Q

What is partial 21-hydroxylase deficiency and how does it differ from complete?

A

Non-classical (partial) CAH is caused by a partial deficiency of 21-hydroxylase. This tends to be identified at the onset of puberty because, unlike in classical (complete) CAH, patients with non-classical CAH will continue to produce minimal amounts of aldosterone and cortisol, thereby preventing a salt-losing crisis. The effects of the extra endogenous sex steroids only become apparent at the onset of puberty - especially in girls who typically appear virilised. Presenting features include a muscular physique, male pattern hair growth, oligomenorrhoea and temporary baldness.

45
Q

What is the main problem in later life if a person has partial 21-hydroxylase deficiency?

A

Hirsutism and virilsation in girls
Precocious puberty in boys due
Both of these problems are due to adrenal testosterone

46
Q

Which hormones are deficient in partial 21-hydroxylase deficiency?

A

Aldosterone and cortisol

47
Q

Which hormones are in excess in partial 21-hydroxylase deficiency?

A

Sex steroids

48
Q

At what age will a person with partial 21-hydroxylase deficiency present?

A

At any age (i.e. later than complete)

49
Q

What happens in 11-hydroxylase deficiency and explain its symptoms?

A

There is an accumulation of 11-deoxycorticosterone due to reduced hydroxylation into corticosterone. 11-deoxycorticsterone exhibits mineralocorticoid aldosterone-like activity therefore when present in excess it causes hypertension and hypokalaemia. Cortisol and aldosterone are deficient, but sex steroids and 11- deoxycorticosterone are in excess.

50
Q

List the consequences of 11-hydroxylase deficiency.

A

Virilisation
Hypertension
Hypokalaemia
Hypernatremia

51
Q

Which hormones are deficient in 17-hydroxylase deficiency?

A

Cortisol and sex steroids

52
Q

Which hormones are in excess in 17-hydroxylase deficiency?

A

11-deoxycorticosterone and aldosterone

53
Q

List the consequences of 17-hydroxylase deficiency.

A

Hypertension
Hypokalaemia
Sex steroid deficiency
Glucocorticoid deficiency → Hypoglycaemia

BRS2 Endocrinology (15 decks)

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