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CEP > Week 9 + 10 > Flashcards

Week 9 + 10 Flashcards

1
Q

What are the main steroid hormone types in the adrenal cortex

A

Glucocorticoids- cortisol
Mineralocorticoids- aldosterone
Adrenal androgens- adrenal androgen precursors
Synthesis, actions, regulation of each (effects of ACTH)

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2
Q

What is produced by the adrenal medulla

A

Catecholamines- adrenaline and noradrenaline

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3
Q

What is the histological zonation of adrenal

A

Outer capsule
Cortex:
Zona glomerulosa- mineralocorticoids (aldosterone) ‘salt’
Zona fasciculata (largest zone)- glucocorticoids (cortisol) ‘sugar’
Zona reticularis- androgens (DHEA) ‘sex’
Medulla:
Catecholamines

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4
Q

Steroidogenesis

A

Cholesterol is the common precursor for all steroid hormones
Metabolised in the adrenal gland
Each step is mediated by an enzyme
Enzymes expressed differentially in various zones of adrenal cortex

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5
Q

Adrenal insufficiency

A

Too little:
Glucocorticoid deficiency
Mineralocorticoid deficiency
Adrenal androgen deficiency

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6
Q

What causes Cushing’s syndrome

A

Glucocorticoid excess, excess of cortisol

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7
Q

What causes Conn’s syndrome

A

Mineralocorticoid excess- excess aldosterone

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8
Q

What causes phaeochromocytoma (tumour of adrenal medulla)

A

Catecholamine excess

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9
Q

What are corticosteroids

A

Lipid soluble- can pass through biological membranes without need of receptor
Bind to specific intracellular receptors
Exact action depends on structure, ability to bind specific receptors
Alter gene transcription directly or indirectly

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10
Q

How do glucocorticoids work

A

Cortisol diffuses across cell membrane into the cell
Cortisol binds to glucocorticoid receptor
Glucocorticoid receptor becomes active and binds to glucocorticoid response element on DNA sequence in nucleus
Coactivators bind to receptor
Gene transcription occurs

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11
Q

Actions of glucocorticoids

A

Important in homeostasis
Have actions on most tissues
Many actions ‘permissive’ (do not directly initiate but allow to occur in presence of other factors) e.g. the effects of catecholamines on vascular tone
‘Permissive’ actions only apparent with deficiency

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12
Q

Effects of glucocorticoids

A

Brain/CNS: depression, psychosis
Eye: glaucoma
Pituitary: decrease LH, FSH release, decrease TSH release
GI tract: peptic ulcerations
Carbohydrate/ lipid metabolism: promote glycogen breakdown and glucose release from liver and muscle,
Increase insulin resistance, type 2 diabetes,
Promotes breakdown of fat in adipose tissue, increasing amount of circulating lipids, promotes visceral central obesity
Cardiovascular/renal: salt and water retention, hypertension
Breakdown protein/ collagen, skin thinning, muscular atrophy
Decrease in bone formation, decrease in bone mass and osteoporosis
Decrease in linear growth
Immune system: anti-inflammatory action, immunosuppression

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13
Q

What are the Actions of glucocorticoids

A

Increase glucose mobilisation:
Augment gluconeogenesis, amino acid generation, increased lipolysis
Maintenance of circulation: vascular tone, salt and water balance
Immunomodulation: dampen immune response

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14
Q

Transport of glucocorticoids

A

Hydrophobic so not able to circulate freely
In the circulation glucocorticoids are heavily bound to proteins- when bound its inactive decreases affects of glucocorticoids
90% bound to corticosteroid-binding globulin (CBG)
5% bound to albumin
5% free cortisol- active part can cross plasma membrane, bioavailable so can exert a biological function
When CBG decreases free cortisol increases vice versa
In clinical practice total not free measured
CBG levels decrease with inflammation/stress so increase free cortisol

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15
Q

Regulation of glucocorticoid synthesis

A

The hypothalamic-pituitary-adrenal (HPA) axis regulates glucocorticoid synthesis
System is sensitive to stimuli such as circadian rhythm, stressors: physical, emotional, fever, hypoglycaemia, hypotension
CRH (corticotrophin-releasing hormone) released by hypothalamus
ACTH (adreno-corticotropic hormone or corticotropin) released by anterior pituitary
Negative feedback occurs

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16
Q

Effect of ACTH on adrenal size

A

ACTH deficiency- atrophy of adrenal gland, decrease in size, can be seen in patients who take glucocorticoids such as for drugs
ACTH excess- hypertrophy of adrenal cortex

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17
Q

Circadian rhythm for cortisol

A

Very low levels of circulating cortisol when sleeping
Peak when we wake up as need more energy
As day progresses cortisol levels decrease
Cortisol regulated by ACTH so follow same pattern

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18
Q

Stress

A

The sum of the bodies responses to adverse stimuli

Infection
Trauma
Haemorrhage
Medical illness
Psychological
Exercise/exhaustion

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19
Q

HPA axis function during acute illness

A

‘Stress’ cytokines
Lower levels of CBG, decrease in synthesis, more bio available cortisol increase impact
Cytokines, local steroid activation
Less negative feedback

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20
Q

Actions of mineralocorticoids

A

Main mineralocorticoids are aldosterone and DOC (deoxycorticosterone)
DOC has 3% Mineralocorticoid activity of aldosterone
Critical to salt (electrolyte) and water balance in kidney, colon, pancreas, salivary glands, sweat glands

21
Q

Site of aldosterone action

A

Nephron
1) renal corpuscle
2) proximal tube
3) loop of Henie (in some nephrons, the loop of Henie is long and plunges into the medulla)
4) Distal tubule. Promote re absorption of Na. Excretion of K. Reabsorption of water. Na is osmotic substance, more Na reabsorbed more water is reabsorbed promote healthy intravascular volume
5) collecting duct

22
Q

Regulation of Mineralocorticoid
The renin-angiotensin-aldosterone system RAAS

A

Circulating blood volume, low-> low renal perfusion pressure (less blood to kidney)-> juxtaglomerular cells in renal corpuscle -> decrease renin (enzyme) release->which activates protein angiotensinogen in liver to angiotensin I-> then converted by ACE (produced by lungs) to angiotensin II(active hormone)->activation of angiotensin II receptor type I ATI receptor in adrenal cortex->aldosterone release-> renal sodium retention and potassium excretion in kidney -> increase blood volume

Higher blood volume, lower production of aldosterone vice versa. Aldosterone promotes higher blood volume

23
Q

Effects of mineralocorticoids

A

Kidney
Pancreas
Sweat glands
Salivary glands
Colon
Sodium and water resorption
Non-classical effects- myocardial collagen production- promotes position of collagen in heart important in conditions with too much aldosterone, patients can develop fibrosis of heart

24
Q

Mineralocorticoid receptors MR specificity

A

Mineralocorticoids and glucocorticoids bind to same receptor, equal affinity
Pre-receptor regulation of kidney MR transactivation
11beta-hydroxysteroid dehydrogenase 2 converts cortisol to cortisone
Liquorice ingestion stops enzyme, cortisol much more abundant, hydro activated mineral cortisol pathway

25
Q

Action of adrenal androgens

A

“Weak” (not good at binding to receptors) androgens generated in adrenal gland
Dehydroepiandrosterone (DHEA) most abundant adrenal steroid (weak androgen)
Androstenedione more androgenic but only 1/10th that of testosterone
Major source of androgens in women
Oestrogen precursors in postmenopausal women

26
Q

Regulation of adrenal androgens

A

Production of adrenal androgens regulated by ACTH rather than gonadotrophins (LH/FSH)
Increase in ACTH an increase in adrenal androgens

27
Q

The adrenal medulla

A

Different embryological origin to cortex
Part of ANS
Specialised ganglia supplied by sympathetic pre-ganglionic neurones (ACh as transmitter)
Synthesised catecholamines (main site for adrenaline synthesis)
(Phenylethanolamine-N-methyl transferase present)

28
Q

Catecholamine synthesis

A

80% adrenaline 20% noradrenaline
Dopamine in small amounts
Normal Catecholamine synthesis dependent on high local cortisol levels (permissive effect)

29
Q

Action of catecholamine

A

Act through the different adrenergic receptors
2 types: alpha and beta receptors, 2 alpha and 3 beta
Released to prepare body for physical activity
Redistribution of circulating volume leads to decreased digestive, excretory, reproductive system activity
Promoting release of easy access energy like cortisol
CNS: increased alertness
Increased breathing rate, increased heart contractility, blood pressure rate
Adipose tissue: lipolysis
Liver: gluconeogenesis, glucose release
Muscles: gluconeogenesis

30
Q

Classification of steroids

A

Pregnane derivatives: 21 carbons. Progesterone, glucocorticoids
Androstane derivatives : 19 carbons, androgens
Estrane derivatives: 18 carbons, oestrogens
Small structural modifications can substantially alter specificity for steroid receptors

31
Q

Too little cortisol- adrenal insufficiency symptoms

A

Weakness, fatigue
Anorexia
Muscle/joint pains
Gastrointestinal symptoms: nausea, vomiting, abdominal pain
Salt craving
Postural dizziness
Loss of libido (women)

32
Q

Too little cortisol- adrenal insufficiency signs

A

Weight loss
Hyperpigmentation
Hypotension
Hyponatraemia- low level of Na in bloodstream
Hyperkalaemia- potassium in plasma in excess
Hypercalcaemia- high level calcium in blood
Hypoglycaemia- low blood sugar
Uraemia- raised level of urea in blood
Anaemia
Vitiligo

33
Q

What is creatinine

A

A breakdown product of creatine phosphate from muscle and protein metabolism, released at a constant rate from body
A creatinine test is a measure of how well kidneys are performing their function of filtering waste from blood

34
Q

Diagnosing adrenal insufficiency

A

The short synacthen test SST:
Uses synacthen to test how well adrenal glands make cortisol, stimulates them
ACTH1-39 (adrenocorticotropic hormone)= peptide with 39 amino acids
ACTH1-24= shorter peptide 24 amino acids, synacthen (europe), cosyntropin(North America)

35
Q

Differential diagnosis of adrenal insufficiency

A

Primary adrenal insufficiency (PAI):
Most frequent cause: autoimmune adrenalitis-> measure adrenal (21-hydroxylase) autoantibodies
If adrenal auto-antibodies negative and male patient: very long chain fatty acids (to exclude adrenoleukodystrophy /adrenomyeloneuropathy)
If both negative: CT adrenals+ exclude tuberculosis
Exclude congenital adrenal hyperplasia
Secondary adrenal insufficiency (SAI):
Most frequent cause: pituitary tumours and their treatment
RAAS intact- no aldosterone replacement needed
Other hypothalamic-pituitary axes might be affected

36
Q

Cortisol and prednisolone

A

Cortisol (hydrocortisone) —(11B-HSD 2)—> cortisone (cortisone acetate)
11B-HSD 1 reverses
Prednisolone —(11B-HSD)—> prednisone

37
Q

Treatment of adrenal insufficiency

A

Long term treatment:
Replace glucocorticoid- hydrocortisone 15mg AM, 10 mg PM
Replace Mineralocorticoid- fludrocortisone 100-200microg/ day
Only in primary
Adrenal androgens- DHEA
Acute adrenal insufficiency:
Rapid onset- medical emergency, treat shock- generous saline infusion, immediate injection of hydrocortisone 100mg, followed by continuous hydrocortisone infusion 200mg/24h

38
Q

What is Addison’s disease

A

Also known as primary adrenal insufficiency or hypoadrenalism
Where the adrenal glands dont produce enough hormones
Lack of energy, weakness, increased thirst, decreased mood

39
Q

Crisis prevention in adrenal insufficiency patients

A

Steroid card and/or medic alert bracket to identify exogenous steroid dependence
Sick day rule 1: moderate stress, in case of fever, infection requiring antibiotics, minor surgery under local anaesthesia- double daily glucocorticoid dose
Sick day rule 2: severe stress, for trauma, major surgery, persistent vomiting, colonoscopy, active labour 100mg hydrocortisone Iv., followed by continuous infusion of 200mg hydrocortisone 24h,
Hydrocortisone emergency self injection kit and training

40
Q

Cushing’s syndrome

A

Prolonged exposure to excess glucocorticoids
Too much cortisol
Purplish stretchmarks= striae, thin skin, easy bruising, proximal myopathy (symmetrical weakness of lower and/or upper limbs), difficulties to get up from chair or climbing stairs. Facial fullness, “buffalo hump”, osteoporosis with vertebral fractures in lumbar spine- loss of height, decreased linear growth in children=weight gain, decreased growth velocity

41
Q

Types of Cushing’s syndrome

A

Iatrogenic: synthetic corticosteroids, chronic glucocorticoid therapy
ACTH-dependent Cushing syndrome: pituitary depending Cushing syndrome=Cushing’s disease, ectopic Cushing due to ectopic ACTH secretion= small lung carcinoma, carcinoids
ACTH-independent = Adrenal Cushing syndrome- adrenocortical adenoma/ carcinoma

42
Q

Diagnosis of Cushing’s syndrome- Dexamethasone

A

Dexamethasone overnight suppression test
1mg Dexamethasone tablet at 11pm
Blood for serum cortisol at 8-9am
Mimics cortisol effects by binding to glucocorticoid receptor but with longer half life, stronger agonist
ACTH downregulated, endogenous cortisol suppressed
In Cushing’s patients cortisol secretion is autonomous and not responsive to feedback regulation-> cortisol remains high

43
Q

Diagnosis of Cushing’s syndrome- 3 highly sensitive tests

A

24 hour urinary free cortisol >130 microg/24 h
Dexamethasone suppression test
Midnight cortisol- serum or saliva

44
Q

Differential diagnosis of Cushing’s

A

9 am plasma ACTH:
ACTH suppressed -> adrenal
ACTH normal-> pituitary or ectopic
Pituitary or ectopic:
High dose dex test
CRH test
Inferior petrosal sinus sampling IPSS
Then imaging CT adrenals/mri pituitary

45
Q

Treatment Cushing’s syndrome

A

Surgery:
Pituitary- transsphenoidal surgery
Bilateral adrenalectomy
Laparascopic adreanlectomy for adrenal adenoma
Open adrenalectomy for adrenocortical carcinoma
Drugs:
Block cortisol- producing adrenal enzymes (metyrapone, ketoconazol, etomidate)
Block the glucocorticoid receptor (RU486)
Disrupt adrenal redox balance and thereby steroidogenesis and cell proliferation (mitotane)

46
Q

Which blood tests would a patient with excessive activity of the parathyroid gland most likely to have

A

High calcium
Low phosphate

47
Q

Symptoms most likely to develop in a patient with phaeochromocytoma

A

Frequent headaches
Excess sweating
Palpitations

48
Q

What cells are the source of the excess hormone in Cushing’s disease

A

Corticotropic cells

CEP (10 decks)

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