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MSc Endocrinology > Adrenal Cortex: Overview > Flashcards

Adrenal Cortex: Overview Flashcards

1
Q

What is the location of the Adrenal Gland?

A

Adrenal Gland found on the kidneys

  • Each gland weighs 4-5G
  • Cortex comprises of 90% of Gland
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2
Q

What is used for make Aldosterone?

A
  • Produced from 11 deoxycorticosterone and 11 deoxycortisol
  • Produced in the Zona Glomerulosa
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3
Q

Which enzymes are involved in producing Aldosterone?

A
  • 18 hydroxylase
  • 18 dehydrogenase only expressed in this region
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4
Q

What is the action of Mineralcorticoid?

A
  • Maintain BP (water homeostasis)
  • Promote renal sodium reabsorption
  • Promote potassium excretion

Acts via mineralocorticoid receptor

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5
Q

What stimulates Renin Production?

A
  • Fall in BP
  • Sympathetic tone/posture
  • Sodium concentration in renal tubules
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6
Q

How is Aldosterone Secretion controlled?

A
  • Mainly via renin-angiotensin
  • Potassium and ACTH have smaller effect on adrenal
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7
Q

What is used to make Androgens?

A
  • Produced in the zona reticularis
  • Extensive interconversion to androstenedione, DHEA, DHEA-S (testosterone)
  • Precursors to Testosterone and Oestrogens. Androgen production also occurs in testes and ovaries
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8
Q

How are Glucocorticoids produced?

A
  • Cortisol produce in the Zona Fasiculata mainly and Reticularis from Corticosterone
    *
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9
Q

How is Cortisol production regulated?

A

Control via ACTH from anterior pituitary. CRH (corticotrophin releasing hormone) from hypothalamus causes release of ACTH.

Episodic ACTH secretion

  • Diurnal variation (highest at 9am)
  • Negative feedback from circulating glucocorticoids (endogenous or synthetic) on hypothalamus and pituitary
  • ACTH also released in response to stress (e.g. trauma, surgery, anxiety)
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10
Q

How does Cortisol act?

A
  • Cortisol acts via glucocorticoid receptor
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11
Q

How is Cortisol circulated around the body?

A
  • Circulates bound to corticosteroid binding globulin (CBG) which is Increased by oestrogen
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12
Q

What is the action of Glucocorticoids?

A

Glucose

  • Decreases tissue glucose uptake
  • Increases hepatic gluconeogenesis

Lipids

  • Increases lipolysis

Bone

  • Inhibits bone formation
  • Increases bone resoption
  • Induces negative calcium balance

Skin

  • Inhibits fibroblast activity causing bruising + poor wound healing

Growth

  • Inhibits growth in children

Immunological

  • Increases neutophils
  • Decreases eosinophils and lymphocytes (susceptible to infections)

Mental

  • Mood, appetite, insomnia

Water balance

  • Mild mineralocorticoid effects (40%)
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13
Q

How is Water Balance controlled by the adrenal hormones?3

A

Cortisol and aldosterone structurally very similar

  • Both activate mineralocorticoid receptor to regulate water balance
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14
Q

How is the mineralcorticoid receptor protected from Cortisol?

A
  • Receptor protected from cortisol via 11 Beta-hydroxysteroid dehydrogenase (type 2)
  • Converts cortisol to cortisone
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15
Q

What Clinical features Cushing’s Syndrome?

A
  • Weight gain (endocrine cause of obesity), central obesity,
  • Proximal wasting, muscle weakness/malaise
  • Buffalo hump
  • Moon face, purple plethora, acne
  • Osteoporosis
  • Hirsuitism
  • Purple striae, skin thinning, bruising
  • Depression, decrease in libido, psychosis
  • Emotional Disturbance
  • Oligo-, amenorrhoea
  • Hypertension
  • IGT/DM
  • Susceptibility to infections
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16
Q

What regulates Androgen production from the Adrenal Glands?

A

Control unclear

  • ACTH and ?other
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17
Q

What are Types of Adrenal Insuffieciency?

A
  • Primary - destruction of adrenal glands e.g Addison’s disease
  • Secondary/Tertiary - pituitary/hypothalamic disease
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18
Q

What causes Primary Adrenal Insufficiency?

A
  • Autoimmune disease (70%)
  • Infection e.g. CMV, AIDS, TB
  • Congenital e.g. enzyme deficiencies, cysts
  • Drugs e.g. ketoconazole
  • Haemorrhage inc heparin treatment
  • Metastatic tumour (lung common)
  • Amyloid
  • Haemochromatosis
  • Sarcoidosis
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19
Q

What causes Secondary Adrenal insufficiency?

A

Decreased ACTH production

  • Isolated deficiency of ACTH very rare
  • In panhypopituitarism, ACTH usually last to be affected
  • In ACTH deficiency, aldosterone normal unlike in primary adrenal failure
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20
Q

What are signs and symptoms of Adrenal insufficiency?

A

Symptoms

  • Fatigue
  • Weight Loss
  • Postural Diziness
  • Anorexia
  • Abdominal Discomfort

Signs

  • Hyperpigmentation on sun exposed area, skin creases, mucosal membranes, scars, areolas of breast
  • Low blood pressure with increased postual drop
  • Failure to thrive in Children
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21
Q

What are signs and symptoms of Adrenal Crisis?

A

Symptoms

  • Severe weakness
  • Syncope
  • Abdominal pain
  • Nausea
  • Vomiting
  • Back pain
  • Confusion

Signs

  • Hypotension and Shock
  • Abdominal tenderness/guarding
  • Reduced Consciousness
  • Unexplained Fever
  • Delirium
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22
Q

What are Biochemical findings for Adrenal Insuffieciency?

A
  • Hyponatraemia
  • Hyperkalaemia
  • Acidosis
  • Mild elevation in Urea
  • Low/normal 9 am cortisol
  • Uncommon: Hypoglycaemia and Hypercalcaemia
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23
Q

What are Lab tests for Adrenal Crisis?

A
  • Hyponatraemia
  • Hyperkalaemia
  • Hypoglycaemia
  • Hypercalcaemia
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24
Q

How does hyperpigmentation occur in the Adrenal Insufficiency?

A
  • Precursor for ACTH is POMC (241aa peptide) - Pro-opiomelanocortin
  • POMC is cleaved which forms MSH (melanocyte stimulating hormone)
  • MSH goes on to stimulate melanin production
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25
Q

What is the criteria to exclude insuffeincy in a 9am cortisol test?

A
  • Random cortisol >418-574 nmol/L to exclude
  • Suspicion if cortisol <600 nmol/L in acutely ill patient
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26
Q

What precipitate Adrenal Crisis and how is it treated?

A
  • Often precipitated by major stress e.g. severe bacterial infection

Treatment

  • Rehydration
  • Replacement - hydrocortisone/prednisolone
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27
Q

How is Short Synacthen test carried out?

A

Short synacthen test

  • Samples for 9 am cortisol and ACTH
  • IV tetracosactrin (synthetic ACTH) 250 µg (lower for children)
  • Sample for cortisol at 30 min
  • Sample for cortisol at 60 min
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28
Q

What are results for Short Synacthen tests?

A

Normal is stimulated cortisol >500 nmol/L (418 – 574 nmol/L).

Usually get flat response for primary and impaired response for secondary. If impaired response

  • ACTH high (>300 ng/L), primary adrenal failure
  • ACTH low (<10 ng/L), secondary adrenal failure so pituitary testing
29
Q

How is Primary Adrenal Failure diagnosed and treated?

A

Investigations

  • Assess renin/aldosterone

Treatment

  • Replace Glucocorticoids (Hydrocortisone) and mineralocorticoids (Fludrocortisone)
  • Monitor cortisol day curve & renin

Androgens often sufficient due to gonadal production

  • Consider DHEA once other treatments optimised if low libido, depression or low energy
30
Q

What causes Hypoaldosteronism?

A
  • Impaired Renin Production: Hyporeninaemic hypoaldosteronism, Diabetic nephropathy
  • Inherited enzyme defects in aldosterone biosynthesis
  • Acquired forms: Heparin therapy (toxic to zona glomerulosa), post-surgery
  • Pseudohypoaldosteronism: Inherited resistance to action of aldosterone
  • Treatment: Fludrocortisone
31
Q

What metabolic and biochemical features of hypoaldosteronism?

A
  • Hyponatraemia
  • Hyperkalaemia
  • Acidosis
  • Mildly elevated urea: Volume depletion
  • Hypotension (postural)
32
Q

What are the investigations for Hyporeninaemic hypoaldosteronism and for Adrenal Causes?

A

Hyporeninaemic Hypoaldosteronism

  • Both renin and aldosterone low
  • Renin/aldo don’t increase in upright posture
  • Renin/aldo don’t increase in response to furosemide stimulation

Adrenal Causes

  • Renin High
  • Aldosterone Low
33
Q

What is Cushing’s Syndrome?

A

Elevated glucocorticoids i.e. cortisol

  • 80% ACTH dependant: 80% of these from pituitary adenoma (Cushing’s disease, 20% of these ectopic ACTH
  • 20% adrenal origin: 65% of these from adrenal adenoma, 30% of these from adrenal carcinoma, 5% of these from nodular hyperplasia
34
Q

What are Etiologies of Ectopic ACTH?

A
  • Pancreatic carcinoid tumour
  • Bronchial carcinoid tumour
  • Small-cell lung tumour
  • Thymic carcinoid tumour
  • Medullary thyroid carcinoma
  • Pancreatic carcinoma
  • Disseminated carcinoid tumour
  • Colonic carcinoma
  • Phaeochromocytoma
  • Gallbladder carcinoma

Source never found

35
Q

What conditons can also lead to Non-Cushing’s Hypercortisolism?

A

Cortisol production can be increased in:

  • Obesity
  • Alcohol
  • Depression
  • PCOS
  • Serious illness/cancer
36
Q

What are test by which Cushing’s Syndrome is diagnosed?

A
  • Overnight 1 mg Dexamethasone Suppresion Test (DST)
  • 48 hr 2 mg Dexamethasone Suppresion Test (DST)
  • Measuring dexamethasone
  • Midnight serum cortisol
37
Q

How is the Overnight 1 mg Dexamethasone Suppresion Test (DST) done?

A
  • 1 mg dexamethasone taken in 2300-0000
  • Cortisol measured 0800-0900
  • Using cut-off of <50 nmol/L sens 95%, spec 80%
38
Q

How is the 48 hr 2 mg Dexamethasone Suppresion Test (DST) carried out?

A
  • Used especially in psychiatric disorders, obesity, alcohol
  • 0.5 mg dex at 0900, 1500, 2100, 0300
  • Measure cortisol at 0900 on 2nd day
  • Using cut-off of <50 nmol/L sens >95%, spec 70%
39
Q

What is Cyclical Cushings and how is it investigated?

A
  • Episodic cortisol secretion. Peaks with intervals of days/months
  • Difficult to demonstrate on DST
  • UFC or salivary cortisol recommended as a screen
40
Q

What is Petrosal Sinus Sampling?

A
  • Bilateral inferior petrosal sinus sampling with ACTH measurement basal and following IV CRH.
  • Central to peripheral ratio >2 suggestive of Cushing’s disease.
    • Ratio >3 sens 90-95%
41
Q

How is Cushing’s Syndrome managed?

A
  • Trans-spheniodal surgery
  • Pituitary radiotherapy
  • Adrenalectomy: Can be for both pituitary or adrenal. It can be bilateral/unilateral
  • Medical treatment (awaiting further treatment)
42
Q

What is the medical treatment of Cushing’s syndrome?

A
  • Metyrapone: Blocks 11b hydroxylase
  • Ketoconazole: 1st line in children. Blocks several P450 enzymes
  • Mitotane: Destroy adrenal cortical cells

N.B. Hydrocortisone (fludrocortisone) replacement

43
Q

What is Nelson’s Syndrome?

A
  • Condition that occurs in patients who have bilateral adrenalectomy as treatment for Cushing’s disease
  • Usually within 2 years of adrenalectomy
  • Incidence 50% within 10 years. Prophylactic radiotherapy
  • Close monitoring of ACTH/MRI pituitary
44
Q

What are features of Nelson’s Syndrome?

A
  • Hyperpigmentation
  • Enlarging pituitary tumour
  • Markedly elevated ACTH
45
Q

What is Primary Hyperaldosteronism and its causes?

A

Excessive aldosterone production originating within adrenal gland which is non-suppressible with sodium loading

Due to

  • Idiopathic adrenal hyperplasia (IAH) - Unilateral/bilateral
  • Aldosterone-producing adrenal adenoma (APA) aka Conn’s syndrome
  • Adrenocortical carcinoma
46
Q

What are feature of Primary Hyperaldosteronism?

A

Causes

  • Hypertension (Up to 10% of hypertensives will have PA)
  • Cardiac damage
  • Suppressed renin
  • Sodium retention
  • Hypokalaemic alkalosis (9-39%)

Also if potassium not lost into urine – not PA

47
Q

Whho should be screened for Primary Hyperaldosteronism?

A
  • BP >160/>100 mmHg
  • Drug resistant hypertension
  • Hypertension and hypokalaemia
  • Hypertension with adrenal incidentaloma
  • Hypertension with FH of early onset hypertension or CVA <40 yrs
  • Hypertension with 1st degree relative with PA
48
Q

How is Screening done for Primary Hyperaldosteronism?

A

Aldosterone-renin ratio

  • Unrestricted dietary salt intake day before test
  • Out of bed for at least 2h and seated for 5-15 min
  • Direct Renin Concentration vs Plasma Renin Activity
  • Most patients will be on anti-hypertensives so will need to discontinue/switch
49
Q

What are factors that may affect Aldosterone-Renin Ratio?

A
  • Discontinue at least 4 wks: Spironolactone, eplerenone, amiloride, triamterene (Potassium wasting diuretics, Liquorice, chewing tobacco). Perform test if equivocal
  • Try alternative therapy and discontinue for 2 wks: Beta blockers, alpha 2 agonists, NSAIDs
  • ?HRT/OCP if DRC
  • Samples not on ice
  • Hypokalaemia (can decrease aldosterone, increase renin)
  • Renal impairment
50
Q

What are the cut offs for Aldosterone Renin Ratio?

A
  • <800: normal
  • 800 – 2000: Possible Primary Aldosteronism so further investigation indicated
  • >2000: Primary Aldosteronism likely if renin suppressed

PRA – nmol/L/hr, aldo pmol/L

51
Q

What are second line tests for Primary Hyperaldosteronism?

A

Saline infusion

  • 2 L 0.9% saline over 4 hrs
  • Aldo cut-off of 194 pmol/L
  • Sens 88%, spec 100%

Oral sodium loading

  • 200 mmol/d (~6 g/d) for 3 d
  • Measurement of urinary aldosterone

Fludrocortisone suppression test

  • 0.1 mg every 6 h for 4 d
  • Upright aldo >167 pmol/L

Captopril challenge test

  • Aldosterone normally suppressed by captopril.
  • Remains elevated if Primary Hyperaldosteronism
52
Q

How is Primary Hyperaldosteronism classified into substypes?

A

Imaging

  • CT-scan

Adrenal vein sampling

  • Unilateral vs bilateral)
  • 95% sensitivity, 100% specificity for detecting unilateral disease
53
Q

How is Primary Hyperaldosteronism treated?

A
  • Unilateral adrenalectomy when appropriate
  • Mineralocorticoid receptor antagonist (Spironolactone, Amiloride, Eplerenone)
54
Q

What can cause Secondary Hyperaldosteronism?

A
  • Nephrosis
  • Cirrhosis
  • Cardiac failure

Associated with oedema and reduced oncotic pressure

55
Q

What are the types of Familial Hyperaldosteronism?

A
  • Type 1: Glucocorticoid remediable aldosteronism (GRA)
  • Type 2: 7p22, function unknown
  • Type 3: Caused by germline mutations in the potassium channel subunit KCNJ5
56
Q

What is Glucocortioid Remedial Aldosterone?

A
  • Autosomal dominant. Chimeric gene
  • Aldosterone expression under ACTH control
  • ACTH suppressed by exogenous glucocorticoids
  • Assess if FH of PA, strokes at young age or onset <20 yrs (genetic testing)
  • Treat with dexamethasone/prednisone. Eplerenone in children
57
Q

What is a Chimeric Gene in Glucocorticoid Remedial Aldosteronism?

A
  • 5’ sequence determining the regulation of 11b hydroxylase and 3’ sequence of aldosterone synthase genes
  • Expression of aldosterone synthase gene in zonae fasiculata and glomerulosa
58
Q

What is Syndrome of Apparent Mineralocorticoid excess?

A
  • Congenital deficiency of 11b-HSD 2 enzyme
  • Acquired form due to excess ingestion of glycyrrhetinic acid (liquorice, cough medicine, chewing tobacco)
  • Acetazolamide – carbonic anhydrase inhibitor
59
Q

What is the effect of Congenital deficiency of 11b-HSD 2 enzyme?

A
  • Leads to cortisol action on mineralocorticoid receptor
  • Hypertension, suppressed renin/aldosterone, hypokalaemic alkalosis, increased cortisol/cortisone ratio
60
Q

What are congenital adrenal hyperplasia?

A
  • Group of autosomal recessive disorders
  • An enzyme deficiency leads to decreased cortisol (& sometimes aldosterone) production. This means a lack of negative feedback so increase in ACTH. So there is overproduction of steroids with intact pathways or proximal to enzyme defect
  • Varying severities & effects depends on which enzyme is deficient
  • Leads to bulky adrenals
61
Q

What is 21-Hydroxylase deficiency?

A
  • Most common: 1 in 5000 births
  • Cortisol and aldosterone affected
  • 17 hydroxyprogesterone very high
  • Excess androgen production lead ambiguous genitalia in female neonates: Clitoromegaly, Fusion of labia
62
Q

What is are metabolic and biochemical feature of 21-Hydroxylase deficiency?

A
  • Severe form leads to early salt loss i.e. low sodium, high potassium & hypotension
  • Hypoglycaemia
  • Dehydration
  • Vomiting
  • Pigmentation
  • Potential for salt-losing (Addisonian type) crisis. Collapse when stressed/ill
  • Mild form causes rapid growth (but overall short stature) and precocious puberty
  • Non-classical form has onset in adulthood: Hirsuitism, virilism, amenorrhoea in females, Similar in presentation to PCOS, SST with 17 OHP
63
Q

What is are metabolic and biochemical feature of 11-Hydroxylase deficiency?

A
  • If severe: Low potassium, High BP, Virilisation of females
  • Milder form: Virilisation
  • 17 hydroxyprogesterone moderately raised
  • 11 deoxycortisol high
64
Q

What is 11-Hydroxylase deficiency?

A
  • 2nd most common: 1 in 10,000
  • Block in aldosterone and cortisol production
  • Increase in 11 deoxycortisol and 11 deoxycorticosterone: Mineralocorticoid action
65
Q

What features of 17-Hydroxylase?

A
  • Males are feminised
  • Females have delayed puberty
  • Aldosterone production is preserved: No salt loss
  • Hypertension
66
Q

What features of 3b-hydroxysteroid dehydrogenase?

A
  • Ambiguous genitalia in both sexes
  • If severe, salt losing crisis
67
Q

What are Cholesterol Side Chain Cleavage?

A
  • Complete adrenal steroid deficiency near normal genitalia in females
  • Male genitalia essentially appears as normal female
  • Also called lipoid CAH so Lipid filled adrenals
68
Q

What is the treatment for CAH?

A

Replace whatever not produced

  • Hydrocortisone (increase dose at times of stress/illness)
  • Fludrocortisone
  • Testosterone/oestrogens

21 hydroxylase, if previously affected child

  • Prenatal diagnosis, free foetal DNA, amniocentesis
  • Steroid cover during pregnancy
  • Prevents virilisation
69
Q

What are investigations for CAH?

A

1st line

  • U&E
  • 9 am cortisol
  • BP & physical exam

2nd line

  • SST with 17 OHP
  • Renin & Aldosterone
  • 11-DOC
  • Karyotyping
  • Androgen profile
  • Urine steroid profiling

MSc Endocrinology (16 decks)

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