Adrenal Cortex: Overview Flashcards
What is the location of the Adrenal Gland?
Adrenal Gland found on the kidneys
- Each gland weighs 4-5G
- Cortex comprises of 90% of Gland
What is used for make Aldosterone?
- Produced from 11 deoxycorticosterone and 11 deoxycortisol
- Produced in the Zona Glomerulosa
Which enzymes are involved in producing Aldosterone?
- 18 hydroxylase
- 18 dehydrogenase only expressed in this region
What is the action of Mineralcorticoid?
- Maintain BP (water homeostasis)
- Promote renal sodium reabsorption
- Promote potassium excretion
Acts via mineralocorticoid receptor
What stimulates Renin Production?
- Fall in BP
- Sympathetic tone/posture
- Sodium concentration in renal tubules
How is Aldosterone Secretion controlled?
- Mainly via renin-angiotensin
- Potassium and ACTH have smaller effect on adrenal
What is used to make Androgens?
- 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
How are Glucocorticoids produced?
- Cortisol produce in the Zona Fasiculata mainly and Reticularis from Corticosterone
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How is Cortisol production regulated?
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)
How does Cortisol act?
- Cortisol acts via glucocorticoid receptor
How is Cortisol circulated around the body?
- Circulates bound to corticosteroid binding globulin (CBG) which is Increased by oestrogen
What is the action of Glucocorticoids?
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%)
How is Water Balance controlled by the adrenal hormones?3
Cortisol and aldosterone structurally very similar
- Both activate mineralocorticoid receptor to regulate water balance
How is the mineralcorticoid receptor protected from Cortisol?
- Receptor protected from cortisol via 11 Beta-hydroxysteroid dehydrogenase (type 2)
- Converts cortisol to cortisone
What Clinical features Cushing’s Syndrome?
- 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
What regulates Androgen production from the Adrenal Glands?
Control unclear
- ACTH and ?other
What are Types of Adrenal Insuffieciency?
- Primary - destruction of adrenal glands e.g Addison’s disease
- Secondary/Tertiary - pituitary/hypothalamic disease
What causes Primary Adrenal Insufficiency?
- 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
What causes Secondary Adrenal insufficiency?
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
What are signs and symptoms of Adrenal insufficiency?
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
What are signs and symptoms of Adrenal Crisis?
Symptoms
- Severe weakness
- Syncope
- Abdominal pain
- Nausea
- Vomiting
- Back pain
- Confusion
Signs
- Hypotension and Shock
- Abdominal tenderness/guarding
- Reduced Consciousness
- Unexplained Fever
- Delirium
What are Biochemical findings for Adrenal Insuffieciency?
- Hyponatraemia
- Hyperkalaemia
- Acidosis
- Mild elevation in Urea
- Low/normal 9 am cortisol
- Uncommon: Hypoglycaemia and Hypercalcaemia
What are Lab tests for Adrenal Crisis?
- Hyponatraemia
- Hyperkalaemia
- Hypoglycaemia
- Hypercalcaemia
How does hyperpigmentation occur in the Adrenal Insufficiency?
- 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
What is the criteria to exclude insuffeincy in a 9am cortisol test?
- Random cortisol >418-574 nmol/L to exclude
- Suspicion if cortisol <600 nmol/L in acutely ill patient
What precipitate Adrenal Crisis and how is it treated?
- Often precipitated by major stress e.g. severe bacterial infection
Treatment
- Rehydration
- Replacement - hydrocortisone/prednisolone
How is Short Synacthen test carried out?
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
What are results for Short Synacthen tests?
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
How is Primary Adrenal Failure diagnosed and treated?
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
What causes Hypoaldosteronism?
- 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
What metabolic and biochemical features of hypoaldosteronism?
- Hyponatraemia
- Hyperkalaemia
- Acidosis
- Mildly elevated urea: Volume depletion
- Hypotension (postural)
What are the investigations for Hyporeninaemic hypoaldosteronism and for Adrenal Causes?
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
What is Cushing’s Syndrome?
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
What are Etiologies of Ectopic ACTH?
- 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
What conditons can also lead to Non-Cushing’s Hypercortisolism?
Cortisol production can be increased in:
- Obesity
- Alcohol
- Depression
- PCOS
- Serious illness/cancer
What are test by which Cushing’s Syndrome is diagnosed?
- Overnight 1 mg Dexamethasone Suppresion Test (DST)
- 48 hr 2 mg Dexamethasone Suppresion Test (DST)
- Measuring dexamethasone
- Midnight serum cortisol
How is the Overnight 1 mg Dexamethasone Suppresion Test (DST) done?
- 1 mg dexamethasone taken in 2300-0000
- Cortisol measured 0800-0900
- Using cut-off of <50 nmol/L sens 95%, spec 80%
How is the 48 hr 2 mg Dexamethasone Suppresion Test (DST) carried out?
- 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%
What is Cyclical Cushings and how is it investigated?
- Episodic cortisol secretion. Peaks with intervals of days/months
- Difficult to demonstrate on DST
- UFC or salivary cortisol recommended as a screen
What is Petrosal Sinus Sampling?
- 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%
How is Cushing’s Syndrome managed?
- Trans-spheniodal surgery
- Pituitary radiotherapy
- Adrenalectomy: Can be for both pituitary or adrenal. It can be bilateral/unilateral
- Medical treatment (awaiting further treatment)
What is the medical treatment of Cushing’s syndrome?
- Metyrapone: Blocks 11b hydroxylase
- Ketoconazole: 1st line in children. Blocks several P450 enzymes
- Mitotane: Destroy adrenal cortical cells
N.B. Hydrocortisone (fludrocortisone) replacement
What is Nelson’s Syndrome?
- 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
What are features of Nelson’s Syndrome?
- Hyperpigmentation
- Enlarging pituitary tumour
- Markedly elevated ACTH
What is Primary Hyperaldosteronism and its causes?
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
What are feature of Primary Hyperaldosteronism?
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
Whho should be screened for Primary Hyperaldosteronism?
- 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
How is Screening done for Primary Hyperaldosteronism?
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
What are factors that may affect Aldosterone-Renin Ratio?
- 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
What are the cut offs for Aldosterone Renin Ratio?
- <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
What are second line tests for Primary Hyperaldosteronism?
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
How is Primary Hyperaldosteronism classified into substypes?
Imaging
- CT-scan
Adrenal vein sampling
- Unilateral vs bilateral)
- 95% sensitivity, 100% specificity for detecting unilateral disease
How is Primary Hyperaldosteronism treated?
- Unilateral adrenalectomy when appropriate
- Mineralocorticoid receptor antagonist (Spironolactone, Amiloride, Eplerenone)
What can cause Secondary Hyperaldosteronism?
- Nephrosis
- Cirrhosis
- Cardiac failure
Associated with oedema and reduced oncotic pressure
What are the types of Familial Hyperaldosteronism?
- Type 1: Glucocorticoid remediable aldosteronism (GRA)
- Type 2: 7p22, function unknown
- Type 3: Caused by germline mutations in the potassium channel subunit KCNJ5
What is Glucocortioid Remedial Aldosterone?
- 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
What is a Chimeric Gene in Glucocorticoid Remedial Aldosteronism?
- 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
What is Syndrome of Apparent Mineralocorticoid excess?
- 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
What is the effect of Congenital deficiency of 11b-HSD 2 enzyme?
- Leads to cortisol action on mineralocorticoid receptor
- Hypertension, suppressed renin/aldosterone, hypokalaemic alkalosis, increased cortisol/cortisone ratio
What are congenital adrenal hyperplasia?
- 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
What is 21-Hydroxylase deficiency?
- 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
What is are metabolic and biochemical feature of 21-Hydroxylase deficiency?
- 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
What is are metabolic and biochemical feature of 11-Hydroxylase deficiency?
- If severe: Low potassium, High BP, Virilisation of females
- Milder form: Virilisation
- 17 hydroxyprogesterone moderately raised
- 11 deoxycortisol high
What is 11-Hydroxylase deficiency?
- 2nd most common: 1 in 10,000
- Block in aldosterone and cortisol production
- Increase in 11 deoxycortisol and 11 deoxycorticosterone: Mineralocorticoid action
What features of 17-Hydroxylase?
- Males are feminised
- Females have delayed puberty
- Aldosterone production is preserved: No salt loss
- Hypertension
What features of 3b-hydroxysteroid dehydrogenase?
- Ambiguous genitalia in both sexes
- If severe, salt losing crisis
What are Cholesterol Side Chain Cleavage?
- Complete adrenal steroid deficiency near normal genitalia in females
- Male genitalia essentially appears as normal female
- Also called lipoid CAH so Lipid filled adrenals
What is the treatment for CAH?
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
What are investigations for CAH?
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
