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
2
Q
What is used for make Aldosterone?
A
- Produced from 11 deoxycorticosterone and 11 deoxycortisol
- Produced in the Zona Glomerulosa
3
Q
Which enzymes are involved in producing Aldosterone?
A
- 18 hydroxylase
- 18 dehydrogenase only expressed in this region
4
Q
What is the action of Mineralcorticoid?
A
- Maintain BP (water homeostasis)
- Promote renal sodium reabsorption
- Promote potassium excretion
Acts via mineralocorticoid receptor
5
Q
What stimulates Renin Production?
A
- Fall in BP
- Sympathetic tone/posture
- Sodium concentration in renal tubules
6
Q
How is Aldosterone Secretion controlled?
A
- Mainly via renin-angiotensin
- Potassium and ACTH have smaller effect on adrenal
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
8
Q
How are Glucocorticoids produced?
A
- Cortisol produce in the Zona Fasiculata mainly and Reticularis from Corticosterone
*
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)
10
Q
How does Cortisol act?
A
- Cortisol acts via glucocorticoid receptor
11
Q
How is Cortisol circulated around the body?
A
- Circulates bound to corticosteroid binding globulin (CBG) which is Increased by oestrogen
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%)
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
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
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
16
Q
What regulates Androgen production from the Adrenal Glands?
A
Control unclear
- ACTH and ?other
17
Q
What are Types of Adrenal Insuffieciency?
A
- Primary - destruction of adrenal glands e.g Addison’s disease
- Secondary/Tertiary - pituitary/hypothalamic disease
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
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
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
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
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
23
Q
What are Lab tests for Adrenal Crisis?
A
- Hyponatraemia
- Hyperkalaemia
- Hypoglycaemia
- Hypercalcaemia
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
25
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
26
What precipitate Adrenal Crisis and how is it treated?
* Often precipitated by major stress e.g. severe bacterial infection
Treatment
* Rehydration
* Replacement - hydrocortisone/prednisolone
27
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
28
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
29
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
30
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
31
What metabolic and biochemical features of hypoaldosteronism?
* Hyponatraemia
* Hyperkalaemia
* Acidosis
* Mildly elevated urea: Volume depletion
* Hypotension (postural)
32
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
33
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
34
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
35
What conditons can also lead to Non-Cushing's Hypercortisolism?
Cortisol production can be increased in:
* Obesity
* Alcohol
* Depression
* PCOS
* Serious illness/cancer
36
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**
37
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%
38
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%
39
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**
40
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%
41
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)
42
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
43
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
44
What are features of Nelson's Syndrome?
* Hyperpigmentation
* Enlarging pituitary tumour
* Markedly elevated ACTH
45
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
46
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
47
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
48
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
49
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
50
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
51
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
52
How is Primary Hyperaldosteronism classified into substypes?
**Imaging**
* CT-scan
**Adrenal vein sampling**
* Unilateral vs bilateral)
* 95% sensitivity, 100% specificity for detecting unilateral disease
53
How is Primary Hyperaldosteronism treated?
* **Unilateral adrenalectomy** when appropriate
* **Mineralocorticoid receptor antagonist** (Spironolactone, Amiloride, Eplerenone)
54
What can cause Secondary Hyperaldosteronism?
* Nephrosis
* Cirrhosis
* Cardiac failure
Associated with oedema and reduced oncotic pressure
55
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
56
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
57
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
58
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
59
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
60
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
61
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
62
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
63
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
64
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
65
What features of 17-Hydroxylase?
* Males are feminised
* Females have delayed puberty
* Aldosterone production is preserved: No salt loss
* Hypertension
66
What features of 3b-hydroxysteroid dehydrogenase?
* Ambiguous genitalia in both sexes
* If severe, salt losing crisis
67
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
68
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
69
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
