Adrenal Gland Physiology and Disorders Flashcards
Histology of the adrenal gland?
From superficial to deep:
• Capsule
• Cortex (consists of zona glomerulosa, fasciculata and reticularis)
• Medulla (consists of chromaffin cells, medullary veins and splanchnic nerves)
Function of each region of the adrenal gland?
Cortex:
• Zona glomerulosa - produces mineralocorticoids (aldosterone) and is regulated by angiotensin 2 and K+
• Zona fasciculata - produces glucocorticoids (cortisol and corticosterone) and is regulated by ACTH
• Zona reticularis - produces adrenal androgens (DHEA and DHEA-sulfate)
Medulla - produces catecholamines (epinephrine and norepinephrine)
Biosynthetic pathway of corticosteroid production in the adrenal cortex?
All have a CHOLESTEROL precursor; rate-limiting step is the conversion of cholesterol to pregnenolone
21-hydroxylase converts progesterone to deoxycorticosterone
Regulation of adrenal corticosteroid production?
Cortisol and androgens regulated by hormones produced by hypothalamus and anterior pituitary gland
Aldosterone regulated by RAAS and plasma K+
Mechanism of action of the RAAS system?
Major regulator of aldosterone production and it is activated in response to decreased BP, leading to:
• Ang II production (vasoconstriction)
• Aldosterone release
Mechanism of action of corticosteroids?
Binds to intracellular receptors and the receptor/ligand complex binds DNA to affect transcription
6 classes of steroid receptors?
- Glucocorticoid
- Mineralocorticoid
- Progestin
- Oestrogen
- Androgen
- Vitamin D
Major actions of glucocorticoid (cortisol)?
Bone/CT tissue - accelerates osteoporosis by decreasing Ca2+, collagen formation and wound healing
CNS:
• Mood lability
• Euphoria/psychosis
• Decreased libido
Immunological - decreased: • Capillary dilatation/permeability • Leukocyte migration • Macrophage activity • Inflammatory cytokines
Metabolic:
• Carb - increased BG
• Lipid - increase lipolysis, central redistribution
• Protein - increased lipolysis
Circulatory/renal - increased:
• CO
• BP
• Renal blood flow and GFR
3 main clinical uses of corticosteroids?
- Suppress inflammation
- Suppress immune system
- Replacement therapy
Where is the mineralocorticoid receptor (MR) located?
Kidneys, salivary glands, gut and sweat glands
Effects of aldosterone via MR?
Na+/K+ balance:
• K+/H+ excretion
• Increased Na+ reabsorption
BP regulation
Regulation of EC volume
Types of adrenal insufficiency?
Primary:
• Addison’s disease
• Congenital Adrenal Hyperplasia (CAH)
• Adrenal TB/malignancy
Secondary:
• Due to lack of CRH/ACTH stimulation
• Iatrogenic (excess exogenous steroid) - most common cause; steroids feedback and reduce ACTH release
• Pituitary/hypothalamic disorders
Occurrence of Addison’s disease?
Commonest cause of primary adrenal insufficiency
What is Addison’s disease?
Autoimmune destruction of the adrenal cortex; around 90% is destroyed before the patient becomes symptomatic
Tends to be assoc. with autoimmune diseases
Signs and symptoms of Addison’s disease?
Anorexia and weight loss
Abdominal pain, vomiting and diarrhoea
Fatigue/lethargy
Dizziness and low BP
Dehydration
Skin pigmentation, due to high ACTH (part. in palmar creases and buckle mucosa)
Ix results in adrenal insuffiency?
Suspicious biochemistry:
• LOW Na+ and HIGH K+
• Hypoglycaemia (more suspicious in children)
Adrenal auto-antibodies (only +ve in 70% of people so cannot exclude diagnosis)
Short SYNACTHEN test (clearly abnormal if the cortisol is low to start with and increases by only a small amount)
ACTH levels (should be high)
Renin/aldosterone levels (abnormal if there is INCREASED RENIN but DECREASED ALDOSTERONE)
Describe how the short synacthen test is done
Measure plasma cortisol before (in the morning, should be >250 nmol/L) and then give synthetic ACTH
Cortisol should increase to >550 nmol/L
Mx of adrenal insufficiency?
DO NOT DELAY TREATMENT to confirm diagnosis; requires life-long cortisol and aldosterone replacement
Hydrocortisone (cortisol replacement):
• If unwell, this is given IV first but, if they are well, daily 15-30mg oral is given in divided doses (mimic diurnal rhythm, so largest dose in morning)
Fludrocortisone as aldosterone replacement (monitor BP and K+)
Educate patient:
• Sick day rules
• Must not suddenly stop hydrocortisone
• Must wear steroid ID card
Exogenous steroids that can suppress CRH and ACTH release?
High dose prednisolone
Dexamethasone
Inhaled corticosteroid
Clinical features of secondary adrenal insufficiency?
Pale skin (as there is no increase in ACTH)
Aldosterone production is intact (regulated by RAAS)
Treatment of secondary adrenal insufficiency?
For tumours, surgery or radiotherapy
Treat with hydrocortisone replacement (fludrocortisone is unnecessary as ACTH does not affect aldosterone production)
Symptoms and signs of Cushing’s disease/syndrome?
Central weight gain
Acne
Facial plethora
Amenorrhoea
Hypertension (only 10% is secondary to a disoder like Cushing’s)
Severe osteoporosis
Easy bruising
Proximal myopathy (weakness) and muscle wasting in this region
Striae that are deep in colour
Testicular atrophy in males
Typical “lemon on matchsticks” appearance
Occurrence of Cushing’s syndrome?
Rare but it is more common in women aged 20-40 years
2 types of Cushing’s syndrome and causes of each type?
ACTH-dependent:
• Pituitary adenoma (most common), which causes Cushing’s DISEASE
• Ectopic ACTH, from carcinoid/carcinoma
• Ectopic CRH
ACTH-independent: • Adrenal adenoma • Adrenal carcinoma • Nodular hyperplasia • Exogenous steroids
Ix for Cushing’s disease/syndrome?
Establish cortisol excess:
• Overnight dexamethasone suppression test
• 24 hour urinary free control
• Late night salivary control (rarely done as inconvenient and difficult)
Low dose
Method of doing overnight dexamethasone suppression test?
Give dexamethasone 1mg; if the result is abnormal, repeat
If it is still abnormal, continue on to do a 2 day dexamethasone test
Occurrence of iatrogenic Cushing’s syndrome?
Commonest cause of cortisol excess, usually due to prolonged high dose steroid therapy, e.g: in asthma, RA, IBD; the therapy is normally oral but it may occur with high dose inhaled or injections
Describe iatrogenic Cushing’s syndrome
Chronic suppression of pituitary ACTH and adrenal atrophy
Consequences of adrenal suppression?
Unable to respond to stress, e.g: during illness or surgery
Require extra steroid doses when ill/surgical procedure
Cannot stop steroids suddenly; gradual withdrawal is requires if >4-6 weeks use
When is hypertension very suspicious?
HYPERTENSION WITH HYPOKALAEMIA is suspicious of primary aldosteronism
What is primary aldosteronism?
AKA Conn’s syndrome - most common cause of secondary hypertension
Autonomous production of aldosterone, independent of its regulators, i.e: Ang II and K+
CV actions of aldosterone?
Increased cardiac collagen
Increased sympathetic outflow
Altered endothelial function with an increased pressor response
Sodium retention
Cytokines and reactive oxygen species generation
ALL CAN LEAD TO CV DAMAGE AND ATHEROMA, etc
Clinical features of Conn’s syndrome?
Significant hypertension
HYPOKALAEMIA
Alkalosis
Sub-types of primary aldosteronism?
Adrenal adenoma (Conn’s syndrome) - usually younger people
Bilateral adrenal hyperplasia - usually older people
Rare causes:
• Genetic mutations (can be acquired or congenital)
• Unilateral hyperplasia
Cause of adrenal aldosterone producing adenomas and hereditary hypertension?
Most common mutation is a somatic one in KCNJ5 channel (rectifying selective channel which maintains membrane hyperpolarisation)
Mutation leads to loss of ion selectivity, allowing Na+ entry and depolarisation instead
Steps in diagnosis of Conn’s syndrome?
Step 1 - confirm aldosterone excess
Step 2 - confirm sub-type
Methods of confirming aldosterone excess?
Measure plasma aldosterone and renin and express as a ratio (aldosterone : renin ratio); demonstrate that their is an excess of aldosterone compared to renin
If ratio raised (assay dependent) then Ix further with saline suppression test; failure of plasma aldosterone to suppress by > 50% with 2 litres of normal saline confirms PA
Methods of confirming sub-type?
Adrenal CT to demonstrate adenoma
Can use adrenal vein sampling to confirm adenoma is the true source of the aldosterone excess; in this cases, the aldosterone : cortisol ratio must be found for both R and L adrenal veins
Then find an R : L ratio
Mx of Conn’s syndrome?
Surgical (for an adrenal adenoma confirmed with adrenal vein sampling) - unilateral laparoscopic adrenalectomy; it cures:
• Hypokalaemia
• Hypertension (in some cases)
Medical treatment (if there is bilateral adrenal hyperplasia): • Use MR antagonists (spironolactone or eplerenon)
What is congenital adrenal hyperplasia?
Rare conditions assoc. with enzyme defects in the steroid pathyway
Most common type of CAH?
95% of cases have a 21α-hydroxylase deficiency, which has autosomal recessive inheritance (i.e: both parents are carriers)
Variants of 21α-hydroxylase deficiency?
Classical which shows:
• Salt wasting
• Simple virilisation
Non-classical:
• Hyperandrogenaemia
Ix results of CAH?
Basal/stimulated 17-OH progesterone (there are increased levels of this precursor as well as of progesterone, androstenedione, testosterone and dihydrotestosterone)
Presentation of classical CAH in males and females?
Males:
• Adrenal insufficiency (often around 2-3 weeks)
• Poor weight gain
• Biochemical pattern (low Na+ and high K+)
Females:
• Ambiguous genitalia
Presentation of non-classical CAH in males and females?
Hirsute
Acne
Oligomenorrhoea
Precocious puberty
Infertility or sub-fertility
Principles of CAH treatment in children?
Glucocorticoid (cortisol) replacement and, in some, mineralocorticoid (aldosterone) replacement
Surgical correction
Principles of CAH treatment in adults?
Control androgen excess
Restore fertility
Avoid steroid over-replacement
How are the catecholamines produced?
Tyrosine is converted to L-DOPA and this is converted to:
- Dopamine
- Noradrenaline
- Adrenaline
Gross appearance of a phaeochromocytoma?
Smooth, well-defined capsule
Large
Ix for phaeochromocytoma?
Biochemistry:
• Mildly elevated noradrenaline but normal adrenaline
• Very high dopamine usually indicates an extra-adrenal tumour
MIBG scan
24 hour urinary catecholamines (in a minority of patients, this is normal despite having the tumour)
Ix for phaeochromocytoma?
Biochemistry:
• Mildly elevated noradrenaline but normal adrenaline; very high dopamine usually indicates an extra-adrenal tumour
• Hyperglycaemia (adrenaline-secreting tumours)
• May have low K+
• High haematocrit, raised Hb
• Mild hypercalcaemia
• Lactic acidosis (in absence of shock)
Confirm catecholamine excess:
• Do 2X 24 hour urinary catecholamines (in a minority of patients, this is normal despite having the tumour)
• Plasma (ideally at time of symptoms)
Identify source of excess:
• MRI scan of abdomen (for phaeochromocytome) and of whole body (for paraganglioma)
• MIBG scan
• PET scan (may be normal with slow-growing tumours)
Classic triad of symptoms of phaeochromocytoma?
LABILE hypertension
Postural hypotension
Paroxysmal sweating, headache, pallor or tachycardia
Much of the time, patients display none of these and there is often insidious onset
Other symptoms inc. palpitations, breathlessness, constipation, anxiety-fear, weight loss, flushing (uncommon)
Can be an incidental finding
Differential diagnosis with phaeochromocytoma?
Alcohol withdrawal Angina Anxiety Arrhythmia, e.g: SVT Autonomic neuropathy
Carcinoid
Drug toxicity
Factitious
Insulinoma
Hypoglycaemia
Mastocytosis
Menopause
Migraine
Pregnancy
Thyrotoxicosis
Signs of phaeochromocytoma?
Hypertension
Postural hypotension (50% of cases)
Pallor
Bradycardia and tachycardia
Pyrexia
Signs of complications in phaeochromocytoma?
Left ventricular failure Myocardial necrosis Stroke Shock Paralytic ileus of bowel
Why is phaeochromocytoma called the 10% tumour?
10% malignant 10% extra-adrenal (probably 20-30%) 10% bilateral 10% assoc. with hyperglycaemia 10% in children 10% familial (probably 25%)
Who should have Ix for phaeochromocytoma?
Family members with syndromes
Resistant hypertension
If young (<50) with hypertension
Classical symptoms
Consider with hypertension and hyperglycaemia
Treatment of phaeochromocytoma?
A before B - full α-blockade and β-blockade:
• Phenoxybenzamine (α-blocker)
• Propranolol, atenolol or metoprolol (β-blocker)
Give both at the same time but start A first
Fluid and/or blood replacement
Surgical:
• Total excision (wherever possible)
• Tumour de-bulking
Chemotherapy if malignant
Cautions with phaeochromocytoma genetically?
Genetic testing must be done and do family tracing and Ix
Clinical syndromes assoc. with phaeochromocytoma?
MEN2
VHL syndrome
Succinate dehyrogenase mutations
Neurofibromatosis
Tuberous sclerosis
Others
Pitfalls in phaeochromocytoma diagnosis?
Catecholamines raised in heart failure
Episodic catecholamine secretion means that the levels in plasma + urine may be normal
Malignant and extra-adrenal tumours are less efficient at catecholamine synthesis, so dopamine > noradrenaline >adrenaline
May be a part of a genetic syndromes
