HPA Axis disorders Flashcards
What hormones are released by the anterior pituitary gland?
TSH
ACTH
FSH and LH
GH
Prolcatin
What hormones are released by the posterior pituitary gland?
Oxytocin
ADH
What is the main blood supply to the adrenal gland?
Superior adrenal artery - from the inferior phrenic artery
Middle adrenal artery - abdominal aorta
Inferior adrenal artery - from renal arteries
What is the main venous drainage of the adrenal gland?
Right adrenal vein into the IVC
Left adrenal vein into the left renal vein
What are the different layers of the adrenal gland?
Capsule
Cortex =
Zone glomerulosa
Zona fasciculata
Zona reticularis
Medulla
What does each section of the adrenal cortex secrete?
What is the basic function of this?
Zona glomerulosa - mineralcorticoids - salt - inc blood pressure
Zona fasiculata - corticosteroids (some androgens) - sugar - stress and inc bg
Zona reticularis - androgens (some corticosteroids) - sex - sexual development
What does the medulla of the adrenal gland do?
has chromaffin cells which secrete catecholamines - flight or fight response
Also secrete enkephalins - pain control
What is the adrenal axis? (HPA)
Hypothalamus releases CRH
Stimulates anterior pituitary to release ACTH
Stimulates adrenal glands to release cortisol
Cortisol has negative feedback effect to suppress CRH + ACTH
What is cortisol?
Where is it produced?
Trends in levels?
A steroid hormones - glucocorticoid - released from zona fasiculata of adrenal gland in response to stress and hypoglycemia.
Diurnal variation - peaks in mornings, lowest in evenings
What are the different actions of cortisol within the body?
Increase alterness
Inhibits bone formation
Raises blood glucose
Inhibits immune system
Increases metabolism
Anti-inflammatory effects
Give an overview of the Renin-Angiotensin-Aldosterone system
JG cells - in afferent arterioles in the kidney release enzyme renin in response to low BP
Converts angiotensinogen (liver) to angiotensin 1.
ACe (lungs) converts to angiotensin 2
Angiotensin 2 = vasoconstriction = inc BP
Angiotensin 2 = stimulates the release of aldosterone from adrenal glands
What are the effects of aldosterone in the nephron?
Increase Na+ reabsorption from the distal tubule
Increase K+ secretion from distal tubule
Increase H+ secretion from the collecting duct
Water follow sodium by osmosis - leading to increased intravascular volume and inc BP
What electrolyte abnormality is seen in aldosterone receptor antagonists?
Hyperkalemia
What are the two types of corticosteroids?
Glucorticoids e.g cortisol
Mineralcorticoids e.g aldosterone
What is the function of glucorticoids?
Increase alertness
Anti-inflammatory
Inhibits immune system
Inhibits bone formation
Raises blood glucose
Increases metabolism
What are the effects of mineral corticoids?
Increase intravascular volume to increase blood pressure
Causes sodium to be adsorbed and potassium to be excreted.
Give some examples of synthetic corticosteroids and where they sit on the glucorticoids/mineralcorticoid spectrum
Mainly gluc some mineral - prednisolone
50/50 = hydrocortisone
Fully gluc -dexamethosome, beclometasone
Fully mineral with some gluc - fludrocortisone
How can we reduce the adverse effect of chronic use of systemic steroids?
Avoid oral preparation whre possible
Use lowest effective dose for the shortest amount of time
Optimise and pre-existing co-morbidities
Monitor patients for adverse effects
Add a PPI for patients also receiving NSAIDs/Anti-coagulants
Doses should always be tapered down rather than stopped abruptly
At what stage of use do steroid become dangerous?
> 5mg pred for 4w+ - risk of HPA axis suppression and adrenal crisis if physiologically stressed
Short erm use increase 30 day risk of sepsis, VTE and fractures
How do exogenous steroids affect the HPA axis?
Mimic endogenous cortisol - act as negative feedback signal to reduce ACTH secretion
Less stimulation of adrenal gland so less endogenous cortisol
Persistent suppression leads to adrenal gland atrophy -> unable to produce adequate cortisol even after exogenous source has been removed = adrenal insufficiency
What are the sick day rules for steroids?
During acute physiological stress (infection or surgery)
Long term steroid dose should be increases
To meet increased requirements of body - adrenal gland suppressed so not able to produce
What are the side effects of long term corticosteroid use?
Cataracts
Ulcers
Skin thinning/brusing, straie
HTN
Infection - oral thursh
Necrosis of the femoral head
Glucose elevation
Osteoporosis/obesity
Immunosuppression and impaired wound healing
Depression/mood changes
Define adrenal insufficiency
When the adrenal glands do not produce enough steroid hormones - cortisol and aldosterone
may also affect androgens and catecholamines
What are the risk factors for adrenal insufficiency?
Female
Autoimmune disease
Hyper-coagulable states
Adrenal haemorrhage (warfarin and DOACs)
What is the common presentation of adrenal insufficiency?
Fatigue
Muscle Weakness
Dizziness and Fainting
Muscle cramps
Thirst and craving salts
Weight loss
Abdominal pain
Depression
Reduced libido
Loss of pubic hair
Hypotension
Hypoglycemia
Hyponatremia, hyperkalemia
What are some signs that can occur in adrenal insufficiency?
Postural hypos
Bronze hyperpigmentation of the skin (skin creases and the oral mucosa) - ACTH stimulates melanocytes
What are the key clinical features of addisons disease?
Bronze pigmentation of the skin
Changes in distribution of body hair
GI disturbances
Weakness
Weight loss
Postural Hypos
Hypoglycemia
What are the signs of an adrenal crisis?
Profound fatigue
Dehydration
Vascular collapse decreases BP
Renal shutdown - decreased serum Na and inc Serum K
What are the primary causes of adrenal insufficiency?
Damaged adrenal glands - cortisol and aldosterone mostly affected
Autoimmune (70%) - addisons disease
Infections
Medications
Metastatic
Adrenal Haemorrhage
Familial
Infiltrative diseases
What is meant by central adrenal insufficiency?
Secondary and tertiary causes (aka not the adrenal gland)
What are the secondary causes of adrenal insufficiency?
Tumours - pituitary adenoma
Surgery to pituiary
radiotherapy
Sheehans syndrome
Trauma
Mechanism:
Damage to the pituitary gland
Inadequate ACTH secretion
Less stimulation of adrenals
Less cortisol produced
What are the causes of tertiary adrenal insufficiency?
Usually long term corticosteroid causes suppression of the hypothalamus
Abrupt stop of exogenous steroids - hypothalamus remains suppressed
What is a key difference between peripheral and central adrenal insufficient?
Peripheral - low cortisol and aldosterone
Central - low cortisol only, aldosterone remains normal as the RAAS system is not affected by the Hypothalamus or pituitary gland
How can blood tests be used to differentiate between primary, secondary and tertiary adrenal insufficiency?
Primary - low cortisol, high ACTH, renin high, aldosterone low
Secondary - low cortisol, low ACTH, high CRH, renin normal, aldosterone normal
Tertiary - low cortisol, low ACTH, low CRH
What bedside investigations should be done for suspected adrenal insufficiency?
Lying standing BP
Capillary blood glucose
How bloods should be done for suspected adrenal insufficiency?
Na+ = low
K+ = high
Urea and creatinine = raised
Morning cortisol - falsely normal
ACTH, Renin, cortisol, aldosterone
What auto-antibodies are present in Addison’s disease?
Adrenal cortex Ab
21-hydroxylase Ab
What imaging may be done in suspected adrenal insufficiency?
CT/MRI of the adrenal glands
MRI - pituitary - not routine
What special test should be done in suspected adrenal insufficiency?
Short synACTHen test
What happens in the short synACTHen test?
- Baseline serum cortisol
- give synthetic ACTH (synacthen)
- Repeat cortisol 30 mins
If cortisol >420nmol/L indicates adequate adrenal gland response
If less - primary adrenal insufficiency.
What is a common source of ectopic ACTH secretion?
small cell lung cancer - neuroendocrine cells - paraneoplastic syndrome
What is the management of adrenal insufficiency?
Replacement steroids:
Hydrocortisone - replace cortisol
Fludrocortisone - replace aldosterone
Steroid ID card, ID tag, emergency letter to alert emergency services
Sick day rules education
Emergency IM hydrocortisone supply with patient education
What is an adrenal (addisonian) crisis)?
How does it present?
Life-threatening - severe adrenal insufficiency
May be first presentation or triggered by infection/trauma
Present - reduced consciousness, severe hypotension, hypoglycemia, hyponatremia, hyperkalemia
How do you manage adrenal (addisonian) crisis?
ABCDE - treat as appropriate
IM/IV hydrocortisone 100mg stat followed by infusion or 6hrly doses
IV fluid resus
Correct hypoglycemia
Monitor electrolytes and fluid balance
What is the relevant epidemiology of Addisons disease?
peak 30 to 40yrs
Twice as common in females
What acid-base abnormality commonly occurs in Addisons disease?
Metabolic acidosis
What are the major aetiologies of addisons disease + primary adrenal insufficiency?
Autoimmune adrenalitis - destruction of the adrenal cortex, isolated or part of a syndrome
Infection - TB, fungal, HIV and cytomegalovirus
Genetic disorders - CYP21A2 - congenital adrenal hyperplasia, AIRE.
Metastatis infiltartions - lungs, breast or melanoma mets
Adrenal haemorrhage
Medication - prolonged glucocorticoids (suppress HPa axis)
What are some important differential diagnosis for Addisons disease?
- insufficiency secondary to pituitary disease - hyperpigmentation does not occur, and aldosterone levels tend to be preserved.
- Adrenal TB -also have fever and night sweats, adrenal calcification
- Sepsis - acute adrenal dysfunction, hypotensive
What are some common complications of Addisons disease?
Adrenal crisis = severe hypotension, hypoglycemia, altered mental status
Chronic - fatigue, weight loss, electrolyte imbalances
Osteoporosis - from long term glucorticoids
Infections - increased susceptibility due to impaired immune function, prompt recognition and treatment is required
What is the most common cause of secondary HTN?
Hyperaldosteronism
Presents in up to 10% of patients
When should hyperaldosteronism by tested for as a cause of HTN?
Younger (under 40yrs)
Fail to respond to treatment
Low potassium (may still be normal)
How does hyperaldosteronism present?
Headache
Muscle weakness
Fatigue
Resistant hypertension
Signs of hypokalemia = cardiac arrhythmias (and muscle weakness)
Metabolic alkalosis = vomiting, nausea, light-headed or confused.
Polyuria and polydipsia.
What are the different causes of primary hyperaldosteronism?
What is it?
Adrenal glands too much aldosterone, inc BP, decrease renin
Bilateral adrenal hyperplasia (most common)
Adrenal adenoma secreting aldosterone (Conn’s syndrome)
Familial hyperaldosteronism (rare)
What is secondary hyperaldosteronism?
what are the common causes?
Excessive renin stimulates the release of axcessive aldosterone -> caused by disproportionately low BP in the kidneys
Renal artery stenosis (atherosclerosis)
Heart Failure
Liver cirrhosis and ascities
What bedside investigations should be done for hyperaldosteronism?
Blood pressure
ECG
What bloods should be done for hyperaldosteronism?
K+ = low
Na+ = raised/normal
Blood gas - metabolic alkalosis (raised bicarb)
Serum aldosterone
Aldosterone to renin ratio = primary high aldo and low renin, secondary high aldosterone and high renin
What imaging should be done for hyperaldosteronism?
CT/MRI of the adrenal gland - hyperplasia or tumour
Renal artery imaging (Doppler, CT angiogram, MR-angiograpghy) for renal artery stenosis
What special tests may be done in hyperaldosteronism?
Adrenal vein sampling
Taking blood for both adrenal veins to locate which side is producing more aldosterone.
What is the treatment for hyperaldosteronism?
Eplerenone and spironolactone - aldosterone antagonists
Treatment of the underlying causes:
- surgical removal of adrenal adenoma
- percutaneous renal artery angioplasty via the femoral artery to treat renal artery stenosis.
What is the relevant epidemiology of primary hyperaldosteronism?
Peak incidence of 40-50yrs
Equal between men and women
What is the relevant pathophysiology of hyperaldosteronism?
Excessive secretion of aldosterone from the adrenal cortex - independently of the RAAS system
Acts on mineralcorticoid receptors in distal tubles and CD of kidney - inc Na+ reabsorption and potassium secretion
Net effect is water retention leading to increased blood volume (HTN and fluid retention) and hypertension - hypokalemia.
Activates PANS due to hypertension - bradycardia and low CO - however insufficient to compensate for high BP.
Renin suppressed
What is the first line investigation for primary hyperaldosteronism?
Aldosterone/renin ratio
What are some important differentials for primary hyperaldosteronism?
Secondary - normal renin
Cushing - central obesity, moon facies, purple striae and hirsutism
Pheochromocytoma - episodic headaches, diaphoresis, palpitations.
Define cushing syndrome /cushing disease
Prolonged high levels of glucorticoid (cortisol) in the body
What is the difference between Cushing syndrome and crushing disease?
Cushing syndrome = clinical manifestation of pathological hypercortisolism
Cushing disease = pituitary adenoma, secreting excessive ACTH, thus stimulating excess cortisol release from adrenal glands/
What are the two forms of Cushings?
Exogenous or iatrogenic = medication or substance containing cortisol
Endogenous = body produced too much cortisol
What are the three forms of endogenous cushing?
Cushing disease - pituitary tumour (adenoma most common) secrete ACTH
Ectopic - paraneoplastic syndrome - ACTH released from small cell lung cancer or pancreatic cancer
Adrenal gland - tumour/hyperplasia
What is the relevant epidemiology of Cushing disease?
Rare
Affect 10-15 people per million every year
More common in women
People aged 20-50yrs.
What is a key sign of ACTH elevation?
Hyperpigmentation
Stimulates melanocytes to produce melanin
What are some physiological causes of hypercortisolism?
Physical stress
Malnutrition
Alcoholism
Depression
Pregnancy
Metabolic syndrome
What are the different metabolic effects of Cushing syndrome?
Hypertension
Cardiac hypertrophy
Type 2 Diabetes
Dyslipidaemia
Osteoporosis
What is the general presentation of Cushing syndrome?
Enlarged fat pad ‘buffalo hump)
Insomina
Anxiety and depression
Limb wasting
Easy bruising
Abdominal striae
Central obesity
Hirsutism
Round ‘moon’ face
What bedside investigation should be done for Cushing syndrome?
24hr urinary free cortisol
Capillary blood glucose
What bloods should be done for Cushing syndrome investigations?
FBC - raised WCC
U&Es - low K+ if adrenal adenoma also secreting aldosterone
ACTH serum level
Morning cortisol
What imaging should be done for Cushing syndrome investigation?
MRI for brain pituitary adenoma
CT chest for small cell lung cancer
CT abdomen for adrenal tumours
What special tests should be done for suspected Cushing syndrome?
Dexamethasone suppression test
Diagnose endogenous cushing syndrome
Normal - dex suppress cortisol due to negative feedback on the HPA axis
Lack of cortisol suppresion = Cushing syndrome
What are the different types of dexamethosone suppresion test?
How does this help diagnose the type of Cushings?
All detect endogenous cushings
1. Low dose overnight - lack of suppresion = cushing
2. Low does 48hr test - lack of suppresion = cushing
3. High dose 48hr test - higher dose can suppress Cushing disease (Pituitary adenoma) but not adrenal adenoma or ectopic ACTH.
What are the common complications of Cushing Syndrome?
Hypertension
Osteoporosis
Fractures
Stroke
Diabetes Mellitus
Frequent infections
Heart attack
Thromboembolism
What is the typical surgical treatment for Cushing syndrome?
Trans-sphenoidal resection of pitutary tumour
Surgical removal of adrenal tumour
Surgical removal or paraneoplastic tumour e.g SCLC
Bilateral adrenalectomy - followed by lifelong steroid replacement therapy
What medication may be given to help treat Cushing syndrome?
Metyrapone - reduce production of cortisol in the adrenals
Ketoconazole - steroidogenic inhibitor - endogenous disease.
LOW CONCERN
What is Nelsons syndrome?
Development of an ACTH producing pituitary tumour following bilateral adrenalectomy
Due to lack of cortisol negative feedback
Causes:
Skin pigmentation
Bitemporal hemianopia
Lack of other pituitary hormones
What is the most common cause of Cushing syndrome?
Exogenous - long term corticosteroid therapy
What are the first line investigations for Cushing syndrome?
Low dose dexamethsone suppresion test
24hr urinary free cortisol
late night salivary cortisol
Define acromegaly
Clinical manifestation of excessive growth hormone secretion after the fusion of the epiphysis
Leading to large extremities and characteristic faces
Define gigantism
The clinical manifestation of excessive growth hormone secretion before the fusion of the long bone epiphysisis
Characterised by tall stature
Paediatric condition
What are the most common causes of acromegaly?
Pituitary adenoma - most common
Ectopic GHRH or GH from a tumour
How does acromegaly present?
Excessive soft tissue growth - frontal bossing, large ears, large nose, large protruding jaw (prognathism), large tongue
If pituitary adenoma cause - bitemporal hemianopia
What investigations should be done for acromegaly?
Growth hormone should NOT be done - unreliable fluctuates throughout the day
IGF-1 -serum, indicates GH levels
GH suppresion test = glucose drink should suppress GH
MRI pituitary - pituitary adenoma (note may be too small to see)
What are some common complications of acromegaly?
Cardiomyopathy
Hypertension
Type 2 diabetes
Carpal tunnel syndrome
Arthiritis
Colonic polyps
What is the management for acromegaly?
Trans-sphenoid resection of pituitary tumour
Radiotherapy may be offered
Surgical removal or paraneoplastic tumour (lung or pancreas)
What medication may be given to treat acromegaly?
Pegvisomant - GH receptor antagonist
Somatostatin analogues - octreotide - block GH release
Dopamine agonist - bromocriptine - block GH release
