Lec 9 The HPA axis - Clinical aspects Flashcards
What type of cells release peptidergic hormones transported by the the pituitary portal system?
Neurosecretory cells
Give examples of neurosecretory cells which release peptidergic hormones transported by the pituitary system to the pituitary gland.
Median eminence
Hypothalamus
What is the enzyme which converts cortisone into cortisol?
11 beta hydroxysteroid dehydrogenase
List the effects of glucocorticoids
Maintenance of homeostasis during stress Regulation of blood pressure Formation of bone and cartilage Energy balance and metabolism Anti-inflammatory Cognitive function, memory and conditioning
What is one of the effects of an individual not producing enough cortisol?
They will have an altered circadian rhythm
What is the name of the enzyme that converts testosterone to oestrogen?
Aromatase
In vitro, because cortisol and aldosterone both have the same affinity for the mineralocorticoid receptor (MR), how if specify conferred?
Through a “pre-receptor” mechanism
Which enzyme inactivates cortisol?
11-beta-hydroxysteroid dehydrogenase
Where is 11 beta hydroxysteroid dehydrogenase (11B-HSD2) found?
In the kidneys
Why is cortisol inactivated to cortisone in the some tissues?
So that you can prevent cortisol from having an effect in some tissues and allow aldosterone to have an effect
What is the function of 11 Beta HSD enzymes?
They allow for tissue specificity by “gating” the GC access to nuclear receptors
What do 11beta HSD enzymes allow to happen?
Amplification of GC signals to target tissues and blocking of the signal to non target tissues
What is Cushing’s syndrome?
Excessive production or presence of excess cortisol
What other factors are associated with Cushing’s Disease?
Weight gain Hypertension Insulin resistance Neuropsychiatric problems Osteoporosis
What is the pathogenesis of Cushing’s Syndrome?
Excess cortisol due to: Pituitary adenoma: ACTH secreting cells Adrenal tumour: adenoma/ carcinoma Ectopic source of ACTH: carcinoid, paraneoplastic e.g. small lung cancer Iatrogenic: steroid treatment
What are the clinical features of Cushing’s syndrome?
Central obesity with thin arms and legs Fat deposition over upper back (buffalo hump) Rounded 'moon' face Thin skin - easy bruising Hirsutism Hypertension Diabetes Psychiatric manifestations Osteoporosis
What is Addison’s disease
An endocrine disorder caused by too little cortisol
What happens to the patient in Addison’s disease?
Gradually falls off in general health
Becomes languid and weak
Indisposed to physical or mental exertion
The body wastes
Slight pain referred to the stomach
Occasional actual vomiting
Discoloration of the skin - Ibiza tan - really dark tan due to ACTH influencing melanin production
What is the pathogenesis in Addison’s disease?
Primary adrenal insufficiency
Usually autoimmune in the UK
Rare causes may be metastases or TB
Decreased production of all adrenocortical hormones
What may be other causes of hypoadrenalism?
Secondary to pituitary disease (rare)
Iatrogenic - steroid hormone given for long time, high dose and then suddenly stopped at a time of stress - the adrenal glands would not be able to keep up
What are the clinical features of Addison’s disease?
Malaise, weakness, anorexia, weight loss
Increased skin pigmentation
Hypotension, postural hypotension
Hypoglycaemia
Not enough cortisol to mobilise glucose and keep blood sugar levels up
What are the two type of Autoimmune Polyendocrine Syndromes?
Type I
Type II
Describe Type 1 autoimmune polyendocrine syndromes
Rare
Onset in infancy
AIRE gene
Common phenotype = Addison’s disease
Hypoparathyroidism
Candidiasis
Describe Type 2 APES
More common but still rare
Onset infancy to adulthood
Polygenic
Common phenotype:
Addison’s
Type 1 diabetes
Autoimmune thyroid disease
Name some autoimmune diseases that may occur together
Type 1 diabetes Autoimmune thyroid disease Coeliac disease Addison's disease Pernicious anaemia Alopecia Vitiligo Hepatitis Premature ovarian failure Myasthenia gravis Gestational/ post partum thyroiditis
What should you have a high index of suspicion with?
Additional autoimmune endocrine disorders
e.g. T1DM with malaise, fatigue and weight loss ? Addison’s
or T1DM with non specific GI symptoms or diarrhoea ?coeliac
When could you consider screening?
In patients with T1DM and or Addison’s disease
What screens would you consider?
Coeliac screen
Thyroid function tests
How would you assess the HPA axis
Basal tests
Blood Cortisol/ACTH
Urine cortisol
Saliva cortisol
What dynamic tests could you do?
Stimulated or suppressed
What is an example of a suppressed test?
Dexamethasone - a synthetic glucocorticoid
How does a dexamethasone suppression test work?
Dexamethasone is a potent steroid
So there should be very low levels of cortisol - suppression of cortisol production
But in pts with Cushing’s they don’t have the suppression because the causes of Cushing’s don’t behave physiologically therefore they continue to pump out ACTH and cortisol
What tests could you do to check for Cushing’s?
24 hour urinary free cortisol - “area under the curve”
Midnight cortisol saliva measurement
9am ACTH paired with cortisol measurement
What tests could you do to check for Addison’s?
9am cortisol
SynACTHen test - adrenal response to ACTH - trophic effect of ACTH on adrenals
Insulin intolerance test
U&E - decreased sodium increased potassium in Addison’s
Glucose concentration - decreased
What are the two golden rules with endocrine conditions?
- Never start investigating a patient for an endocrine condition unless their symptoms and signs suggest they may have it - due to risk of false positives
- Do not image an endocrine glands unless there is a diagnosis established biochemically
Once you have estabished pt has Cushing’s biochemically, what imaging would you do?
CXR
MRI pituitary
CT adrenals
What imaging would you do on an Addison’s pt?
Nothing - don’t need imaging unless you are concerned they have TB or metastatic cancer
What is the management for Cushing’s Syndrome?
Surgerical: Transphenoidal adenectomy or Adrenalectomy
Pituitary radiotherapy
What is the management for Addison’s
Glucocorticoid replacement therapy - usually hydrocortisone or prednisolone
Mineralocorticoid replacement therapy - fludrocortisone
What do patients with secondary adrenal insufficiency have for management?
GC replacement therapy only - no need for fludrocortisone
What needs to be considered in dosing of GCs?
Dose needs to be increases to cover “stresses” e.g. illness such as flu
Operations/ post op period
Pts may need IV or IM steroid if nil by mouth and vomiting - unable to take orally
Patients might be on long term high dose steroids for a number of reasons/conditions, name some
Severe asthma,
COPD
Temporal arteritis
Polymyalgia rheumatic
Why would pts be on these high dose long term steroids?
For their anti-inflammatory, immunosuppressive effects
What can happen to the endogenous adrenal functions of patients on long term high dose steroid therapy?
Their endogenous adrenal function may be suppressed
Why is it significant that they may have suppression of their endogenous adrenal function?
They wouldn’t be able to mount an adequate stress response
They should ensure that the steroids are not stopped suddenly
If the pt needs an operation, they need increased steroid cover
They should be given a Steroid Treatment Card to remind them and their doctors that they’re on steroids
