Week 4 Flashcards
What is acromegaly caused by
Excess growth hormone
Describe the process of releasing growth hormones and its negative feedback mechanism
1) GHRH (growth hormone releasing hormone) released from the hypothalamus into anterior pituitary gland
2) This stimulates the somatotropes in anterior pituitary gland to secrete GH (growth hormone) into the blood
3) GH stimulates the release of IGF-1 from the liver
The release of IGF-1 and GH inhibits the release of GHRH and stimulates the release of somatostatin
Somatostatin is a negative regulator of GH as well
Role of somatostatin in growth hormone production
Inhibits release of growth hormone
What is IGF-1
Insulin-like growth factor released by the liver which stimulates systemic body growth and has anabolic effects
What is gigantism
Excess growth hormone during childhood causing unusually tall stature and rapid growth
Which cells secrete GH in the anterior pituitary gland
Somatotropes
Most common cause of acromegaly
Pituitary adenoma
Acromegaly can be caused by malignancy in which cells of the pituitary gland
Somatotropes
Causes of acromegaly
Pituitary adenoma
Ectopic release of GH
Ectopic release of GHRH
Hypothalamic tumours
Which cancers can cause ectopic release of GHRH
Carcinoid (neuroendocrine tumour)
Small cell lung cancer
Symptoms of acromegaly
Large hands and feet
Frontal bossing
Bulging out of lower jaw (prognathism)
Macroglossia
Obstructive sleep apnea
Enlarged nose
Visual loss
Headaches
Joint pain
What can cause visual loss
Pituitary adenomas compressing the optic chiasm
What is usually seen due to tumours compressing the optic chiasm
Bitemporal hemianopia
What is bitemporal hemianopia
partial blindness where vision is missing in the outer half of both the right and left visual field
Which conditions are at increased risk due to acromegaly
Hypertension
CVD
Colon cancer
Insulin resistance
Osteoporosis
Why may acromegaly cause obstructive sleep apnea
Due to enlarged nasopharynx; acromegaly causes thickened soft tissues
Why may hypopituitarism occur in acromegaly
Due to large pituitary adenoma causing infarction of pituitary tissue hence impairing function of the rest of the pituitary gland
What lab tests can be done to diagnose acromegaly
IGF-1 level
Oral glucose tolerance test
Why is IGF-1 level measured instead of GH
Because GH level is highly variable whereas IGF-1 is relatively constant hence more reliable
When should you do glucose tolerance test for acromegaly
If IGF-1 is raised or uncertain to confirm the diagnosis
What would the lab test results be for acromegaly (IGF-1 levels and glucose tolerance test)
Raised IGF-1 level
GH level not suppressed after administration of glucose
Why would the GH level be suppressed after administration of glucose in normal healthy people
Because GH acts like glucagon which would be suppressed due to high levels of insulin
Why may growth decrease if you eat lots of refined sugars and carbs during childhood
Because these food raises insulin level the most which would inhibit GH secretion
Except IGF-1 level and glucose tolerance test, what other tests may be done for acromegaly if patients present certain symptoms
MRI / CT / PET scan
Visual field test
Test for deficiencies in other pituitary hormones
Management of acromegaly
Surgery is first line
Drugs second
Radiotherapy third
What drugs may be used for acromegaly
Somatostatin analogues
GH antagonists (but not really used)
Examples of somatostatin analogues
Lanreotide
Octreotide
Sandostatin LAR
Effects of somatostatin analogues
Reduces GH (remember somatostatin is a negative regulator for GH)
Shrinks tumour
Relieves headache
Side effects of somatostatin analogues
Local stinging
Flatulence
Diarrhea
Abdominal pain
Gallstones
Why is GH antagonist last line for drug therapy
It doesn’t shrink tumour size
Decreases IGF-1 but serum GH concentration may increase
When is radiotherapy used to treat acromegaly
For those where surgery and drug therapy failed
Why is radiotherapy avoided in those of reproductive age
It can cause hypopituitarism and it is associated with thyroid cancer
Describe the structure of the adrenal gland
Outer layer - cortex, made of 3 layers
Center- medulla
What are the 3 layers of the cortex
Zona glomerulosa
Zona fasciculata
Zona reticularis
Function of adrenal gland
Synthesis and release of steroid hormones and catecholamines
Which steroid is synthesised and released by zone glomerulosa
Mineralcorticoids
Which layer of the adrenal cortex secretes glucocorticoids
Zona fasciculata
Which hormones are secreted by zone reticularis
Adrenal androgens
What does the medulla of adrenal gland secrete
Catecholamines
Main glucocorticoid secreted by the adrenal gland
Cortisol
Main mineralocorticoid secreted by the adrenal gland
Aldosterone
What are the catecholamines secreted by the adrenal medulla
Epinephrine (adrenaline)
Norepinephrine (noradrenaline)
Dopamine
Which cells make up the most of medulla
Chromaffin cells
What is the starting material for the synthesis of all steroids
Cholesterol
Aldosterone is regulated by which systems
Renin-angiotensin system
Cortisol and androgens are regulated by which system
Hypothalamis-pituitary- adrenal axis (HPA)
What factors can trigger the production of CRH from hypothalamus
Stress
Time of day
Illness
Describe the HPA axis
Hypothalamus secretes CRH in response to stress/illness/time of day -> CRH stimulates the release of ACTH from anterior pituitary gland -> ACTH travels through blood to the adrenal cortex to stimulate the synthesis and secretion of cortisol
Describe how dose cortisol level vary throughout the day
Highest during the day
Lowest in the night
Describe the renin-angiotensin system
1) trigger factors stimulating release of renin from kidneys
2) Renin cleaves angiotensin into angiotensin I
3) ACE cleaves angiotensin I into angiotensin II
4) Angiotensin II exerts its effects and stimulates release of aldosterone and ADH
Function of RAAS
to regulate blood pressure and fluid balance
What are the triggers for RAAS
Decrease in blood pressure (renal hypotension)
Sympathetic stimulation
Reduced sodium
Where is ACE found
Vascular endothelium of the lungs
How does angiotensin II increase blood pressure
Stimulate release of aldosterone
Stimulate release of ADH
Stimulate vasoconstriction
Increases sodium reabsorption at proximal tubule (hence water)
How does aldosterone increase blood pressure
Increases sodium retention by increasing sodium potassium channels in epithelial sodium channels in distal tubule
= increases sodium reabsorption and potassium excretion
How does ADH increase blood pressure
Insert aquaporin channels to increase permeability of the collecting duct to water
Increase sodium reabsorption at ascending limb of loop of hence (hence water)
= more water retained instead of excreted into urine
Why does high level of aldosterone lead to lower levels of potassium
Because aldosterone increases the activity of sodium potassium pump which pumps sodium in and potassium out.
How do steroids exert an action
Bind to intracellular receptors to affect transcription of certain genes
Cortisol (glucocorticoids) actions on circulation
Increase cardiac output
Increase in blood pressure
Increase in renal blood flow and filtration rate
Cortisol actions on metabolism
Increases blood sugar
Increases lipolysis
Increases proteolysis
Increases osteoclast activity
Effect on bones due to long term steroid use
Accelerated osteoporosis
Immunological effects of the cortisol
Decrease in capillary diltatation
Decrease in macrophage activity
Decrease in leukocyte migration
Dcrease in inflammatory cytokine production
Use of steroids
Suppress inflammation
Suppress immune system
Examples of when is steroid used
Asthma
RA
Ulcerative colitis, Crohn’s disease (IBD)
Effects of aldosterone through binding to mineralocorticoid receptor
Regulates blood pressure
Sodium/Potassium balance
Regulation of extracellular volume
What is Addison’s disease
= primary adrenal insufficiency (including all the primary causes)
Most common primary cause of adrenal insufficiency
Autoimmune destruction
Primary causes of adrenal insufficiency (Addison’s)
Autoimmune destruction
Surgery
Trauma
Infections
Haemorrhage (Waterhouse Friderichsen Syndrome)
Sarcoidosis / neoplasm
Which infection is associated with Addison’s
TB
Most common secondary cause of adrenal insufficiency
Chronic exogenous steroid
How may excess exogenous steroid lead to adrenal insufficiency
- steroids exert negative feedback on ACTH production hence ACTH may be suppressed for a long term -> Unable to produce enough ACTH during metabolic stress when they stop taking steroids -> adrenal insufficiency
- atrophic adrenal glands unable to respond to ACTH
Secondary causes of adrenal insufficiency
Excess exogenous steroid
Panhypopituitarism
CRH deficiency
Addison’s disease is associated with which other autoimmune diseases
T1 diabetes
Autoimmune thyroiditis (Hashimoto’s / grave’s)
Pernicious anemia
Clinical features of adrenal insufficiency
Unexplained weight loss / anorexia
Skin hyperpigmentation
Fatigue
Hypotension
Hypoglycaemia
Abdominal pain
Vomiting
Loss of pubic hair / axillary hair
Mneumonic for symptoms of adrenal insufficiency (W STEROID)
Sugar and sodium low
Tired
Electrolyte imbalance (hyperkalaemia and hyponatraemia)
Reproductive changes (loss of pubic hair / axillary hair)
O lOw blood pressure
Increased skin pigmentation
Diarrhea and vomiting
What causes skin hyperpigmentation in Addison’s disease
Due to high ACTH level stimulates melanocytes to produce melanin
Why would there be high ACTH levels in Addison’s disease
Due to low level of steroids -> less negative feedback -> ACTH and CRH not inhibited
Lab tests for adrenal insufficiency
Blood tests - Na+, K+ levels, glucose level
ACTH levels
SYNACTHEN test
Renin/aldosterone level
21 hydroxylaze autoantibodies
CT scan / MRI
What is synacthen test for adrenal insufficiency
Injection of synthetic ACTH and measure cortisol level before and 30 minutes after injection
Synacthen test that suggests adrenal insufficiency
low cortisol level 30 minutes after injection
Renin Aldosterone level that suggests adrenal insufficiency
High renin
Low aldosterone
What Na+ and K+ levels can suggest adrenal insufficiency
Hyponatraemia
Hyperkalaemia
What is the characteristic trio of lab results suggesting adrenal insufficiency
Hypoglycaemia
Hyponatraemia
Hyperkalaemia
Management of Adrenal insufficiency
Hydrocortisone
+ Fludrocortisone if aldosterone is insufficient
(usually both are used)
Sick day rules and education
Hydrocortisone is the synthetic replacement for which steroid
Cortisol
What are the sick day rules for adrenal insufficiency
Double the dose during moderate intercurrent illness
Self inject IV hydrocortisone during severe intercurrent illness
Cannot miss a dose of steroids, they need steroids for life
What is Addisonian (adrenal) crisis
Exacerbation of adrenal insufficiency where the absence of steroid hormones can lead to life-threatening situations
Symptoms of Addisonian (adrenal) crisis
Hypotension
Reduced consciousness
hypoglycaemia
Hyponatraemia
Hyperkalaemia
Very unwell
Management of Addisonian crisis
Do not delay treatment, treat ASAP
IV hydrocortisone
IV fluid resuscitation
Treat underlying cause
Monitor electrolytes, blood pressure continuously
What can trigger Addisonian crisis
Acute illness
Trauma
Infection
Withdrawal / forgot to take steroids
these causes stress which increases demand for cortisol
What happens to the adrenal gland in absence of ACTH / CRH
Atrophy due to long term failure to be exposed to and stimulated by ACTH / CRH
What are some differences in clinical features between primary and secondary adrenal insufficiencies
Primary adrenal insufficiency causes skin hyperpigmentation but secondary adrenal insufficiency will not due to no increase in ACTH
Aldosterone will not be affected because it is regulated by renin-aldosterone system instead of by ACTH / CRH
Secondary does not have hyperkalaemia
What may be excluded in the management of secondary adrenal insufficiency
The use of fludrocortisone because aldosterone is not deficient
Pathogenesis of osteoporosis
Activity of osteoclasts > activity of osteoblasts leading to decrease in bone density (bone loss)