endocrinology Flashcards
what are the 5 anterior pituitary hormones and what do they stimulate?
growth hormone - growth
prolactin - lactation
TSH - T3 and T4
LH/FSH - gonad hormones
ACTH - cortisol
what are the 3 types of gland failure caused by anterior pituitary failure?
thyroid
adrenal cortex
gonads
what is the difference between primary and secondary disease?
primary - gland itself fails
secondary - failure caused by something else
what is primary hypothyroidism?
T3 and T4 fall, TSH increases
no negative feedback
(also TRH increase but this is not measured)
what is secondary hypothyroidism?
(e.g) cells in pituitary cannot produce TSH
TSH falls
T3 and T4 fall
what happens in primary hypoadrenalism?
cortisol falls
ACTH increases to try and drive adrenal gland to work (can cause tanning in things like Addison’s disease as one of the byproducts is melanin)
(CRH would also be high but is not measured)
what happens in secondary hypoadrenalism?
ACTH not made
ACTH falls - no tanning as seen in Addison’s disease
therefore cortisol falls
what happens in
primary hypogonadism?
testosterone/oestrogen fall
LH, FSH increase (trying to force gonads to work)
(GnRH would also be high)
what happens in secondary hypogonadism?
anterior pituitary cannot produce LH/FSH
LH/FSH fall
therefore testosterone/oestrogen fall
how is congenital hypopituitarism caused and what are the effects?
rare
due to mutations of transcription factor genes needed for normal anterior pituitary development
children may be short due to missing growth hormone
MRI can show underdeveloped anterior pituitary to catch
how is acquired hypopituitarism caused?
tumours - adenoma, metastases, cysts
radiation - damage hypothalamus/pituitary damage
infection - e.g. meningitis
traumatic brain injury
pituitary surgery
inflammatory - hypophysitis (autoimmune)
pituitary apoplexy - haemorrhage or less commonly infarction
peri-partum infarction (Sheehan’s syndrome)
what is total loss of anterior and posterior pituitary called?
panhypopituitarism
how does radiotherapy induced hypopituitarism occur?
pituitary and hypothalamus sensitive to radiation (either direct - to treat pituitary acromegaly - or indirect - e.g to treat nasal carcinoma)
extent of damage depends on total dose of radiotherapy
some hormones are more sensitive to damage
- GH and gonadotrophins most sensitive
- prolactin can increase due to loss of hypothalamic dopamine
how does a lack of FSH/LH present?
(less testosterone/oestrogen)
reduced libido
secondary amenorrhoea
erectile dysfunction
reduced pubic hair
how does a lack of ACTH present?
no cortisol
fatigue
weight loss
(not a salt losing crisis because aldosterone is still present and works under the renin angiotensin axis)
how does a lack of TSH present?
fatigue
how does a lack of GH present?
reduced quality of life (needed for psychological wellbeing)
short stature in children
how does a lack of prolactin present?
inability to breastfeed
what are the causes of Sheehan’s syndrome?
post partum hypopituitarism secondary to hypotension - post partum haemorrhage
more common in developing countries as it is related to how much blood is lost during delivery
anterior pituitary enlarges in pregnancy (lactotroph hyperplasia - preparing to produce prolactin)
post partum haemorrhage: larger pituitary needs more blood supply, haemorrhage leads to hypotension so pituitary does not receive the blood that is needed, leads to pituitary infarction
how does Sheehan’s syndrome present?
lethargy, anorexia, weightloss - TSH/ACTH/GH deficicieny
failure of lactation - no PRL supply
failure to resume menses post-delivery (no FSH/LH)
posterior pituitary usually not affected
what is the best radiological way to examine the pituitary?
MRI (CT not so good at delineating pituitary)
may reveal specific pathology - e.g haemorrhage or adenoma
empty sella - thin rim of pituitary -indicates issue
what are the causes of pituitary apoplexy?
intra pituitary haemorrhage or less commonly infarction
often dramatic presentation in patients with pre existing pituitary tumours (adenoma) that hasn’t been detected
can be precipitated by anti-coagulants
how does pituitary apoplexy present?
severe sudden onset headache
compressed optic chiasm- bitemporal hemianopia
cavernous sinus (involves internal carotid) involvement (blood may leak into sinus) may lead to cranial nerve issues - diplopia (IV, VI), ptosis (III)
what are the general problems with biochemical diagnosis of hypopituitarism?
caution interpreting basal plasma hormone concentrations
- cortisol depends on time of day (diurnal)
T4 - long half life (around 6 days) might be normal for longer
FSH/LH - cyclical in women
GH/ACTH - pulsatile
how does dynamic pituitary function in hypopituitarism diagnosis work?
- ACTH and GH = ‘stress’ hormones
hypoglycaemia induced by giving insulin
stimulates GH and ACTH (measure cortisol) release
- TRH stimulates TSH - measure TSH
- GnRH stimulates FSH and LH
combo injection of insulin, TRH, GnRH given and take measurements over long time period
how should the effects of pituitary dysfunction be treated?
cannot replace prolactin
replace all others (GH, TSH, FSH, LH)
how can GH deficiency be treated?
confirm deficiency on dynamic pituitary function test
assess quality of life from questionnaire
daily injection
measure response by
- improvement in QoL
- increase plasma IGF-1
how can TSH deficiency be treated?
straightforward
replace with daily levothyroxine
TSH will be low in secondary hypothyroidism so you can’t use this to adjust dose as in primary hypothyroidism
aim for fT4 above middle of reference range
how can ACTH deficiency be treated?
must replace cortisol rather than ACTH
difficult to mimic diurnal variation
main options use synthetic glucocorticoids
- prednisolone, 1 daily
hydrocortisone, 3 times per day to try and mimic diurnal variation
what are sick day rules for ACTH deficiency and why are they important?
patients with ACTH or Addison’s are at risk of adrenal crisis triggered by intercurrent illness (lack of aldosterone)
crisis features - dizziness, hypotension, vomiting, weakness, may result in collapse and death
patients who take replacement steroid must take every day therefore sick day rules
- steroid alert pendant, bracelet so nurses know to give dosage
- double steroid dose if fever/intercurrent illness
- unable to take tablets (e.g. vomiting) - inject IM or go to A&E
how can FSH/LH deficiency in men be treated?
if no fertility needed
replace testosterone - topical or intramuscular
measure plasma testosterone
if fertility needed FSH must also be injected
induce spermatogenesis by gonadotropin injection
best response if secondary hypogonadism has developed after puberty
sperm production may take a long time (6-12 months)
how can FSH/LH deficiency in women be treated?
no fertility
replace oestrogen with oral or topical
addition progestogen if intact uterus to prevent endometrial hyperplasia
if fertility required
induce ovulation by timed gonadotropin injection (i.e IVF)
what part of the brain is the posterior pituitary anatomically continuous with?
hypothalamus
what do hypothalamic magnocellular neurons contain and how are they arranged?
containing AVP/oxytocin
long, originate in supraoptic and paraventricular hypothalamic nuclei
(nuclei to stalk to posterior pituitary)
what is vasopressin also known as?
anti diuretic hormone
what is diuresis?
production of urine
what is the main physiological action of vasopressin?
stimulation of water reabsorption in renal collecting duct to concentrate urine
how does vasopressin allow water reabsorption in the collecting duct?
acts through V2 receptor in kidney
causes signalling cascade within the cell
allows aquaporin 2 to bind to apical membrane (water moves from tubular lumen into cell)
allows aquaporin 3 to bind to basolateral membrane (water moves from cell to plasma)
what is the other function of vasopressin (other than water reabsorption in the collecting duct)?
vasoconstrictor via V1 receptor
stimulates ACTH release from anterior pituitary
how can the posterior pituitary be identified on an MRI?
posterior pituitary = “bright spot” on MRI
not visualised in all healthy individuals so absence may be normal variant
how does an osmotic stimulus cause vasopressin release?
rise in plasma osmolality sensed by osmoreceptors
how does a non-osmotic stimulus cause vasopressin release?
decrease in atrial pressure sensed by atrial stretch receptors
what structures in the brain are used to detect an osmotic stimulus and cause vasopressin release?
organum vasculosum and subfornical organ
these nuclei sit around 3rd ventricle - circumventricular
no blood brain barrier so neurons respond to systemic circulation
neurons project to supraoptic nucleus (site of vasopressinergic neurons)
contain osmoreceptors
how do osmoreceptors regulate vasopressin?
osmoreceptors are sensitive to changes in systemic circulation
e.g. water moves out due to increased extracellular sodium
therefore receptor shrinks, causing increasing osmoreceptor firing
causes release of AVP from hypothalamic neurons
what is the mechanism by which a non-osmotic stimulus causes vasopressin release?
atrial stretch receptors detect pressure in the right atrium and normally inhibit vasopressin via vagal afferents to hypothalamus
reduction in circulating volume (e.g. by haemorrhage) means less stretch of atrial receptors therefore less inhibition of vasopressin
why is AVP released following haemorrhage?
vasopressin means water reabsorption in kidney, which restores some circulating volume (via V2 receptor)
vasoconstriction (via V1 receptor)
(renin aldo system also important (sensed by JG apparatus))
what is the normal physiological response to water deprivation?
increased plasma osmolality
stimulation of osmoreceptors
water loss causes thirst and increased AVP
increased water reabsorption from renal collecting ducts into systemic circulation
reduce urine volume and increase in osmolality of urine
(reduce osmolality of plasma)
what are the presenting features of diabetes insipidus?
polyuria
nocturia
extreme thirst
polydipsia
what is the difference between diabetes mellitus and diabetes insipidus?
in diabetes mellitus (far more common) the symptoms are very similar, but are due to osmotic diuresis (hyperglycaemia)
in diabetes insipidus these are due to a problem with arginine vasopressin, not glucose
what are the two types of diabetes insipidus and how are they different?
cranial: problem is with hypothalamus and/or posterior pituitary, therefore unable to make arginine vasopressin
nephrogenic: hypothalamus and posterior pituitary makes vasopressin but kidney collecting duct does not respond
how common are congenital causes of cranial diabetes insipidus?
very rare
what are the acquired causes of cranial diabetes insipidus?
traumatic brain injury
pituitary surgery
pituitary tumours
metastasis to the pituitary gland
granulomatous infiltration of pituitary stalk (e.g. TB, sarcoidosis) - vasopressin cannot flow down stalk due to thickening
autoimmune
what are the congenital causes of nephrogenic diabetes insipidus?
very rare
e.g. mutation in gene encoding V2 receptor, aquaporin 2 water channel
what are the acquired causes of nephrogenic diabetes insipidus?
drugs (e.g. lithium) that damage ability to respond to vasopressin
how does diabetes insipidus present with respect to the urine?
very dilute (hypo osmolar)
large volumes produced
causes dehydration and affects plasma
(cannot reabsorb water)
how does diabetes insipidus present with respect to the plasma?
increased concentration (hyper osmolar) as dehydration occurs
increased sodium (hypernatraemia)
glucose is normal
why do these symptoms (polyuria, nocturia, extreme thirst, polydipsia) occur in diabetes insipidus?
arginine vasopressin (either not enough or kidney does not respond)
impaired concentration of urine in renal collecting duct
large volumes of dilute urine
increase in plasma osmolality (and sodium)
stimulation of osmoreceptors to produce thirst (polydipsia)
drinking water maintains circulating volume - as long as patient has access to water they can manage the effects
how can diabetes insipidus cause death?
increase in plasma osmolality and sodium due to impaired concentration of urine in renal collecting duct
stimulation of osmoreceptors to produce thirst (polydipsia)
if no access to water, causes dehydration and death
what is the difference between psychogenic polydipsia and diabetes insipidus?
similar presentation to diabetes insipidus
however there is no problem with arginine vasopressin - problem is that the patient drinks water all the time
plasma osmolality falls
less AVP secreted by posterior pituitary
large volumes of dilute hypotonic urine passes
plasma osmolality goes back to normal
how can diabetes insipidus and psychogenic polydipsia be differentiated?
water deprivation test
no access to water
over time, measure urine volumes, urine osmolality, plasma osmolality
concentration - psychogenic a bit lower than normal, insipidus very low and stays the same throughout the test
weigh regularly; stop test if losing more that 3% body weight - marker of significant dehydration which can occur in diabetes insipidus (may lead to negative consequences)
how can a water deprivation test distinguish between cranial and nephrogenic diabetes insipidus?
give ddAVP (desmopressin), works like vasopressin
cranial: body responds to ddAVP and urine concentrates as kidneys can still respond
nephrogenic: no change in urine osmolality as kidneys can’t respond
how does plasma osmolality vary from the normal range in diabetes insipidus as opposed to psychogenic polydipsia?
diabetes insipidus: plasma osmolality goes up
psychogenic polydipsia: plasma osmolality goes down
how can cranial diabetes insipidus be treated?
replace vasopressin with desmopressin
selective for V2 receptor as no need for vasoconstriction
can give intranasally as a spray or orally as a tablet
how can nephrogenic diabetes insipidus be treated?
rare, difficult to treat successfully
use thiazide diuretics e.g. bendofluazide
paradoxical, mechanism unclear
what is syndrome of inappropriate anti-diuretic hormone (SIADH)?
too much arginine vasopressin leads to reduced urine output and water retention
what are the features of syndrome of inappropriate anti-diuretic hormone (SIADH)?
high urine osmolality
low plasma osmolality
dilutional hyponatraemia
what are the causes of syndrome of inappropriate anti-diuretic hormone (SIADH)?
CNS
- head injury, stroke, tumour
pulmonary disease
- pneumonia, bronchiectasis
malignancy
- lung cancer (small cell)
drug related
- carbamazepine, serotonin reuptake inhibitors (SSSRIs)
idiopathic (i.e. unknown)
how can syndrome of inappropriate anti-diuretic hormone (SIADH) be managed?
common cause of prolonged hospital stay
restrict fluid
can use vasopressin antagonist (vaptan) to bind to V2 receptor in kidney but this is very expensive
what do somatotrophs secrete and what condition is caused by its over secretion?
growth hormone
acromegaly
what do lactotrophs secrete and what condition is caused by its over secretion?
prolactin
prolactinoma (most common)
what do thyrotrophs secrete and what condition is caused by its over secretion?
TSH
TSHoma (very rare)
what do gonadotrophs secrete and what condition is caused by its over secretion?
LH and FSH
gonadotrophinoma (very rare)
what do corticotrophs secrete and what condition is caused by its over secretion?
ACTH
Cushing’s disease (corticotroph adenoma)
what is the difference between Cushing’s disease and syndrome?
Cushing’s disease = corticotroph adenoma causes high ACTH and high cortisol
Cushing’s syndrome = high cortisol for any reason
how can pituitary tumours be classified using radiological methods (MRI)?
by size
- microadenoma <1cm
- macroadenoma >1cm
sellar or suprasellar (has tumour has grown towards sella turcica boundary and optic chiasm?)
compressing optic chiasm?
invading cavernous sinus?
why is it difficult to remove a pituitary tumour that has invaded the cavernous sinus?
too difficult to surgically remove (likelihood of damage to cranial nerves, carotid etc.)
what is a functional tumour?
excess secretion of a specific pituitary hormone
e.g. prolactinoma
what is a non-functional tumour?
no excess secretion of pituitary hormone (non functioning adenoma)
why are pituitary tumours dangerous with respect to histology?
pituitary carcinoma very rare
however, pituitary adenomas can display benign histology but have malignant behaviour (grow into optic chiasm, cavernous sinus etc)
how is a cell determined to be cancerous?
check mitotic index for high division rate
benign has < 3% score
how does hyperprolactinaemia cause issues like amenorrhoea?
prolactin binds to prolactin receptors on kisspeptin neurons in hypothalamus
inhibits kisspeptin release
decrease downstream GnRH, LH, FSH, testosterone, oestrogen
causes oligo-amenorrhoea, low libido, infertility, osteoporosis
what is a prolactinoma?
commonest functioning pituitary adenoma
serum prolactin reaches >5000 mU/L
size of tumour proportional to serum prolactin level
how does a prolactinoma present?
menstrual disturbance
erectile dysfunction
reduced libido
galactorrhoea
subfertility
what are some physiological causes of prolactin elevation?
pregnancy/breastfeeding
stress: exercise, seizure, venepuncture
nipple/chest wall stimulation
what are some pathological causes of prolactin elevation?
primary hypothyroidism
polycystic ovarian syndrome
chronic renal failure
what are some iatrogenic causes of prolactin elevation?
antipsychotics (increases dopamine, which usually inhibits prolactin production)
SSRIs
anti emetics
high dose of oestrogen
opiates
what should be done if it is suspected that the “true” elevation of serum prolactin is false?
many false positives
no diurnal variation, not affected by food
if mild elevation but no clinical features or anything on the drug list then look for other options (macroprolactin, venepuncture stress)
how can macroprolactin cause an apparent rise in serum prolactin?
majority of circulating prolactin is monomeric and biologically active
macroprolactin is a ‘sticky’ protein and so forms polymeric form of prolactin with IgG (antigen-antibody complex)
causes elevation of prolactin to be recorded on assay
how can you prevent stress of venepuncture from causing an apparent rise in serum prolactin?
exclude by cannulated prolactin series
sequential serum prolactin measurement 20 mins apart with indwelling cannula to minimise venepuncture stress
what should be done after a true elevated prolactin has been confirmed?
pituitary MRI
how is a prolactinoma treated?
medical (no surgical intervention)
dopamine receptor agonists (e.g. cabergoline)- bind to dopamine (D2) receptors on lactotrophs to prevent binding of dopamine from hypothalmic dopaminergic neurones and therefore prevent secretion of prolactin
safe in pregnancy
aim is to normalise serum prolactin and shrink prolactinoma
microprolactinoma needs smaller doses than macroprolactinoma
what effect does an excess of GH have on children?
gigantism
what effect does an excess of GH have on adults?
acromegaly - increase in soft tissue
how does acromegaly present?
insidious presentation - long time to present in an obvious way
sweatiness
headache
coarsening of facial features
- macroglossia (enlarged tongue)
- prominent nose
large jaw - prognathism
increased hand and feet size
snoring and obstructive sleep apnoea
hypertension
impaired glucose tolerance/diabetes mellitus
how is acromegaly diagnosed?
some typical features presenting
GH is pulsatile so random measurement is unhelpful
elevated serum IGF 1
give oral glucose tolerance test (failed suppression of GH - GH goes up in acromegaly rather than down - paradoxical)
prolactin can also be raised (co-secretion of GH and prolactin) so pituitary MRI can be used to visualise tumour once GH excess is confirmed
how is acromegaly treated?
increased cardiovascular risk if not treated
surgical - transsphenoidal pituitary surgery
aim to normalise GH and IGF-1
can use medical treatment to shrink tumour before surgery/if surgical resection is incomplete
- somatostatin analogues (e.g. octreotide)
endocrine cyanide, stop GH secretion
- dopamine agonists (e.g. cabergoline), GH secreting pituitary tumours often have D2 receptors
radiotherapy can be used, but it is very slow
what are the presenting features of Cushing’s syndrome?
red cheeks
moon face
easy bruising
purple striae (stretch marks)
pendulous abdomen
poor wound healing
proximal myopathy (muscle weakness, thin arms and legs)
impaired glucose tolerance, diabetes mellitus
high blood pressure
thin skin
fat pads (buffalo hump)
mental changes (depression)
osteoporosis
why does Cushing’s syndrome occur?
excess cortisol or other glucocorticoid
too many steroids (common)
pituitary dependent Cushing’s disease (pituitary adenoma)
ectopic ACTH (lung cancer)
adrenal adenoma or carcinoma
what are the ACTH dependent causes of Cushing’s syndrome?
Cushing’s disease (corticotroph adenoma)
ectopic ACTH (lung cancer)
what are the ACTH independent causes of Cushing’s syndrome?
taking steroids by mouth (common)
adrenal adenoma or carcinoma
how is Cushing’s disease investigated?
elevation of 24h urine free cortisol (increased cortisol secretion)
high late night cortisol (salivary or blood test)
failure to suppress cortisol after oral dexamethasone (exogenous glucorticoid)
what steps should be taken after hypercortisolism is confirmed?
measure ACTH
if high ACTH is noted after hypercortisolism is confirmed, what should be done?
pituitary MRI
what visual disturbance do patients with non-functioning pituitary adenomas often present with?
bitemporal hemianopia
what hormonal disturbance do patients with non-functioning pituitary adenomas often present with?
(can present with hypopituitarism)
serum prolactin can be raised - dopamine can’t travel down pituitary stalk from hypothalamus
what is the function of the thyroid follicular cell?
TSH from anterior pituitary stimulates take up of iodine to form thyroxine (T4)
stored in follicular cell
TSH also stimulates activation of proteolytic enzymes which are needed to release thyroxine from follicular cell
what happens to the level of TSH in patients with primary hypothyroidism (autoimmune)?
high TSH in patient with damaged thyroid
try to stimulate thyroid to produce T4
how are the effects of primary hypothyroidism on TSH treated?
give oral TSH
increase dose till TSH falls to normal
what is the mechanism of Graves’ disease and its presenting symptoms?
autoimmune
antibodies bind to and stimulate TSH receptor in thyroid
causes growth of thyroid gland (goitre) and hyperthyroidism
different antibodies bind to muscle behind the eyes and makes them bigger (exophthalmos) because growth receptor
antibodies cause pretibial myxoedema (hypertrophy), causes swelling on shins, growth of soft tissue
what are the symptoms of Graves’ disease?
perspiration, facial flushing, sweaty hands
muscle wastage, weakness and fatigue
shortness of breath - tachycardia, palpitations, rapid pulse
pretibial myxoedema
weight loss despite increased appetite
oligomenorrhoea/amenorrhoea
exophthalmos (if extreme, may also have clubbing of fingers)
tremor
nervousness, excitability
restlessness, emotional instability, insomnia
bruit in goitre (blood rushing through thyroid)
goitre is smooth and regular (iodine uptake regular across entire thyroid)
what is Plummer’s disease and how does it differ from Graves’ disease?
single hot nodule/toxic nodular goitre
benign adenoma, overactive at making thyroxine
(not autoimmune,
no exophthalmos, no pretibial myxoedema)
iodine only taken up only on one side of thyroid, goitre on only one side
what are the effects of thyroxine on the sympathetic nervous system?
sensitises beta adrenoceptors to ambient levels of adrenaline and noradrenaline (i.e. small levels of thyroxine goes a long way)
causes apparent sympathetic activation (tachycardia, palpitations, tremor in hands, lid lag)
what are the principal features of hyperthyroidism?
weight loss despite appetite
can’t work far or fast - breathlessness
palpitations, tachycardia
sweating, heat intolerance
diarrhoea
lid lag, other sympathetic features
how is hyperthyroidism treated?
thyroidectomy
radioidodine
drugs
what is lid lag an effect of?
too much adrenaline (excess thyroxine causing stimulation)
why does a thyroid storm occur and what are its features?
caused by undiagnosed Graves’ disease
hyperpyrexia >41 degrees
accelerated tachycardia/arrhythmia
cardiac failure
delirium, psychosis
hepatocellular dysfunction; jaundice
high mortality (50%)
how are drugs used to treat hyperthyroidism?
thionamides (thiourylenes; anti thyroid drugs)
- propylthiouracil
- carbimazole
potassium iodide
radioiodine
blocks thyroid oxidase (convert iodide to iodine) and thyroid peroxidase - hence T3/4 synthesis and secretion is stopped
why are beta blockers used in the treatment of hyperthyroidism?
clinical effect of drugs like PTU and CBZ takes weeks although biochemical effects are quick (due to long half life and storage of thyroxine)
non selective beta blockers (e.g. propranolol) work immediately to relieve symptoms make patient feel better
i.e. reduced tremor, slower heart rate, less anxiety
what are the side effects of thionamides?
rashes
agranulocytosis - (usually reduction in neutrophils) - rare, reversible on withdrawal of drug
how is a course of treatment by drugs for hyperthyroidism followed up?
stop drugs after 18 months
review regularly
how is iodide (usually potassium iodide) used to treat hyperthyroidism?
only lasts 10 days, not effective long term - but symptoms reduce within 1-2 days
used in prep or hyperthyroid patients for surgery (smaller gland and less vascularisation within 10-14 days, therefore less likelihood of bleeding, clotting etc.)
also in thyroid storm (thyrotoxic crisis)
what is the mechanism of potassium iodide in treating hyperthyroidism?
inhibits iodination of thyroglobulin, inhibits hydrogen peroxide generation and thioperoxides
therefore inhibition of thyroid hormone synthesis and secretion (Wolff-Chaikoff effect - presumed autoregulatory effect of ingesting iodine)
what are the side effects of surgery to treat hyperthyroidism?
risk of voice change
risk losing parathyroid glands
scar
anaesthetic
how is radioiodine used to treat hyperthyroidism?
swallow capsule of isotope I
contraindicated in pregnancy (avoid children and pregnant mothers)
for scans only (not treatment), 99-Tc pertechnetate is an option (cheaper)
what is the general process taken to treat hyperthyroidism?
start beta blockage
add anti thyroid drugs
what are the symptoms of viral (de Quervain’s) thyroiditis?
painful dysphagia
malaise
pain radiating to ear
hyperthyroidism
tender pre-tracheal lymph nodes
pyrexia
inflammation of thyroid - visibly enlarged (more so on one side), tender
what is the process of viral thyroiditis?
virus attacks thyroid follicle to cause pain
thyroid stops making thyroxine and makes virus
therefore no iodine uptake
all stored thyroxine released, fT4 rises, TSH falls - becomes hypothyroid after a month
after a further month, slow recovery occurs, patient becomes euthyroid again
what is postpartum thyroiditis?
similar to viral thyroiditis
no pain
occurs only after pregnancy
(immune system modulated during pregnancy)
what are the 3 types of corticosteroid produced by the adrenal cortex?
mineralocorticoids (aldosterone)
glucocorticoids (cortisol)
sex steroids (androgens, oestrogens)
what are the effects of angiotensin II on the adrenals to produce aldosterone?
bind to adrenal receptor
side chain cleavage
activates enzymes
- 3-Hydroxysteroid dehydrogenase
- 21-hydroxylase
- 11-hydroxylase
- 18-hydroxylase
what is the action of aldosterone?
controls blood pressure, sodium, lowers potassium
what is the steroid synthetic pathway to produce aldosterone?
cholesterol converted to progesterone
21-hydroxylase converts progesterone to 11-deoxycorticosterone
11-hydroxylase converts 11-deoxycorticosterone
to corticosterone
18-hydroxylase converts corticosterone to aldosterone
what is the steroid synthetic pathway to produce cortisol?
cholesterol converted to progesterone
17-hydroxylase converts progesterone to 17-hydroxyprogesterone
21-hydroxylase converts 17-hydroxyprogesterone to 11-deoxycorticosterone
11-hydroxylase converts 11-deoxycorticosterone
to cortisol
what is Addison’s disease?
adrenal glands don’t produce enough steroid hormone, pituitary starts secreting lots of ACTH and hence MSH (melanocyte stimulating hormone)
caused by
- primary adrenal failure
- autoimmune disease where the immune system decides to destroy the adrenal cortex (commonest cause in UK)
- tuberculosis of the adrenal glands (commonest cause worldwide)
increased pigmentation
autoimmune vitiligo
no cortisol or aldosterone, so low blood pressure
weakness
weight loss
gastrointestinal effects: nausea, diarrhoea, vomiting, constipation, abdominal pain
what is pro-opio-melanocortin (POMC)?
large precursor protein
cleaved to form a number of smaller peptides - e.g. ACTH, MSH and endorphins
thus people who have pathologically high levels of ACTH may become tanned
what are the 3 main causes of adrenocortical failure?
tuberculous Addison’s (most common worldwide)
autoimmune Addison’s (commonest in UK)
congenital adrenal hyperplasia (not enough hormone)
consequences: low blood pressure, loss of salt in urine, increased plasma potassium, fall in glucose due to glucocorticoid deficiency, high ACTH resulting in increased pigmentation
what are the acute presenting features of Addison’s?
breathlessness
exhaustion
weight loss
postural hypotension, dizziness
tanned
what tests are taken for Addison’s disease?
clinical suspicion -
9am cortisol blood test - low
ACTH - high
short synACTHen test - typical cortisol response
how is adrenal failure treated?
half life of aldosterone is too short for safe once daily administration
aldosterone substitute (fludrocortisone - fluoride ion is not easily biodegradable, binds to MR and GR)
how is a cortisol deficiency treated?
oral hydrocortisone has short half life - too short for once daily administration
1-2 dehydro-hydrocortisone, prednisolone once daily - longer half life, more potent, higher binding affinity
can mimic the diurnal rhythm
what is congenital adrenal hyperplasia?
commonest caused by 21-hydroxylase deficiency (complete or partial)
can’t produce aldosterone or cortisol
in newborns - baby’s ACTH increases to try and force synthesis of hormones, causing hyperplasia (before birth foetus gets steroids across placenta)
what is the effect of complete 21-hydroxylase deficiency?
can’t produce aldosterone or cortisol
causing more sex steroid (excess testosterone)
causes ambiguous sex presentation in female newborns (hirsutism and virilisation), indication of approaching adrenal crisis - possibility of death
what is the effect of partial 21-hydroxylase deficiency?
some aldosterone and cortisol produced, can get by
high testosterone - hirsutism and virilisation in females, precocious puberty in males
present at any age, but early apparent puberty
what is the effect of 11-hydroxylase deficiency?
cortisol and aldosterone are deficient
excess sex steroids and testosterone - virilisation
11-deoxycorticosterone (behaves like aldosterone - excess causes hypertension and low potassium)
what is the effect of 17-hydroxylase deficiency?
deficient in sex steroids, no cortisol
excess aldosterone and 11-deoxycorticosterone - causes hypertension, low potassium
glucocorticoid deficiency (low glucose)
which inhibitors of steroid biosynthesis are used to control excess cortisol in Cushing’s syndrome?
metyrapone
ketoconazole
what is Conn’s syndrome?
excess aldosterone
how does metyrapone work to control cortisol levels?
11-hydroxylase inhibitor - prevents synthesis
steroid synthesis in the zona fasciculata and reticularis halted at 11-deoxycortisol stage
11-deoxycortisol has no negative feedback effect on the hypothalamus and pituitary gland
control before surgery - lower cortisol
- improves patient’s symptoms and promotes better recovery (better wound healing, less infection)
control symptoms after radiotherapy
how does ketoconazole work to control cortisol levels?
inhibits 17-hydroxylase to inhibit cortisol (prevents conversion of progesterone to 17-
hydroxyprogesterone)
treatment and control of symptoms of Cushing’s before surgery
what are the side effects of taking metyrapone?
high blood pressure, high K (11-deoxycorticosterone accumulates, promoting salt )retention
excess testosterone (hirsutism)
what are the side effects of taking ketoconazole?
liver damage
how is adrenal Cushing’s syndrome treated?
bilateral adrenalectomy
unilateral adrenalectomy for 1 adrenal mass
metyrapone/ketoconazole
what is Conn’s syndrome?
benign adrenal cortical tumour in zona glomerulosa
aldosterone in excess
hypertension and hypokalemia
how is Conn’s syndrome diagnosed?
Conn’s is primary hyperaldosteronism
suppress renin-angiotensin system to eliminate secondary hyperaldosteronism
how is Conn’s syndrome treated?
mineralocorticoid receptor antagonist
- spironolactone
- epleronone
how does spironolactone work to treat Conn’s syndrome?
converted to several active metabolites including canrenone (competitive antagonist of MR)
blocks sodium reabsorption and potassium excretion in kidney tubules (also used as hypertension treatment)
what are the side effects of spironolactone?
menstrual irregularities (increased progesterone receptor expression)
gynaecomastia (less androgen receptor expression)
how does epleronone work to treat Conn’s syndrome?
MR antagonist
similar affinity to MR
what is a
phaeochromocytoma?
tumour of adrenal medulla and secrete catecholamine
tachycardia - more adrenaline (affects heart) and noradrenaline (affects blood pressure)
what are the clinical features of a phaeochromocytoma?
intermittent episodes of severe hypertension- more frequent as tumour gets larger (can cause MI or stroke)
hypertension in young people (unusual)
more common in certain inherited conditions
high adrenaline can cause ventricular fibrillation and death
how is a phaeochromocytoma treated?
eventually need surgery (however anaesthetic can precipitate a hypertensive crisis)
alpha blockade, give fluid
beta blockade to prevent tachycardia
how is the level of serum calcium increased?
vitamin D (synthesised in skin or intake via diet)
parathyroid hormone (PTH) - secreted by parathyroid glands
main regulators of calcium and phosphate homeostasis via actions on kidney, bone and gut
how is the level of serum calcium decreased?
calcitonin (secreted by thyroid parafollicular)
can reduce calcium acutely, but no negative effect if parafollicular cells are removed (e.g. thyroidectomy)
what is the process of vitamin D synthesis?
UV light converts 7-dehydrocholesterol to pre-vitamin D3
vitamin D3 OR vitamin D2 (taken in through diet) taken to liver
first hydroxylation: vitamin D to 25-cholecalciferol (via 25-hydroxylase)
second hydroxylation: in kidney, 25-cholecalciferol to 1,25-dihydroxycholecalciferol (calcitriol) (via 1-alpha hydroxylase)
vitamin D (calcitriol) regulates its own synthesis by decreasing transcription of 1-alpha hydroxylase
what are the effects of calcitriol?
gut: absorb calcium and phosphate
kidney: reabsorb calcium and phosphate
bone: increases osteoblast activity (bone strength and mineralisation)
what are the actions of PTH?
gut: increases calcium and phosphate absorption by increasing calcitriol synthesis
bone: increase calcium, stimulates osteoclasts to reabsorb it
kidney: phosphate excretion, calcium reabsorption, increased 1-alpha hydroxylase activity
stimulates 1-alpha hydroxylase activity in kidney to increase calcitriol
all this increases plasma calcium
what is FGF23?
factor released from bone
gut: inhibits calcitriol synthesis, causes less phosphate reabsorption from the
kidneys: prevent phosphate reabsorption by inhibiting sodium-phosphate transporters
serum phosphate low due to increased urine phosphate excretion
what are the symptoms of hypocalcaemia?
sensitises excitable tissues, muscle cramps, tetany (cramping), tingling
paraesthesia (hands, mouth, feet, lips) (Chvosteks’ sign)
convulsions (Trousseau’s sign - carpopedal spasm)
arrythmias
tetany
how do low PTH levels (hypoparathyroidism) cause hypocalcaemia?
surgical (neck surgery - e.g. thyroid surgery)
auto immune
Mg deficiency (needed for PTH release from parathyroid)
congenital (agenesis, rare)
how do low vitamin D levels cause hypocalcaemia?
deficiency - diet, UV light, malabsorption, impaired production (renal failure)
what are the signs of hypercalcaemia?
reduced neuronal excitability - atonal muscles
stones, renal effects
- nephrocalcinosis - kidney stones, renal colic
“abdominal moans”, GI effects
- anorexia, nausea, dyspepsia
“psychic groans”, CNS effects
- fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)
how can primary hyperparathyroidism cause hypercalcaemia?
too much PTH
(usually due to a PT gland adenoma)
no negative feedback - high PTH but high calcium
how can malignancy cause hypercalcaemia?
bony metastases produce local factors to activate osteoclasts, release lots of calcium into circulation
certain cancers (e.g. squamous cell carcinoma) secrete PTH related peptide that acts at PTH receptors
how common is it for a vitamin D excess to cause hypercalcaemia?
very rare
what is the relationship between PTH and calcium?
calcium sensing receptors present on parathyroid gland
if calcium low, then it is detected and PTH goes up
if calcium goes up, it is detected and PTH goes down
what is primary hyperparathyroidism?
adenoma of one gland
increased PTH production
therefore increased calcium (increased absorption from gut, increased 1-alpha hydroxylase etc)
no negative feedback do to autonomous PTH secretion
what is the biochemistry of primary hyperparathyroidism?
high calcium
low phosphate - increased renal phosphate excretion (inhibition of sodium/phosphate co transporter in kidney by FGF23)
high PTH (not suppressed by hypercalcaemia)
how is primary hyperthyroidism treated?
parathyroidectomy
what are the risks of untreated primary hyperparathyroidism?
osteoporosis - osteoclasts stimulated by PTH, have increased activity
increased calcium being filtered through kidney causes deposits - renal calculi (stones)
psychological impact of hypercalcaemia - mental function, mood
what is secondary hyperparathyroidism?
initial low calcium
sensed by parathyroid gland, PTH stimulated (normal physiological response to hypocalcaemia)
PTH is high secondary to low calcium
what are the causes of secondary hyperparathyroidism?
vitamin D deficiency - diet, sunlight access
less common - renal failure, cannot make calcitriol
how is secondary hyperparathyroidism treated?
vitamin D replacement
normal renal function: give 25-hydroxy vitamin D, patient can convert to calcitriol via 1-alpha hydroxylase
renal failure (no 1-alpha hydroxylase): give alfacalcidol - 1-alpha hydroxycholecalciferol
what is tertiary hyperparathyroidism?
(rare)
initial chronic renal failure, causes chronic vitamin D deficiency
over time calcium is very low
initially PTH increases (hyperparathyroidism)
hyperplasia of parathyroid glands
eventually all 4 glands become autonomous, cause hypercalcaemia
how is tertiary hyperparathyroidism treated?
parathyroidectomy
what is the diagnostic approach to hypercalcaemia?
if high calcium, look at PTH (if normal response, PTH should be low)
if PTH is low, then hypercalcaemia is due to other causes (not primary hyperparathyroidism)- e.g. hypercalcaemia due to to malignancy
if PTH is raised, hyperparathyroidism
- if renal function is normal, then primary hyperparathyroidism
- if renal failure, tertiary hyperparathyroidism
if calcium is low, PTH is high, then secondary
how are vitamin D levels measured?
calcitriol difficult to measure
therefore measured as 25-hydroxy vitamin D
what is infertility?
A disease of the reproductive system defined by the failure to achieve a clinical pregnancy after ≥12 months of regular (every 2-3 days) unprotected sexual intercourse
what is primary infertility?
when have not had a previous live birth
what is secondary infertility?
when have had a live birth >12 months previously
how common is infertility?
affects 1 in 7 couples
55% will seek help in UK - association with socioeconomic status
what are most common causes of infertility in a couple?
female factors (30%)
male factors (30%)
combined (30%)
unknown (10%)
what is the impact of infertility on a couple?
psychological distress
- impact on couple
- impact on larger family
- investigations
- treatments may not work
what is the impact of infertility on society?
fewer births
less tax income
investigation costs
treatment costs
what are the pre-testicular causes of male infertility?
congenital and acquired endocrinopathies
- Klinefelter’s 47 XXY
- Y chromosome deletion
- HPG, T, PRL
what are the testicular causes of male infertility?
congenital
cryptorchidism
infection (STDs)
immunological (anti sperm antibodies)
vascular (variococoele)
trauma/surgery
toxins (chemotherapy, DXT, drugs, smoking)
what are the post-testicular causes of male infertility?
congenital (absence of vas deference in cystic fibrosis)
obstructive azoospermia (no sperm)
erectile dysfunction
- retrograde ejaculation
- mechanical impairment
- psychological
iatrogenic
- vasectomy
what is cryptorchidism?
undescended testis
what are the ovarian causes for female infertility?
40%
anovulation (endocrinal cause)
corpus luteum insufficiency
what are the tubal causes for female infertility?
30%
tubopathy due to:
- infection
- endometriosis
- trauma
what are the uterine causes for female infertility?
10%
unfavourable endometrium due to:
- chronic endometritis (e.g. caused by TB)
- fibroid
- adhesions (synechiae)
- congenital malformation
what are the cervical causes for female infertility?
5%
ineffective sperm penetration due to:
- chronic cervicitis
- immunological (anti sperm antibodies)
what are the pelvic causes for female infertility?
endometriosis
adhesions
how does endometriosis cause infertility (not endocrine)?
functioning endometrial tissue outside the uterus
responds to oestrogen
what are the symptoms of endometriosis?
increased menstrual pain
menstrual irregularities
deep dyspareunia (pain during sexual intercourse)
infertility
how is endometriosis treated?
hormonal (e.g. continuous OCP, progesterone)
laparoscopic ablation
hysterectomy
bilateral salpingo-oophorectomy
how do fibroids cause infertility (not endocrine)?
benign tumours of myometrium
1-20% of pre menopausal women (increases with age)
respond to oestrogen
what are the symptoms of fibroids?
usually asymptomatic
increased menstrual pain
menstrual irregularities
deep dyspareunia (pain during sexual intercourse)
infertility
what is the treatment for fibroids?
hormonal (e.g. continuous OCP, progesterone, continuous GnRH agonists)
hysterectomy
what is the hypothalamic - pituitary - gonadal (HPG) axis?
kisspeptin neurons in hypothalamus
GnRH neurons stimulated
GnRH released into hypophyseal portal circulation, reaches anterior pituitary
gonadotrophs stimulated -
release LH and FSH
into systemic circulation
reaches gonads to stimulate
negative feedback from oestrogen for regulation
what hormonal pattern is shown in hyperprolactinaemia?
LH, FSH, T all decrease
what hormonal pattern is shown in primary testicular failure (e.g. Klinefelter’s)?
LH, FSH increases
T decreases
what factors in the hypothalamus cause male infertility?
decreased GnRH (not measurable)
decreased testosterone (hypogonadism)
LH, FSH decrease (hypogonadotrophism)
congenital: anosmic (Kallmann syndrome) or normosmic
acquired: low BMI, excess exercise, stress
hyperprolactinaemia
what factors in the anterior pituitary cause male infertility?
(hypogonadotrophism, hypogonadism)
hypopituitarism
- tumour
- infiltration
- apoplexy (no blood supply)
- surgery
- radiation
what factors in the gonads cause male infertility?
(hypergonadotrophism, hypogonadism)
primary hypogonadism- congenital: Klinefelter’s
acquired:
- cryptorchidism
- trauma
- chemotherapy
- radiation
what is Kallmann syndrome and what hormonal features are present?
congenital defect in failure of migration of GnRH neurons with
olfactory fibres
low GnRH, LH, FSH, T
what are the reproductive features of Kallmann syndrome?
cryptorchidism
failure of puberty
infertility
what is Klinefelter’s syndrome?
47 XXY karyotype
hypergonadotrophic hypogonadism
what are the features of Klinefelter’s syndrome?
tall stature
mildly impaired IQ
narrow shoulders
reduced facial and chest hair
wide hips
low bone density
female-type pubic hair pattern
small penis and testes
infertility (accounts for up to 3% of cases)
what history should be taken in male infertility?
duration
previous children
pubertal milestones
associated symptoms (e.g. T deficiency, PRL symptoms, CHH features)
medical and surgical history
family history
social history
medications or drugs
what examinations should be made in male infertility?
BMI
sexual characteristics
testicular volume
epididymal hardness
presence of vas deferens
other endocrine signs
syndromic features,
anosmia
what blood tests should be done in male infertility?
LH, FSH, PRL
morning fasting testosterone (as diurnal)
sex hormone binding globulin (SHBG)
albumin (binds to testosterone), iron studies (affects pituitary)
pituitary/thyroid
karyotyping
what microbiology tests should be done in both female and male infertility?
urine test
chlamydia swab
what imaging tests should be done in male infertility?
scrotal US/doppler
(varicocoele)
MRI pituitary
(if low FSH/LH or high PRL)
what lifestyle changes should be made to treat male infertility?
optimise BMI
smoking cessation
alcohol reduction
what specific treatments should be given for male infertility?
hyperprolactinaemia - dopamine agonist
for fertility - gonadotrophin treatment (will also increase testosterone)
if no fertility required, take testosterone to treat symptoms
surgery (e.g. micro testicular sperm extraction)
what are the main disorders of the menstrual cycle?
menstrual cycles
- 28-day cycle (24-35 days).
- ±2 days each month.
primary amenorrhoea
- alter than 16yrs is regarded as abnormal
secondary amenorrhoea
- common for periods to be irregular / anovulatory for first 18 months.
- periods start but then stop for at at least 3-6 months
amenorrhoea (absence of periods)
- no periods for at least 3-6 months.
- or up to 3 periods per year
oligo-menorrhoea - (few periods)
- irregular or infrequent periods >35day cycles
- or 4-9 cycles per year
what hormonal pattern is seen in premature ovarian insufficiency?
high LH, FSH
low oestradiol
how is premature ovarian insufficiency diagnosed?
high FSH >25 iU/L (x2 at least 4wks apart)
what are the causes of premature ovarian insufficiency?
autoimmune
genetic
cancer therapy
what hormonal pattern is seen in anorexia induced amenorrhoea?
low FSH, LH, oestradiol
what factors in the hypothalamus cause female infertility?
decreased oestrogen (hypogonadism)
LH, FSH decrease (hypogonadotrophism)
congenital: anosmic (Kallmann syndrome) or normosmic
acquired: low BMI, excess exercise, stress
hyperprolactinaemia
hypothalamic amenorrhoea
what factors in the anterior pituitary cause female infertility?
(hypogonadotrophism, hypogonadism)
hypopituitarism
- tumour
- infiltration
- apoplexy (no blood supply)
- surgery
- radiation
what factors in the gonads cause male infertility?
(hypergonadotrophism, hypogonadism)
PCOS
congenital: Turner’s syndrome (45X0), Premature Ovarian Insufficiency (POI)
acquired: Premature Ovarian Insufficiency (POI), surgery, trauma, chemotherapy, radiation
how is PCOS diagnosed?
exclude other disorders
Rotterdam PCOS diagnostic criteria, meet 2 out of 3
oligo/anovulation: normally assessed by menstrual frequency as oligomenorrhoea: <21d or >35d cycles <8-9 cycles/y >90d for any cycle
if necessary anovulation can be proven by:
lack of progesterone rise or US
clinal +/- biochemical hyperandrogenism
- clinical: acne, hirsutism, alopecia
- biochemical: raised androgens (e.g. testosterone)
polycystic ovaries
- more than 20 follicles on either ovary
how are the respective risks of PCOS treated?
irregular periods
- metformin
- oral contraceptive
infertility
- clomiphene, letrozole
- IVF
hirsutism
- anti androgens
- creams, waxing, laser
increased insulin resistance (impaired glucose homeostasis - T2DM, gestational DM)
- diet and lifestyle
- metformin
increased risk of endometrial cancer
- metformin
- progesterone courses
what are the symptoms of Turner’s syndrome (45 X0)?
Idecreased testosterone, high LH, FSH)
short stature
characteristic facies
webbed neck
low hairline
shield chest
coarctation of aorta
wide-spaced nipples
poor breast development
elbow deformity
short 4th metacarpal
underdeveloped reproductive tract
small fingernails
brown nevi
amenorrhoea
what history should be taken in female infertility?
duration
previous children
pubertal milestones
associated symptoms (e.g. oestrogen deficiency, PRL symptoms, CHH features)
medical and surgical history
family history
social history
medications or drugs
breastfeeding
menstrual history: oligomenorrheoa/amenorrhoea, associated symptoms
what examinations should be done in female infertility?
BMI
sexual characteristics
other endocrine signs
syndromic features,
anosmia
hyperandrogenism signs
pelvic examination
what blood tests should be done in female infertility?
LH, FSH, PRL
sex hormone binding globulin (SHBG)
albumin (binds to testosterone), iron studies (affects pituitary)
pituitary/thyroid
oestradiol, androgens
foll phase 17-OHP, mid luteal progesterone
what imaging tests should be done in female infertility?
pregnancy test
- urine or serum hCG
US (transvaginal)
hysterosalpingogram
MRI of pituitary
(if low LH/FSH or high PRL)
how is primary hypogonadism treated in males?
difficult to treat
how is secondary hypogonadism treated?
deficiency of gonadotrophins i.e. hypogonadotrophic hypogonadism
treat with gonadotrophins to induce spermatogenesis:
- LH stimulates Leydig cells to increase intra-testicular testosterone to much higher levels
- FSH stimulates seminiferous tubule development and spermatogenesis
what treatment should be given for male infertility?
avoid testosterone to men needing fertility (will lower LH/FSH and reduce spermatogenesis in secondary hypogonadism)
give hCG injections which act on LH receptors
if no response after 6 months, add FSH injections
does male congenital secondary hypogonadism (e.g. Kallmann syndrome) have better, same or worse prognosis than acquired secondary hypogonadism (e.g. pituitary tumour)? how is this treated?
worse
have had no puberty due to no GnRH deficiency
FSH during mini-puberty (after birth) important to grow spermatogonia and germ cells
2-4 months pre-treatment with FSH before hCG treatment
pre-treatment testicular size (seminiferous tubules ) >6ml have better prognosis
if fertility is not required, when and how is testosterone replaced?
symptoms: loss of morning erections, decreased libido, decreased energy, less shaving
check for hypogonadism
at least 2 low testosterone measurements before 11am (them investigate cause)
testosterone replacement:
- daily gel (risk of contaminating partner)
- 3 weekly intramuscular injection
- 3 monthly intramuscular injection
- less common (implants, oral preparations)
what are the risks of testosterone replacement?
increased haematocrit (more viscous and likely to clot - risk of stroke)
risk of stimulating prostate - might increase prostate size
in a case of PCOS, what is the general principle behind ovulation induction?
develop one ovarian follicle (risk of multiple pregnancy increases if both follicles are developed)
aim to increase FSH by small amount
how is ovulation restored in PCOS?
lifestyle/weight loss/ metformin
letrozole (aromatase inhibitor
clomiphene (oestradiol receptor antagonist)
FSH stimulation
how does letrozole work to restore ovulation in PCOS?
aromatase inhibitor
prevents conversion of testosterone to oestradiol
no negative feedback to hypothalamus and pituitary, so increased GnRH, LH, FSH
stimulate follicle growth
how does clomiphene work to restore ovulation in PCOS?
blocks oestradiol receptors in hypothalamus and pituitary
decreased negative feedback so increased GnRH, LH, FSH
stimulate follicle growth
what is the process of IVF?
high doses of FSH to stimulate follicle growth
prevent ovulation from occurring by preventing premature LH surge (otherwise egg will leave the uterus)
- short protocol: give GnRH antagonist after starting FSH
- long protocol: give GnRH agonist before FSH
hCG trigger to give LH for maturation of eggs
(eggs go from being diploid to haploid from metaphase 1 and 2 - now has capability to be fertilised)
retrieve eggs
fertilise in vitro
- natural sperm action
- intra cytoplasmic sperm injection if male factor is not functioning
incubation of embryo for 3-5 days
transfer some embryos to endometrium
why are both GnRH agonists and GnRH antagonists effective to prevent premature ovulation (i.e. preventing premature LH surge)?
if GnRH is given in a pulsatile way, stimulation of LH occurs
if a continuous high dose of GnRH (non pulsatile), desensitisation of receptors prevents production of LH
what can cause ovarian hyper stimulation syndrome and what are the symptoms?
triggered by hCG (given during IVF to trigger egg maturation, causes excessive ovarian stimulation)
symptoms:
- pleural effusion
- ascites
- renal failure
- ovarian torsion
what are the 5 non-permanent types of contraception?
barrier: male / female condom/ diaphragm or cap with spermicide
combined oral contraceptive pill (OCP)
progestogen-only pill (POP)
long acting reversible contraception (LARC)
emergency contraception
(vasectomy, female sterilisation are permanent)
what are the positives of barrier contraception?
easy to obtain – free from clinics
no need to see a healthcare professional
protect against STI’s
no contra-indications as with some hormonal methods
what are the negatives of barrier contraception?
can interrupt sex
can interfere with erections
some skill to use properly
(e.g. ensure no air, not too large or small)
how does an oral contraceptive pill work?
consists of oestrogen and progesterone
negative feedback to stop LH and FSH production
what are the effects of the oral contraceptive pill to prevent pregnancy?
anovulation
thickening of cervical mucus
thinning of endometrial lining (reduces implantation)
what are the positives of the combined oral contraceptive pill?
easy to take (one pill daily)
effective
doesn’t interrupt sex
can take several packets back to back and avoid withdrawal bleeds
weight neutral in 80%
reduce endometrial and ovarian cancer risk
what are the negatives of the combined oral contraceptive pill?
may be hard to remember
no protection against STIs
risk of P450 inducers lessening efficacy during metabolism of OCP
cannot be taken when breastfeeding
side effects:
- spotting
- nausea
- sore breasts
- mood changes/ changes in libido
- increased hunger
- (rare - blood clots in legs or lungs)
what are the non-contraceptive benefits of taking the combined oral contraceptive pill?
periods lighter and less painful
(endometriosis or period pain or menorrhagia)
withdrawal bleeds regular
PCOS: reduce LH and hyperandrogenism
what are the positives of the progesterone only pill?
can be used during breastfeeding
often suitable if can’ttake oestrogen
easy to take – one pill a day, every day with no break
doesn’t interrupt sex
can help heavy or painful periods
periods may stop (temporarily)
what are the negatives of the progesterone only pill?
less reliably inhibits ovulation (compared to combined pill)
may be difficult to remember
shorter acting (must be taken at the same time each day)
side effects:
- irregular bleeding
- headaches
- sore breasts
- changes in mood
- changes in sex drive
how does a copper coil IUD act as a contraceptive (LARC)?
prevent implantation decreases sperm and egg survival as copper is toxic to them
can also be used as emergency contraception (fitted up to 5 days after sex)
what are the negatives of a copper coil IUD?
can cause heavy periods
some come out
how does a mirena coil IUS act as a contraceptive (LARC)?
secretes progesterone
thins lining of womb and thickens cervical mucus (can also be used to help with heavy bleeding)
what are the 3 forms of long acting reversible contraceptives (LARC)?
IUD
IUS
progestogen only injectable contraceptives or subdermal implants
how does ulipristal acetate work in an emergency contraceptive pill?
stops progesterone function, prevents ovulation
must be taken within 5 days of sex
how does levonorgestrel work in an emergency contraceptive pill?
synthetic progesterone prevents ovulation (don’t cause abortion)
must be taken within 3 days of sex
what are the considerations to make when choosing a contraception method?
risk of thromboembolism/CVD/stroke - avoid OCP if:
- migraine with aura
- smoking if older than 35 yrs
- stroke or CVD history
- current breast cancer
- liver cirrhosis
- diabetes with retinopathy/nephropathy/neuropathy
other conditions that may benefit from OCP (e.g. menorrhagia, endometriosis, fibroids)
need to prevent STIs
concurrent medication:
- P450 liver enzyme-inducing drugs (e.g. anti-epileptics,some antibiotics)
- teratogenic drugs (e.g. lithium, warfarin)
more effective methods of contraception needed
(e.g. progestogen-only implant, intrauterine contraception)
what are the risks of HRT?
venous thromboembolism risk:
- transdermal is safer than oral oestrogen, especially with a BMI above 30
breast cancer:
- slight increase in breast cancer risk only in women on combined
HRT (oestrogen and progesterone)
- risk related to duration of treatment, reduces after stopping
- continuous worse than sequential
(assess background risk for each woman)
ovarian cancer:
- small increase in ovarian cancer risk only after long-term use
endometrial cancer:
- must prescribe progestogens
- assess safety at 3 months and then annually
- unscheduled bleeding common within first 3 months
- post menopausal bleeding could indicate endometrial cancer
increased risk of CVD?:
- none if started before 60yrs
- increased if started 10 years after menopause
- possible benefits of oestrogen supplementation for younger women
risk of stroke
- small
- oral gives higher risk than transdermal
- combined gives higher risk than POP
what are the benefits of HRT?
relief of symptoms of low oestrogen
e.g. flushing, disturbed sleep, decreased libido, low mood
fewer osteoporosis related fractures
what is the process of gender reassignment for transgender men?
if pre-pubertal - GnRH agonist for pubertal suppression and give sex steroids
gender reassigning surgery after 2-3 years
give testosterone side effects: - polycythaemia - lower HDL - obstructive sleep apnoea
give progesterone to suppress menstrual bleeding if needed
effects in 6 months:
- balding (depending on your age and family pattern)
- deeper voice
- acne
- increased and coarser facial and body hair
- change in the distribution of your body fat
- enlargement of the clitoris
- menstrual cycle stops
- increased muscle mass and strength
what is the process of gender reassignment for transgender women?
if pre-pubertal - GnRH agonist for pubertal suppression and give sex steroids
gender reassigning surgery after 2-3 years
give oestrogen side effects: - dose-related venous thromboembolism risk - high BP - CVD - high triglyceride - hormone sensitive cancer risk
reduce testosterone through:
- GnRH agonists (induce desensitization of HPG axis)
- anti-androgen medications (e.g. cyproterone acetate, spirnolactone)
1-3 months:
- decrease in sexual desire/function
- baldness slows
3-6 months:
- softer skin and change in body fat distribution
- decrease in testicular size
- breast development and tenderness
6-12 months:
- hair may become soft and finer
what is obesity?
condition of abnormal or excessive fat accumulation in adipose tissue to the extent that health is impaired
how is obesity usually measured?
BMI
why is BMI sometimes inaccurate?
muscle mass
increases BMI
what drives obesity?
genetics
- 60-80%
environment
when in an unhealthy environment, being genetically prone/genetically averse to obesity has a huge impact
what are some things that contribute to an obesogenic environment?
food
- availability
- food price (cheap)
- sugar and fat
what factors are associated with obesity?
not as many outdoor spaces
increased car use
increased screen time
education level and achievement
poverty, social deprivation
what are some comorbidities associated with obesity?
depression
stroke
MI
hypertension
diabetes
peripheral vascular disease
gout
bowel cancer
osteoarthritis
sleep apnoea
(associated with mortality)
how is obesity treated?
determine degree of obesity
assess lifestyle, comorbidities, willingness to change - implement lifestyle changes and drug treatment
consider referral to specialist care - specialist assessment and management
consider surgery and follow up
what kind of diet should be followed to try and manage obesity?
higher vegetable and fruit content
combine with exercise
what drugs are used to manage obesity?
orlistat
derivative of an endogenous lipstatin produced by Streptomyces toxytricini
gastric and pancreatic lipase inhibitor
reduces dietary fat absorption by around 30%.
what are some of the issues with orlistat?
meta-analysis of 11 placebo-controlled trials of 1 year in 6021 overweight or obese patients, orlistat reduced weight by only 2·9%
attrition rates were high ~33%
fatty and oily stool, faecal urgency, oily spotting, faecal incontinence in 7%
possible deficiencies of fat-soluble vitamins
no long-term data on orlistat on obesity-related morbidity and mortality
when is bariatric surgery an option?
consider as first-line option for adults with a BMI of higher than 50
BMI of 40 or more
BMI of 35-40 with comorbidities
BMI of 30-35 for newly diagnosed type 2 diabetes
– non-surgical measures have failed to achieve or maintain adequate clinically beneficial weight loss for at least 6 months
– receiving or will receive intensive specialist management
– generally fit for anaesthesia and surgery
– commit to the need for long-term follow-up
surgery is effective but impractical for large numbers
how does a gastric bypass work?
the top part of your stomach is joined to the small intestine
feel fullersooner, do not absorb as many calories from food
how does a gastric band work?
band is placed around stomach
do not need to eat as much to feel full
how does a sleeve gastrectomy work?
some of your stomach is removed
cannot eat as much as before, feelfull sooner
early type 1
lots of immune cells
in the end there is fibrosis around islet
why can diabetes classification be complicated?
autoimmune diabetes leading to insulin deficiency can present in later life - clinicians must differentiate between adult-onset type 1 from large numbers of type 2
T2DM can present in childhood
diabetic ketoacidosis can be feature T2DM
monogenic diabetes can present phenotypically as Type 1 or Type 2 diabetes (eg. MODY, mitochondrial diabetes)
diabetes may present following pancreatic damage or other endocrine disease
how does type 1 diabetes develop?
initial genetic predisposition
precipitating event (e.g. virus, stress) triggers autoimmune reaction
initially insulin secretion and blood sugar stays the same, but progressive loss of insulin release causes glucose to rise
eventually no C-peptide (cleavage product of pro-insulin) is present
what is the histological difference between early type 1 diabetes and long standing T1D?
early type 1: lots of immune cells surround
long duration type 1: no immune cells surrounding islet, fibrosis around islet
some continue to produce small amounts of insulin (not all beta cells destroyed) - reduced risk of further risks, although it does not negate the need for insulin therapy
why is the immune basis important?
increased prevalence of other autoimmune disease
risk of autoimmunity in relatives
more complete destruction of beta cells
auto antibodies can be useful clinically - measure diagnosis
immune modulation offers possibility of new treatments
what is the immunological response in type 1 diabetes?
presentation of auto antigen to autoreactive CD4+ T lymphocytes
CD4+ activate CD8+ lymphocytes
CD8+ travel to islets, lyse beta cells expressing auto antigens
exacerbated by release of pro-inflammatory cytokines
defects in regulatory T-cells that fail to regulate (i.e. auto antigens shouldn’t be present)
the HLA-DR allele is often a factor in risk of type 1 - which alleles increase risk and which provide protection?
some fit into 2 categories
protective: DR2, DR6, DR7 (although DR7 presents risk if African descent)
neutral: DR6, DR8
slight risk: DR1, DR5, DR8
significant risk: DR3, DR4, DR9 (in Chinese, Japanese, Korean)
what environmental factors are associated with type 1 diabetes?
multiple factors implicated, causality not established
- enteroviral infection
- cow’s milk protein exposure
- seasonal variation (link to viral infection)
- changes in microbiota
what is the diagnostic significance of pancreatic auto-antibodies?
detectable in sera of people with Type 1 at diagnosis (but not generally needed)
- insulin antibodies (IAA)
- glutamic acid decarboxylase (GADA) – widespread neurotransmitter
- insulinoma-associated-2 autoantibodies (IA-2A)-Zinc-transporter 8 (ZnT8)
what symptoms present in type 1 diabetes?
excessive urination (polyuria)
nocturia
excessive thirst (polydipsia)
blurring of vision
recurrent infection (e.g. thrush)
weight loss
fatigue
what symptoms present in type 1 diabetes?
dehydration
cachexia
hyperventilation
smell of ketones
glycosuria
ketonuria
(diagnosis is based on clinical features and presence of ketones - in some cases pancreatic autoantibodies/C-peptide may also be measured)
effects of insulin deficiency - proteinolysis produces AAs, increased hepatic glucose output, lipolysis produces glycogen and NEFA
what are the aims of treatment of type 1 diabetes?
maintain glucose levels without excessive hypoglycaemia
restore close-to-physiological insulin profile
prevent acute metabolic decompensation
prevent microvascular and macrovascular complications
what are the acute complications of hyperglycaemia caused by type 1 diabetes?
diabetic ketoacidocis
what are the chronic microvascular complications of hyperglycaemia caused by type 1 diabetes?
retinopathy
neuropathy
nephropathy
what are the chronic macrovascular complications of hyperglycaemia caused by type 1 diabetes?
ischaemic heart disease
cerebrovascular disease
peripheral vascular disease
what are the complications of the treatment of type 1 diabetes itself?
hypoglycaemia
how is type 1 diabetes managed?
insulin treatment
dietary support/structured education
technology
transplantation
(self-management of condition)
what are the forms of short/quick-acting insulin (taken with meals)?
human insulin - exact molecular replicate of human insulin (actrapid)
insulin analogue (Lispro, Aspart, Glulisine)
what are the forms of long-acting/basal insulin (once daily)?
bound to zinc/protamine (neutral protamine hagedorn, NPH)
insulin analogue (Glargine, Determir, Degludec)
how does insulin pump therapy in the treatment of type 1 diabetes?
continuous delivery of short acting insulin analogue e.g. novorapid via pump
delivery of insulin into subcutaneous space
programme the device to deliver fixed units/hour through the day
still need bolus (increased delivery of insulin) after meals
what are the advantages of an insulin pump in the treatment of type 1 diabetes?
variable basal rates
extended boluses
greater flexibility
what dietary advice is given to people with type 1 diabetes?
dose adjustment for carbohydrate content of food
all people with type 1 diabetes should be given training for carbohydrate counting (NICE guidelines)
where possible, substitute refined carbohydrate containing foods (sugary/high glycaemic index) with complex carbohydrates (starchy/low glycaemic index)
how does a closed loop/artificial pancreas work in the treatment of type 1 diabetes?
real time continuous glucose sensor
algorithm to use glucose value to calculate insulin requirement
insulin pump delivers calculated insulin
change in glucose level
cycle repeats
(still progressing)
how does an islet cell transplant work in the treatment of type 1 diabetes?
isolate human islets from pancreas of deceased donor
transplant into hepatic portal vein
(requires lifelong immunosuppression)
how does a simultaneous pancreas and kidney transplant work in the treatment of type 1 diabetes?
better survival rate of pancreas graft when transplanted with kidneys - therefore only used in cases of renal failure
what are the negatives of pancreas transplants in the treatment of type 1 diabetes?
life long immunosuppression
availability of donors
risk of rejection
what tests are used to monitor diabetes control overall?
glycated haemoglobin
capillary (finger prick) blood glucose monitoring
continuous glucose monitoring (restricting availability, NICE guidelines)
how is HbA1c used to test for diabetes?
reflect 3 months (RBC lifespan) of glycaemia
biased to last 30 days preceding measurement
glycated NOT glycosylated (enzymatic) - therefore linear relationship
irreversible reaction
what are the limitations of an HbA1c test?
erythropoiesis
- increased Hb1Ac: iron, vitamin B12 deficiency, decreased erythropoiesis
- decreased Hb1Ac: administration of erythropoietin, iron, vitamin B12, reticulocytosis, chronic liver disease
altered haemoglobin:
genetic/chemical alterations in Hb: haemoglobinopathies, HbF, methaemoglobin, may increase/decrease HbA1c
glycation
- increased Hb1Ac: alcoholism, chronic renal failure, decreased intra-erythrocyte pH
- decreased Hb1Ac: aspirin, vitamin C and E, certain haemoglobinopathies, increased intra-erythrocyte pH
- variable HbA1c: genetic determinants
erythrocyte destruction
- increased Hb1Ac; increased erythrocyte life span: splenectomy
- decreased A1c; decreased erythrocyte life span: haemoglobinopathies, splenomegaly, rheumatoid arthritis, drugs such as antiretrovirals, ribavirin, dapsone
what is used to guide insulin doses in treatment of type 1 diabetes?
self monitoring of blood glucose results at home
HbA1c results every 3-4 months
increase or decrease insulin doses
what are the acute complications of type 1 diabetes?
diabetic ketoacidosis
uncontrolled hyperglycaemia
hypoglycaemia
when does diabetic ketoacidosis occur?
can be a presenting feature of new-onset type 1 diabetes
occurs in those with established type 1 diabetes
acute illness
missed insulin doses
inadequate insulin doses
life-threatening complication
can occur in any type of diabetes
criteria for diagnosis
- pH <7.3
- ketones increased (urine or capillary blood)
- HCO3 <15 mmol/L
- glucose >11mmol/L
when does hypoglycaemia occur with reference to type 1 diabetes?
an inevitable feature of self management of type 1
may become debilitating with increased frequency
numerical definition is variable but <3.6mmol/L
severe hypoglycaemia: any event requiring 3rd party assistance
what are the adrenergic (initial) symptoms of hypoglycaemia?
tremors
palpitations
sweating
hunger
(sometimes no symptoms present - very dangerous)
what are the neuroglycopaenic symptoms of hypoglycaemia?
somnolence
confusion
incoordination
seizures
coma
when does hypoglycaemia become problematic (in type 1 diabetes treatment)?
excessive frequency
impaired awareness
nocturnal hypoglycaemia
recurrent severe hypoglycaemia
what are the risks of hypoglycaemia?
seizure/coma/death
impacts on emotional well-being
impacts on driving
impacts on day to day function
impacts on cognition
who is at risk/what are the risk factors for becoming hypoglycaemic with type 1 diabetes?
exercise
missed meals
inappropriate insulin regime
alcohol intake
lower HbA1c
lack of training
(all people with type 1 diabetes at risk)
what are some strategies to support problematic hypoglycaemia as a result of type 1 diabetes treatment?
indication for insulin-pump therapy (CSII)
may try different insulin analogues
revisit carbohydrate counting / structured education
behavioural psychology support
transplantation
what measures are taken for the acute management of hypoglycaemia if the patient is alert and orientated?
oral carbohydrates
rapid acting - juice/sweet
longer acting - sandwich
what measures are taken for the acute management of hypoglycaemia if the patient is drowsy?
buccal glucose
e.g. hypostop/glucogel
complex carbohydrate
what measures are taken for the acute management of hypoglycaemia if the patient is unconscious?
IV access
20% glucose IV
what is type 2 diabetes?
condition in which the combination of insulin resistance and beta-cell failure result in hyperglycaemia
how is type 2 diabetes managed?
hyperglycaemia
associated with obesity but not always
resultant chronic hyperglycaemia may initially be managed by changes to diet / weight loss and may even be reversible
with time glucose lowering therapy including insulin, is needed
when does type 2 diabetes present?
traditionally thought to be a condition of late adulthood
now good evidence that it can present throughout every decade of life
increasing in all age groups but rapidly in early-adulthood
prevalence of T2DM varies enormously
increasing prevalence
especially in people of lower socioeconomic backgrounds - access to cheap and unhealthy food
occurring and being diagnosed younger
greatest in ethnic groups that move from rural to urban lifestyle
what are normal levels of fasting glucose, 2 hour glucose, Hba1c, and insulin?
less than 6
less than 7.7
less than 42
insulin resistance higher than production
what are intermediate levels of fasting glucose, 2 hour glucose, Hba1c, and insulin?
impaired fasting glycaemia
impaired glucose tolerance
pre diabetes/non diabetic hyperglycaemia
insulin production and resistance increases - eventually resistance increases past production
what are type 2 diabetes levels of fasting glucose, 2 hour glucose, Hba1c, and insulin?
larger than 7
larger than 11
larger than 48
insulin production drops, resistance stays high
how can insulin deficiency be defined in type 2 diabetes?
relative deficiency
insulin produced by pancreatic beta cells - not enough to overcome resistance, but enough to suppress generation of ketone bodies
therefore relative deficiency
therefore hyperglycaemia dos not cause ketosis under usual circumstances
how does beta cell function change in type 2 diabetes?
biggest contributory factory to type 2 development - by the time someone presents, some loss of beta cell functional capacity (otherwise no presentation of hypoglycaemia)
long duration type 2 - beta cell failure may progress to complete insulin deficiency
usually on insulin at this point in any case by important not to stop as at risk of ketoacidosis
what is the pathophysiology of type 2 diabetes?
genetic susceptibility, intrauterine environment (intrauterine growth retardation increases risk) and adult environment
(perturbations in gut microbiota can also play a role:
- obesity, insulin resistance T2DM
- bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids
- inflammation, signaling metabolic pathways)
insulin resistance and insulin secretion defects
fatty acids important in pathogenesis and complications
heterogenous -
people develop T2D at variable BMI, ages, progress differently
what is the effect of type 2 diabetes on first phase insulin release?
normal response - in response to a meal, stored insulin is released and more is produced
people with T2DM or those who are about to develop diabetes -do not have this stored insulin, less insulin released
how does reduced insulin in type 2 diabetes affect glucose?
reduced insulin action causes less uptake of glucose into skeletal muscle
hepatic glucose production is also increased due to:
- reduction in insulin action (fails to inhibit hepatic glucose production)
- increase in glucagon action (as insulin action decreases, glucagon action naturally increases)
how does glucagon action contribute to increased levels of glucose in type 2 diabetes?
less ability to store or oxidize glucose in muscle due to impaired insulin activity
- reduces the metabolic clearance rate of glucose
- excessive amount of glucose converted to lactate
lactate returns to liver to be metabolized back to glucose (Cori cycling) - early increase in fasting plasma glucose in progression to T2DM is often a result of Cori cycling from previous night’s meal
inadequate insulin action also causes an increased flux of substrates (glycerol and free fatty acids) to the liver - results in increased gluconeogenesis
inappropriate glucagon secretion induces continued glucose production by stimulating
- glycogenolysis
- gluconeogenesis
impaired insulin-mediated glucose disposal and excessive glucagon-mediated glucose output in the liver increase fasting plasma glucose in T2DM
if FPG increases but <140 mg/dL - fasting hepatic glucose production is less evident
if FPG >140 mg/dL - fasting HGP is increased, further exacerbating the problem
what is the relationship between insulin resistance and secretion?
non- linear
as sensitivity decreases (increased resistance), secretion increases to overcome it
rather than being able to change insulin secretion for reduced sensitivity people with T2DM “fall off the curve” - i.e. for any given degree of insulin sensitivity, they are secreting less insulin than standard
what are the consequences of insulin resistance in the body?
liver
- usually insulin is driving glucose-6-phosphate to glycogen
- produce excess glucose
adipocytes
- insulin usually promotes glucose uptake into adipocytes, promotes triglyceride formation
- lack of insulin decreases glucose uptake increases triglyceride conversion from NEFAs
muscles
- usually insulin promotes uptake via a transporter
- no uptake, so less glucose
what is insulin sensitivity?
define how effective insulin will be at clearing glucose from the circulation
(more effective = more sensitive)
what effects does the excess of inflammatory adipokines produced as a consequence of T2DM pathogenesis have? (NB do not have to know all of each)
TNF alpha IL-6
endocannabinoids
leptin
resistin
apelin
fatty acids
adiponectin
glucocorticoids
visfatin
effects on beta cell function, metabolic rate, organ fat etc.
what is monogenic type 2 diabetes?
single gene mutation leads to diabetes
MODY (maturity onset diabetes of the young)
always going to develop type 2 diabetes no matter what
what is polygenic type 2 diabetes?
polymorphism increasing risk of diabetes
high risk - T2DM may develop later depending on other factors, does not need strong environmental trigger
how do genes and environment interact in the development of type 2 diabetes?
lower genetic risk - need strong environmental trigger to develop
high genetic risk - only need weak environmental trigger to develop
high genetic risk and strong environmental triggers - very likely to develop T2DM
(and vice versa)
what have GWAS in type 2 diabetes sufferers shown about single nucleotide polymorphisms and their impact in T2DM development?
in studies, nucleotide changes are present in T2DM group but not controls
each individual SNP has only mild effect on risk, cumulative effect of all SNP’s have bigger effect
polygenic scores - can work out risk based on combination of SNPs
what is the role of obesity in the development of type 2 diabetes?
major risk factor of diabetes
fatty acids and adipocytokines important
central vs visceral obesity (higher visceral fat content - higher risk)
how does type 2 diabetes present?
hyperglycaemia
overweight
dyslipidaemia
fewer osmotic symptoms (may not get dramatic weight loss as in type 1)
with complications
insulin resistance
later insulin deficiency
what are the risk factors for development of type 2 diabetes?
age
PCOS
increased BMI
family Hx
ethnicity
inactivity
what is the process for diagnosing type 2 diabetes?
osmotic symptoms
infections
screening test: incidental finding
at presentation of complication
- acute: hyperosmolar hyperglycaemic state
- chronic: ischaemic heart disease, retinopathy
first line test for diagnosis is HbA1c
- 1x HbA1c >=48mmol/L with symptoms
- or 2x HbA1c >=48 mmol/mol if asymptomatic
(random glucose won’t help if no symptoms, oral glucose/fasting glucose takes time)
what is the hyperosmolar hyperglycaemic state?
people can present with it (slower onset than diabetic ketoacidosis)
insufficient insulin for prevention of hyperglycaemia but sufficient insulin for suppression of lipolysis and ketogenesis
therefore absence of significant acidosis
often identifiable precipitating event (infection, MI)
presents commonly with renal failure
unchecked gluconeogenesis produces hyperglycaemia, osmotic diuresis produces dehydration
how is type 2 diabetes managed?
diet
oral medication
structured education
may need insulin later
may lead to remission / reversal
what are the principles of a T2DM consultation?
glycaemia: HbA1c, glucose monitoring if on insulin, medication review
weight assessment (assess calorie intake, change from refined to complex carbohydrates)
blood pressure
dyslipidaemia: cholesterol profile
screening for complications: foot check, retinal screening
what are the dietary recommendations and necessary education for type 2 diabetes?
total calories control
reduce calories as fat
reduce calories as refined carbohydrate
increase calories as complex carbohydrate
increase soluble fibre
decrease sodium
how is excess hepatic glucose production managed in type 2 diabetes?
reduce hepatic glucose production
use metformin
how is resistance to action of circulating insulin managed in type 2 diabetes?
improve insulin sensitivity
use metformin, thiozolidinediones
how is inadequate insulin production for extent of insulin resistance managed in type 2 diabetes?
boost insulin secretion
use sulphonylureas, DPP4-inhibitors, GLP-1 agonists
how is excess glucose in circulation managed in type 2 diabetes?
inhibit carbohydrate gut absorption
or inhibit renal glucose resorption
use alpha glucosidase inhibitor, SGLT-2 inhibitor
how is metformin used in treatment of type 2 diabetes?
biguanide, insulin sensitiser
first line if dietary / lifestyle adjustment has made no difference
reduces insulin resistance, hepatic glucose output
increases peripheral glucose disposal
(can have GI side effects)
contraindicated in severe liver, severe cardiac or moderate renal failure
how are sulphonylureas used to treat type 2 diabetes?
normal insulin release requires closing of ATP-sensitive K+ channel to cause membrane depolarisation
sulphonylureas (e.g. gliclazide) bind to channel and close it, independent of glucose / ATP
how is pioglitazone used in the treatment of type 2 diabetes?
insulin sensitiser, mainly peripheral
agonist at PPAR (peroxisome proliferator-activated receptor) gamma receptor
adipocyte differentiation modified, causes weight gain but peripheral not central
improvement in glycaemia and lipids
evidence base on vascular outcomes
side effects of older types: hepatitis, heart failure
(slightly outdated but useful if metformin does not work at all)
what is GLP-1 (glucagon-like-peptide 1)?
gut hormone secreted in response to nutrients in gut
transcription product of pro-glucagon gene, mostly from L-cell
stimulates insulin, suppresses glucagon
promotes satiety (feeling of ‘fullness’)
short half life due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPP4)
used in treatment of diabetes mellitus - people feel full sooner
how does a GLP 1 agonist (e.g. liraglutide, semaglutide) work in treatment of type 2 diabetes?
injectable –daily, weekly
boost insulin production - decrease glucagon and glucose
causes weight loss
how does a DPP-4 inhibitor work in treatment of type 2 diabetes?
increase half life of exogenous GLP-1
decrease glucagon and glucose
neutral on weight
how does an SGLT-2 inhibitor (e.g. empagliflozin, dapagliflozin, canagliflozin) work in treatment of type 2 diabetes?
inhibits Na-Glu transporter, increases glycosuria
HbA1c lower
lower all cause mortality, heart failure risk
improve CKD
since beta cell function continues to decline even with medication, what treatments can be used to induce remission of type 2 diabetes?
gastric bypass
DIRECT/DROPLET study - low calorie diet
how is blood pressure managed in type 2 diabetes?
hypertension very common in T2DM
clear benefits for reduction especially with use of ACE-inhibitors
how is lipid managed in type 2 diabetes?
in diabetes -
- total cholesterol, triglycerides raised
- HDL cholesterol reduced
clear benefit to lipid-lowering therapy
what are the 3 major sites of microvascular complications caused by type 2 diabetes (hyperglycaemia)?
retinal arteries
renal glomerular arterioles
vasa nervorum - tiny blood vessels that supply nerve
what is the largest factor associated with development of microvascular disease?
high blood pressure
what is the relationship of risk of microvascular complications with rising HbA1c?
extent of hyperglycaemia (as judged by HbA1c) strongly associated with the risk of developing microvascular complications
relative risk increases non-linearly at 48mmol/mol HbA1c
clear relationship between the development of other microvascular complications (e.g. MI) and HbA1c
small changes in HbA1c make a big difference to risk - good in treatment
what is the relationship between hypertension and risk of microvascular complications?
clear relationship between rising systolic BP and risk of MI and microvascular complications (both T2DM and T1DM)
therefore prevention of complications requires reduction in HbA1c and BP control
relatively linear relationship - therefore try to lower BP as much as tolerated
what factors can lead to development of microvascular complications?
severity of hyperglycaemia
hypertension
genetic factors (e.g. ethnicity - African Caribbean ethnicity more likely to develop diabetic kidney disease) – some people develop complications despite reasonable control
hyperglycaemic memory – inadequate glucose control early on can result in higher risk of complications later, even if HbA1c improved
duration- increased duration can increase risk
glucose variability - i.e. actual glucose levels can fluctuate hugely even if they end up with an average HbA1c (unclear how this affects)
what is the mechanism of damage for microvascular complications?
hyperglycaemia and hyperlipidemia leads to:
1 - oxidative stress
- toxic environment for beta cells
2 - advanced glycated end products (AGEs)
- stable proteins (e.g. in structural locations like blood vessel wall) become glycated, disrupting their function
3 - hypoxia
- drives activation of pro-inflammatory cytokines via inflammatory signalling cascades
inflammation causes neuropathy, retinopathy, nephropathy
specific pathways can cause specific issues (e.g. polyol pathway influences neuropathy)
protein kinase C, hexosamine activation can also cause complications
mechanism of damage
hyperglycaemia and hyperlipidemia leads to
- AGE-RAGE
- oxidative stress
- hypoxia (p
inflammatory signalling cascades
local activation of pro inflammatory cytokines
vascular endothelial dysfunction - causes retinal ischaemia
produces factors that increase permeability of endothelium - causes diabetic macular oedema
neovascularisation - new vessels are usually fragile
inflammation
(polyol pathway)
how is retinopathy as a microvascular complication of type 2 diabetes detected?
early stages are asymptomatic
therefore screening is needed to detect retinopathy at a stage at which it can be treated before it causes visual disturbance / loss
after detecting diabetic retinopathy, how is it followed up?
any type of diabetes:
annual retinal screening, which involves retinal imaging (national screening programme)
advanced retinopathy: referred to specialist for treatment, may be seen more frequently
what are the stages of diabetic retinopathy?
background retinopathy
pre-proliferative
proliferative
(maculopathy can occur during any stage)
what are the features of background retinopathy?
hard exudates - fluid and associated proteins leak out(cheese colour, lipid)
microaneurysms (“dots”)
blot haemorrhages
what are the features of pre-proliferative retinopathy?
cotton wool spots also called soft exudates
represent retinal ischaemia, cotton wool spots occur where blood vessels are damaged
what are the features of proliferative retinopathy?
visible new vessels (neovascularisation)
on disk or elsewhere in retina
what are the features of maculopathy?
hard exudates near the macula, can also have cotton wool spots
same disease as background, but happens to be near macula
can threaten direct vision
what are the general principals of treating diabetic retinopathy?
improve HbA1c
good blood pressure control
how is background diabetic retinopathy treated?
continued annual surveillance
feedback to person living with diabetes
how is pre-proliferative diabetic retinopathy treated?
if left alone will progress to neovascularisation
therefore early panretinal photocoagulation (laser vessels off)
how is proliferative diabetic retinopathy treated?
panretinal photocoagulation
how is diabetic maculopathy treated?
oedema - anti-VEGF injections (vascular endothelial growth factor)
grid photocoagulation (laser burns new vessels in grid formation around macula)
how is diabetic nephropathy characterised?
hypertension
progressively increasing proteinuria
progressively deteriorating kidney function - measured by eGFR
classic histological features
how is diabetic nephropathy screened for?
people with any type of diabetes are at risk of developing diabetic nephropathy
actively screened for and monitored with by measurement of albumin in urine
can be done in a spot urine sample (rather than a 24-hr collection)
expressed as a ratio to creatinine: urine albumin creatinine ratio
why is nephropathy important?
associated with progression to end-stage renal failure requiring haemodialysis
healthcare burden
associated with increased risk of cardiovascular events
diabetes with kidney disease increases risk of macrovascular complications (congestive heart failure, acute MI, cerebrovascular accident or transient ischaemic attack, peripheral vascular disease, atherosclerotic vascular disease)
what are the histological features of diabetic nephropathy?
glomerular changes
- mesangial expansion
- basement membrane thickening
- glomerulosclerosis
what is the epidemiology of diabetic nephropathy?
T1DM: 20-40% after 30-40 years
T2DM: probably equivalent, but must bear in mind:
- age at development of disease
- ethnic differences
- age at presentation
how is diabetic nephropathy diagnosed?
progressive proteinuria (urine ACR)
increased blood pressure
deranged renal function (eGFR)
advanced: peripheral oedema
proteinuria
- normal range: <30mg/24hrs
- microalbuminuric: 30 - 300mg/24hrs
- asymptomatic: 300 - 3000mg/24hrs
- nephrotic: >3000mg/24hr
microalbuminuria
>2.5 mg/mmol (men)
>3.5 mg/mmol (women)
Proteinuria = ACR > 30mg/mmol
what is the mechanism of diabetic nephropathy?
diabetes causes hyperglycaemia and hypertension
glomerular hypertension causes destruction of glomeruli
causes proteinuria, interstitial fibrosis, decreases filtration rate - eventual renal failure
what are the strategies for intervention in diabetic nephropathy?
decreasing HbA1c reduces risk of microvascular complications in general
manage blood pressure usually through ACEi or A2RB - slows decline in filtration ability, reduces albumin
inhibit renal-angiotensin-aldosterone system
- decreases baseline creatinine
SGLT-2 inhibition
(studies coming out now, so will probably make it into guidelines)
stop smoking
why does blocking RAS work in treating diabetic nephropathy?
angiotensin-2
- mediation of glomerular hypertension
pro-inflammatory at a molecular level
involved in the inflammatory tissues that are damaging glomeruli and causing leaky glomerular vessels
how does diabetic neuropathy occur?
most common cause of neuropathy and therefore lower limb amputation
small vessels supplying nerves are called vasa nervorum, neuropathy results when these get blocked
this causes:
- peripheral polyneuropathy (most common manifestation)
- mononeuropathy
- mononeuritis multiplex
- radiculopathy (spinal)
- autonomic neuropathy
- diabetic amyotrophy
how does peripheral neuropathy manifest?
usually starts in feet as longest nerves supply feet (most peripheral, therefore more likely to be damaged)
more common in tall people
manifests as loss of sensation
could lead to ulceration and diabetic foot disease
all people with diabetes: annual foot check with GP
what are the clinical features of diabetic neuropathy (foot)?
initial:
- loss of vibration sense
- loss of temperature sensation
more advanced:
- loss of sensation in foot (10g monofilament)
- loss of proporioception
- loss of ankle jerks
classic ‘glove and stocking’ distribution - starts at tips of toes; as it progresses up the legs, symptoms start to develop in the fingers as well (nerves that go from spinal cord to fingertips are shorter than the ones that go to feet)
what is the danger of neuropathy?
not sensing an injury to the foot
how is peripheral neuropathy managed (prevention)?
regular inspection of feet by affected individual
good footwear (bad footwear may cause damage but individual may not notice)
avoid barefoot walking (risk of stepping on something and not noticing)
podiatry and chiropody if needed
how is peripheral neuropathy with ulceration managed?
multidisciplinary diabetes foot clinic - microbiology, vascular surgeon, orthopaedic surgeon
offloading
revascularisation if concomitant PVD (improve blood flow)
antibiotics if infected
orthotic footwear
amputation if all else fails
what are the features of mononeuropathy (diabetic neuropathy)?
usually sudden motor loss - wrist drop, foot drop
cranial nerve palsy:
double vision due to 3rd nerve palsy
3rd nerve palsy with pupil sparing (pupil not dilated) as parasympathetic fibres not compromised
what are the features of autonomic neuropathy (diabetic neuropathy)?
loss of sympathetic and parasympathetic nerves to GI tract, bladder, cardiovascular system
GI tract:
- difficulty swallowing
- delayed gastric emptying: nausea and vomiting
- constipation / nocturnal diarrhoea
- bladder dysfunction
cardiovascular:
- postural hypotension, can be disabling (collapsing on standing etc.)
- cardiac autonomic supply: case reports of sudden cardiac death
how is autonomic neuropathy diagnosed?
diagnose on R-R interval changes
or no change in heart rate on Valsalva manoeuvre
gastric emptying studies
what are the macrovascular complications caused by diabetes?
early widespread atherosclerosis (renal artery stenosis)
ischaemic heart disease
cerebrovascular disease
peripheral vascular disease
what are the markers for atherosclerosis (diabetes)?
fasting glucose >6.0mmol/l
HDL
men<1.0
women<1.3
hypertension
BP>135/80
waist circumference
men>102
women>88
(central adiposity has more effect on intermediate metabolism)
what are the metabolic factors contributing to atherosclerosis?
insulin resistance
inflammation CRP
adipocytokines
urine microalbumin
what is the relationship between HbA1c and risk of MI in type 2 diabetes?
higher HbA1c, higher risk of MI and other complications
which people are more at risk of cerebrovascular disease associated with diabetes?
usually in older people
occurs earlier, more widespread in diabetic individuals
what are the effects of peripheral vascular disease as a macrovascular complication of diabetes?
contributes to diabetic foot problems with neuropathy
narrowed arteries decrease blood supply to peripheries - can cause gangrene
what can renal artery stenosis contribute to?
hypertension
renal failure
occlusion of renal artery decreases blood supply in kidneys
what is the overall pathway to foot ulceration as a result of type 2 diabetes?
sensory neuropathy
motor neuropathy
limited joint mobility
autonomic neuropathy
peripheral vascular disease
trauma – repeated minor/discrete episode
reduced resistance to infection
other diabetic complications (e.g. retinopathy)
what is the incretin effect?
relative increase in insulin in response to oral glucose relative to intravenous glucose
what is the mechanism of diabetic retinopathy?
hyperglycaemia causes activation of pathways that should not be activated
effects: oxidative stress, advanced glycated end products, protein kinase C activation, inflammation, sorbitol, RAS
high glucose delivered to retina by retinal vessels, causes vascular endothelial dysfunction
endothelium needed for oxygenation etc. - dysfunction likely to cause retinal ischaemia
ischaemia causes release of factors (carbonic anhydrase, vascular endothelial growth, growth factor-insulin growth factor, erythropoietin) that increase permeability of the vascular endothelium - results in diabetic macular oedema
erythropoietin release increase haemoglobin production - causes retinal neovascularisation that can lead to proliferative diabetic retinopathy (including retinal detachment and vitreous haemorrhage)
what is mononeuritis multiplex (diabetic neuropathy)?
random combination of peripheral nerve lesions
what is radiculopathy (diabetic neuropathy)?
pain over spinal nerves, usually affecting a dermatome on the abdomen or chest wall
how does atherosclerosis develop over time (diabetic)?
from first decade:
- initial lesion - histologically ‘normal’, macrophage infiltration, isolated foam cells within artery wall
- fatty streak from intracellular lipid accumulation
from 3rd decade:
- intermediate lesion - intracellular lipid accumulation
- atheroma - intracellular lipid accumulation, core of extracellular lipid (visible to naked eye)
from 4th decade
- fibroatheroma - multiple lipid cores, fibrotic/calcific layers; increased smooth muscle and collagen
- complicated lesion - surface defect, haematoma-haemorrhage, thrombosis; showers and platelets will go on to block smaller arteries distally
what is the pathogenesis of atherosclerosis (diabetic)?
initial and intermediate lesion growth is with lipid
- related to diabetic dyslipidaemia, increased LDL and decreased HDL
- clinically silent
smooth muscle hypertrophy as body tries to wall off lesions
fibroatheroma - development of collagen
complicated lesions - risk of thrombosis, haematoma showering further down
what is the effect of type 2 diabetes on life expectancy?
hyperglycaemia associated with significantly reduced life expectancy
the younger a person is at diagnosis, the lower the expected age of death (bigger effect on longevity)
insulin resistance associated with cardiovascular events - total cardiovascular disease, CHD, heart failure, intermittent claudication (all higher risk in women), stroke (higher risk in men)
what is the difference between microvascular and macrovascular complications caused by type 2 diabetes?
microvascular: causes morbidity
macrovascular: causes morbidity and mortality
where is macrovascular disease present?
systemic disease
commonly present in multiple arterial beds
how is diabetes related to ischaemic heart disease?
major cause of morbidity and mortality in diabetes
mechanisms are similar with and without diabetes, just occurs younger
elevated ST waves
how can cerebrovascular disease cause brain damage?
occlusion in cerebral circulation
areas of brain affected can no longer control areas that they used to (infarct)
what effect does treatment targeted to hyperglycaemia have on risk of cardiovascular disease?
hyperglycaemia treatment has minor effect on increased CVD (although some studies show benefits for mitigating risk of CHD)
what does prevention of macrovascular disease require?
aggressive management of multiple risk factors
mechanistically, insulin resistance is importance before hyperglycaemia starts contributing
what are the non-modifiable risk factors for macrovascular disease associated with diabetes?
age
sex
birth weight
FHx/genes
what are the modifiable risk factors for macrovascular disease associated with diabetes?
dyslipidaemia
high blood pressure
smoking
diabetes
what is the most beneficial aspect of treating macrovascular complications in diabetes?
lipid control
- use of statins, fewer acute coronary events etc.
also control blood pressure
what is steno-2?
multifactorial intensive therapy for diabetes to reduce risk of macrovascular events
what are the targets for blood pressure management in type 2 diabetes (macrovascular event risk reduction)?
<140/80 mmHg
(if nephropathy, retinopathy or cerebrovascular damage, <130/80mm Hg
if on antihypertensives at diagnosis:
- review BP control and medication use
- make changes only if BP poorly controlled or will negatively impact microvascular or metabolic problems
if BP reaches and remains at target:
- monitor every 4-6 months, check for adverse effects of antihypertensives, including low blood pressure
what are the targets for blood lipid management in type 2 diabetes (macrovascular event risk reduction)?
review CV risk status annually:
- assess risk factors, including features of metabolic syndrome, waist circumference
- changes in personal/family history?
- full lipid profile - also perform after diagnosis, repeat before starting lipid-modifying therapy
- if history of high elevated TG, full fasting lipid profile
high risk unless
- not overweight (include ethnicity)
- normotensive without antihypertensives
- no microalbuminuria
- non smoker
- no high risk lipid profile
- no history of CVD
why is central adiposity more dangerous than visceral adiposity in diabetes?
central fat drains through liver - greater effect on intermediary metabolism
more metabolically active - turns over more rapidly than peripheral fat
more active in terms of agents like adiponectin resistin etc.
what are the complications of diabetes predisposing to foot disease?
neuropathy: sensory, motor, autonomic
peripheral vascular disease
how is sensory neuropathy detected in the pathway to foot ulceration?
test sensation using 10g monofilament - can predict ulceration
how does motor neuropathy present in foot ulceration?
clawed toes - increased pressure on metatarsal heads (especially big toe) so toes are flexed
why does motor neuropathy cause clawed feet in foot ulceration?
difference between the long flexors and the long extensors - toes apply pressure inappropriately on foot’s plantar surface
greatest risk is on great toe metatarsal head
how does motor neuropathy cause clawed hands (unable to press palms together)?
glycosylation of tendons in hands
cannot bend palms and fingers properly
what causes limited joint mobility in the process of foot ulceration?
abnormal pressure loading
what effect does autonomic neuropathy on foot ulceration?
dry, flaking skin (also exacerbated by poor care)
how does autonomic neuropathy cause dry, flaking skin in foot ulceration?
autonomic nervous system important to sweating and controlling of grease in the feet
how does peripheral vascular disease contribute to foot ulceration?
arterial runoff through the legs down to the feet is reduced with atheroma widespread
what can occur due to sensory neuropathy in the foot?
trauma
damages foot through minor/discrete episodes
what are the features of the neuropathic foot?
numb
warm
dry
palpable foot pulses
ulcers at points of high pressure loading
what are the features of the ischaemic foot?
cold
pulseless
ulcers at foot margins
what are the features of the neuro-ischaemic foot?
numb
cold
dry
pulseless
ulcers at points of high pressure loading and at foot margins
how is pain felt in the ulcerated foot?
will not feel pain due to sensory neuropathy
patients may feel pain due to osteomyelitis but initial soft tissue infection and ischaemia can be painless (typical of arterial problem - peripheral vascular disease)
how does infection spread in the ulcerated foot?
infection will spread to soft tissue and eventually bone
how is the foot of a diabetic patient assessed?
appearance - weight loading? deformity - thick skin/callus associated with ulceration?
feel - hot/cold? dry?
foot pulses - dorsalis pedis / posterior tibial pulse (autonomic neuropathy)
neuropathy - vibration sensation, temperature, ankle jerk reflex, fine touch sensation
what is the preventative management strategy for diabetic foot ulceration?
control diabetes - glycaemia/lipids/BP
inspect feet daily
have feet measured when buying shoes, buy shoes with laces and square toe box
inspect inside of shoes for foreign objects
attend chiropodist
cut nails straight across (risk of cutting skin at edges otherwise)
care with heat
never walk barefoot
what does a diabetic foot MDT look like?
diabetes nurse
vascular surgeon (improve blood flow)
orthotist
diabetologist (control of diabetes)
chiropodist
orthopaedic surgeon (altering pressure across foot)
limb fitting centre
how is foot ulceration managed?
relief of pressure
- bed rest (although this risks DVT, heel ulceration)
- redistribution of pressure/total contact cast
antibiotics, possibly long term
debridement (dead tissue is a source of further infection, must remove)
revascularization
- angioplasty
- arterial bypass surgery
- difficult if multiple small vessels are affected
amputation (eventual, last resort)
what does Charcot’s foot look like?
rocker bottom foot (U-shaped)
on X-ray - tibia starting to push through bones of the tarsus
(originally pain and neuropathy described in relation to syphilis but also applies to diabetes)
how does Charcot’s foot occur in relation to diabetes?
abnormal pressure loading
what characteristic of Charcot’s foot makes it difficult to differentiate from osteomyelitis?
sinus at bottom of foot affected - possibility of infection in the foot spreading amongst plantar fascia
difficult to differentiate between inflammation on all joint surfaces due to Charcot’s and widespread osteomyelitis
how can you differentiate between Charcot’s foot and osteomyelitis?
use MRI
osteomyelitis
- hot, red foot with ulcer
- MRI - marrow oedema in forefoot and hindfoot near ulcer
active Charcot’s
- hot, red foot without ulcer
- MRI - marrow oedema in midfoot subchondral
how is Charcot’s foot managed?
special weight bearing cast to alleviate pressure loading
