endocrinology

Question 1

what are the 5 anterior pituitary hormones and what do they stimulate?

Answer 1

growth hormone - growth

prolactin - lactation

TSH - T3 and T4

LH/FSH - gonad hormones

ACTH - cortisol

Question 2

what are the 3 types of gland failure caused by anterior pituitary failure?

Answer 2

thyroid

adrenal cortex

gonads

Question 3

what is the difference between primary and secondary disease?

Answer 3

primary - gland itself fails

secondary - failure caused by something else

Question 4

what is primary hypothyroidism?

Answer 4

T3 and T4 fall, TSH increases

no negative feedback

(also TRH increase but this is not measured)

Question 5

what is secondary hypothyroidism?

Answer 5

(e.g) cells in pituitary cannot produce TSH

TSH falls

T3 and T4 fall

Question 6

what happens in primary hypoadrenalism?

Answer 6

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)

Question 7

what happens in secondary hypoadrenalism?

Answer 7

ACTH not made

ACTH falls - no tanning as seen in Addison’s disease

therefore cortisol falls

Question 8

what happens in

primary hypogonadism?

Answer 8

testosterone/oestrogen fall

LH, FSH increase (trying to force gonads to work)

(GnRH would also be high)

Question 9

what happens in secondary hypogonadism?

Answer 9

anterior pituitary cannot produce LH/FSH

LH/FSH fall

therefore testosterone/oestrogen fall

Question 10

how is congenital hypopituitarism caused and what are the effects?

Answer 10

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

Question 11

how is acquired hypopituitarism caused?

Answer 11

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)

Question 12

what is total loss of anterior and posterior pituitary called?

Answer 12

panhypopituitarism

Question 13

how does radiotherapy induced hypopituitarism occur?

Answer 13

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

Question 14

how does a lack of FSH/LH present?

Answer 14

(less testosterone/oestrogen)
reduced libido

secondary amenorrhoea

erectile dysfunction

reduced pubic hair

Question 15

how does a lack of ACTH present?

Answer 15

no cortisol

fatigue

weight loss

(not a salt losing crisis because aldosterone is still present and works under the renin angiotensin axis)

Question 16

how does a lack of TSH present?

Answer 16

fatigue

Question 17

how does a lack of GH present?

Answer 17

reduced quality of life (needed for psychological wellbeing)

short stature in children

Question 18

how does a lack of prolactin present?

Answer 18

inability to breastfeed

Question 19

what are the causes of Sheehan’s syndrome?

Answer 19

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

Question 20

how does Sheehan’s syndrome present?

Answer 20

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

Question 21

what is the best radiological way to examine the pituitary?

Answer 21

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

Question 22

what are the causes of pituitary apoplexy?

Answer 22

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

Question 23

how does pituitary apoplexy present?

Answer 23

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)

Question 24

what are the general problems with biochemical diagnosis of hypopituitarism?

Answer 24

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

Question 25

how does dynamic pituitary function in hypopituitarism diagnosis work?

Answer 25

• 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

Question 26

how should the effects of pituitary dysfunction be treated?

Answer 26

cannot replace prolactin

replace all others (GH, TSH, FSH, LH)

Question 27

how can GH deficiency be treated?

Answer 27

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

Question 28

how can TSH deficiency be treated?

Answer 28

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

Question 29

how can ACTH deficiency be treated?

Answer 29

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

Question 30

what are sick day rules for ACTH deficiency and why are they important?

Answer 30

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

Question 31

how can FSH/LH deficiency in men be treated?

Answer 31

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)

Question 32

how can FSH/LH deficiency in women be treated?

Answer 32

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)

Question 33

what part of the brain is the posterior pituitary anatomically continuous with?

Answer 33

hypothalamus

Question 34

what do hypothalamic magnocellular neurons contain and how are they arranged?

Answer 34

containing AVP/oxytocin

long, originate in supraoptic and paraventricular hypothalamic nuclei

(nuclei to stalk to posterior pituitary)

Question 35

what is vasopressin also known as?

Answer 35

anti diuretic hormone

Question 36

what is diuresis?

Answer 36

production of urine

Question 37

what is the main physiological action of vasopressin?

Answer 37

stimulation of water reabsorption in renal collecting duct to concentrate urine

Question 38

how does vasopressin allow water reabsorption in the collecting duct?

Answer 38

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)

Question 39

what is the other function of vasopressin (other than water reabsorption in the collecting duct)?

Answer 39

vasoconstrictor via V1 receptor

stimulates ACTH release from anterior pituitary

Question 40

how can the posterior pituitary be identified on an MRI?

Answer 40

posterior pituitary = “bright spot” on MRI

not visualised in all healthy individuals so absence may be normal variant

Question 41

how does an osmotic stimulus cause vasopressin release?

Answer 41

rise in plasma osmolality sensed by osmoreceptors

Question 42

how does a non-osmotic stimulus cause vasopressin release?

Answer 42

decrease in atrial pressure sensed by atrial stretch receptors

Question 43

what structures in the brain are used to detect an osmotic stimulus and cause vasopressin release?

Answer 43

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

Question 44

how do osmoreceptors regulate vasopressin?

Answer 44

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

Question 45

what is the mechanism by which a non-osmotic stimulus causes vasopressin release?

Answer 45

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

Question 46

why is AVP released following haemorrhage?

Answer 46

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))

Question 47

what is the normal physiological response to water deprivation?

Answer 47

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)

Question 48

what are the presenting features of diabetes insipidus?

Answer 48

polyuria
nocturia
extreme thirst
polydipsia

Question 49

what is the difference between diabetes mellitus and diabetes insipidus?

Answer 49

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

Question 50

what are the two types of diabetes insipidus and how are they different?

Answer 50

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

Question 51

how common are congenital causes of cranial diabetes insipidus?

Answer 51

very rare

Question 52

what are the acquired causes of cranial diabetes insipidus?

Answer 52

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

Question 53

what are the congenital causes of nephrogenic diabetes insipidus?

Answer 53

very rare

e.g. mutation in gene encoding V2 receptor, aquaporin 2 water channel

Question 54

what are the acquired causes of nephrogenic diabetes insipidus?

Answer 54

drugs (e.g. lithium) that damage ability to respond to vasopressin

Question 55

how does diabetes insipidus present with respect to the urine?

Answer 55

very dilute (hypo osmolar)

large volumes produced

causes dehydration and affects plasma
(cannot reabsorb water)

Question 56

how does diabetes insipidus present with respect to the plasma?

Answer 56

increased concentration (hyper osmolar) as dehydration occurs

increased sodium (hypernatraemia)

glucose is normal

Question 57

why do these symptoms (polyuria, nocturia, extreme thirst, polydipsia) occur in diabetes insipidus?

Answer 57

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

Question 58

how can diabetes insipidus cause death?

Answer 58

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

Question 59

what is the difference between psychogenic polydipsia and diabetes insipidus?

Answer 59

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

Question 60

how can diabetes insipidus and psychogenic polydipsia be differentiated?

Answer 60

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)

Question 61

how can a water deprivation test distinguish between cranial and nephrogenic diabetes insipidus?

Answer 61

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

Question 62

how does plasma osmolality vary from the normal range in diabetes insipidus as opposed to psychogenic polydipsia?

Answer 62

diabetes insipidus: plasma osmolality goes up

psychogenic polydipsia: plasma osmolality goes down

Question 63

how can cranial diabetes insipidus be treated?

Answer 63

replace vasopressin with desmopressin

selective for V2 receptor as no need for vasoconstriction

can give intranasally as a spray or orally as a tablet

Question 64

how can nephrogenic diabetes insipidus be treated?

Answer 64

rare, difficult to treat successfully

use thiazide diuretics e.g. bendofluazide

paradoxical, mechanism unclear

Question 65

what is syndrome of inappropriate anti-diuretic hormone (SIADH)?

Answer 65

too much arginine vasopressin leads to reduced urine output and water retention

Question 66

what are the features of syndrome of inappropriate anti-diuretic hormone (SIADH)?

Answer 66

high urine osmolality

low plasma osmolality

dilutional hyponatraemia

Question 67

what are the causes of syndrome of inappropriate anti-diuretic hormone (SIADH)?

Answer 67

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)

Question 68

how can syndrome of inappropriate anti-diuretic hormone (SIADH) be managed?

Answer 68

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

Question 69

what do somatotrophs secrete and what condition is caused by its over secretion?

Answer 69

growth hormone

acromegaly

Question 70

what do lactotrophs secrete and what condition is caused by its over secretion?

Answer 70

prolactin

prolactinoma (most common)

Question 71

what do thyrotrophs secrete and what condition is caused by its over secretion?

Answer 71

TSH

TSHoma (very rare)

Question 72

what do gonadotrophs secrete and what condition is caused by its over secretion?

Answer 72

LH and FSH

gonadotrophinoma (very rare)

Question 73

what do corticotrophs secrete and what condition is caused by its over secretion?

Answer 73

ACTH

Cushing’s disease (corticotroph adenoma)

Question 74

what is the difference between Cushing’s disease and syndrome?

Answer 74

Cushing’s disease = corticotroph adenoma causes high ACTH and high cortisol

Cushing’s syndrome = high cortisol for any reason

Question 75

how can pituitary tumours be classified using radiological methods (MRI)?

Answer 75

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?

Question 76

why is it difficult to remove a pituitary tumour that has invaded the cavernous sinus?

Answer 76

too difficult to surgically remove (likelihood of damage to cranial nerves, carotid etc.)

Question 77

what is a functional tumour?

Answer 77

excess secretion of a specific pituitary hormone

e.g. prolactinoma

Question 78

what is a non-functional tumour?

Answer 78

no excess secretion of pituitary hormone (non functioning adenoma)

Question 79

why are pituitary tumours dangerous with respect to histology?

Answer 79

pituitary carcinoma very rare

however, pituitary adenomas can display benign histology but have malignant behaviour (grow into optic chiasm, cavernous sinus etc)

Question 80

how is a cell determined to be cancerous?

Answer 80

check mitotic index for high division rate

benign has < 3% score

Question 81

how does hyperprolactinaemia cause issues like amenorrhoea?

Answer 81

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

Question 82

what is a prolactinoma?

Answer 82

commonest functioning pituitary adenoma

serum prolactin reaches >5000 mU/L

size of tumour proportional to serum prolactin level

Question 83

how does a prolactinoma present?

Answer 83

menstrual disturbance

erectile dysfunction

reduced libido

galactorrhoea

subfertility

Question 84

what are some physiological causes of prolactin elevation?

Answer 84

pregnancy/breastfeeding

stress: exercise, seizure, venepuncture

nipple/chest wall stimulation

Question 85

what are some pathological causes of prolactin elevation?

Answer 85

primary hypothyroidism

polycystic ovarian syndrome

chronic renal failure

Question 86

what are some iatrogenic causes of prolactin elevation?

Answer 86

antipsychotics (increases dopamine, which usually inhibits prolactin production)

SSRIs

anti emetics

high dose of oestrogen

opiates

Question 87

what should be done if it is suspected that the “true” elevation of serum prolactin is false?

Answer 87

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)

Question 88

how can macroprolactin cause an apparent rise in serum prolactin?

Answer 88

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

Question 89

how can you prevent stress of venepuncture from causing an apparent rise in serum prolactin?

Answer 89

exclude by cannulated prolactin series

sequential serum prolactin measurement 20 mins apart with indwelling cannula to minimise venepuncture stress

Question 90

what should be done after a true elevated prolactin has been confirmed?

Answer 90

pituitary MRI

Question 91

how is a prolactinoma treated?

Answer 91

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

Question 92

what effect does an excess of GH have on children?

Answer 92

gigantism

Question 93

what effect does an excess of GH have on adults?

Answer 93

acromegaly - increase in soft tissue

Question 94

how does acromegaly present?

Answer 94

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

Question 95

how is acromegaly diagnosed?

Answer 95

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

Question 96

how is acromegaly treated?

Answer 96

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

Question 97

what are the presenting features of Cushing’s syndrome?

Answer 97

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

Question 98

why does Cushing’s syndrome occur?

Answer 98

excess cortisol or other glucocorticoid

too many steroids (common)

pituitary dependent Cushing’s disease (pituitary adenoma)

ectopic ACTH (lung cancer)

adrenal adenoma or carcinoma

Question 99

what are the ACTH dependent causes of Cushing’s syndrome?

Answer 99

Cushing’s disease (corticotroph adenoma)

ectopic ACTH (lung cancer)

Question 100

what are the ACTH independent causes of Cushing’s syndrome?

Answer 100

taking steroids by mouth (common)

adrenal adenoma or carcinoma

Question 101

how is Cushing’s disease investigated?

Answer 101

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)

Question 102

what steps should be taken after hypercortisolism is confirmed?

Answer 102

measure ACTH

Question 103

if high ACTH is noted after hypercortisolism is confirmed, what should be done?

Answer 103

pituitary MRI

Question 104

what visual disturbance do patients with non-functioning pituitary adenomas often present with?

Answer 104

bitemporal hemianopia

Question 105

what hormonal disturbance do patients with non-functioning pituitary adenomas often present with?

Answer 105

(can present with hypopituitarism)

serum prolactin can be raised - dopamine can’t travel down pituitary stalk from hypothalamus

Question 106

what is the function of the thyroid follicular cell?

Answer 106

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

Question 107

what happens to the level of TSH in patients with primary hypothyroidism (autoimmune)?

Answer 107

high TSH in patient with damaged thyroid

try to stimulate thyroid to produce T4

Question 108

how are the effects of primary hypothyroidism on TSH treated?

Answer 108

give oral TSH

increase dose till TSH falls to normal

Question 109

what is the mechanism of Graves’ disease and its presenting symptoms?

Answer 109

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

Question 110

what are the symptoms of Graves’ disease?

Answer 110

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)

Question 111

what is Plummer’s disease and how does it differ from Graves’ disease?

Answer 111

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

Question 112

what are the effects of thyroxine on the sympathetic nervous system?

Answer 112

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)

Question 113

what are the principal features of hyperthyroidism?

Answer 113

weight loss despite appetite

can’t work far or fast - breathlessness

palpitations, tachycardia

sweating, heat intolerance

diarrhoea

lid lag, other sympathetic features

Question 114

how is hyperthyroidism treated?

Answer 114

thyroidectomy

radioidodine

drugs

Question 115

what is lid lag an effect of?

Answer 115

too much adrenaline (excess thyroxine causing stimulation)

Question 116

why does a thyroid storm occur and what are its features?

Answer 116

caused by undiagnosed Graves’ disease

hyperpyrexia >41 degrees

accelerated tachycardia/arrhythmia

cardiac failure

delirium, psychosis

hepatocellular dysfunction; jaundice

high mortality (50%)

Question 117

how are drugs used to treat hyperthyroidism?

Answer 117

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

Question 118

why are beta blockers used in the treatment of hyperthyroidism?

Answer 118

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

Question 119

what are the side effects of thionamides?

Answer 119

rashes

agranulocytosis - (usually reduction in neutrophils) - rare, reversible on withdrawal of drug

Question 120

how is a course of treatment by drugs for hyperthyroidism followed up?

Answer 120

stop drugs after 18 months

review regularly

Question 121

how is iodide (usually potassium iodide) used to treat hyperthyroidism?

Answer 121

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)

Question 122

what is the mechanism of potassium iodide in treating hyperthyroidism?

Answer 122

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)

Question 123

what are the side effects of surgery to treat hyperthyroidism?

Answer 123

risk of voice change

risk losing parathyroid glands

scar

anaesthetic

Question 124

how is radioiodine used to treat hyperthyroidism?

Answer 124

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)

Question 125

what is the general process taken to treat hyperthyroidism?

Answer 125

start beta blockage

add anti thyroid drugs

Question 126

what are the symptoms of viral (de Quervain’s) thyroiditis?

Answer 126

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

Question 127

what is the process of viral thyroiditis?

Answer 127

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

Question 128

what is postpartum thyroiditis?

Answer 128

similar to viral thyroiditis

no pain

occurs only after pregnancy

(immune system modulated during pregnancy)

Question 129

what are the 3 types of corticosteroid produced by the adrenal cortex?

Answer 129

mineralocorticoids (aldosterone)

glucocorticoids (cortisol)

sex steroids (androgens, oestrogens)

Question 130

what are the effects of angiotensin II on the adrenals to produce aldosterone?

Answer 130

bind to adrenal receptor

side chain cleavage

activates enzymes

• 3-Hydroxysteroid dehydrogenase
• 21-hydroxylase
• 11-hydroxylase
• 18-hydroxylase

Question 131

what is the action of aldosterone?

Answer 131

controls blood pressure, sodium, lowers potassium

Question 132

what is the steroid synthetic pathway to produce aldosterone?

Answer 132

cholesterol converted to progesterone

21-hydroxylase converts progesterone to 11-deoxycorticosterone

11-hydroxylase converts 11-deoxycorticosterone
to corticosterone

18-hydroxylase converts corticosterone to aldosterone

Question 133

what is the steroid synthetic pathway to produce cortisol?

Answer 133

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

Question 134

what is Addison’s disease?

Answer 134

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

Question 135

what is pro-opio-melanocortin (POMC)?

Answer 135

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

Question 136

what are the 3 main causes of adrenocortical failure?

Answer 136

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

Question 137

what are the acute presenting features of Addison’s?

Answer 137

breathlessness

exhaustion

weight loss

postural hypotension, dizziness

tanned

Question 138

what tests are taken for Addison’s disease?

Answer 138

clinical suspicion -

9am cortisol blood test - low

ACTH - high

short synACTHen test - typical cortisol response

Question 139

how is adrenal failure treated?

Answer 139

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)

Question 140

how is a cortisol deficiency treated?

Answer 140

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

Question 141

what is congenital adrenal hyperplasia?

Answer 141

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)

Question 142

what is the effect of complete 21-hydroxylase deficiency?

Answer 142

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

Question 143

what is the effect of partial 21-hydroxylase deficiency?

Answer 143

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

Question 144

what is the effect of 11-hydroxylase deficiency?

Answer 144

cortisol and aldosterone are deficient

excess sex steroids and testosterone - virilisation

11-deoxycorticosterone (behaves like aldosterone - excess causes hypertension and low potassium)

Question 145

what is the effect of 17-hydroxylase deficiency?

Answer 145

deficient in sex steroids, no cortisol

excess aldosterone and 11-deoxycorticosterone - causes hypertension, low potassium

glucocorticoid deficiency (low glucose)

Question 146

which inhibitors of steroid biosynthesis are used to control excess cortisol in Cushing’s syndrome?

Answer 146

metyrapone

ketoconazole

Question 147

what is Conn’s syndrome?

Answer 147

excess aldosterone

Question 148

how does metyrapone work to control cortisol levels?

Answer 148

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

Question 149

how does ketoconazole work to control cortisol levels?

Answer 149

inhibits 17-hydroxylase to inhibit cortisol (prevents conversion of progesterone to 17-
hydroxyprogesterone)

treatment and control of symptoms of Cushing’s before surgery

Question 150

what are the side effects of taking metyrapone?

Answer 150

high blood pressure, high K (11-deoxycorticosterone accumulates, promoting salt )retention

excess testosterone (hirsutism)

Question 151

what are the side effects of taking ketoconazole?

Answer 151

liver damage

Question 152

how is adrenal Cushing’s syndrome treated?

Answer 152

bilateral adrenalectomy

unilateral adrenalectomy for 1 adrenal mass

metyrapone/ketoconazole

Question 153

what is Conn’s syndrome?

Answer 153

benign adrenal cortical tumour in zona glomerulosa

aldosterone in excess

hypertension and hypokalemia

Question 154

how is Conn’s syndrome diagnosed?

Answer 154

Conn’s is primary hyperaldosteronism

suppress renin-angiotensin system to eliminate secondary hyperaldosteronism

Question 155

how is Conn’s syndrome treated?

Answer 155

mineralocorticoid receptor antagonist

• spironolactone
• epleronone

Question 156

how does spironolactone work to treat Conn’s syndrome?

Answer 156

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)

Question 157

what are the side effects of spironolactone?

Answer 157

menstrual irregularities (increased progesterone receptor expression)

gynaecomastia (less androgen receptor expression)

Question 158

how does epleronone work to treat Conn’s syndrome?

Answer 158

MR antagonist

similar affinity to MR

Question 159

what is a

phaeochromocytoma?

Answer 159

tumour of adrenal medulla and secrete catecholamine

tachycardia - more adrenaline (affects heart) and noradrenaline (affects blood pressure)

Question 160

what are the clinical features of a phaeochromocytoma?

Answer 160

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

Question 161

how is a phaeochromocytoma treated?

Answer 161

eventually need surgery (however anaesthetic can precipitate a hypertensive crisis)

alpha blockade, give fluid

beta blockade to prevent tachycardia

Question 162

how is the level of serum calcium increased?

Answer 162

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

Question 163

how is the level of serum calcium decreased?

Answer 163

calcitonin (secreted by thyroid parafollicular)

can reduce calcium acutely, but no negative effect if parafollicular cells are removed (e.g. thyroidectomy)

Question 164

what is the process of vitamin D synthesis?

Answer 164

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

Question 165

what are the effects of calcitriol?

Answer 165

gut: absorb calcium and phosphate
kidney: reabsorb calcium and phosphate
bone: increases osteoblast activity (bone strength and mineralisation)

Question 166

what are the actions of PTH?

Answer 166

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

Question 167

what is FGF23?

Answer 167

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

Question 168

what are the symptoms of hypocalcaemia?

Answer 168

sensitises excitable tissues, muscle cramps, tetany (cramping), tingling

paraesthesia (hands, mouth, feet, lips) (Chvosteks’ sign)

convulsions (Trousseau’s sign - carpopedal spasm)

arrythmias

tetany

Question 169

how do low PTH levels (hypoparathyroidism) cause hypocalcaemia?

Answer 169

surgical (neck surgery - e.g. thyroid surgery)

auto immune

Mg deficiency (needed for PTH release from parathyroid)

congenital (agenesis, rare)

Question 170

how do low vitamin D levels cause hypocalcaemia?

Answer 170

deficiency - diet, UV light, malabsorption, impaired production (renal failure)

Question 171

what are the signs of hypercalcaemia?

Answer 171

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)

Question 172

how can primary hyperparathyroidism cause hypercalcaemia?

Answer 172

too much PTH
(usually due to a PT gland adenoma)

no negative feedback - high PTH but high calcium

Question 173

how can malignancy cause hypercalcaemia?

Answer 173

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

Question 174

how common is it for a vitamin D excess to cause hypercalcaemia?

Answer 174

very rare

Question 175

what is the relationship between PTH and calcium?

Answer 175

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

Question 176

what is primary hyperparathyroidism?

Answer 176

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

Question 177

what is the biochemistry of primary hyperparathyroidism?

Answer 177

high calcium

low phosphate - increased renal phosphate excretion (inhibition of sodium/phosphate co transporter in kidney by FGF23)

high PTH (not suppressed by hypercalcaemia)

Question 178

how is primary hyperthyroidism treated?

Answer 178

parathyroidectomy

Question 179

what are the risks of untreated primary hyperparathyroidism?

Answer 179

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

Question 180

what is secondary hyperparathyroidism?

Answer 180

initial low calcium

sensed by parathyroid gland, PTH stimulated (normal physiological response to hypocalcaemia)

PTH is high secondary to low calcium

Question 181

what are the causes of secondary hyperparathyroidism?

Answer 181

vitamin D deficiency - diet, sunlight access

less common - renal failure, cannot make calcitriol

Question 182

how is secondary hyperparathyroidism treated?

Answer 182

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

Question 183

what is tertiary hyperparathyroidism?

Answer 183

(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

Question 184

how is tertiary hyperparathyroidism treated?

Answer 184

parathyroidectomy

Question 185

what is the diagnostic approach to hypercalcaemia?

Answer 185

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

Question 186

how are vitamin D levels measured?

Answer 186

calcitriol difficult to measure

therefore measured as 25-hydroxy vitamin D

Question 187

what is infertility?

Answer 187

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

Question 188

what is primary infertility?

Answer 188

when have not had a previous live birth

Question 189

what is secondary infertility?

Answer 189

when have had a live birth >12 months previously

Question 190

how common is infertility?

Answer 190

affects 1 in 7 couples

55% will seek help in UK - association with socioeconomic status

Question 191

what are most common causes of infertility in a couple?

Answer 191

female factors (30%)

male factors (30%)

combined (30%)

unknown (10%)

Question 192

what is the impact of infertility on a couple?

Answer 192

psychological distress

• impact on couple
• impact on larger family
• investigations
• treatments may not work

Question 193

what is the impact of infertility on society?

Answer 193

fewer births

less tax income

investigation costs

treatment costs

Question 194

what are the pre-testicular causes of male infertility?

Answer 194

congenital and acquired endocrinopathies

• Klinefelter’s 47 XXY
• Y chromosome deletion
• HPG, T, PRL

Question 195

what are the testicular causes of male infertility?

Answer 195

congenital

cryptorchidism

infection (STDs)

immunological (anti sperm antibodies)

vascular (variococoele)

trauma/surgery

toxins (chemotherapy, DXT, drugs, smoking)

Question 196

what are the post-testicular causes of male infertility?

Answer 196

congenital (absence of vas deference in cystic fibrosis)

obstructive azoospermia (no sperm)

erectile dysfunction

• retrograde ejaculation
• mechanical impairment
• psychological

iatrogenic
- vasectomy

Question 197

what is cryptorchidism?

Answer 197

undescended testis

Question 198

what are the ovarian causes for female infertility?

Answer 198

40%

anovulation (endocrinal cause)

corpus luteum insufficiency

Question 199

what are the tubal causes for female infertility?

Answer 199

30%

tubopathy due to:

• infection
• endometriosis
• trauma

Question 200

what are the uterine causes for female infertility?

Answer 200

10%

unfavourable endometrium due to:

• chronic endometritis (e.g. caused by TB)
• fibroid
• adhesions (synechiae)
• congenital malformation

Question 201

what are the cervical causes for female infertility?

Answer 201

5%

ineffective sperm penetration due to:

• chronic cervicitis
• immunological (anti sperm antibodies)

Question 202

what are the pelvic causes for female infertility?

Answer 202

endometriosis

adhesions

Question 203

how does endometriosis cause infertility (not endocrine)?

Answer 203

functioning endometrial tissue outside the uterus

responds to oestrogen

Question 204

what are the symptoms of endometriosis?

Answer 204

increased menstrual pain

menstrual irregularities

deep dyspareunia (pain during sexual intercourse)

infertility

Question 205

how is endometriosis treated?

Answer 205

hormonal (e.g. continuous OCP, progesterone)

laparoscopic ablation

hysterectomy

bilateral salpingo-oophorectomy

Question 206

how do fibroids cause infertility (not endocrine)?

Answer 206

benign tumours of myometrium

1-20% of pre menopausal women (increases with age)

respond to oestrogen

Question 207

what are the symptoms of fibroids?

Answer 207

usually asymptomatic

increased menstrual pain

menstrual irregularities

deep dyspareunia (pain during sexual intercourse)

infertility

Question 208

what is the treatment for fibroids?

Answer 208

hormonal (e.g. continuous OCP, progesterone, continuous GnRH agonists)

hysterectomy

Question 209

what is the hypothalamic - pituitary - gonadal (HPG) axis?

Answer 209

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

Question 210

what hormonal pattern is shown in hyperprolactinaemia?

Answer 210

LH, FSH, T all decrease

Question 211

what hormonal pattern is shown in primary testicular failure (e.g. Klinefelter’s)?

Answer 211

LH, FSH increases

T decreases

Question 212

what factors in the hypothalamus cause male infertility?

Answer 212

decreased GnRH (not measurable)

decreased testosterone (hypogonadism)

LH, FSH decrease (hypogonadotrophism)

congenital: anosmic (Kallmann syndrome) or normosmic
acquired: low BMI, excess exercise, stress

hyperprolactinaemia

Question 213

what factors in the anterior pituitary cause male infertility?

Answer 213

(hypogonadotrophism, hypogonadism)

hypopituitarism

• tumour
• infiltration
• apoplexy (no blood supply)
• surgery
• radiation

Question 214

what factors in the gonads cause male infertility?

Answer 214

(hypergonadotrophism, hypogonadism)

primary hypogonadism- congenital: Klinefelter’s

acquired:
- cryptorchidism
- trauma
- chemotherapy
- radiation

Question 215

what is Kallmann syndrome and what hormonal features are present?

Answer 215

congenital defect in failure of migration of GnRH neurons with
olfactory fibres

low GnRH, LH, FSH, T

Question 216

what are the reproductive features of Kallmann syndrome?

Answer 216

cryptorchidism

failure of puberty

infertility

Question 217

what is Klinefelter’s syndrome?

Answer 217

47 XXY karyotype

hypergonadotrophic hypogonadism

Question 218

what are the features of Klinefelter’s syndrome?

Answer 218

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)

Question 219

what history should be taken in male infertility?

Answer 219

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

Question 220

what examinations should be made in male infertility?

Answer 220

BMI

sexual characteristics

testicular volume

epididymal hardness

presence of vas deferens

other endocrine signs

syndromic features,

anosmia

Question 221

what blood tests should be done in male infertility?

Answer 221

LH, FSH, PRL

morning fasting testosterone (as diurnal)

sex hormone binding globulin (SHBG)

albumin (binds to testosterone), iron studies (affects pituitary)

pituitary/thyroid

karyotyping

Question 222

what microbiology tests should be done in both female and male infertility?

Answer 222

urine test

chlamydia swab

Question 223

what imaging tests should be done in male infertility?

Answer 223

scrotal US/doppler
(varicocoele)

MRI pituitary
(if low FSH/LH or high PRL)

Question 224

what lifestyle changes should be made to treat male infertility?

Answer 224

optimise BMI

smoking cessation

alcohol reduction

Question 225

what specific treatments should be given for male infertility?

Answer 225

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)

Question 226

what are the main disorders of the menstrual cycle?

Answer 226

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

Question 227

what hormonal pattern is seen in premature ovarian insufficiency?

Answer 227

high LH, FSH

low oestradiol

Question 228

how is premature ovarian insufficiency diagnosed?

Answer 228

high FSH >25 iU/L (x2 at least 4wks apart)

Question 229

what are the causes of premature ovarian insufficiency?

Answer 229

autoimmune

genetic

cancer therapy

Question 230

what hormonal pattern is seen in anorexia induced amenorrhoea?

Answer 230

low FSH, LH, oestradiol

Question 231

what factors in the hypothalamus cause female infertility?

Answer 231

decreased oestrogen (hypogonadism)

LH, FSH decrease (hypogonadotrophism)

congenital: anosmic (Kallmann syndrome) or normosmic
acquired: low BMI, excess exercise, stress

hyperprolactinaemia

hypothalamic amenorrhoea

Question 232

what factors in the anterior pituitary cause female infertility?

Answer 232

(hypogonadotrophism, hypogonadism)

hypopituitarism

• tumour
• infiltration
• apoplexy (no blood supply)
• surgery
• radiation

Question 233

what factors in the gonads cause male infertility?

Answer 233

(hypergonadotrophism, hypogonadism)

PCOS
congenital: Turner’s syndrome (45X0), Premature Ovarian Insufficiency (POI)

acquired: Premature Ovarian Insufficiency (POI), surgery, trauma, chemotherapy, radiation

Question 234

how is PCOS diagnosed?

Answer 234

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

Question 235

how are the respective risks of PCOS treated?

Answer 235

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

Question 236

what are the symptoms of Turner’s syndrome (45 X0)?

Answer 236

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

Question 237

what history should be taken in female infertility?

Answer 237

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

Question 238

what examinations should be done in female infertility?

Answer 238

BMI

sexual characteristics

other endocrine signs

syndromic features,

anosmia

hyperandrogenism signs

pelvic examination

Question 239

what blood tests should be done in female infertility?

Answer 239

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

Question 240

what imaging tests should be done in female infertility?

Answer 240

pregnancy test
- urine or serum hCG

US (transvaginal)

hysterosalpingogram

MRI of pituitary
(if low LH/FSH or high PRL)

Question 241

how is primary hypogonadism treated in males?

Answer 241

difficult to treat

Question 242

how is secondary hypogonadism treated?

Answer 242

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

Question 243

what treatment should be given for male infertility?

Answer 243

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

Question 244

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?

Answer 244

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

Question 245

if fertility is not required, when and how is testosterone replaced?

Answer 245

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)

Question 246

what are the risks of testosterone replacement?

Answer 246

increased haematocrit (more viscous and likely to clot - risk of stroke)

risk of stimulating prostate - might increase prostate size

Question 247

in a case of PCOS, what is the general principle behind ovulation induction?

Answer 247

develop one ovarian follicle (risk of multiple pregnancy increases if both follicles are developed)

aim to increase FSH by small amount

Question 248

how is ovulation restored in PCOS?

Answer 248

lifestyle/weight loss/ metformin

letrozole (aromatase inhibitor

clomiphene (oestradiol receptor antagonist)

FSH stimulation

Question 249

how does letrozole work to restore ovulation in PCOS?

Answer 249

aromatase inhibitor

prevents conversion of testosterone to oestradiol

no negative feedback to hypothalamus and pituitary, so increased GnRH, LH, FSH

stimulate follicle growth

Question 250

how does clomiphene work to restore ovulation in PCOS?

Answer 250

blocks oestradiol receptors in hypothalamus and pituitary

decreased negative feedback so increased GnRH, LH, FSH

stimulate follicle growth

Question 251

what is the process of IVF?

Answer 251

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

Question 252

why are both GnRH agonists and GnRH antagonists effective to prevent premature ovulation (i.e. preventing premature LH surge)?

Answer 252

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

Question 253

what can cause ovarian hyper stimulation syndrome and what are the symptoms?

Answer 253

triggered by hCG (given during IVF to trigger egg maturation, causes excessive ovarian stimulation)

symptoms:

• pleural effusion
• ascites
• renal failure
• ovarian torsion

Question 254

what are the 5 non-permanent types of contraception?

Answer 254

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)

Question 255

what are the positives of barrier contraception?

Answer 255

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

Question 256

what are the negatives of barrier contraception?

Answer 256

can interrupt sex

can interfere with erections

some skill to use properly
(e.g. ensure no air, not too large or small)

Question 257

how does an oral contraceptive pill work?

Answer 257

consists of oestrogen and progesterone

negative feedback to stop LH and FSH production

Question 258

what are the effects of the oral contraceptive pill to prevent pregnancy?

Answer 258

anovulation

thickening of cervical mucus

thinning of endometrial lining (reduces implantation)

Question 259

what are the positives of the combined oral contraceptive pill?

Answer 259

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

Question 260

what are the negatives of the combined oral contraceptive pill?

Answer 260

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)

Question 261

what are the non-contraceptive benefits of taking the combined oral contraceptive pill?

Answer 261

periods lighter and less painful
(endometriosis or period pain or menorrhagia)

withdrawal bleeds regular

PCOS: reduce LH and hyperandrogenism

Question 262

what are the positives of the progesterone only pill?

Answer 262

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)

Question 263

what are the negatives of the progesterone only pill?

Answer 263

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

Question 264

how does a copper coil IUD act as a contraceptive (LARC)?

Answer 264

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)

Question 265

what are the negatives of a copper coil IUD?

Answer 265

can cause heavy periods

some come out

Question 266

how does a mirena coil IUS act as a contraceptive (LARC)?

Answer 266

secretes progesterone

thins lining of womb and thickens cervical mucus (can also be used to help with heavy bleeding)

Question 267

what are the 3 forms of long acting reversible contraceptives (LARC)?

Answer 267

IUD

IUS

progestogen only injectable contraceptives or subdermal implants

Question 268

how does ulipristal acetate work in an emergency contraceptive pill?

Answer 268

stops progesterone function, prevents ovulation

must be taken within 5 days of sex

Question 269

how does levonorgestrel work in an emergency contraceptive pill?

Answer 269

synthetic progesterone prevents ovulation (don’t cause abortion)

must be taken within 3 days of sex

Question 270

what are the considerations to make when choosing a contraception method?

Answer 270

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)

Question 271

what are the risks of HRT?

Answer 271

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

Question 272

what are the benefits of HRT?

Answer 272

relief of symptoms of low oestrogen
e.g. flushing, disturbed sleep, decreased libido, low mood

fewer osteoporosis related fractures

Question 273

what is the process of gender reassignment for transgender men?

Answer 273

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

Question 274

what is the process of gender reassignment for transgender women?

Answer 274

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

Question 275

what is obesity?

Answer 275

condition of abnormal or excessive fat accumulation in adipose tissue to the extent that health is impaired

Question 276

how is obesity usually measured?

Answer 276

BMI

Question 277

why is BMI sometimes inaccurate?

Answer 277

muscle mass

increases BMI

Question 278

what drives obesity?

Answer 278

genetics
- 60-80%

environment

when in an unhealthy environment, being genetically prone/genetically averse to obesity has a huge impact

Question 279

what are some things that contribute to an obesogenic environment?

Answer 279

food

• availability
• food price (cheap)
• sugar and fat

Question 280

what factors are associated with obesity?

Answer 280

not as many outdoor spaces

increased car use

increased screen time

education level and achievement

poverty, social deprivation

Question 281

what are some comorbidities associated with obesity?

Answer 281

depression

stroke

MI

hypertension

diabetes

peripheral vascular disease

gout

bowel cancer

osteoarthritis

sleep apnoea

(associated with mortality)

Question 282

how is obesity treated?

Answer 282

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

Question 283

what kind of diet should be followed to try and manage obesity?

Answer 283

higher vegetable and fruit content

combine with exercise

Question 284

what drugs are used to manage obesity?

Answer 284

orlistat

derivative of an endogenous lipstatin produced by Streptomyces toxytricini

gastric and pancreatic lipase inhibitor

reduces dietary fat absorption by around 30%.

Question 285

what are some of the issues with orlistat?

Answer 285

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

Question 286

when is bariatric surgery an option?

Answer 286

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

Question 287

how does a gastric bypass work?

Answer 287

the top part of your stomach is joined to the small intestine

feel fullersooner, do not absorb as many calories from food

Question 288

how does a gastric band work?

Answer 288

band is placed around stomach

do not need to eat as much to feel full

Question 289

how does a sleeve gastrectomy work?

Answer 289

some of your stomach is removed

cannot eat as much as before, feelfull sooner

Question 290

early type 1

Answer 290

lots of immune cells

in the end there is fibrosis around islet

Question 291

why can diabetes classification be complicated?

Answer 291

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

Question 292

how does type 1 diabetes develop?

Answer 292

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

Question 293

what is the histological difference between early type 1 diabetes and long standing T1D?

Answer 293

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

Question 294

why is the immune basis important?

Answer 294

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

Question 295

what is the immunological response in type 1 diabetes?

Answer 295

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)

Question 296

the HLA-DR allele is often a factor in risk of type 1 - which alleles increase risk and which provide protection?

Answer 296

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)

Question 297

what environmental factors are associated with type 1 diabetes?

Answer 297

multiple factors implicated, causality not established

• enteroviral infection
• cow’s milk protein exposure
• seasonal variation (link to viral infection)
• changes in microbiota

Question 298

what is the diagnostic significance of pancreatic auto-antibodies?

Answer 298

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)

Question 299

what symptoms present in type 1 diabetes?

Answer 299

excessive urination (polyuria)

nocturia

excessive thirst (polydipsia)

blurring of vision

recurrent infection (e.g. thrush)

weight loss

fatigue

Question 300

what symptoms present in type 1 diabetes?

Answer 300

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

Question 301

what are the aims of treatment of type 1 diabetes?

Answer 301

maintain glucose levels without excessive hypoglycaemia

restore close-to-physiological insulin profile

prevent acute metabolic decompensation

prevent microvascular and macrovascular complications

Question 302

what are the acute complications of hyperglycaemia caused by type 1 diabetes?

Answer 302

diabetic ketoacidocis

Question 303

what are the chronic microvascular complications of hyperglycaemia caused by type 1 diabetes?

Answer 303

retinopathy

neuropathy

nephropathy

Question 304

what are the chronic macrovascular complications of hyperglycaemia caused by type 1 diabetes?

Answer 304

ischaemic heart disease

cerebrovascular disease

peripheral vascular disease

Question 305

what are the complications of the treatment of type 1 diabetes itself?

Answer 305

hypoglycaemia

Question 306

how is type 1 diabetes managed?

Answer 306

insulin treatment

dietary support/structured education

technology

transplantation

(self-management of condition)

Question 307

what are the forms of short/quick-acting insulin (taken with meals)?

Answer 307

human insulin - exact molecular replicate of human insulin (actrapid)

insulin analogue (Lispro, Aspart, Glulisine)

Question 308

what are the forms of long-acting/basal insulin (once daily)?

Answer 308

bound to zinc/protamine (neutral protamine hagedorn, NPH)

insulin analogue (Glargine, Determir, Degludec)

Question 309

how does insulin pump therapy in the treatment of type 1 diabetes?

Answer 309

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

Question 310

what are the advantages of an insulin pump in the treatment of type 1 diabetes?

Answer 310

variable basal rates

extended boluses

greater flexibility

Question 311

what dietary advice is given to people with type 1 diabetes?

Answer 311

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)

Question 312

how does a closed loop/artificial pancreas work in the treatment of type 1 diabetes?

Answer 312

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)

Question 313

how does an islet cell transplant work in the treatment of type 1 diabetes?

Answer 313

isolate human islets from pancreas of deceased donor

transplant into hepatic portal vein

(requires lifelong immunosuppression)

Question 314

how does a simultaneous pancreas and kidney transplant work in the treatment of type 1 diabetes?

Answer 314

better survival rate of pancreas graft when transplanted with kidneys - therefore only used in cases of renal failure

Question 315

what are the negatives of pancreas transplants in the treatment of type 1 diabetes?

Answer 315

life long immunosuppression

availability of donors

risk of rejection

Question 316

what tests are used to monitor diabetes control overall?

Answer 316

glycated haemoglobin

capillary (finger prick) blood glucose monitoring

continuous glucose monitoring (restricting availability, NICE guidelines)

Question 317

how is HbA1c used to test for diabetes?

Answer 317

reflect 3 months (RBC lifespan) of glycaemia

biased to last 30 days preceding measurement

glycated NOT glycosylated (enzymatic) - therefore linear relationship

irreversible reaction

Question 318

what are the limitations of an HbA1c test?

Answer 318

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

Question 319

what is used to guide insulin doses in treatment of type 1 diabetes?

Answer 319

self monitoring of blood glucose results at home

HbA1c results every 3-4 months

increase or decrease insulin doses

Question 320

what are the acute complications of type 1 diabetes?

Answer 320

diabetic ketoacidosis

uncontrolled hyperglycaemia

hypoglycaemia

Question 321

when does diabetic ketoacidosis occur?

Answer 321

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

Question 322

when does hypoglycaemia occur with reference to type 1 diabetes?

Answer 322

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

Question 323

what are the adrenergic (initial) symptoms of hypoglycaemia?

Answer 323

tremors

palpitations

sweating

hunger

(sometimes no symptoms present - very dangerous)

Question 324

what are the neuroglycopaenic symptoms of hypoglycaemia?

Answer 324

somnolence

confusion

incoordination

seizures

coma

Question 325

when does hypoglycaemia become problematic (in type 1 diabetes treatment)?

Answer 325

excessive frequency

impaired awareness

nocturnal hypoglycaemia

recurrent severe hypoglycaemia

Question 326

what are the risks of hypoglycaemia?

Answer 326

seizure/coma/death

impacts on emotional well-being

impacts on driving

impacts on day to day function

impacts on cognition

Question 327

who is at risk/what are the risk factors for becoming hypoglycaemic with type 1 diabetes?

Answer 327

exercise

missed meals

inappropriate insulin regime

alcohol intake

lower HbA1c

lack of training

(all people with type 1 diabetes at risk)

Question 328

what are some strategies to support problematic hypoglycaemia as a result of type 1 diabetes treatment?

Answer 328

indication for insulin-pump therapy (CSII)

may try different insulin analogues

revisit carbohydrate counting / structured education

behavioural psychology support

transplantation

Question 329

what measures are taken for the acute management of hypoglycaemia if the patient is alert and orientated?

Answer 329

oral carbohydrates

rapid acting - juice/sweet

longer acting - sandwich

Question 330

what measures are taken for the acute management of hypoglycaemia if the patient is drowsy?

Answer 330

buccal glucose

e.g. hypostop/glucogel

complex carbohydrate

Question 331

what measures are taken for the acute management of hypoglycaemia if the patient is unconscious?

Answer 331

IV access

20% glucose IV

Question 332

what is type 2 diabetes?

Answer 332

condition in which the combination of insulin resistance and beta-cell failure result in hyperglycaemia

Question 333

how is type 2 diabetes managed?

Answer 333

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

Question 334

when does type 2 diabetes present?

Answer 334

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

Question 335

what are normal levels of fasting glucose, 2 hour glucose, Hba1c, and insulin?

Answer 335

less than 6

less than 7.7

less than 42

insulin resistance higher than production

Question 336

what are intermediate levels of fasting glucose, 2 hour glucose, Hba1c, and insulin?

Answer 336

impaired fasting glycaemia

impaired glucose tolerance

pre diabetes/non diabetic hyperglycaemia

insulin production and resistance increases - eventually resistance increases past production

Question 337

what are type 2 diabetes levels of fasting glucose, 2 hour glucose, Hba1c, and insulin?

Answer 337

larger than 7

larger than 11

larger than 48

insulin production drops, resistance stays high

Question 338

how can insulin deficiency be defined in type 2 diabetes?

Answer 338

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

Question 339

how does beta cell function change in type 2 diabetes?

Answer 339

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

Question 340

what is the pathophysiology of type 2 diabetes?

Answer 340

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

Question 341

what is the effect of type 2 diabetes on first phase insulin release?

Answer 341

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

Question 342

how does reduced insulin in type 2 diabetes affect glucose?

Answer 342

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)

Question 343

how does glucagon action contribute to increased levels of glucose in type 2 diabetes?

Answer 343

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

Question 344

what is the relationship between insulin resistance and secretion?

Answer 344

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

Question 345

what are the consequences of insulin resistance in the body?

Answer 345

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

Question 346

what is insulin sensitivity?

Answer 346

define how effective insulin will be at clearing glucose from the circulation

(more effective = more sensitive)

Question 347

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)

Answer 347

TNF alpha IL-6

endocannabinoids

leptin

resistin

apelin

fatty acids

adiponectin

glucocorticoids

visfatin

effects on beta cell function, metabolic rate, organ fat etc.

Question 348

what is monogenic type 2 diabetes?

Answer 348

single gene mutation leads to diabetes

MODY (maturity onset diabetes of the young)

always going to develop type 2 diabetes no matter what

Question 349

what is polygenic type 2 diabetes?

Answer 349

polymorphism increasing risk of diabetes

high risk - T2DM may develop later depending on other factors, does not need strong environmental trigger

Question 350

how do genes and environment interact in the development of type 2 diabetes?

Answer 350

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)

Question 351

what have GWAS in type 2 diabetes sufferers shown about single nucleotide polymorphisms and their impact in T2DM development?

Answer 351

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

Question 352

what is the role of obesity in the development of type 2 diabetes?

Answer 352

major risk factor of diabetes

fatty acids and adipocytokines important

central vs visceral obesity (higher visceral fat content - higher risk)

Question 353

how does type 2 diabetes present?

Answer 353

hyperglycaemia

overweight

dyslipidaemia

fewer osmotic symptoms (may not get dramatic weight loss as in type 1)

with complications

insulin resistance

later insulin deficiency

Question 354

what are the risk factors for development of type 2 diabetes?

Answer 354

age

PCOS

increased BMI

family Hx

ethnicity

inactivity

Question 355

what is the process for diagnosing type 2 diabetes?

Answer 355

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)

Question 356

what is the hyperosmolar hyperglycaemic state?

Answer 356

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

Question 357

how is type 2 diabetes managed?

Answer 357

diet

oral medication

structured education

may need insulin later

may lead to remission / reversal

Question 358

what are the principles of a T2DM consultation?

Answer 358

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

Question 359

what are the dietary recommendations and necessary education for type 2 diabetes?

Answer 359

total calories control

reduce calories as fat

reduce calories as refined carbohydrate

increase calories as complex carbohydrate

increase soluble fibre

decrease sodium

Question 360

how is excess hepatic glucose production managed in type 2 diabetes?

Answer 360

reduce hepatic glucose production

use metformin

Question 361

how is resistance to action of circulating insulin managed in type 2 diabetes?

Answer 361

improve insulin sensitivity

use metformin, thiozolidinediones

Question 362

how is inadequate insulin production for extent of insulin resistance managed in type 2 diabetes?

Answer 362

boost insulin secretion

use sulphonylureas, DPP4-inhibitors, GLP-1 agonists

Question 363

how is excess glucose in circulation managed in type 2 diabetes?

Answer 363

inhibit carbohydrate gut absorption

or inhibit renal glucose resorption

use alpha glucosidase inhibitor, SGLT-2 inhibitor

Question 364

how is metformin used in treatment of type 2 diabetes?

Answer 364

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

Question 365

how are sulphonylureas used to treat type 2 diabetes?

Answer 365

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

Question 366

how is pioglitazone used in the treatment of type 2 diabetes?

Answer 366

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)

Question 367

what is GLP-1 (glucagon-like-peptide 1)?

Answer 367

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

Question 368

how does a GLP 1 agonist (e.g. liraglutide, semaglutide) work in treatment of type 2 diabetes?

Answer 368

injectable –daily, weekly

boost insulin production - decrease glucagon and glucose

causes weight loss

Question 369

how does a DPP-4 inhibitor work in treatment of type 2 diabetes?

Answer 369

increase half life of exogenous GLP-1

decrease glucagon and glucose

neutral on weight

Question 370

how does an SGLT-2 inhibitor (e.g. empagliflozin, dapagliflozin, canagliflozin) work in treatment of type 2 diabetes?

Answer 370

inhibits Na-Glu transporter, increases glycosuria

HbA1c lower

lower all cause mortality, heart failure risk

improve CKD

Question 371

since beta cell function continues to decline even with medication, what treatments can be used to induce remission of type 2 diabetes?

Answer 371

gastric bypass

DIRECT/DROPLET study - low calorie diet

Question 372

how is blood pressure managed in type 2 diabetes?

Answer 372

hypertension very common in T2DM

clear benefits for reduction especially with use of ACE-inhibitors

Question 373

how is lipid managed in type 2 diabetes?

Answer 373

in diabetes -

• total cholesterol, triglycerides raised
• HDL cholesterol reduced

clear benefit to lipid-lowering therapy

Question 374

what are the 3 major sites of microvascular complications caused by type 2 diabetes (hyperglycaemia)?

Answer 374

retinal arteries

renal glomerular arterioles

vasa nervorum - tiny blood vessels that supply nerve

Question 375

what is the largest factor associated with development of microvascular disease?

Answer 375

high blood pressure

Question 376

what is the relationship of risk of microvascular complications with rising HbA1c?

Answer 376

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

Question 377

what is the relationship between hypertension and risk of microvascular complications?

Answer 377

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

Question 378

what factors can lead to development of microvascular complications?

Answer 378

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)

Question 379

what is the mechanism of damage for microvascular complications?

Answer 379

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

Question 380

mechanism of damage

Answer 380

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)

Question 381

how is retinopathy as a microvascular complication of type 2 diabetes detected?

Answer 381

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

Question 382

after detecting diabetic retinopathy, how is it followed up?

Answer 382

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

Question 383

what are the stages of diabetic retinopathy?

Answer 383

background retinopathy

pre-proliferative

proliferative

(maculopathy can occur during any stage)

Question 384

what are the features of background retinopathy?

Answer 384

hard exudates - fluid and associated proteins leak out(cheese colour, lipid)

microaneurysms (“dots”)

blot haemorrhages

Question 385

what are the features of pre-proliferative retinopathy?

Answer 385

cotton wool spots also called soft exudates

represent retinal ischaemia, cotton wool spots occur where blood vessels are damaged

Question 386

what are the features of proliferative retinopathy?

Answer 386

visible new vessels (neovascularisation)

on disk or elsewhere in retina

Question 387

what are the features of maculopathy?

Answer 387

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

Question 388

what are the general principals of treating diabetic retinopathy?

Answer 388

improve HbA1c

good blood pressure control

Question 389

how is background diabetic retinopathy treated?

Answer 389

continued annual surveillance

feedback to person living with diabetes

Question 390

how is pre-proliferative diabetic retinopathy treated?

Answer 390

if left alone will progress to neovascularisation

therefore early panretinal photocoagulation (laser vessels off)

Question 391

how is proliferative diabetic retinopathy treated?

Answer 391

panretinal photocoagulation

Question 392

how is diabetic maculopathy treated?

Answer 392

oedema - anti-VEGF injections (vascular endothelial growth factor)

grid photocoagulation (laser burns new vessels in grid formation around macula)

Question 393

how is diabetic nephropathy characterised?

Answer 393

hypertension

progressively increasing proteinuria

progressively deteriorating kidney function - measured by eGFR

classic histological features

Question 394

how is diabetic nephropathy screened for?

Answer 394

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

Question 395

why is nephropathy important?

Answer 395

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)

Question 396

what are the histological features of diabetic nephropathy?

Answer 396

glomerular changes

• mesangial expansion
• basement membrane thickening
• glomerulosclerosis

Question 397

what is the epidemiology of diabetic nephropathy?

Answer 397

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

Question 398

how is diabetic nephropathy diagnosed?

Answer 398

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

Question 399

what is the mechanism of diabetic nephropathy?

Answer 399

diabetes causes hyperglycaemia and hypertension

glomerular hypertension causes destruction of glomeruli

causes proteinuria, interstitial fibrosis, decreases filtration rate - eventual renal failure

Question 400

what are the strategies for intervention in diabetic nephropathy?

Answer 400

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

Question 401

why does blocking RAS work in treating diabetic nephropathy?

Answer 401

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

Question 402

how does diabetic neuropathy occur?

Answer 402

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

Question 403

how does peripheral neuropathy manifest?

Answer 403

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

Question 404

what are the clinical features of diabetic neuropathy (foot)?

Answer 404

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)

Question 405

what is the danger of neuropathy?

Answer 405

not sensing an injury to the foot

Question 406

how is peripheral neuropathy managed (prevention)?

Answer 406

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

Question 407

how is peripheral neuropathy with ulceration managed?

Answer 407

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

Question 408

what are the features of mononeuropathy (diabetic neuropathy)?

Answer 408

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

Question 409

what are the features of autonomic neuropathy (diabetic neuropathy)?

Answer 409

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

Question 410

how is autonomic neuropathy diagnosed?

Answer 410

diagnose on R-R interval changes

or no change in heart rate on Valsalva manoeuvre

gastric emptying studies

Question 411

what are the macrovascular complications caused by diabetes?

Answer 411

early widespread atherosclerosis (renal artery stenosis)

ischaemic heart disease

cerebrovascular disease

peripheral vascular disease

Question 412

what are the markers for atherosclerosis (diabetes)?

Answer 412

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)

Question 413

what are the metabolic factors contributing to atherosclerosis?

Answer 413

insulin resistance

inflammation CRP

adipocytokines

urine microalbumin

Question 414

what is the relationship between HbA1c and risk of MI in type 2 diabetes?

Answer 414

higher HbA1c, higher risk of MI and other complications

Question 415

which people are more at risk of cerebrovascular disease associated with diabetes?

Answer 415

usually in older people

occurs earlier, more widespread in diabetic individuals

Question 416

what are the effects of peripheral vascular disease as a macrovascular complication of diabetes?

Answer 416

contributes to diabetic foot problems with neuropathy

narrowed arteries decrease blood supply to peripheries - can cause gangrene

Question 417

what can renal artery stenosis contribute to?

Answer 417

hypertension

renal failure

occlusion of renal artery decreases blood supply in kidneys

Question 418

what is the overall pathway to foot ulceration as a result of type 2 diabetes?

Answer 418

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)

Question 419

what is the incretin effect?

Answer 419

relative increase in insulin in response to oral glucose relative to intravenous glucose

Question 420

what is the mechanism of diabetic retinopathy?

Answer 420

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)

Question 421

what is mononeuritis multiplex (diabetic neuropathy)?

Answer 421

random combination of peripheral nerve lesions

Question 422

what is radiculopathy (diabetic neuropathy)?

Answer 422

pain over spinal nerves, usually affecting a dermatome on the abdomen or chest wall

Question 423

how does atherosclerosis develop over time (diabetic)?

Answer 423

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

Question 424

what is the pathogenesis of atherosclerosis (diabetic)?

Answer 424

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

Question 425

what is the effect of type 2 diabetes on life expectancy?

Answer 425

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)

Question 426

what is the difference between microvascular and macrovascular complications caused by type 2 diabetes?

Answer 426

microvascular: causes morbidity
macrovascular: causes morbidity and mortality

Question 427

where is macrovascular disease present?

Answer 427

systemic disease

commonly present in multiple arterial beds

Question 428

how is diabetes related to ischaemic heart disease?

Answer 428

major cause of morbidity and mortality in diabetes

mechanisms are similar with and without diabetes, just occurs younger

elevated ST waves

Question 429

how can cerebrovascular disease cause brain damage?

Answer 429

occlusion in cerebral circulation

areas of brain affected can no longer control areas that they used to (infarct)

Question 430

what effect does treatment targeted to hyperglycaemia have on risk of cardiovascular disease?

Answer 430

hyperglycaemia treatment has minor effect on increased CVD (although some studies show benefits for mitigating risk of CHD)

Question 431

what does prevention of macrovascular disease require?

Answer 431

aggressive management of multiple risk factors

mechanistically, insulin resistance is importance before hyperglycaemia starts contributing

Question 432

what are the non-modifiable risk factors for macrovascular disease associated with diabetes?

Answer 432

age

sex

birth weight

FHx/genes

Question 433

what are the modifiable risk factors for macrovascular disease associated with diabetes?

Answer 433

dyslipidaemia

high blood pressure

smoking

diabetes

Question 434

what is the most beneficial aspect of treating macrovascular complications in diabetes?

Answer 434

lipid control
- use of statins, fewer acute coronary events etc.

also control blood pressure

Question 435

what is steno-2?

Answer 435

multifactorial intensive therapy for diabetes to reduce risk of macrovascular events

Question 436

what are the targets for blood pressure management in type 2 diabetes (macrovascular event risk reduction)?

Answer 436

<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

Question 437

what are the targets for blood lipid management in type 2 diabetes (macrovascular event risk reduction)?

Answer 437

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

Question 438

why is central adiposity more dangerous than visceral adiposity in diabetes?

Answer 438

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.

Question 439

what are the complications of diabetes predisposing to foot disease?

Answer 439

neuropathy: sensory, motor, autonomic

peripheral vascular disease

Question 440

how is sensory neuropathy detected in the pathway to foot ulceration?

Answer 440

test sensation using 10g monofilament - can predict ulceration

Question 441

how does motor neuropathy present in foot ulceration?

Answer 441

clawed toes - increased pressure on metatarsal heads (especially big toe) so toes are flexed

Question 442

why does motor neuropathy cause clawed feet in foot ulceration?

Answer 442

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

Question 443

how does motor neuropathy cause clawed hands (unable to press palms together)?

Answer 443

glycosylation of tendons in hands

cannot bend palms and fingers properly

Question 444

what causes limited joint mobility in the process of foot ulceration?

Answer 444

abnormal pressure loading

Question 445

what effect does autonomic neuropathy on foot ulceration?

Answer 445

dry, flaking skin (also exacerbated by poor care)

Question 446

how does autonomic neuropathy cause dry, flaking skin in foot ulceration?

Answer 446

autonomic nervous system important to sweating and controlling of grease in the feet

Question 447

how does peripheral vascular disease contribute to foot ulceration?

Answer 447

arterial runoff through the legs down to the feet is reduced with atheroma widespread

Question 448

what can occur due to sensory neuropathy in the foot?

Answer 448

trauma

damages foot through minor/discrete episodes

Question 449

what are the features of the neuropathic foot?

Answer 449

numb

warm

dry

palpable foot pulses

ulcers at points of high pressure loading

Question 450

what are the features of the ischaemic foot?

Answer 450

cold

pulseless

ulcers at foot margins

Question 451

what are the features of the neuro-ischaemic foot?

Answer 451

numb

cold

dry

pulseless

ulcers at points of high pressure loading and at foot margins

Question 452

how is pain felt in the ulcerated foot?

Answer 452

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)

Question 453

how does infection spread in the ulcerated foot?

Answer 453

infection will spread to soft tissue and eventually bone

Question 454

how is the foot of a diabetic patient assessed?

Answer 454

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

Question 455

what is the preventative management strategy for diabetic foot ulceration?

Answer 455

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

Question 456

what does a diabetic foot MDT look like?

Answer 456

diabetes nurse

vascular surgeon (improve blood flow)

orthotist

diabetologist (control of diabetes)

chiropodist

orthopaedic surgeon (altering pressure across foot)

limb fitting centre

Question 457

how is foot ulceration managed?

Answer 457

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)

Question 458

what does Charcot’s foot look like?

Answer 458

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)

Question 459

how does Charcot’s foot occur in relation to diabetes?

Answer 459

abnormal pressure loading

Question 460

what characteristic of Charcot’s foot makes it difficult to differentiate from osteomyelitis?

Answer 460

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

Question 461

how can you differentiate between Charcot’s foot and osteomyelitis?

Answer 461

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

Question 462

how is Charcot’s foot managed?

Answer 462

special weight bearing cast to alleviate pressure loading