Endocrinology

Question 1

what are thiazolidinediones?

Answer 1

Thiazolidinediones are a class of agents used in the treatment of type 2 diabetes mellitus. They are agonists to the PPAR-gamma receptor and reduce peripheral insulin resistance.

e.g. pioglitazone

Question 2

Adverse effects of Thiazolidinediones?

Answer 2

Adverse effects
weight gain
liver impairment: monitor LFTs
fluid retention - therefore contraindicated in heart failure. The risk of fluid retention is increased if the patient also takes insulin
recent studies have indicated an increased risk of fractures
bladder cancer: recent studies have shown an increased risk of bladder cancer in patients taking pioglitazone (hazard ratio 2.64)

Question 3

What is Bartter’s syndrome?

Answer 3

Bartter’s syndrome is an inherited cause (usually autosomal recessive) of severe hypokalaemia due to defective chloride absorption at the Na+ K+ 2Cl- cotransporter (NKCC2) in the ascending loop of Henle.

Loop diuretics work by inhibiting NKCC2 - think of Bartter’s syndrome as like taking large doses of furosemide

Question 4

Features of Bartter’s syndrome?

Answer 4

usually presents in childhood, e.g. Failure to thrive
polyuria, polydipsia
hypokalaemia
normotension
weakness

Question 5

Pregnant ladies with hypothyroid - how much do they need their hypothyroid treatment increasing by?

Answer 5

thyroxine is safe during pregnancy
serum thyroid-stimulating hormone measured in each trimester and 6-8 weeks post-partum
women require an increased dose of thyroxine during pregnancy
by up to 50% as early as 4-6 weeks of pregnancy
breastfeeding is safe whilst on thyroxine

Question 6

what may untreated severe hyponatraemia lead to?

Answer 6

cerebral oedema

Question 7

what is considered acute or chronic hyponatraemia?

Answer 7

acute: develops over a period of < 48 hours
chronic: develops over a period > 48 hours

Question 8

symptoms of hyponatraemia?

Answer 8

patients with mild hyponatraemia may be symptomatic
early symptoms may include: headache, lethargy, nausea, vomiting, dizziness, confusion, and muscle cramps
late symptoms may include: seizures, coma, and respiratory arrest

Question 9

How is hypovolaemic hyponatraemia managed?

Answer 9

normal, i.e. isotonic, saline (0.9% NaCl)
this may sometimes be given as a trial
if the serum sodium rises this supports a diagnosis of hypovolemic hyponatraemia
if the serum sodium falls an alternative diagnosis such as SIADH is likely

Question 10

what is the management of euvolemic and hypervolemic hyponatreamia?

Answer 10

If a euvolemic cause is suspected
fluid restrict to 500-1000 mL/day
consider medications:
demeclocycline
vaptans (see below)

If a hypervolemic cause is suspected
fluid restrict to 500-1000 mL/day
consider loop diuretics
consider vaptans

Question 11

management of acute hyponatraemia?

Answer 11

Patients with acute, severe (<120 mmol/L) or symptomatic hyponatraemia require close monitoring, preferably in an HDU or above setting.

Hypertonic saline (typically 3% NaCl) is used to correct the sodium level more quickly than would be done in patients with chronic hyponatraemia.

Question 12

complications of hyponatraemia treatment?

Answer 12

can occur due to over-correction of severe hyponatremia
pathophysiology:
thought to develop secondary to astrocyte (and possibly oligodendrocyte) apoptosis
astrocytes and oligodendrocytes (cells of the glial syncytium) are crucial for normal myelination
chronic hyponatraemia → loss of osmotically active organic osmolytes (such as myoinositol, glutamate, glutamine) from astrocytes. These provide protection against cerebral oedema
organic osmolytes cannot be replaced quickly enough when the brain volume begins to shrink in response to the correction of hyponatraemia
the dehydrated astrocytes and oligodendrocytes undergo apoptosis or other forms of injury → demyelination
to avoid this, Na+ levels are only raised by 4 to 6 mmol/l in a 24-hour period
symptoms usually occur after 2 days and are usually irreversible: dysarthria, dysphagia, paraparesis or quadriparesis, seizures, confusion, and coma
patients are awake but are unable to move or verbally communicate, also called ‘Locked-in syndrome’

Question 13

Physiological response to hypoglycaemia ?

Answer 13

hormonal response: the first response of the body is decreased insulin secretion. This is followed by increased glucagon secretion. Growth hormone and cortisol are also released but later
sympathoadrenal response: increased catecholamine-mediated (adrenergic) and acetylcholine-mediated (cholinergic) neurotransmission in the peripheral autonomic nervous system and in the central nervous system

Question 14

causes of hypoglycaemia?

Answer 14

Causes
insulinoma - increased ratio of proinsulin to insulin
self-administration of insulin/sulphonylureas
liver failure
Addison’s disease
alcohol
causes exaggerated insulin secretion
mechanism is thought to be due to the effect of alcohol on the pancreatic microcirculation → redistribution of pancreatic blood flow from the exocrine into the endocrine parts → increased insulin secretion
nesidioblastosis - beta cell hyperplasia

Question 15

Investigations for acromegaly?

Answer 15

1st line - serum IGF-1 levels
The OGTT test is recommended to confirm the diagnosis if IGF-1 levels are raised.

Serum IGF-1 may also be used to monitor disease

Oral glucose tolerance test
in normal patients GH is suppressed to < 2 mu/L with hyperglycaemia
in acromegaly there is no suppression of GH
may also demonstrate impaired glucose tolerance which is associated with acromegaly

A pituitary MRI may demonstrate a pituitary tumour

Question 16

What is Gitelman’s syndrome?

Answer 16

Gitelman’s syndrome is due to a defect in the thiazide-sensitive Na+ Cl- transporter in the distal convoluted tubule.

Question 17

what are the features of Gitelman’s syndrome?

Answer 17

Features
normotension
hypokalaemia
hypocalciuria
hypomagnesaemia
metabolic alkalosis

Question 18

what causes thyroid eye disease?

Answer 18

Thyroid eye disease affects between 25-50% of patients with Graves’ disease.

Pathophysiology
it is thought to be caused by an autoimmune response against an autoantigen, possibly the TSH receptor → retro-orbital inflammation
the inflammation results in glycosaminoglycan and collagen deposition in the muscles

Question 19

how do you prevent thyroid eye disease?

Answer 19

smoking is the most important modifiable risk factor for the development of thyroid eye disease
radioiodine treatment may increase the inflammatory symptoms seen in thyroid eye disease. In a recent study of patients with Graves’ disease around 15% developed, or had worsening of, eye disease. Prednisolone may help reduce the risk

Question 20

what are the features of thyroid eye disease?

Answer 20

the patient may be eu-, hypo- or hyperthyroid at the time of presentation
exophthalmos
conjunctival oedema
optic disc swelling
ophthalmoplegia
inability to close the eyelids may lead to sore, dry eyes. If severe and untreated patients can be at risk of exposure keratopathy

Question 21

What is the management of thyroid eye disease?

Answer 21

smoking cessation
topical lubricants may be needed to help prevent corneal inflammation caused by exposure
steroids
radiotherapy
surgery

Question 22

complications of thyroid eye disease?

Answer 22

exposure keratopathy - due to eyelid retraction and proptosis - cornea becomes excessively exposed, disrupting the normal tear film → dryness, irritation, and corneal ulceration
symptoms include foreign body sensation, pain, and photophobia

Optic neuropathy - ccurs when enlarged extraocular muscles compress the optic nerve at the apex of the orbit → a reduction in visual acuity, colour vision deficits, and visual field defect

Strabismus and diplopia - fibrosis and enlargement of the extraocular muscles can result in restrictive strabismus → misalignment of the eyes → double vision (diplopia)
this not only affects visual function but can also significantly impair the quality of life.

Question 23

diagnostic thresholds for gestational diabetes?

Answer 23

fasting glucose is >= 5.6 mmol/L
2-hour glucose is >= 7.8 mmol/L

Question 24

Management of gestational diabetes?

Answer 24

if the fasting plasma glucose level is < 7 mmol/l a trial of diet and exercise should be offered
if glucose targets are not met within 1-2 weeks of altering diet/exercise metformin should be started
if glucose targets are still not met insulin should be added to diet/exercise/metformin
gestational diabetes is treated with short-acting, not long-acting, insulin
if at the time of diagnosis the fasting glucose level is >= 7 mmol/l insulin should be started
if the plasma glucose level is between 6-6.9 mmol/l, and there is evidence of complications such as macrosomia or hydramnios, insulin should be offered
glibenclamide should only be offered for women who cannot tolerate metformin or those who fail to meet the glucose targets with metformin but decline insulin treatment

Question 25

what may be used to treat galactorrhea?

Answer 25

Dopamine acts as the primary prolactin releasing inhibitory factor and hence dopamine agonists such as bromocriptine may be used to control galactorrhoea.

Question 26

causes of raised prolactin?

Answer 26

prolactinoma
pregnancy
oestrogens
physiological: stress, exercise, sleep
acromegaly: 1/3 of patients
polycystic ovarian syndrome
primary hypothyroidism (due to thyrotrophin releasing hormone (TRH) stimulating prolactin release)

Question 27

what drugs can cause raised prolactin?

Answer 27

metoclopramide, domperidone
phenothiazines
haloperidol
very rare: SSRIs, opioids

Question 28

what are the antibodies in graves disease?

Answer 28

IgG antibodies to the thyroid-stimulating hormone (TSH) receptor
IgG Anti-thyroid peroxidase antibodies

Question 29

what do non-functioning pituitary adenomas result in?

Answer 29

Non-functioning pituitary adenomas can result in panhypopituitarism due to infiltration of the normal pituitary tissue. Compression of the pituitary stalk can result in hyperprolactinaemia due to decreased transport of dopamine from the hypothalamus to the pituitary. Dopamine acts to suppress prolactin release

Question 30

what is the mechanism of action of orlistat?

Answer 30

orlistat acts as a pancreatic lipase inhibitor. Orlistat works by binding reversibly to pancreatic lipase in the gastrointestinal tract, preventing the breakdown of dietary triglycerides into absorbable free fatty acids and monoglycerides. This results in approximately 30% of ingested fat passing through the gut unabsorbed, thereby reducing caloric intake and promoting weight loss.

Question 31

when should orlistat be prescribed?

Answer 31

It should only be prescribed as part of an overall plan for managing obesity in adults who have:
BMI of 28 kg/m^2 or more with associated risk factors, or
BMI of 30 kg/m^2 or more
continued weight loss e.g. 5% at 3 months
orlistat is normally used for < 1 year

Question 32

how do sulfonylureas work?

Answer 32

They work by increasing pancreatic insulin secretion and hence are only effective if functional B-cells are present. On a molecular level they bind to an ATP-dependent K+(KATP) channel on the cell membrane of pancreatic beta cells.

Question 33

adverse effects of sulfonylureas?

Answer 33

Common adverse effects
hypoglycaemic episodes (more common with long-acting preparations such as chlorpropamide)
weight gain

Rarer adverse effects
hyponatraemia secondary to syndrome of inappropriate ADH secretion
bone marrow suppression
hepatotoxicity (typically cholestatic)
peripheral neuropathy

should be avoided in breast feeding and pregnancy

Question 34

management of Hirsutism and acne in PCOS?

Answer 34

a COC pill may be used help manage hirsutism. Possible options include a third generation COC which has fewer androgenic effects or co-cyprindiol which has an anti-androgen action. Both of these types of COC may carry an increased risk of venous thromboembolism
if doesn’t respond to COC then topical eflornithine may be tried
spironolactone, flutamide and finasteride may be used under specialist supervision

Question 35

key points of levothyroxine therapy?

Answer 35

start on 25mcg if over 50
other patients should be started on 50-100
following a change in thyroxine dose thyroid function tests should be checked after 8-12 weeks

goal is normalisation of TSH level

iron, calcium carbonate
absorption of levothyroxine reduced, give at least 4 hours apart

Question 36

side effects of thyroxine therapy ?

Answer 36

hyperthyroidism: due to over treatment
reduced bone mineral density
worsening of angina
atrial fibrillation

Question 37

what are the features of insulinoma?

Answer 37

of hypoglycaemia: typically early in morning or just before meal, e.g. diplopia, weakness etc
rapid weight gain may be seen
high insulin, raised proinsulin:insulin ratio
high C-peptide

Question 38

Diagnosis of insulinoma?

Answer 38

supervised, prolonged fasting (up to 72 hours)
CT pancreas

Whilst supervised fasting is normally the investigation of choice if this option is not given then insulin + C-peptide levels during an acute hypoglycaemic episode are useful.

Question 39

what is primary hyperparathyroidism?

Answer 39

Primary hyperparathyroidism is caused by excess secretion of PTH resulting in hypercalcaemia. It is the most common cause of hypercalcaemia in outpatients and is often diagnosed following an incidental finding of an elevated serum calcium concentration. In 85% of cases a parathyroid adenoma is responsible.

Causes of primary hyperparathyroidism
85%: solitary adenoma
10%: hyperplasia
4%: multiple adenoma
1%: carcinoma

Question 40

what are the features of primary hyperparathyroidism?

Answer 40

80% of patients are asymptomatic

polydipsia, polyuria
depression
anorexia, nausea, constipation
peptic ulceration
pancreatitis
bone pain/fracture
renal stones
hypertension

Question 41

Investigations for primary hyperparathyroidism?

Answer 41

bloods
raised calcium, low phosphate
PTH may be raised or (inappropriately, given the raised calcium) normal
technetium-MIBI subtraction scan
x-ray findings
pepperpot skull
osteitis fibrosa cystica

Question 42

what is the treatment for primary hyperparathyroidism?

Answer 42

the definitive management is total parathyroidectomy
conservative management may be offered if the calcium level is less than 0.25 mmol/L above the upper limit of normal AND the patient is > 50 years AND there is no evidence of end-organ damage
patients not suitable for surgery may be treated with cinacalcet, a calcimimetic
a calcimimetic ‘mimics’ the action of calcium on tissues by allosteric activation of the calcium-sensing receptor

Question 43

what is the management of myxoedemic coma?

Answer 43

Myxoedemic coma is treated with thyroxine and hydrocortisone

Question 44

what is hungry bone syndrome?

Answer 44

Hungry bone syndrome is an uncommon entity but can occur after parathyroidectomy if the hyperparathyroidism has been long-standing. The mechanism is thought to be thus: high pre-operative levels of parathyroid hormone provide a constant stimulus for osteoclast activity creating the hypercalcaemic state by de-mineralizing the bones. This process can result in x-ray changes very similar to metastatic lytic lesions if left untreated. Upon removal of the parathyroid adenoma the hormone levels fall rapidly (they have a very short half-life) and the osteoclast activity is subsequently diminished and the bones rapidly begin re-mineralisation - ‘hungry bone syndrome’. This process can be uncomfortable and also result in systemic hypocalcaemia.