Endocrinology Flashcards
What happens to thyroxine-binding globulin (TBG) levels during pregnancy?
There is an increase in TBG levels during pregnancy.
This increase causes an increase in total thyroxine levels but does not affect free thyroxine levels.
What are the risks associated with untreated thyrotoxicosis in pregnancy?
Untreated thyrotoxicosis increases the risk of:
* fetal loss
* maternal heart failure
* premature labour
These complications can have serious implications for both the mother and the fetus.
What is the most common cause of thyrotoxicosis in pregnancy?
Graves’ disease is the most common cause of thyrotoxicosis in pregnancy.
Activation of the TSH receptor by HCG may also occur, termed transient gestational hyperthyroidism.
What is the traditional antithyroid drug of choice in pregnancy?
Propylthiouracil has traditionally been the antithyroid drug of choice.
However, it is associated with an increased risk of severe hepatic injury.
When is propylthiouracil generally used during pregnancy?
Propylthiouracil is generally used in the first trimester of pregnancy.
It is used in place of carbimazole due to carbimazole’s association with congenital abnormalities.
What should maternal free thyroxine levels be kept at during pregnancy?
Maternal free thyroxine levels should be kept in the upper third of the normal reference range.
This is to avoid fetal hypothyroidism.
When should thyrotrophin receptor stimulating antibodies be checked during pregnancy?
Thyrotrophin receptor stimulating antibodies should be checked at 30-36 weeks gestation.
This helps to determine the risk of neonatal thyroid problems.
What management strategies should not be used in pregnancy?
Block-and-replace regimes should not be used in pregnancy.
Additionally, radioiodine therapy is contraindicated.
Is thyroxine safe during pregnancy?
Yes, thyroxine is safe during pregnancy.
It is important for maintaining proper thyroid function.
How often should serum thyroid-stimulating hormone be measured during pregnancy?
Serum thyroid-stimulating hormone should be measured in each trimester and 6-8 weeks post-partum.
This monitoring ensures appropriate thyroid hormone levels are maintained.
How much of an increased dose of thyroxine do women require during pregnancy?
Women require an increased dose of thyroxine during pregnancy by up to 50% as early as 4-6 weeks of pregnancy.
This adjustment is critical for both maternal and fetal health.
Is breastfeeding safe while on thyroxine?
Yes, breastfeeding is safe while on thyroxine.
Thyroxine does not pose a risk to the breastfeeding infant.
what is Gitelman’s syndrome?
Gitelman’s syndrome is due to a defect in the thiazide-sensitive Na+ Cl- transporter in the distal convoluted tubule.
What are the features of Gitelman’s syndrome?
normotension
hypokalaemia
hypocalciuria
hypomagnesaemia
metabolic alkalosis
what causes acromegaly?
In acromegaly there is excess growth hormone secondary to a pituitary adenoma in over 95% of cases. A minority of cases are caused by ectopic GHRH or GH production by tumours e.g. pancreatic.
what are the features of acromegaly?
coarse facial appearance, spade-like hands, increase in shoe size
large tongue, prognathism, interdental spaces
excessive sweating and oily skin: caused by sweat gland hypertrophy
features of pituitary tumour: hypopituitarism, headaches, bitemporal hemianopia
raised prolactin in 1/3 of cases → galactorrhoea
6% of patients have MEN-1
What are the complications of acromegaly?
hypertension
diabetes (>10%)
cardiomyopathy
colorectal cancer
what is a contraindication to piaglitazone?
heart failure
what are thiazolidinediones?
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.
Pioglitazone is a thiazolidinedione
What are adverse effects of thiazolidinediones?
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)
what is hashimoto’s thyroiditis?
Hashimoto’s thyroiditis (chronic autoimmune thyroiditis) is an autoimmune disorder of the thyroid gland. It is typically associated with hypothyroidism although there may be a transient thyrotoxicosis in the acute phase. It is 10 times more common in wome
Features of Hasimoto’s thyroiditis?
features of hypothyroidism
goitre: firm, non-tender
anti-thyroid peroxidase (TPO) and also anti-thyroglobulin (Tg) antibodies
Associations with Hashimoto’s thyroiditis?
other autoimmune conditions e.g. coeliac disease, type 1 diabetes mellitus, vitiligo
Hashimoto’s thyroiditis is associated with the development of MALT lymphoma
what can Raised total T3 and T4 but normal fT3 and fT4 suggest?
Raised total T3 and T4 but normal fT3 and fT4 suggest high concentrations of thyroid binding globulin, which can be seen during pregnancy
Elevated oestrogen levels produced in pregnancy stimulate the expression of thyroid binding globulin (TBG) from the liver. As TBG binds to free thyroxine (fT4) and free triiodothyronine (fT3), an increase in TBG results in an initial lowering of fT4 and fT3. This in turn causes a secondary increase in thyroid-stimulating hormone (TSH). The net result is a new equilibrium between free and bound thyroid hormones with an increase in bound-T3 and T4 but an overall unaffected fT3 and fT4 level. As it’s the fT4 and fT3 that are responsible for clinic features of thyrotoxicosis these cases rarely produce clinical signs or symptoms, nor do they require treatment.
When is GLP-1 released?
glucagon-like peptide-1 (GLP-1), a hormone released by the small intestine in response to an oral glucose load
In normal physiology an oral glucose load results in a greater release of insulin than if the same load is given intravenously - this known as the incretin effect. This effect is largely mediated by GLP-1 and is known to be decreased in T2DM.
what are examples of GLP-1 mimetics?
Exenatide is an example of a glucagon-like peptide-1 (GLP-1) mimetic. These drugs increase insulin secretion and inhibit glucagon secretion. One of the major advances of GLP-1 mimetics is that they typically result in weight loss, in contrast to many medications such as insulin, sulfonylureas and thiazolidinediones. They are sometimes used in combination with insulin in T2DM to minimise weight gain.
Liraglutide is the other GLP-1 mimetic currently available. One the main advantages of liraglutide over exenatide is that it only needs to be given once a day.
when would you consider adding exenatide to metformin and a sulfonylurea?
BMI >= 35 kg/m² in people of European descent and there are problems associated with high weight, or
BMI < 35 kg/m² and insulin is unacceptable because of occupational implications or weight loss would benefit other comorbidities.
How should Exenatide be given?
Exenatide must be given by subcutaneous injection within 60 minutes before the morning and evening meals. It should not be given after a meal.
Adverse effects of GLP-1 mimetics?
The major adverse effect of GLP-1 mimetics is nausea and vomiting.
The Medicines and Healthcare products Regulatory Agency has issued specific warnings on the use of exenatide, reporting that is has been linked to severe pancreatitis in some patients.
NICE guidlines for continuing GLP-1 mimetics?
NICE like patients to have achieved a > 11 mmol/mol (1%) reduction in HbA1c and 3% weight loss after 6 months to justify the ongoing prescription of GLP-1 mimetics.
Examples of DPP-4 inhibitors?
Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. Vildagliptin, sitagliptin)
How do DDP-4 inhibitors work?
dipeptidyl peptidase-4, DPP-4 inhibitors increase levels of incretins (GLP-1 and GIP) by decreasing their peripheral breakdown
When might DDP-4 inhibitor be used in preferance to a thiaxolidinedione?
NICE suggest that a DPP-4 inhibitor might be preferable to a thiazolidinedione if further weight gain would cause significant problems, a thiazolidinedione is contraindicated or the person has had a poor response to a thiazolidinedione
What is Graves’ disease?
An autoimmune thyroid disease where the body produces IgG antibodies to the TSH receptor
What is the most common cause of thyrotoxicosis?
Graves’ disease
In which age group is Graves’ disease typically seen?
Women aged 30-50 years
What percentage of patients with Graves’ disease experience eye signs?
30%
What is exophthalmos?
Protrusion of the eyes, a feature of Graves’ disease
What is ophthalmoplegia?
Paralysis or weakness of the eye muscles, associated with Graves’ disease
What is pretibial myxoedema?
Thickening of the skin on the shins, a feature specific to Graves’ disease
What is thyroid acropachy?
A triad of symptoms including digital clubbing, soft tissue swelling, and periosteal new bone formation
What are the components of the triad associated with thyroid acropachy?
- Digital clubbing
- Soft tissue swelling of the hands and feet
- Periosteal new bone formation
What type of autoantibodies are present in Graves’ disease?
- TSH receptor stimulating antibodies (90%)
- Anti-thyroid peroxidase antibodies (75%)
What does thyroid scintigraphy reveal in Graves’ disease?
Diffuse, homogenous, increased uptake of radioactive iodine
Side effects of steroids?
Glucocorticoid side-effects
* endocrine
impaired glucose regulation
increased appetite/weight gain
hirsutism
hyperlipidaemia
- Cushing’s syndrome
moon face
buffalo hump
striae - musculoskeletal
osteoporosis
proximal myopathy
avascular necrosis of the femoral head - immunosuppression
increased susceptibility to severe infection
reactivation of tuberculosis - psychiatric
insomnia
mania
depression
psychosis - gastrointestinal
peptic ulceration
acute pancreatitis - ophthalmic
glaucoma
cataracts
suppression of growth in children
intracranial hypertension
neutrophilia
The relative glucocorticoid and mineralocorticoid activity of commonly used steroids
What are Sulfonylureas?
Sulfonylureas are oral hypoglycaemic drugs used in the management of type 2 diabetes mellitus.
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
Adverse effects of sulfonylureas?
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
Are sulfonylureas safe in pregnancy?
Sulfonylureas should be avoided in breastfeeding and pregnancy.
What is Maturity-Onset Diabetes of the Young (MODY)?
A form of monogenic diabetes characterized by autosomal dominant inheritance, onset before 25 years, and impairment in insulin secretion with minimal defects in insulin action.
What percentage of diabetes mellitus patients are thought to have MODY?
1-2%.
What are the two most common types of MODY?
- MODY2 (GCK mutation)
- MODY3 (HNF1A mutation)
others include MODY1 (HNF4A), MODY4 (PDX1), MODY5 (HNF1B), and so on.
What percentage of MODY cases does MODY3 account for?
Around 60%.
What is the typical clinical presentation of patients with MODY?
Mild non-ketotic hyperglycemia, often detected incidentally or during routine screening.
Unlike Type 1 diabetes, patients with MODY usually do not present with diabetic ketoacidosis except under severe stress conditions, and unlike Type 2 diabetes, they are often of normal weight and do not exhibit signs of insulin resistance.
What distinguishes MODY from Type 1 and Type 2 diabetes regarding weight and insulin resistance?
Patients with MODY are often of normal weight and do not exhibit signs of insulin resistance.
What are the common complications associated with MODY3 or MODY1?
- Retinopathy
- Nephropathy
- Cardiovascular disease
What should prompt suspicion of MODY diagnosis?
Persistent, asymptomatic hyperglycemia detected before age 25 without typical features of Type 1 or Type 2 diabetes.
How is the diagnosis of MODY confirmed?
Through genetic testing.
What is a common treatment for MODY2?
Often does not require specific treatment due to mild hyperglycemia.
What treatment is usually effective for MODY associated with HNF1A?
Low-dose sulfonylureas.
What is a potential need for insulin therapy in MODY patients?
Especially during pregnancy or if sulfonylureas are contraindicated or ineffective.
List the genetic mutations associated with the following MODY types: 1, 2, 3, 4, 5.
- MODY1 - HNF4A
- MODY2 - GCK
- MODY3 - HNF1A
- MODY4 - PDX1
- MODY5 - HNF1B
What is the typical weight status of a MODY patient?
Normal weight.
What is the significance of precise genetic diagnosis in MODY?
It guides treatment strategy and genetic counselling.
Mechanism of action of sulfonylureas?
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.
when should second drug be added to metformin in T2DM?
It’s worthwhile thinking of the average patient who is taking metformin for T2DM, you can titrate up metformin and encourage lifestyle changes to aim for a HbA1c of 48 mmol/mol (6.5%), but should only add a second drug if the HbA1c rises to 58 mmol/mol (7.5%)
Dietary advice in T2DM?
encourage high fibre, low glycaemic index sources of carbohydrates
include low-fat dairy products and oily fish
control the intake of foods containing saturated fats and trans fatty acids
limited substitution of sucrose-containing foods for other carbohydrates is allowable, but care should be taken to avoid excess energy intake
discourage the use of foods marketed specifically at people with diabetes
initial target weight loss in an overweight person is 5-10%
HbA1c targerts in T2DM?
HbA1c should be checked every 3-6 months until stable, then 6 monthly
first line treatment for T2DM?
Metformin remains the first-line drug of choice in type 2 diabetes mellitus.
metformin should be titrated up slowly to minimise the possibility of gastrointestinal upset
if standard-release metformin is not tolerated then modified-release metformin should be trialled
SGLT-2 inhibitors
should also be given in addition to metformin if any of the following apply:
the patient has a high risk of developing cardiovascular disease (CVD, e.g. QRISK ≥ 10%)
the patient has established CVD
the patient has chronic heart failure
metformin should be established and titrated up before introducing the SGLT-2 inhibitor
SGLT-2 inhibitors should also be started at any point if a patient develops CVD (e.g. is diagnosed with ischaemic heart disease), a QRISK ≥ 10% or chronic heart failure
What should be given in T2DM if metformin is contraindicated?
If metformin is contraindicated
if the patient has a risk of CVD, established CVD or chronic heart failure:
SGLT-2 monotherapy
if the patient doesn’t have a risk of CVD, established CVD or chronic heart failure:
DPP-4 inhibitor or pioglitazone or a sulfonylurea
SGLT-2 may be used if certain NICE criteria are met
Second line therapy if hba1c targets not met?
Second-line therapy
Dual therapy - add one of the following:
metformin + DPP-4 inhibitor
metformin + pioglitazone
metformin + sulfonylurea
metformin + SGLT-2 inhibitor (if NICE criteria met)
Third line therapy if hba1c targets not met?
If a patient does not achieve control on dual therapy then the following options are possible:
metformin + DPP-4 inhibitor + sulfonylurea
metformin + pioglitazone + sulfonylurea
metformin + (pioglitazone or sulfonylurea or DPP-4 inhibitor) + SGLT-2 if certain NICE criteria are met
insulin-based treatment
If triple therapy is not effective or not tolerated in T2DM what may be considered?
If triple therapy is not effective or tolerated consider switching one of the drugs for a GLP-1 mimetic:
BMI ≥ 35 kg/m² and specific psychological or other medical problems associated with obesity or
BMI < 35 kg/m² and for whom insulin therapy would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities
only continue if there is a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body weight in 6 months
what is an insulioma?
An insulinoma is a neuroendocrine tumour deriving mainly from pancreatic Islets of Langerhans cells
It is the most common pancreatic endocrine tumour
Features of insulinoma?
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
How is insulinoma diagnosed?
supervised, prolonged fasting (up to 72 hours)
CT pancreas
Management of insulinoma?
surgery
diazoxide and somatostatin if patients are not candidates for surgery
what are examples of acute phase proteins?
CRP*
procalcitonin
ferritin
fibrinogen
alpha-1 antitrypsin
caeruloplasmin
serum amyloid A
serum amyloid P component**
haptoglobin
complement
what are negative acute pahse proteins?
During the acute phase response the liver decreases the production of other proteins (sometimes referred to as negative acute phase proteins). Examples include:
albumin
transthyretin (formerly known as prealbumin)
transferrin
retinol binding protein
cortisol binding protein
Is ESR an acute phase protein?
ESR, or erythrocyte sedimentation rate, is not a protein but rather a test that indirectly measures how much inflammation is in the body. It does this by measuring the rate at which red blood cells settle in a test tube over one hour. The faster the red blood cells fall, the more likely it is there are high levels of inflammation.
when shoudl iron/calcium carbonate tablets be taken in patients on levothyroixine?
Iron / calcium carbonate tablets can reduce the absorption of levothyroxine - should be given 4 hours apart
what should the initial starting dose of levthyroixine be?
initial starting dose of levothyroxine should be lower in elderly patients and those with ischaemic heart disease. The BNF recommends that for patients with cardiac disease, severe hypothyroidism or patients over 50 years the initial starting dose should be 25mcg od with dose slowly titrated. Other patients should be started on a dose of 50-100mcg od
when should TFTs be chacked after changing lebothyroxine dose?
ollowing a change in thyroxine dose thyroid function tests should be checked after 8-12 weeks
what is the therpaeutic goal in levothyroxine therapy?
the therapeutic goal is ‘normalisation’ of the thyroid stimulating hormone (TSH) level. As the majority of unaffected people have a TSH value 0.5-2.5 mU/l it is now thought preferable to aim for a TSH in this range
side effects of levothyroixine therapy?
hyperthyroidism: due to over treatment
reduced bone mineral density
worsening of angina
atrial fibrillation
What hormonal levels are commonly seen in PCOS?
Both hyperinsulinaemia and high levels of luteinizing hormone.
What is a recommended management step for weight reduction in PCOS?
Weight reduction if appropriate.
What can be used to regulate menstrual cycles in women with PCOS who require contraception?
A combined oral contraceptive (COC) pill.
What may be used for hirsutism management in PCOS?
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.
What treatment may be tried if a COC does not respond for hirsutism?
Topical eflornithine.
Spironolactone, flutamide, and finasteride.
What is a potential risk associated with anti-oestrogen therapies like clomifene?
Potential risk of multiple pregnancies.
Management of infetility in PCOS?
weigh reduction
There is an ongoing debate as to whether metformin, clomifene or a combination should be used to stimulate ovulation
What are fenofibrates?
Fibrates are used in the management of hyperlipidaemia, particularly raised triglycerides.
Fibrates work through activating PPAR alpha receptors resulting in an increase in LPL activity reducing triglyceride levels.
Side effects of finofibrate?
gastrointestinal side-effects are common
increased risk of thromboembolism
what happens to the levels of GLP-1 in T2DM?
Decreased levels of GLP-1 are seen in type 2 diabetes mellitus
What is Nelson’s syndrome?
Nelson’s syndrome is a rare clinical manifestation that occurs as a complication of bilateral adrenalectomy, which is a procedure used to control hypercortisolism in patients with Cushing’s disease. It is associated with a clinical triad of hyperpigmentation, excessive adrenocorticotropin secretion, and a corticotroph adenoma.
Causes of cushing syndrome?
atrogenic: corticosteroid therapy
ACTH-dependent causes
Cushing’s disease (a pituitary adenoma → ACTH secretion)
ectopic ACTH secretion secondary to a malignancy
ACTH-independent causes
adrenal adenoma
General findings on bloods in patients with cushing syndrom?
A hypokalaemic metabolic alkalosis may be seen, along with impaired glucose tolerance.
Ectopic ACTH secretion (e.g. secondary to small cell lung cancer) is characteristically associated with very low potassium levels.
Tests to confirm cushing syndrome?
The three most commonly used tests are:
* overnight (low-dose) dexamethasone suppression test
this is the most sensitive test and is now used first-line to test for Cushing’s syndrome
patients with Cushing’s syndrome do not have their morning cortisol spike suppressed
* 24 hr urinary free cortisol
two measurements are required
* bedtime salivary cortisol
two measurements are required
what is the high dose dexamthasone supression test?
The high-dose dexamethasone suppression test may be used to localise the pathology resulting in Cushing’s syndrome. This test may be interpreted as follows:
What is impaired fasting gluose?
A fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l implies impaired fasting glucose (IFG)
Impaired glucose tolerance (IGT) is defined as fasting plasma glucose less than 7.0 mmol/l and OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l
Diabetes UK suggests:
‘People with IFG should then be offered an oral glucose tolerance test to rule out a diagnosis of diabetes. A result below 11.1 mmol/l but above 7.8 mmol/l indicates that the person doesn’t have diabetes but does have IGT.’
What would you expect to see in TFTs in pregnancy?
Raised total T3 and T4 but normal fT3 and fT4 suggest high concentrations of thyroid binding globulin, which can be seen during pregnancy
Causes of predominantly hypertriglyceridaemia?
diabetes mellitus (types 1 and 2)
obesity
alcohol
chronic renal failure
drugs: thiazides, non-selective beta-blockers, unopposed oestrogen
liver disease
Causes of predominantly hypercholesterolaemia?
nephrotic syndrome
cholestasis
hypothyroidism
What are incretins?
Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism. Some incretins also inhibit glucagon release from the alpha cells of the islets of Langerhans.
what is the most common cause of primary hyperaldosteronism?
what are other causes of primary hyperaldosteronism?
bilateral idiopathic adrenal hyperplasia is the most common cause
bilateral idiopathic adrenal hyperplasia: the cause of around 60-70% of cases
adrenal adenoma: 20-30% of cases
unilateral hyperplasia
familial hyperaldosteronism
adrenal carcinoma
What woud be seen on a blood gas in cushings?
A hypokalaemic metabolic alkalosis may be seen, along with impaired glucose tolerance.
what are the features of primary hyperaldosteronism?
hypertension
increasingly recognised but still underdiagnosed cause of hypertension
hypokalaemia
e.g. muscle weakness
this is a classical feature in exams but studies suggest this is seen in only 10-40% of patients, and is more common with adrenal adenomas
metabolic alkalosis
Investigations of primary hyperaldosteronism?
guidelines vary but certain patients should be screened for primary hyperaldosteronism, e.g.
hypertension with hypokalemia
treatment-resistant hypertension
the 2016 Endocrine Society recommend that a plasma aldosterone/renin ratio is the first-line investigation in suspected primary hyperaldosteronism
should show high aldosterone levels alongside low renin levels (negative feedback due to sodium retention from aldosterone)
following this a high-resolution CT abdomen and adrenal vein sampling is used to differentiate between unilateral and bilateral sources of aldosterone excess
if the CT is normal adrenal venous sampling (AVS) can be used to distinguish between unilateral adenoma and bilateral hyperplasia
What is the mechanism of action of carbimazole?
blocks thyroid peroxidase from coupling and iodinating the tyrosine residues on thyroglobulin → reducing thyroid hormone production
in contrast propylthiouracil as well as this central mechanism of action also has a peripheral action by inhibiting 5’-deiodinase which reduces peripheral conversion of T4 to T3
What are the adverse effects of carbimazole?
agranulocytosis
crosses the placenta, but may be used in low doses during pregnancy
why may you get polycythaemia in uterine fibroids?
rarely you get polycythaemia secondary to autonomous production of EPO
what are the two main types of impaired glucose regulation?
impaired fasting glucose (IFG) - due to hepatic insulin resistance
impaired glucose tolerance (IGT) - due to muscle insulin resistance
patients with IGT are more likely to develop T2DM and cardiovascular disease than patients with IFG
a fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l implies impaired fasting glucose (IFG)
impaired glucose tolerance (IGT) is defined as fasting plasma glucose less than 7.0 mmol/l and OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l
How is MODY inherited?
AD
What are the main two causes of hypercalcaemia?
Two conditions account for 90% of cases of hypercalcaemia:
1. Primary hyperparathyroidism: commonest cause in non-hospitalised patients
2. Malignancy: the commonest cause in hospitalised patients. This may be due to a number of processes, including;
PTHrP from the tumour e.g. squamous cell lung cancer
bone metastases
myeloma,: due primarily to increased osteoclastic bone resorption caused by local cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells
for this reason, measuring parathyroid hormone levels is the key investigation for patients with hypercalcaemia
What are other causes of hypercalcaemia?
sarcoidosis
other causes of granulomas may lead to hypercalcaemia e.g. tuberculosis and histoplasmosis
vitamin D intoxication
acromegaly
thyrotoxicosis
Milk-alkali syndrome
drugs:
thiazides
calcium-containing antacids
dehydration
Addison’s disease
Paget’s disease of the bone
usually normal in this condition but hypercalcaemia may occur with prolonged immobilisation
What is congenital adrenal hyperplasia?
A group of AR disorders that impair adrenal steroid biosynthesis.
The deficiency in cortisol production leads to compensatory over production of ACTH by the anterior pituitary.
ACTH levels increase the production of adrogens, which can result in the virillization of female infancts and affect genital development.
causes of congenital adrenal hyperplasia?
- 21-hydroxylase deficiency (90%)
impairs the conversion of 17-hydroxyprogesterone to 11-deoxycortisol, leading to cortisol deficiency and excess androgen production - 11-beta hydroxylase deficiency (5%)
results in hypertension due to excess deoxycorticosterone - 17-hydroxylase deficiency (very rare)
leads to mineralocorticoid excess with low androgen and estrogen levels
Clincial features of congenitl adrenal hypertension?
Depends on the enzyme deficiency
common presentation include
- virillization (female infants may present with ambiguous genitalia due to excessive androgen exposure in utero)
- sal wasting crisis (his severe form occurs in about 75% of cases with 21-hydroxylase deficiency
it is characterized by dehydration, hypotension, and electrolyte imbalances, and can be life-threatening if not treated promptly.)
- precocious puberty
- inferitility
- height and growth abnormalitis
21-hydroxylase deficiency features
virilisation of female genitalia
precocious puberty in males
60-70% of patients have a salt-losing crisis at 1-3 wks of age
11-beta hydroxylase deficiency features
virilisation of female genitalia
precocious puberty in males
hypertension
hypokalaemia
17-hydroxylase deficiency features
non-virilising in females
inter-sex in boys
hypertension
Causes of hypokalaemia with alkalosis?
vomiting
thiazide and loop diuretics
Cushing’s syndrome
Conn’s syndrome (primary hyperaldosteronism)
Causes of hypokalaemia with acidosis?
diarrhoea
renal tubular acidosis
acetazolamide
partially treated diabetic ketoacidosis
9 am cortisol in addisons?
> 500 nmol/l makes Addison’s very unlikely
< 100 nmol/l is definitely abnormal
100-500 nmol/l should prompt a ACTH stimulation test to be performed
what is seen on bloods in RTA?
All three types of renal tubular acidosis (RTA) are associated with hyperchloraemic metabolic acidosis (normal anion gap).
Electrolyte abnormalities seen in addisons?
hyperkalaemia
hyponatraemia
hypoglycaemia
metabolic acidosis
Features of renal tubukar acidosis type 1?
inability to generate acid urine (secrete H+) in distal tubule
causes hypokalaemia
complications include nephrocalcinosis and renal stones
causes include idiopathic, rheumatoid arthritis, SLE, Sjogren’s, amphotericin B toxicity, analgesic nephropathy
Features of type 2 RTA?
Type 2 RTA (proximal)
decreased HCO3- reabsorption in proximal tubule
causes hypokalaemia
complications include osteomalacia
causes include idiopathic, as part of Fanconi syndrome, Wilson’s disease, cystinosis, outdated tetracyclines, carbonic anhydrase inhibitors (acetazolamide, topiramate)
Features of T3 RTA?
Type 3 RTA (mixed)
extremely rare
caused by carbonic anhydrase II deficiency
results in hypokalaemia
Features of T4 RTA?
Type 4 RTA (hyperkalaemic)
reduction in aldosterone leads in turn to a reduction in proximal tubular ammonium excretion
causes hyperkalaemia
causes include hypoaldosteronism, diabetes
what can interfere with accurate HbA1c interpretation?
Cushing syndrome causes?
ACTH dependent causes
Cushing’s disease (80%): pituitary tumour secreting ACTH producing adrenal hyperplasia
ectopic ACTH production (5-10%): e.g. small cell lung cancer is the most common causes
ACTH independent causes
iatrogenic: steroids
adrenal adenoma (5-10%)
adrenal carcinoma (rare)
Carney complex: syndrome including cardiac myxoma
micronodular adrenal dysplasia (very rare)
Pseudo-Cushing’s
mimics Cushing’s
often due to alcohol excess or severe depression
causes false positive dexamethasone suppression test or 24 hr urinary free cortisol
insulin stress test may be used to differentiate
What is a thyroid storm?
What are the precipitating events?
Thyroid storm is a rare but life-threatening complication of thyrotoxicosis. It is typically seen in patients with established thyrotoxicosis and is rarely seen as the presenting feature. Iatrogenic thyroxine excess does not usually result in thyroid storm.
Precipitating events:
thyroid or non-thyroidal surgery
trauma
infection
acute iodine load e.g. CT contrast media
Clincial features of thyroid storm?
Clinical features include:
fever > 38.5ºC
tachycardia
confusion and agitation
nausea and vomiting
hypertension
heart failure
abnormal liver function test - jaundice may be seen clinically
Management of thyroid storm?
symptomatic treatment e.g. paracetamol
treatment of underlying precipitating event
beta-blockers: typically IV propranolol
anti-thyroid drugs: e.g. methimazole or propylthiouracil
Lugol’s iodine
dexamethasone - e.g. 4mg IV qds - blocks the conversion of T4 to T3
Why is propythiouracil preferred to carbomazole in thyroid storm?
because carbimazole will only prevent the release of thyroid hormones, and will not prevent the conversion of T4 to T4 peripherally.
what clinical sign is highly specific for graves disease?
pretibial myxoedema, this is a highly specific sign for Graves’ disease.
what is pre-tibial myxoedema?
Pretibial myxoedema, also known as thyroid dermopathy, occurs in approximately 1-2% of patients with Graves’ disease and is almost pathognomonic for this condition. It presents as waxy, indurated plaques typically on the anterior shin area, caused by glycosaminoglycan deposition in the dermis. When present, it is virtually diagnostic of Graves’ disease, particularly when accompanied by thyroid eye disease.
What are the features of metabolic syndrome?
raised uric acid levels
non-alcoholic fatty liver disease
polycystic ovarian syndrome
Treatment for toxic multinodular goitre?
The treatment of choice is radioiodine therapy.
what is an insulin stress test and when is it used?
used in investigation of hypopituitarism
IV insulin given, GH and cortisol levels measured
with normal pituitary function GH and cortisol should rise
