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What is the epidemiology of Paget's disease?

- most common in UK and british ancestry
- men more than women
- prevalence doubles each decade after 40
- incidentally elevated ALP
- unknocn cause, often genetic component.


What is the pathophysiology of Paget's Disease?

High bone turnover and disorganised osteoid formation.

Unknown cause.


What are the clinical findings in Paget's disease?

- can be mild and asymptomatic
- one bone (monostotic) or multiple (polyostotic)
- skull, femur, tibia, pelvis and humerus
- bones involved immediately, additional bones don't get involved during it's course
- pain is first symptom, either in involved bone or adjacent joint featuring degenerative arthtitis
- bones can soften --> bowed tibias, kyphosis, chalkstick fractures with slight trauma
- skull involvement - headaches and increased hat size.  
- deafness
- vascular steal syndromes due to increase vascularity over involved bones (which are also warm to touch)


What are the lab findings of Paget's disease?

Markedly elevated ALP.
Serum bone specific ALP if normal, or to distinguish source of elevated ALP.
Serum C-telopeptide (CTx) is high
Urinary hydroxyproline is high in active disease
Elevated serum Ca esp if bed rested
Screen for OHD deficiency which can also present with elevated ALP and bone pain - correct before prescribing a bisphosphonate.


What is the evidence for calcium and vitamin D supplementation/

The strongest evidence for fracture benefits of supplements is observed when both calcium and vitamin D are used by institutionalised women with low vitamin D levels and low dietary intake of calcium


What are the imaging findings in Paget's disease?

- ostelytic with focal radiolucencies 'osteoporosis circumscripta' in the skull or advancing flame shaped lytic lesions in long bones
Bones subsequently become sclerotic or mixed scleoritc and lytic, then thickened and deformed
Technetium pyrophosphate bone scans can help show activity of bone lesions before radiologic changes are evident.


What is multisystem proteinopathy?

- constellation of Paget disease, inclusion body myopathy, and FTD
- caused by a mutation in gene that encodes valosin-containing protein.


What are the important differentials of Paget disease?

- osteogenic sarcoma
- multiple myeloma
- fibrous dysplasia
- secondary bone lesions: metastatic Ca and osteititis fibrosa cystica


What are the complications of Paget's disease?

Hypercalcaemia and renal calculi
Vertebral collapse and spinal cord or root compression - radiculopathy or paralysis
High output cardiac failure due to increased vascularity
Arthritis in adjacent joints
Cranial nerve palsies from impingement of the neural foramina
Petrous temporal bone involvement frequently causes mixed hearing loss
Vascular steal syndrome - in the skull this can cause somnolence, stroke or optic nerve involvement and loss of vision
Misaligned teeth if jaw involved
Osteosarcoma rarely in longstanding lesions - marked increase in bone pain, sudden rise in ALP and new lytic bone lesion


What is the treatment of Paget's disease?

Surveillance if asymptomatic unless extensive involvement of skull, long bones, or vertebrae

Bisphosphnates are treatment of choice - given until ALP normalised, then a break for about 3 months or until ALP rises again
May get paradoxical increase in pain - first dose effects and go away.
If given IV - Improvement lasts several months

May get asthma in aspirin sensitive patients.

IV zoledronic acid more effective than daily risedronate.

Nasal calcitonin-salmon is used but bisphosphonates better


What is the prognosis of Paget's disease?

Good unless sarcoma
Prognosis worse if it starts early in life

In severe forms: intractable pain, deformity and cardiac features.  Rare with prompt bisphosphonate tx.


What are the general symptoms of chronic adrenocortical insuffiency (Addison's disease)?

- weakness & fatigueability
- sparse axillary hair, crease & nipple pigmentation
- hypotension and small heart


What are the general biochemical features of Addison disease?

Eosinophilia and relative lymphocytosis


What happens to cortisol in chronic adrenocortical insufficiency? (Addison disease)

Low plasma cortisol levels that fail to rise after administration of corticotropin

Elevated ACTH


What is the difference between primary and secondary adrenal insufficiency?

Primary - dysfunction or absence of adrenal cortices

Secondary - deficient secretion of ACTH


What does 21-hydroxylase do?  What happens if you break it?

Catalyses conversion of progesterone to deoxycorticosterone which later becomes aldosterone.

Catalyses conversion of 17-alpha-hydroxyprogesterone to deoxycortisol which becomes cortisol.

Breaking it means cortisol and aldosterone insufficiency and sex steroid excess which is congenital adrenal hyperplasia


What is the most common cause of Addison disease?

Autoimmune destruction of the adrenals.


What is the mechanism of polyglandular autoimmune syndrome Type 1? (Type 1 PGA)

Defect in T-cell mediated immunity inherited as an autosomal recessive trait.


What are the non-autoimmune causes of Addison's disease?

- Tuberculosis
- Bilateral adrenal haemorrhage during sepsis, HITs, anticoagulation or antiphospholipid syndrome - presents at 1 week post
- Adrenoleukodystrophy


What is adrenoleukodystrophy?

X-linked peroxisomal disorder causing accumulation of very long chain fatty acids.

Accumulate in adrenals, testes, brain, and spinal cord.

Occurs at any age and accounts for 1/3 of Addison disease in boys.


What do peroxisomes do?

Break down very long chain fatty acids.


What does 17 hydroxylase do?

What does a deficiency cause?

Catalyses conversion of pregnenolone and progesterone to 17a-hydroxypregnenolone and 17a-hydroxyprogesterone respectively.
These get converted to DHEA (pregnenlonone) and androstenedione (progesterone) respectively.

Deficiency forces progesterone and pregnenlone down the mineralocorticoid pathway only.

This results in hypertension, hyperkalemia, and primary hypogonadism. 

It's a rare form of CAH.


What will a mild deficiency of 21 hydroxylase result in?

Women with hirstutism in adolescene but adequate cortisol.

Known as 'late onset' congenital adrenal hyperplasia


What nail changes are evident in Addison disease?

Longitudinal pigmented bands


What skin condition may be associated with Addison disease?



What effect does Addison disease have on blood pressure?

- hypotensive and orthostatic
- most have systolic BP less than 110


What do you screen for in young men with idiopathic Addison disease?



Very long chain fatty acid levels - they'll be really high


How is the diagnosis of primary adrenal insufficiency made?  (Addison's disease)

What is the role of doing a morning cortisol test?

A diagnosis of primary adrenal insufficiency is confirmed by the combination of:

1.  a positive short Synacthen test (ie an absent or severely blunted plasma cortisol response to tetracosactrin 30 to 60 minutes after injection)

2.  elevated adrenocorticotrophic hormone (ACTH)

3.  elevated plasma renin (measured by direct concentration or plasma renin activity).

Measuring diurnal (morning and afternoon) plasma or serum cortisol concentrations is not useful for evaluating adrenal insufficiency.


What does hypercalcaemia in Addison disease mean?

Heralds an Addisonian crises


What happens to the blood glucose in Addison disease?

Fasting blood glucose is low because there is no cortisol to help glycogenolysis


Which drug must you avoid giving before a short synacthen test?

Hydrocortisone must not be given for at least 8 hours prior.

Other corticosteroids do not interfere with the assay and can be given.


What is the common precursor to male female sex hormones?

Androstenedione is the common precursor of male and female sex hormones


What does aromatase do?

It transforms androstenedione to estrone and testosterone to estradiol.

Estradiol is the primary premenopausal oestrogen and is made in the ovary from testosterone.

Estrone is in postmenopausal women and is made in adipose tissue.


What is the role of serum DHEA in Addison disease?

Suppressed in Addison disease
Normal or elevated excludes
Low level not diagnostic because some of the population have low levels.


What feature of congenital adrenal hyperplasia makes it diagnosable at birth?

What is required for diagnosis?

Ambiguous genitalia

Elevated 17-OH progesterone


Aside from aiding in the diagnosis of Addison disease, how else is an elevated plasma renin useful?

- indicated intravascular volume depletion and need for higher doses of fludricortisone


What happens to the serum adrenaline in Addison disease?


Not enough cortisol required to induce the PNMT enzyme in the adrenal medulla which synthesies adrenalin from noradrenalin


What antibodies are found in autoimmune Addison disease?

- anti-adrenal antibodies in 50%
- antibodies to thyroid in 45%


What imaging is done in Addison disease?

If not clearly autoimmune --> CXR to look for TB, fungal infection or cancer

CT abdo will show small noncalcified adrenals in autoimmune addisons (calcified if TB or other causes)

Enlarged if metastatic or granulomatous causes.


What is the DDx for Addison disease?

- secondary (hypopituitarism) - but lack ACTH and have normal skin pigmentation

- ACTH deficiency --> normal mineralocorticoid production and do not develop hyperkalemia.

- Haemochromatosis can cause skin pigmentation.  Can also cause Addison, hypoPTHism and diabetes

- AIDS can cause hypocortisolism and frank adrenal insufficiency

- CAH - but will have features of androgen excess


Which oral contraceptive component causes hyperkalemia?

Drosperinone.  Progestin component of Yaz/Yazmin.


What are the causes of hyperreninaemic hypoaldosteronism?

Myotonic dystrophy
Aldosterone synthase deficiency
17 hydroxylase deficiency (salt wasting CAH)


What are the causes of hyporeninaemic hypoaldosteronism?

due to decreased angiotensin 2 production as well as intra-adrenal dysfunction

Diabetic nephropathy
Hypertensive nephrosclerosis
Tubulointerstitial disease


Describe the mineralocorticoid, glucocorticoid and sex steroid pathway.


What is the general management of Addison disease?

Hydrocortisone is the drug of choice - 15-30mg daily in 2 divided doses.

Fludrocortisone retains sodium. Used in presence of hyponatraemia, postural hypotension or hyperkalemia (gets exchanged for sodium).  Titrate to postural BP, serum K+ and plasma renin (increase if renin elevated)

DHEA - improved sexual function in women and sense of general wellbeing in both, may increase lean body mass and bone density but not confirmed and replacement is not routine.


What is the role of fludrocortisone in Addison disease?

- better symptom control when they receive routine mineralocorticoid therapy as well as gluco corticoid

- allows good control at a lower glucocorticoid dose, minimising side effects

- no need to adjust dose in times of stress


What are the goals of therapy in Addison disease?

How is this limited?

Normal Blood pressure, sodium and potassium

Plasma renin at upper end of normal range.

Limited by plasma renin as increasing fludrocort causes oedema and hypokalemia.


What is the prognosis of treated Addison disease?

Reasonably normal

Increased all-cause mortality, mainly from cardiovascular disease, malignancy and infection

May have ongoing chronic low-grade fatigue.


What are the general clinical findings of hypercortisolism (Cushing Syndrome)?

Central obesity
Muscle wasting
Thin skin
Purple striae
Psych changes
Poor wound healing


What are the biochemical and serum changes of hypercortisolism (Cushing's Syndrome)?

Hyperglycaemia and glycosuria

Elevated serum cortisol and urinary free cortisol without suppression by dexamethasone


What is the general cause of Cushing syndrome?


Only rarely due to excessive corticosteroids produced by adrenal cortex


What is Cushing disease?

ACTH hypersecretion by the pituitary.

Usually a benign pituitary adenoma that is <5mm and located in the anterior pituitary.

3x more common in women


What party drug can induce ACTH-dependent Cushing syndrome?



Aside from drugs and benign pituitary adenoma, what else causes Cushing syndrome?

Autonomous adrenal secretion independent of ACTH which is low, usually due to a unilateral adrenal tumour.

Nonpituitary ACTH secreting neoplasms (i.e. SCLC) that produce excessive ectopic ACTH.  Usually hypokalaemic and hyperpigmented.  Masses are usually large.

15% of cases are of unknown origin.


Other than osteoporosis, what else does cortisol do to bone?

Avascular necrosis.


What effect does excess cortisol have on the gonads?

Erectile dysfunction in men

Amenorrhoea or oligomenorrhea in women.


What is the cause of polyuria in hypercortisolism?

Due to increased free water clearance - diabetes with glycosuria may worsen it.


When is pharmacological blockade of corticosteroid production required?  How do you do it?

- the patient requires control of hypercortisolism preoperatively
- the source of ACTH excess is unclear
- surgical resection has been unsuccessful.

Ketoconazole is the treatment of choice


What is the screening test for Cushing syndrome?

Dex suppression test - 1mg given at 11pm then morning cortisol performed.  
Low morning cortisol excludes Cushing - HOWEVER if still clinically expected, need to test further as this is only a screening test.


How is the diagnosis of hypercortisolism made?

24 hour urine collection for free cortisol and creatinine - abnormally high free cortisol or cortisol/creatinine ration confirms hypercortisolism.

Creatinine is secreted constantly while cortisol is under diurnal control. Having the creatinine there makes sure enough urine was collected.


What is the role of the midnight cortisol test?

Cortisol lowest at midnight (normally)

Even in Cushing's, morning serum cortisol may be normal, an elevated midnight cortisol can distinguish it form other conditions that cause a high urine free cortisol (pseudo-Cushings).  

A later night salivary version can be done too which is sensitive and specific.


Which drugs can result in a lack of cortisol suppression on the dexamethasone suppression test and why?

Phenytoin and rifampicin accelerate dexamethasone metabolism, meaning that cortisol doesn't get suppressed.

Estrogens i.e. in pregnancy or OCP can also stop suppression by dexamethasone.


What are the non-Cushing's causes of hypercortisolism?

Anorexia nervosa
Familial cortisol resistance


What is ACTH-independent macronodular adrenal hyperplasia?

Hypercortisolism due to the adrenal cortex' cells abnormal stimulation by hormones such as caetcholamines, vasopressin, serotonin, HCG or GIP

When stimulated by GIP (gastric inhibitory polypeptide) --> cortisolism will be intermittent and food dependentent, ACTH may not be completely suppressed.


Once hypercortisolism has been confirmed, which test should come next?

Serum ACTH
- low = probable adrenal tumor
- high = pituitary or ACTH secreting tumor


In ACTH independent Cushing syndrome, what will CT of the adrenals show?

Usually a benign adrenal adenoma


When should an adrenal carcinoma in the setting of hypercortisolism be suspected?

- diameter >4cm
- nodule growth
- atypical imaging ie density on noncon CT
- >10 Hounsfield units or high CT contrast washout


What is the basic use of Hounsfield units?

Tissue differentiation on CT.

Zero is water
Greater than 10 tends to be organ or tissue (i.e kidney, blood, muscle, brain)
Greater than 100 tends to be soft tissue
Greater than 700 is bone.

Less than zero is fat down to -500, then lung, then air (1000)


What imaging modality is required to confirm ACTH-dependent Cushing syndrome?

- will demonstrate pituitary lesion in 50% of cases often with premature cerebral atrophy
- if less than 5mm, further investigation (inferior petrosal venous sinus sampling) is required


When is inferior petrosal venous sinus sampling in hypercortisolism required?

When equivocal on MRI but evidence of ACTH secretion

If more than twice peripheral venous ACTH levels, this is indicative of pituitary Cushing's disease.

Can be done during CRH administration which will cause inf. petrosal sinus levels to b 3x greater than peripheral ACTH when the pituitary is the source.


What testing is employed when inferior petrosal sinus sampling does not reveal a source of ACTH dependent hypercortisolism?

Chest CT/Abdo looking for carcinoid or SCLC.  Also look at the thymus, pancreas and adrenals.
- must biopsy a chest mass as more risk of infection and may be infection rather than ACTH secreting mass.

If CT scanning fails - in octreaotide scan may help.

FDG-PET is not useful.

If unable to be found, bilateral adrenalectomy with ongoing investigation with imaging as the ectopic source may become detectable later.


How is the hypercortisolism of severe obesity differentiated from the Cushing's syndrome?

Both will have abnormal dex suppression test but urine free cortisol and diurnal variation of cortisol usually normal in the obese.


What is Nelson syndrome?

Rapid enlargement of a pituitary adenoma following bilateral adrenalectomy (this is done v rarely now).

Can cause visual field defect and hyperpigmentation


What is the treatment of Cushing disease?

Transphenoidal resection of the pituitary adenoma
Pituitary corticotrophs remained suppressed for up to 3 years - may need hydrocort or pred replacement in the meantime
Recurrence managed with cabergoline.
Lap adrenalectomy if unresponsive


What is the treatment of refractory Cushing disease?

Pasireotide - a somastatin analog that targets multiple receptors


What are the features of Pasireotide?

a somastatin analog that targets multiple receptors


What are the indications for octreotide?

- symptom control and reduction of GH and IGF-1 in acromegaly, inc where surg/rtx/dopamine agonist treatment has failed.
- Acromegaly when unable to undergo surgery or awaiting tx effect of RTx
- symptomatic relief of carcinoid and VIPomas (but NOT curative)
- reduction of pancreatic surgery complications


What is cortisol withdrawal syndrome?

Happens in patients successfully treated for Cushings, even with replacement steroids

- hypotension, nausea, fatigue, arthalgia and flaking skin

- increase hydrocort can improve the sx.


What are the prognostic features of Cushing syndrome?

Residual MCI, muscle weakness and OP
Good survival
May get relapse if growth of an adrenal remnant post bilateral adrenalectomy


What are the pathophysiological features of PCOS?

- Autosomal dominant functional disorder of the ovaries
- adrenal and ovarian androgen hypersecretion
- elevated serum testosterone or free 


What is the diagnostic criteria of PCOS?

 For a diagnosis of PCOS, two of the following criteria must apply—menstrual irregularity, hyperandrogenism and polycystic appearance of the ovaries (which are not necessarily always present in PCOS)


Which two hormones are implicated in PCOS?

Excessive LH release by the anterior pituitary, causing the ovaries to produce excess testosterone

High insulin levels increase GnRh pulse frequency, which further forces LH over FSH dominance.


What is the source of androgen hypersecretion in PCOS?

Both adrenal and ovarian androgen hypersecretion.

Testosterone is best measure.


How is the menstrual irregularity of PCOS treated?

Goal is to restore predictable uterine bleeding and effective endometrial shedding.

Combined OCP is most effective way to regulate menses and does not cause insulin resistance

Metformin can be used when COCP and OCP (progestin) aren't tolerated and can improve menstrual frequence, although not as well.


What happens if you don't treat a baby girl with classic 21-hydroxylase deficiency?

Without corticosteroid, they will become virilized due to their ambiguous genitalia.


What are the general features of androgen excess?

- increased hair (chin, upper lip, abdomen and chest)
- acne
- Menstrual irregularity
- defeminization - loss of breast, hips
- virilization - frontal balding, muscularity, clitoromegaly, voice deepening


How should hirstutism and suspected androgen excess be investigated?

Serum or free testosterone
If elevated --> pelvic exam and ultrasound
If negative --> adrenal CT scan

Elevated androstenedione --> ovarian or adrenal neoplasm

Elevated DHEAs - adrenal source as this only produced by the adrenal gland.  Usually due to adrenal hyperplasia --> do a CT

Elevated 17-hydroprogesterone in CAH (because 21 is missing)


Why would serum LH and FSH be elevated in an amenorrheic woman?

What LH:FSH ratio is common in patients with PCOS?

Ovarian failure

LH:FSH ratio >2


What is the treatment of severe hyperandrogenism?

Lap bilateral oophorectomy if CT adrenals is normal since small hilar cell tumors of the ovary may not be visible.
Also for salt-wasting and infertility CAH, or treatment resistant hyperandrogenism.


Finasteride (inhibits 5-alpha reductase) improves hirtsutism but spironolactone is better

Flutamide suppresses testosterone and lowers corticosteroid dose required for CAH.


What is the role of simvastatin in PCOS?

When used with OCP, aside from improving lipid profile, greater decreases in hirsutism and serum free testosterone levels


What is the treatment of choice for women with PCOS and infertility?



How does clomiphene work?

Clomifene inhibits estrogen receptors in the hypothalamus, inhibiting negative feedback of estrogen on gonadotropin release, leading to up-regulation of the hypothalamic–pituitary–gonadal axis.

It is a selective oestrogen receptor modulator (SERM)


What are the general features of primary aldosteronism?

Resistant hypertension
Elevated plasma and urine aldosterone levels and low plasma renin that does not correct with sodium loading.


What happens in excessive aldosterone production?

Increased sodium retention
Suppressed plasma renin
Increased renal potassium excretion --> hypokalemia
Increased cardiovascular events (moreso than essential HTN)


What are the causes of primary hyperaldosteronism?

- Aldosterone producing adrenal adenoma (Conn syndrome), 40% of which have a mutation potassium channel gene

- Unilateral or bilateral adrenal hyperplasia

- Bilateral form may be corticosteroid suppressible due to an autosomal dominant genetic defect allowing ACTH stimulation of aldosterone production


What the clinical findings of primary hyperaldosteronism?

Moderate hypertension or isolated diastolic hypertension
Hypokalaemia --> muscle weakness
Parasthesia, tetany, headache
Polyuria and polydipsia


What are the causes of secondary hyperaldosteronism? (Mineralocorticoid excess with high plasma renin)

Usually Hypertensive
Renovascular disease (atherosclerotic, fibromuscular hyperplasia)
Coarctation of the aorta
Renin-secreting tumors

Usually Normo- or Hypotensive
Reduced Circulating Blood Volume:
Gitelman’s Syndrome
Bartter’s Syndrome
Pseudohypoaldosteronism Type I
Diuretic Use (surreptitious or prescribed therapy)

Reduced ‘Effective’ Circulating Blood Volume:
Congestive Heart Failure
Hepatic cirrhosis
Nephrotic Syndrome


How is suspected hyperaldosteronism investigated?

- Plasma renin, plasma aldosterone plus ratio.  If elevated, test further
- Hypokalemia helpful but normal in 50%
- may have metabolic alkalosis with increased HCO3
- further ix with sodium loading and morning plasma renin, with aldosterone measured as well.  Normal or elevated makes primary aldosteronism unlikely.

- dx confirmed with 24 hour urine collection of aldosterone, free cortiisol and creatine.  Low plasma renin plus high urine aldosterone = primary aldosteronism.


What must be done before properly testing for primary aldosteronism?

Stop diuretics for 3 weeks
Stop dihydropyridine CCBs as can normal aldosterone secretion
Stop b-blockers as they suppress renin in essential htn

Useable anti-HTs are ACEIs, alpha blockers, verapamil, and hydralazine


Why can't a low plasma renin alone confirm hyperaldosteronism?

Occurs in many with with essential hypertension


Why can't a renin:aldosterone ratio diagnose primary hyperaldosteronism?

Not diagnostic - need to confirm with 24 hour urine

The two tests use different units and measurements


How do you distinguish between unilateral and bilateral aldosteronism?  

When is this indicated?

Adrenal vein sampling - gold standard

Only to direct surgeon to correct adrenal and should only be performed if surgery is being considered

Good test if not hypokalemic, over 40 or have an adrenal adenoma <1cm.  Right adrenal vein hard to catheterise.

Samples are assayed for both aldosterone and cortisol during a synacthen infusion to ensure that sampking has got both.


What is the role of imaging in hypercotisolism?

All patients with biochemically confirmed primary aldosteronism gets a thin section CT scan of the adrenals to screen for a rare adrenal carcinoma.

In the absence of a large mass, cannot distinguish between unilateral and bilat excess.


What is the management of primary hyperaldosteronism?

Trial of spironolactone or eplerenone if no carcinoma or obvious source on adrenal CT and not for surgery


What is the difference between spironolactone and eplenerone?

Spironolactone --> antiandrogen activity resulting in breast tenderness, gynecomastia and reduced libido

Eplerenone --> better for men since does not have anti-androgenic effects


What is the mechanism of action of spironolactone?

 antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone dependent sodium potassium exchange site in the distal convoluted renal tubule


Who should be screened for hyperaldosteronism?

BP >160/100

Drug resistant hypertension

Hypertension with spontaneous or diuretic induced hypokalemia?

Hypertension with adrenal incidentaloma

Hypertension with an FHx of early onset hypretension or stroke before age 40

Hypertension and a first degree relative with primary aldosteronism


What is the ddx of primary hyperaldosteronism?

- chronic intravascular depletion or renal vascular disease (but will have high renin)

- excessive ingestion of licorice can cause hypertension and hypokalemia as it contains a metabolite tha inhibits adrenal 11b hydroxysteroid dehydrogenase type 2 that normally inactivates cortisol in the renal tubule

- high renal tubular cortisol activates aldosterone receptors --> absorption of sodium and excretion of potassium

- excessive corticosteroid secretion will also cause hypertension with hypokalemia (i.e. CAH 17-hydroxylase deficiency)


What are the complications of primary hyperaldosteronism?

Higher rate of CVS complications than essential hypertension

Following unilateral adrenalectomy for Conn syndrome, suppression of the contralateral adrenal may result in temporary postop hypoaldosteronism --> hyperkalemia and hypotension


What is the treatment of primary hyperaldosteronism?

Conns (unilateral adenoma) --> lap adrenalectomy or long term spiro/eplerenone

Bilateral adrenal hyerplasia --> long term spironolactone or eplerenone

Need to monitor BP daily as will get a significant BP drop when added to other anti-HTs

Reversible in about 2/3rds of cases


What are the general features of phaeo and paraganglionoma?

- attacks of headache, perspiration, palpitation and anxiety
- paroxysmal hypertension esp during surgery or delivery
- elevated urinary catecholamines or their metabolites
- normal serum T4 and TSH


What is a phaeochromocytoma?

What is a paraganglionoma?

Phaeo:  Adrenaline and noradrenaline secreting tumour of the adrenal medulla

Para:  sympathetic paraganglia tumor that often metastasises and secretes norad or is nonsecretory.  May be in the adrenals or along the sympathetic chain


In phaeo, how do adrenalin and norad differ in their symptomatology?

Adrenaline:  Tachyarrythmia

Norad:  Hypertension


Which diseases are associated with phaeochromocytoma?

Type 2 VHL

MEN 2A and 2B

Recklinghausen Neurofibromatosis Type 1 (NF-1)

Familial paraganglioma


What is the chance of harboring a germline mutation in a patient with a family history of phaeo/paraganglionoma?


These account for about 25% of patients with phaeos.


What are the lethal manifestations of a phaeochromocytoma?

Catastrophic hypertensive crisis
Fatal cardiac arrhythmia


What are the features of a paroxysmal attack of a phaeo?

Hypertension, headache, sweating, palpitations and anxiety


What can trigger hypertensive attacks with a phaeo?

IV contrast
Needle biopsy / surgery
Exercise, bending, lifting or emotional stress
Certain drugs


Which drugs can trigger a hypertensive attack in phaeochromocytoma?

Caffeine & nicotine
IV contrast


What is the common main mechanism of phaeochromocytoma associated ACS, stroke, aortic aneurysm rupture, and ischaemic bowel?

Vasospasm due to excess adrenalin release.


What is the single most sensitive test for phaeochromocytoma? 

Is it diagnostic?

Plasma free metanephrines.  Normal levels rule it out.

Not diagnostic as physical/emotional stress, sleep apnoea and MAO-Is (amongst others will elevated).

You need to do a 24 hour urine for fractionated metanephrines and creatinine which will confirm most phaeos.  97% sensitive.


Aside from metanephrines, what are the other lab findings of phaeo?

- serum chromogranin A is elevated in 90% and correlate with tumor size, higher in metastatic disease - but elevated in azotemia, hypergastrinemia, exogenous steroids and PPIs.

- neuron specific enolase is positive and implicate a malignant phaeo, normal levels are unhelpful.  Often a tumor marker for SCLC

Mild hyperglycemia and leukocytosis
Elevated plasma renin activity


What genetic tests should be performed in a patient with phaeochromocytoma or paraganglionoma?

VHL, ret proto-oncogene and SDHB/SDHD mutations


What disease does mutation of the ret-proto-oncogene cause?

MEN2a and 2b


What is the role and considerations of CT in phaeochromocytoma?

- performed when biochemically or genetically suspected
- non-contrast thin section adrenal CT followed by a contrast using nonionic contrast which reduces the risk of catecholamine release --> hypertensive crisis
- no glucagon should be used for the same reasons
- IV contrast itself can precipitate crisis especially when hypertension is uncontrolled


What is the role and considerations of MRI in phaeochromocytoma?

- doesn't need IV contrast or use radiation
- used in pregnancy and childhood

For CT and MRI
- sensitive for adrenal tumors >0.5cm
- less sensitive for recurrent tumors, mets and extra-adrenal paraganglionomas
- if no tumor: C/A/P performed


What is the role of nuclear imaging in phaeochromocytoma?

I-MIBG can localise tumors but less sensitive for MEN2A/B disease or mets.  
Used when CT cannot locate a phaeo, making a paraganglionoma more likely.

In-labelled octreotide scanning is sensitive for extra-adrenal disease and locating tumours missed by I-MIBG

FDG-PET similarly may find missed tumours and when combined with non-con CT, is highly sensitive.


What is the management of phaeochromocytoma?

- surgical removal of phaeo or paraganglionomas is the treatment of choice.

- alpha blockers are given prior to surgery - BP must be maintained 4-7 days prior to surgery or until ECG changes have normalised (may be  months)

- must give alpha or calcium blockers first as starting b-blockers first results in unopposed alpha-adrenergic action --> hypertensive crisis.  Labetalol has alpha blocking activity but can still cause paradoxical hypertension.


What is the perioperative management of phaeo?

Tachyarrthymia intraop - atenolol
Hypertension intra-op - short acting CCB or nitroprusside
Post-op hypotension (caused by desentisisation of alpha receptors) --> preop auto-transfusion of 1-2 units of PRBCs 12 hours prior can help prevent
Post-op shock --> IV saline and IV norad.
Post-op hypoglycaemia prevention --> IV 5% dex


How do you tell if a phaeo is malignant?

Histopath does not reliably determine if tumour is malignant
Recheck plasma metanephrines 2-4 weeks postop and when minimal pain
MIBG scan 3 months post-op - undetected mets may reveal themselves
BP and symptom monitoring for life
Plasma metanephrines 6 monthly for 5 years
EBRTx for osteolytic bone mets


What is the treatment for metastatic phaeo or paraganglionoma?

If sufficient uptake on diagnostic I-MIBG, then can have therapy with high-activity I-MIBG


What are the features of vitamin-D resistant rickets?

- impaired renal tubular phosphate reabsorption
- normal serum Ca+, low phos, elevated ALP
- high dose Vit-D and oral phos is tx
- presence as failure to thrive in infancy, X-linked dominant


What are the features of Von-Hippel Laundau syndrome?

cerebellar haemangiomas
retinal haemangiomas: vitreous haemorrhage
renal cysts (premalignant)
extra-renal cysts: epididymal, pancreatic, hepatic
endolymphatic sac tumours


What are the general features of hypothyroidism?

Elevated TSH in primary hypothyroidism
Low FT4
Delayed deep tendon reflexes, bradycardia, and dry skin
Fatigue, cold, constipated, fat, hoarse and depressed


What tests should be used for screening for hypo/hyperthyroidism?

TSH - most sensitive for primary hypo and hyperthyroidism

Free Thyroxine (Free T4)


What tests should be performed for hypothyroidism and what will they show?

Serum TSH - high in primary and low in secondary hypothyroidism

Anti-thyroglobulin and anti-thyroperoxidase antibodies - both elevated in Hashimoto thyroiditis


What tests should be performed for hyperthyroidism and what will they show?

Serum TSH - suppressed unless pituitary TSHoma/hyperplasia (rare)
T3 or FT3 - elevated
Antithyroglobulin and antimicrosomal (TPO) antibodies - elevated
Anti-TSHr (TRab) antibodies - 65% positive in Graves disease

123-I uptake and scan - diffuse increased uptake (as opposed to 'hot' area)


What tests should be performed for thyroid nodules and what will they show?

FNA - best method for thyroid cancer
123-I uptake and scan - cancer usually 'cold
99m Tc scan - vascular vs avascular
U/S - assists FNA bx, assesses malignancy risk (multinodular goitre or pure cysts are less likely to be malignant.  Monitors nodules and patients post-op for carcinoma.


What is the mechanism of myxedma in hypothyroidism?

Interstitial accumulation of hydrophilic mucopolysaccharides --> lymphoedema


What is the mechanism of hyponatraemia in hypothyroidism?

Impaired renal NA+-K+-ATPase activity --> reduced renal tubular reabsorption of sodium


What is the most common cause of hypothyroidism?

Hashimoto thyroiditis


Which TKI causes transient primary hypothyroidism?

Sunitinib - used to treat GIST


When does amiodarone-induced hypothyroidism most occur?
What happens to the TSH and T4?

What is the role of thyroxine replacement?

Pre-existing auto-immune thyroiditis who are not iodine deficient.

Elevated TSH w/ low or normal T4

Given just enough thyroxine to relieve symptoms


Which infectious disease is an associated with an increased risk of auto-immune thyroiditis and how does treatment of that disease affect it?


Risk of dysfunction even high when treated with either IFN-a or IFN-b


What happens to a hypothyroid woman's period?



What cardiopulmonary manifestations may less commonly occur with hypothyroidism?

Cardiac enlargement 'myxedema heart'
Pericardial effusion


What autoimmune conditions are associated with Hashimoto thyroiditis?

Coeliac disease
Also - Addison, hypoPTH, DM, pernicious anaemia, Sjogren, vitiligo, and PBC.


What will deficiencies of the fat soluble vitamins cause?

Vitamin K - easy bruising
Vitamin A - hyperkeratosis & night blindness
Vitamin D - bone pain
Vitamin E - neuropathy/ataxia (also B12)


What lab abnormalities may be seen in hypothyroidism other than thyroid-specific ones?

Increased LDL, TGL, lipoprotein-a
Increased liver enzymes and CK
Increased prolactin
Elevated ANA (but not indicative of lupus)


What is subclinical hypothyroidism?
What is the treatment?

Serum TSH in upper range of normal with normal T4 levels
Usually asymptomatic or subtle signs (fatigue, depression, hyperlipidemia)

No need to replace if asymptomatic - associated with familial longevity
Monitor - may become hypothyroid later


What imaging is used in hypothyroidism?

Not usually necessary.

May get enlargement of pituitary gland due to hyperplasia which could be mistaken for pituitary adenoma as often have concomitant hyperprolactinaemia.

May get thymic enlargement in autoimmune thyroiditis.  


What is Reverse T3?

What is the order of appearance in the body of the other thyroid hormones?

Third-most common iodothyronine the thyroid gland releases into the bloodstream

T4 constitutes 90% and T3 is 9%. 

However, 95% of rT3 in human blood is made elsewhere in the body, as enzymes remove a particular iodine atom from T4.


What are the features of euthyroid sick syndrome?

The most common hormone pattern in sick euthyroid syndrome is a low total and unbound T3 levels with normal T4 and TSH levels.

Affected patients may have normal, low, or slightly elevated TSH depending on the spectrum of illness. Total T4 and T3 levels may be altered by binding protein abnormalities, and medications. Reverse T3 levels are generally increased signifying inhibition of normal Type 1 enzyme or reduced clearance of reverse T3. Generally the levels of Free T3 will be lowered, followed by the lowering of Free T4 in relation to severity of the disease. 

Low serum T4 (very low = poor prognosis), low levels of free T4 
Accelerated metabolism of T4 to rT3
Increased levels of rT3 due to stable production and decreased clearance
May have normal or low TSH

Critically ill patients have a circulating inhibitor to thyroxine binding globulin resulting in computed levels of protein-bound T3 and T4 to be low.


What is the important differential of sick euthyroid in a severely ill patient?

A low serum T4 with no elevation in TSH may also be due to pituitary insufficiency however without a prior brain lesion or hypopituitarism, it's unlikely to suddenly develop it.
If suspected hypopituituarism, DI or CNS endocrine lesion, can give T4 empirically.

Some antiseizure medications will call low serum FT4 by accelerating hepatic conversion of T4 to T3 and will also have normal TSH levels

Dopamine may suppress TSH in prolonged dopamine infusion.


What infectious disease are patients with severe hypothyroidism more at risk of?

- bacterial pneumonia


What is myxedema crisis?

What population is it seen in?

What drug do you need to be wary about?

Severe life threatening hypothyroidism
Impaired cognition to coma
Severe hypothermia & hypoventilation
Hyponatraemia, hypoglycaemia and hypotension
Rhabdo and AKI
Hyponatraemia may be severe and refractory

Myxedema coma - elderly women who have had a stroke or stopped taking their meds
Also if underlying illness

Unusually sensitive to opioids - regular dosing may cause death.


What must you assess for in a hypothyroid patient prior to starting levothyroxine?

Adrenal insufficiency and angina as these must be treated first.


What is the target TSH in treated hypothyroidism?

Who needs a higher dose?

When should you take it?

Aim to keep between 0.4 and 2.0 and maintain clinical response

Pregnant women

After an overnight fast as food interferes a little with absorption


What are the considerations for levothyroxine treatment in patients with heart disease or over age 60?

Smaller initial doses

If known IHD, should have angio or bypass first.


How is myxedema crisis treated?

High dose IV levothyroxine since myxedema interferes with intestinal absorption of PO

Hypothermia - warming blankets only as faster can precipitate cardiovascular collapse.

Hydrocort if concomitant adrenal insufficiency


In treated hypothyroidism, what does an elevated TSH indicate?

Which test should be maintained within the reference range?

Usually indicates the need for higher levo dose.

Serum T3.  

Normal serum TSH and FT4 levels do not determine euthyroid status.


Which drugs increase hepatic metabolism and conversion T4 to T3?

Anticonvulsants:  Carbamazepine, phenytoin
Antibiotics:  Rifampicin
TKIs:  Sunitinib and Glivec


Which drugs cause malabsorption of levothyroxine and worsening of hypothyroidism?

Iron (beware multivitamins!)
PPIs by reducing gastric acidity


Which two states require an increased levothyroxine dose for hypothyroidism?

Pregnancy or on oral estrogen therapy

Requirements decrease after delivery and menopause


What are the principles of hypothyroidism in pregnancy?

Fetus is partly dependent on maternal T4 for CNS development especially in the third trimester with requirement starting very early in pregnancy.

Levo should be increased by approx 30 as soon as pregnancy is confirmed.  This increases to nearly 50% by mid pregnancy.


What are the mechanisms of increased FT4 requirement of pregnancy?

1.  Rising estrogen --> increases thyroxine binding globulin concentration --> free T4 reduced

2.  Placental deiodinase promotes turnover of T4

3.  Prenatal multivitamins (containing iron and Ca) binds to oral T4 and reduces intestinal absorption


Why do serum TSH levels drop while T4 rises during the first trimester of pregnancy?

Probably due to high levels of HCG (structurally homologous to TSH) stimulating thyroid hormone production.

Low TSH patients in first trimester are euthyroid.  


In short bowel syndrome and resultant malabsorption of thyroxine, what can be given to improve it?

Medium chain triglyceride oil


What can cause transient or false elevations in TSH?

- psych illness or recovery from a nonthyroidal illness
- autoimmune disease can interfere with an assay
- thyrotropin secreting tumors
- increased by phenothiazines and atypical antipsychotics


In hypothyroid patients who have a normal serum TSH but still feel unwell, what might the reason be?

Suboptimal T3 - may need to increase levo dose


What is a low TSH?


0.4-4 is low

<0.03 is suppressed


In a patient with a low serum TSH and no signs of hyperthyroidism, what should you consider?

Hypopituitarism or severe nonthyroidal illness

Medications:  NSAIDS, opioids, nifedipine, verapamil and short term high dose steroids


What illnesses can mimic hypothyroidism in a hypothyroid patient who has a low TSH controlled on levo?

What test is most helpful?

Adrenal insufficiency
Coeliac disease

Serum T3


When should you do a free T3 instead of a serum T3?

Pregnancy and in women receiving oral oestrogens


What is the long term risk of a hypothyroid patient with a low TSH (0.04-0.4) on replacement thyroxine?

What about if they're suppressed? (<0.03)

No long term increased risk of cardiovascular disease, dysrhythmia or fractures.

Suppressed - increased risk of all of the above - need monitoring for atrial arrhythmias and osteoporosis


What is the mortality rate of myxedema crisis?


Untreated hypothyroidism progresses to this


What are the general symptoms of Graves disease?

Palpitations, anxiety, weight loss, loose stools, heat intolerance, fatigue, menstrual irregularity


What are the general signs of hyperthyroidism?

Tachycardia, warm moist skin, stare and tremor.
In Graves:  Goiter with bruit, opthalmopathy


What are the general lab findings of hyperthyroidism?

Suppressed TSH in primary hyperthyroidism'; increased T4, FT4, T3, and FT3


What is the other name for Graves disease?

Basedown disease


What is the pathophysiology of Graves disease?

Autoantibodies bind TSH receptor in thyroid cell membranes and stimulate the gland to hyperfunction --> increase in synthesis and release of thyroid hormones

Thymus gland is typically enlarged and serum ANA are usually elevated


What signs are commonly associated with Graves disease?

Infiltrative opthalmopathy (Graves exopthalmos)

Less commonly - infiltrative dermopathy (pretibial myxoedema)


What are the genetic associations with Graves disease?

Familial tendency
HLA-B8 and HLA-DR3 association


What can trigger Graves disease?

Dietary iodine supplementation
Potassium iodide reatment


What diseases are people with Graves disease also at risk of getting?

Sjogren syndrome
Perncious anaemia
Addison disease
Coeliac disease
DM Type 1
Myasthenia gravis


What is Jod-Basedow disease?

Iodine-induced hyperthyroidism

May occur in large multinodular goiters after large intake of dietary iodine, IV contrast, amiodarone

Not associated with opthalmolpathy or dermopathy


What are the features of subacute (de quervain) thyroiditis?

- enlarged tender thyroid and hyperthyroidism
- due to a viral infection
- followed by hypothyroidism


What is Struma Ovarii?

- hyperthyroidism due to autonomously secreting thyroid tissue
- found in 3% of ovarian dermoid tumours and teratomas
- may secrete in concert with toxic nodule, MNG, or Graves


What are the laboratory features of hyperthyroidism due to a pituitary tumour?

- elevated or normal serum TSH in the presence of true thyrotoxicosis
- diminished feedback effect of T4 on the pituitary
- rare


What are the causes of hyperthyroid thyroiditis?

Hashimotos will cause transient hyperthyroidism during the initial destructive phase
IFN-A, IFN-B, interleukin-2
Postpartum thyroiditis = Hashimoto's within first 6 months of delivery


What are the features of hyperthyroidism in pregnancy?

Increased neonatal risk of IUGR, prematurity and transient thyrotoxicosis from transplacental transfer of thyrotropin receptor antibody (TRab)

- very high serum levels of HCG may cause sufficient receptor activation to cause thyrotoxicosis in spite of their low affinity for the thyroid receptor


When does mild gestational hyperthyroidism occur?


First 4 months of pregnancy

Due to very high HCG levels


When are pregnant women more likely to have thyrotoxicosis and hyperemesis gravidarum?

If they have high serum levels of asialo-HCG, a subfraction of HCG with greater affinity for TSH receptors


What type of damage does iodinated IV contrast do to the thyroid?

Induces a destructive subacute thyroiditis that may be painful and similar to type 2 amiodarone-induced thyrotoxicosis


When can hyperthyroidism occur with amiodarone?

4 months to 3 years after initiation


What are the general features of type 1 amiodarone-induced thyrotoxicosis?

- may cause toxic MNG in setting of iodine deficiency w/ autonomous thyroid nodules
- excess free iodine can trigger immunologic attack on thyroid resulting in Graves disease
- diffuse thyroid enlargement and antithyroid peroxidase antibodies (70%)


What are the differences on imaging between type 1 and 2 amiodarone thyrotoxicosis?

Type 1 - diffuse enlargement, color flow doppler --> increased vascularity and blood flow velocity.  Thyroidal radioiodine uptake can be low/normal/increased

Type 2 - no enlargement, no increase in vascularity, and very low thyroidal radioiodine uptake


What is type 2 amiodarone induced thyrotoxicosis?

- Due to destructive thyroiditis
- Stored thyroid hormone released from damage cells
- Can last 1-3 months and may be followed by hypothyroidism


What are the features of chronic thyrotoxicsois?

Swelling of the fingers (acropachy)


What are the cardiopulmonary manifestations of hyperthyroidism?

- Tachycardia
- AF w/ RVR
- reversible pulmonary hypertension (mainly PaH) 


What are the eye manifestations that can occur with hyperthyroidism of any aetiology?

Upper eyelid retraction (Dalrymple sign)
Lid lag with downward gaze (von Graefe sign)
Staring appearance (Kocher sign)


What eye manifestation is exclusive to Graves disease and type-1 amiodarone induced thyrotoxicosis?

- opthalmopathy
- conjunctival oedema (chemosis)
- conjunctivitis
- mild exopthalmos (proptosis)


What are the manifestations of severe exopthalmos of Graves?

- increased retro-orbital and eye muscles that have been thickened by lymphocytic infiltration
- diplopia from extraocular muscle entrapment
- weakness of upward gaze (Stellwag sign)
- optic nerve compression --> progressive loss of colour vision, fields, and acuity


How does thyroid eye disease correlate with thyrotoxicosis?

It doesn't - some patients with Graves opthalmopathy are clinically euthyroid


What extra test should be performed on all patients with confirmed Graves disease and why?


Document degree of exopthalmos and detect progression of orbitopathy


What is the differential diagnosis for Graves opthalmopathy?

What are it's features?

Coexistent ocular myasthenia gravis

More common in Graves
Usually mild with selective eye involvement
ACHr Abs only elevated in 40%
Thymoma in 9%


What are the features of Graves dermopathy (pre-tibial myxoedema)?

- more common with high levels of TSH-stiulating Ig and in severe Graves opthalmopathy
- glycosaminoglycan accumulation and lymphoid infiltration occurs in infected skin which becomes erythematous with a thickened rough texture


What is thyroid acropachy?

- extreme and rare
- digital clubbing, swelling of fingers and toes and periosteal reaction of extremity bones
- most patients are smokers
- indicates severity of autoimmunity - high titres of thyroid-stimulating Ig


What are the features of hyperthyroidism related tetany?

- rare
- due to incresaed renal excretion of magnesium
- severe depletion causes hypoparathyroidism that results in hypocalcaemia


What effect does Graves disease have on pregnancy and vice versa?

- Increased risk of thyroid storm, eclampsia, CCS, prem, abruption
- TSHrAb crosses the placenter - if maternal serum TSHrab levels >500% in third tri --> risk of transient neonatal graves


Which weird disease no one's ever heard of occurs with thyrotoxicosis?  What are the features?

- Hypokalemic periodic paralysis - Asians and Native American men
- symmetric flaccid paralysis often after oral carbs, vigorous exercise or IV dextrose
- attacks last 7-72 hours


What is 'subclinical hyperthyroidism'?

- asymptomatic individual
- low serum TSH w/ normal FT4 and T3
- risk of progression higher with MNG


What are the other lab findings in hyperthryoidism generally?

Increased ALP
Thyrotoxic periodic paralyisis:  Hypokalemia and hypophosphataemia


What are the general lab findings in Graves disease?

Detectable TSHRabs (65%)

Antithyroglobulin or anti TPO can be elevated by not specific

Elevated ANA/dsDNA w/o evidence of lupus or collagen-vascular disease


What are the general lab findings in subacute thyroiditis?

Increased ESR
No anti-thyroid antibodies
TSHRaBs are negative


What are the general lab findings in iodine induced hyperthyroidism?

Undetectable TSHrAbs
No anti TPO antibodies
Elevated urinary iodine concentration


How do you distinguish thyrotoxicosis factitia from other causes of hyperthyroidism?

Serum thyroglobulin levels will be low


What are the lab findings of hyperthyroidism during pregnancy?

Elevated FT4
Suppressed TSH - although failure to suppress may be due to misidentification of HCG
T3 resin uptake is low because of high TBG concentration
In Graves - beneficial effect, decreasing antibody tires and decreasing FT4 as pregnancy progresses


What must be present along with the elevated T4 of amiodarone induced hyperthyroidism?

Suppressed TSH - patients taking amiodarone will have high T4 and FT4 levels regardless of whether or not they're hyperthyroid.


What findings are diagnostic of type 1 amiodarone induced thyrotoxicosis?

Proptosis and TSH Ig


What interleukin is markedly elevated in type 2 amiodarone induced hyperthyroidism?



In which thyroid conditions will you get a high radioactive iodine uptake?

Toxic nodular goitre


In which thyroid conditions will you get a normal-low radioactive iodine uptake?

Type 1 amiodarone-induced thyrotoxicosis - usually detectable but low


In which thyroid conditions will you get a low radioactive iodine uptake?

Subacute thyroiditis
Iodine induced hyperthyroidism
Type 2 amiodarone induced thyrotoxicosis


When is radioactive iodine imaging helpful?

- determine the cause of hyperthyroidism
- not necessary if obvious Graves (TSHrabs or associated Graves opthalmopathy)
- never in pregnant women


When should a radioactive iodine scan be extended to include the abdomen?

Screen for concomitant struma ovarii  in women with Graves


When is thyroid ultrasound useful?

Hyperthyroid patients particularly with palpable nodules


When is thyroid color flow doppler u/s useful?

Distinguish between type-1 amiodarone induced thyrotoxicosis (increased blood flow velocity and vascularity) and type 2 (reduced vascularity)


When it orbital imaging indicated in thyroid disease and why?

MRI or CT visualises Graves opthalmopathy affecting the extraocular muscles

Required in severe or unilateral cases, or in euthyroid exopthalmos that must be distinguished from orbital pseudotumor, tumors, and other lesions


What is the ddx of thyrotoxicosis?

- hypermetabolic states ie anaemia, leukaemia, polycythaemia dn cancer
- Pheo
- Acromegaly
- cardiac disease suggests possibility of 'apathetic' hyperthyroidism
- other causes of opthalmoplegia ie MG and exopthalmos ie tumor
- must consider thyrotoxicosis in ddx of muscle weakness and thyrotoxicosis
- may have concomitant DM or Addison disease


What are some complications of hyperthyroidism?

Decreased libidio, gynecomastia , erectile dysfunction and sperm motility
Thyrotoxic hypokalemic periodic paralysis


What is the role of Propranolol in Graves diseae?

- symptomatic relief of tachycardia, tremor, sweats anxiety
- initial treatment of choice for thyroid storm
- treatment for periodic paralysis


What is the role of thiourea drugs in hyperthyroidism?

- methimazole/carbimazole or PTU
- young patients with mild thyrotoxicosis, small goiters or fear of isotopes
- elderly respond well
- presurgical preparation
- no permanent thyroid damage, assoc w/ lower chance of posttreatment hypothyroidism (c/w surgery or RAI)

- contraindicated in breastfeeding


What affects long term remission in patients with hyperthyroidism?

- better likelihood if:
1.  small goiter or mild hyperthyroidism
2.  requiring small doses of thiourea
3.  high tpo and tg antibodies 2 years after therapy only have a 10% relapse rate


What is the main notable side effect of methimazole and PTU?

Genetic link
Not improved by G-CSF

Also: pruritus


If a patient has a major allergic reaction to carbimazole, can you give them PTU?

No - because they're too similar


What are the features of carbimazole?

1st line for thyrotoxicosis - induction of permanent remission, prethyroidectomy, before and after radioactive iodine

- less likely to cause fulminant hepatic necrosis and I131 treatment failure
- risk of fetal anomalies, switch to PTU


What are the features of propylthiouracil?

Drug of choice for breastfeeding
Favored in pregnancy
Complications: Arthritis, lupus, aplastic anaemia, thrombocytopaenia, hypoprothrombinaemia

In pregnancy:  can be switched to carbimazole in second tri


What is the role of iodinated contrast agents as a treatment for thyrotoxicosis?

- effective temporary treatment for thyrotoxicosis of any cause

- Graves:  blocked with carbimazole then replaced with iodinated agent

- useful for symptomatic thyrotoxicosis

- option for T4 overdose, subacute thyroiditis, amiodarone-induced thyrotoxicosis, intolerance to thiorureas and newborns with thyrotoxicosis secondary to maternal Graves


What is the role of radioactive iodine in treatment of hyperthyroidism?

- destruction of overactive thyroid tissue (diffue or toxic nodular goiter)
- no increased risk of subsequent thyroid cancer, leukaemia or other malignancy
- normal rates of congenital abn

- should not be given to pregnant women due to fetal radiation being harmful


What affects treatment success of radioactive I131?

- Graves + a thiourea of any sort
- can improve effectiveness if discontinue at least 4 days prior and if I131 dose is adjusted up


What is a noteable side effect of I131 therapy in Graves disease?

Grave opthalmopathy - much more likely if patient a smoker.

Pre-existent opthalmopathy worsens unless you give prophylactic prednisone 2 months prior esp if severe orbital involvement.  Smoking decreases effectiveness of pred


What happens to the lab results of a thyrotoxic patient treated with I131?

FT4 levels may drop within 2 months then go up to thyrotoxic levels during which time RAI uptake is low

- due to release of stored thyroid hormone from injured cells, not treatment failure --> FT4 will eventually fall abruptly to hypothyroid levels


What increased risks are there for patients with Graves disease treated with I131?

- increased lifetime risk of hyperparathyroidism particularly if radioidine given in childhood/adolescence

- need lifetime followup with serum TSH, FT4 and calcium


What are the indications for thyroidectomy in thyrotoxic patients?

Pregnant women with thyrotoxicosis not controlled with low doses of thioureeas
Women who want to get pregnant in vvery near future
Option for nodular goiters when there is a suspicion of malignancy


What are the types of thyroid surgery?

Hartley-Dunhill - treatment of choice for Graves having surgery
 - total resection of one lobe and a subtotal resection of the other lobe

- subtotal thyroidectomy of both lobes - but 9% recurrence rate

- total thyrodectomy - increased risk of hypoparathyroidism and damage to the recurrent laryngeal nerves


What is the perioperative management for thyrotoxic patients undergoing thyroid surgery?

- rendered euthyroid preop with a thiourea
- propranolol is given until euthyroid
- may given iodine to reduce vascularity
- if thyrotoxic during surgery --> needs higher doses of propranolol


What is the morbidity associated with thyroidectomy?

- recurrent laryngeal nerve palsy and vocal cord paralysis
- if both damages --> airway obstruction --> intubation --> trache


What is the general management of a toxic solitary thyroid nodule?

Usually benign if no surgery --> FNA
Symptomatic:  Propranolol ER and carbi/PTU as for Graves
- keep TSH slightly suppressed so stimulated growth of the nodule is reduced

- under 40:  surgery
- over 40/poor health:  I131 , keeping TSH suppressed prior in order to reduce I131 uptake by the normal thyroid


How is toxic MNG treated?

- propranolol and carbi but 95% recurrence rate if stopped
- definitive:  surgery - either to release pressure or cosmetic
- I131 - must stop carbimazole 4 days prior and follow low iodine diet to enhance RAI uptake


How does carbimazole work?

Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents the thyroid peroxidase enzyme from coupling and iodinating the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine).


How does PTU work?

Central - inhibits thyroperoxidase whichhelps iodine addition onto thyroglobulin - an essential step in T4 production

Peripheral:  PTU also acts by inhibiting the enzyme 5'-deiodinase (tetraiodothyronine 5' deiodinase), which converts T4 to the active form T3. (This is in contrast to methimazole, which shares propylthiouracil's central mechanism, but not its peripheral one.)


What side effect is peculiar to I131 therapy for diffusely nodular toxic goiter?

May induce Graves and Graves eye disease.


What is the management of subacute thyroiditis?

Propranolol for symptom relief if thyrotoxic

NSAID or aspirin for pain

Pred if severe

Thioureas and RAI are unhelpful as thyroid production is actually low

May have hypothyroidism afterward, need to monitor


What is the management of hyperthyroidism during pregnancy and lactation?

- PTU in first tri then switch to lower risk of foetal abnormalities
- both cross the placenta and can induce fetal hypothyroidism and TSH hypersecretion
- T3 and T4 do not cross the placenta but fetal hypothyroidism is rare if mothers hyperthyroidism is controlled with small doses of thioureas


What are the trimester specific thyroid function tests?

First tri
 - lower TSH
 - higher FT3
 - normal FT4

Second tri
- TSH should return to normal, may not
- higher FT3
- lower later

Third tri
- as for second
- higher FT3
- lower FT4


How is type 2 amiodarone induced thyrotoxicosis managed?

Propranolol for sx
May be able to continue amiodarone
Carbimazole is ineffective


What is the management when the diagnosis of amiodarone types 1 and 2 is unclear?

1 month trial of carbimazole
Pred if severe or when carbi fails to correct
Amiodarone is discontinued if possible


Why isn't PTU first line anymore?

Higher risk of fulminant hepatic necrosis


Which drugs can aggravate Graves opthalmopathy?

Thiazolidinediones (glitazones)


What is the treatment for acute progressive exopthalmos of Graves?

IV methyl pred (superior to oral)
Doesn't work as well for smokers

Can also give retrorobulbar radiation with oral pred - although response less good if chronic proptosis and orbital muscle restriction.

- orbital decompression if severe and may save vision but diplopia often persists


What is the role of Digoxin in the AF of hyperthyroidism?? Why not a B-Blocker?

Slows RVR
Need larger than normal doses due to increased clearence and increased number of cardiac sodium pumps needing inhibition
Dose reduces as AF does

B-blockers second line as negative inotropic effect may precipitate CHF


When are anticoagulants used in hyperthyroidism?

- LA enlargement on TTE
- global LV dysfunction
- recent CHF
- hypertension
- recurrent AF
- hx prev VTE

- smaller doses of Warfarin needed because there is an accelerated clearance of vitamin-K dependent clotting factors


How does apathetic hyperthyroidism present?

- angina pectoris
- reverse hyperthyroidism and reverse angina, thus avoiding the need for angioplasty


What are the features of a thyroid storm?

- triggered by stress, surg or RAI admin
- severe delirium, tachy, vomiting, high fever
- high mortality rate
- Give hydrocort
- avoid aspirin 
- delay definitive treatment until euthyroid


Why must you avoid aspirin in a thyroid storm?

Displaces T4 from TBG raising FT4 levels.


How is the hyperthyroidism of postpartum thyroiditis managed?

Propranalol during hyperthyroid phase, levo during hypothyroid phase


How is Graves dermopathy managed?

- topical corticosteroid with nocturnal plastic occlusive dressings


What is the management of thyrotoxic hypokalemic periodic paralysis?

Propranolol - normalise potassium and phosphate, reverses paralysis within 2-3 hours
Avoid IV dextrose and oral CHO - aggravates
Treat underlying hyperthyroidism

No potassium or phosphate replacement usually required


What is the long term risk to women with treated Graves disease?

Increased long-term risk of death from thyroid disease, cardiovascular disease, stroke, and fracture of the femur.

Post-treatment hypothyroidism is common


What is the prognosis of Graves disease that presents in early pregnancy?

30% chance of spontaneous remission before the third tri


What impact on bone physiology does subclinical hyperthyroidism have?

- most don't have accelerated bone loss but if there is osteopenia, need to do regular followup BMDs.


How is an asymptomatic person with subclinical hyperthyroidism managed?

People with very low TSH are closely monitored but are not treated unless AF or other manifestations of hyperthyroidism appear


What are the general features of Hashimoto thyroiditis?

- most common
- b-lymphocytic invasian
- Anti-TPO and antithyroglobulin antibodies


What is the epidemiology of Hashimoto thyroiditis?

Women 6x
Childhood/occ exposure to head/neck external beam radiation


What predicts long term hypothyroidism after Hashimoto thyroiditis?

High serum thyroid peroxidase levels


What are the disease associations with Hashimoto thyroiditis?

Polyglandular autoimmunity
Celiac disease
Turner Syndrome


What are the features of painless postpartum thyroiditis?

- occurs soon after delivery
- may be due to accumulation of fetal cells in the maternal thyroid during pregnancy (microchimerism)
- 70% chance of recurrence in subsequent pregnancies
- occurs mostly if high levels of anti-TPO antibodies in first tri, or immediately after delivery


What is de Quervain thyroiditis?

- also known as subacute, granulomatous or giant cell thyroiditis
- usually post viral URTI
- incidence peaks in summer
- young and middle aged women


What is the rarest form of thyroiditis?

Riedel or fibrous thyroiditis.  Usually found in elderly women as a manifestation of systemic fibrosis.


What are the clinical findings in Hashimoto thyroiditis?

- diffusely enlarged, firm, and finely nodular thyroid, sometimes with lobular assymmetry
- absence of pain
- may be assoc w/ mild myasthenia gravis affecting extraocular muscles with low detectable AChR Ab or thymic disease


What are the clinical findings of postpartum thyroiditis?

- hyperthyroidism 1-6 months after delivery
- persists for 1-2 months
- hypothyroidism develops 4-8 months after delivery


What are the clinical findings of subacute thyroiditis?

Acute and painful enlarged thyroid gland
Low grade fever and fatigue
Thyrotoxicosis in 50% and lasts several weeks followed by hypothyroidism that lasts 4-6 months


What are the lab findings of Hashimoto thyroiditis?

Increased anti-TPO antibodies
Increased anti-thyroglobulin antibodies
No need to monitor once diagnosed
Antibodies decline during pregnancy and are undetectable by third tri.


What additional tests should you do after confirming Hashimoto thyroiditis?

Coeliac workup:
Serum IgA endomysial aB or TTG
Serum IgA
Must not be on a gluten-free diet at thet ime


What are the lab findings in subacute thyroiditis?

Markedly elevated ESR
Low antithyroid antibody titres

(Leuks elevated in suppurative thyroiditis)


How do thyroid hormone levels differ between the thyrotoxicosis of thyroiditis and Graves?

Thyroiditis - serum FT4 levels proportinally higher than T3 since the hyperthyroidism is due to passive release of stored thyroid hormone (predominantly T4).

Graves/toxic NG --> T3 is relatively more elevated and hyperthyroidism more severe as T3 more active


What are the findings of imaging of Hashimoto thyroiditis?

U/S - diffuse hetergenous density and hypogenecity - distuingishes thyroiditis from MNG or suss nodules, guides FNA

Color flow doppler - distuingishes from Graves (hypervascular) as normal or reduced vascularity

RAI - very low in subacute thyroiditis but otherwise unhelpful in making dx of Hashimoto


What is the role of FNA in Hashimoto thyroiditis?

Do it if they have a thyroid nodule
RIsk of papillary cancer about 8%

Not required for deQuervain (subacute) thyroiditis)


What is the risk to perimenopausal women with Hashimoto thyroiditis?

Higher relative risk of depression if high serum anti-TPO antibodies


What is the role of antibody-specific tests in Hashimoto thyroiditis?

Sensitive but not specific (If negative you've ruled it out, if positive it could be other stuff)
Also positive in MNG, malignancy and concurrent Graves


What is the treatment of Hashimoto thyroiditis?

- levo if hypothyroid
- if large goitre --> lots of levo to drive down TSH and shrink the goiter
- if euthyroid - monitor, may become hypothyroid years later

-simvastatin and selenium may have a role but no long term data


What is the mx of subacute thyroiditis?

Aspirin - relieves pain and inflammation
Propranolol if thyrotoxic and symptomatic 
Iodinated contrast causes prompt fall in serum T3 and thyrotoxic symptoms


What is the treatment of the really really rare fibrosing Riedel thyroiditis?



What is the prognosis of Hashimoto?

Excellent - even if they become hypothyroid, it's easily treated


What is the prognosis of postpartum thyroiditis?

80% return to normal
50% develop permanent hypothyroidism within 7 years
More common if multiparous or spontaneous abortion
Papillary cancer plus Hashimoto has a good prognosis


What are the general features of thyroid nodules?

Common and mostly benign
Same cancer risk if multiple compared with one
Higher risk if hx head-neck radiation, total body radiation for bone marrow transplant/exp to fallout, FHx, hx malignancy


What are the general clinical features of a goitre?

Cosmetic embarassment
If retrosternal --> dyspnoea due to tracheal compression
Large substernal --> SVC syndrome


What are the general lab findings for thyroid nodules?

If abnormal TSH --> need imaging to determine if hyperfunctioning (and if so, they are rarely malignant)
Antibody tests --> very high if Hashimoto
If thyroiditis must check for malignancy as often coexists


In a patient with a thyroid nodule and a family member with familial medullary thyroid carcinoma or MEN2, what test should be performed?

Serum calcitonin


What are the features of imaging with thyroid nodules?

U/S - do to see if palpable nodule is part of MNG
RAI - limited usefulness - only to determine if 'hot' or 'cold' but can't differentiate malignancy
CT - larger nodules, degree of tracheal compression and mediastinal extension


What are the concerning features of a thyroid nodule on ultrasound?

- irregular or distinct margins
- heterogenous nodule echogenecity
- intranodular vascularity
- microcalcifications
- diameter >1cm


How are thyroid nodules with suspicious findings on ultrasound assessed?

FNA - best method
Can be done on anticoagulation/aspirin
Four largest (>1cm) in MNG should be biopsied so you don't miss it


For a solitary thyroid nodule, when is FNA biopsy indicated?

- >5mm with suspicious appearance
- assoc w/ abnormal lymph nodes
- >1cm and solid or have microcalcifications
- mixed cystic-solid nodules >1.5cm in diameter with any suspicious features on U/s
- >2cm and benign on U/S
- spongiform and 2cm


What is the management of a thyroid nodule that is found to be cystic on u/s?

Observe - pure cystic nodules are benign and don't need biopsy.


What is the risk of a thyroid nodule being malignant when the FNA cytology reads "suspicious follicular lesion"?

- about 20-25%
- higher if much younger or older than age 50
- bloody aspirate higher chance of malignancy
- surgery usually indicated on suspicious cytology


What happens if you give someone with MNG iodinated contrast or IV iodine?

Toxic MNG!


What is the role of levothyroxine suppression therapy in patients with nodular goitres?

- replaced if elevated TSH
- suppression most therapy in iodine deficient ares of the world
- long term tx keeps nodules from enlarging and may reduce emergence of new nodules


When is levothyroxine suppression therapy for goitre not used?

Cardiac disease - increases risk for angina and AF
Also causes a small lose in BMD in post-menopausal women if serum TSH is suppressed
Low baseline TSH because that means there is autonomous thyroid secretion, meaning levo won't work and will cause thyrotoxicosis instead


What is the role of percutaneous ethanol in treating thyroid nodules?

Shrinks benign cysts quite well as if you suck out the fluid it just comes back.  Needs to be repeated but has 80% success rate.


What is the role of I131 therapy in patients with thyroid nodules?

Option for hyperthyroid patients with toxic adenoma, MNG or Graves
Can be used to shrink benign nontoxic nodules
May be used for MNG but may induce Graves
Risk of hypothyroidism years after therapy


What is the prognosis of thyroid nodules?

90% will increase in size over 5 years, cystic ones remain fairly stable
MNGs persist or grow slowly 
Small incidentalomas require u/s followup ever 1-2 years but low risk


What are the general features of thyroid cancer?

Painless swelling
Normal thyroid function tests
Past history of irradiation to head and neck
Positive thyroid needle aspiration


What is the most common thyroid cancer?

Papillary carcinoma


What are the general features of papillary carcinoma?

Usually from a single nodule but can come out of an MNG - commonly multifocal within the gland
Slow growing, may be more aggressive in older patients with local invasion and spread to the lungs
Hx of head and neck irradiation, medical, Chernobyl etc.


What is the underlying pathophysiology of papillary thyroid carcinoma?

- activating mutation of ras oncogene can cause benign adenoma or nodular goiter
- additional activation mutation in BRAF or TRK genes can lead to papillary carcinoma
- 45% caused by overexpression of RET oncogene (medical radiation - retPTC-1, nuclear fallout retPTC-3)


What can cause progession of papillary thyroid carcinoma to anaplastic thyroid carcinoma?

Additional loss of p53 tumor suppressor gene in presence of activation mutation of ret oncogene and BRAF/TRK mutations


What are the disease associations for papillary thyroid ca?

Autosomal dominant familial syndromes
- familial thyroid ca
- familial polyposis
- Gardner & Turcot syndromes


Which is the least aggressive thyroid malignancy?

Papillary carcinoma
- 80% have microscopic mets but no increased mortality rate
- if lymph nodes, only the risk of local recurrence increases


What is the second most common thyroid cancer?

Follicular thyroid ca and it's variants (i.e. Hurthle cell ca)
Generally more aggressive than papillary


What are the features of follicular thyroid ca?

- avidly absorb iodine so v treatable
- mets to nodes, bones and lungs
- high risk of poorly differentiated or Hurthle cell variants (both don't take up RAI)


What mutations cause benign follicular adenomas?

- aberrant DNA methylation
- ras oncogene
- MEN1 gene


What are the features of medullary thyroid Ca?

- 3% of thyroid cancer
- 1/3 sporadic, 1/3 familial, 1/3 MEN2
- ret oncogene mutation on chromosome 10


What additional mandatory testing should be performed in a patient with confirmed medullary thyroid Ca?

Genetic analysis of peripheral white blood cells for the germline mutation of ret oncogene in exon 16.

If positive - related family members must be tested for that gene defect.

If no mutation, can still identify gene carriers with family linkage analysis, or if no defect at all, 6 monthly thyroid surveillance is required.


What is the pathophysiology of medullary thyroid ca?

- arise from parafollicular thyroid cells that secrete calcitonin, prostaglandins, serotonin, ACTH, CRH and more
- can be used as tumor markers
- metastasises and does not concentrate iodine


What are the features of anaplastic thyroid ca?

Older patients with rapidly enlarging mass in a MNG
Most aggressive and metastasizes early
Does not concentrate iodine


What are the clinical features peculiar to medullary thyroid ca?

Flushing and persistent diarrhoea - may be the initial clinical features
Cushing syndrome in about 5% due to secretion of ACTH or CRH


What is the role of serum thyroglobulin in thyroid ca?

- high in most papillary and follicular tumours making it a marker for recurrent or metastatic disease
- MUST measure antithyroglobulin antibodies as elevation of these can affect the test
- may be misleadingly elevated in thyroiditis which can coexist with Ca
- some assays falsely report elevated levels after total thyroidectomy and tumor resection causing unneeded concern about mets.


What considerations must be taken when using calcitonin as a tumour marker for medullary thyroid ca?

- may also be elevated in thyroiditis, pregnancy, azotemia, hypercalcemia and other malignancies
- measure with CEA pre-op, then postop every 4 months for 5 years, then every 6 months for life
- if extensive mets, need to do it with serial dilutions
- the best indication for recurrence is a rising level of calcitonin, not simply a high one as may remain elevated.


What is the role of RAI scanning in thyroid Ca?

Thyroid and whole body used post thyroidectomy for surveillance along with U/s


What is the role of CT and MRI in thyroid Ca?

CT - particularly good for localising and monitoring lung mets but not good for neck mets

MRI - particularly useful for bone mets.  Medullary ca calcified in thyroid, nodes and liver but lung mets rarely do.


What is the role of PET scanning in thyroid Ca?

- mets that don't have good iodine uptake on RAI
- enhanced if hypothyroid or on thyrotropin which increases metabolic activity of differentiated thyroid ca
- low SUV = better prognosis


What are the complications of thyroid ca?

1/3 of medullary secrete serotonin and prostaglandins --> flushing and diarrhoea and have coexistent phaeo or hyperparathyroidism
- risks of radical neck surgery inc hypoPTH, vocal cord palsy
- permanent hypothyroidism is expected post-op and should be treated


What is the treatment of differentiated thyroid Ca?

Surgical removal with preop neck u/s for LN involvement as may need neck dissection (esp if >1cm diameter)


What is the surgical mx of an indeterminate thyroid nodule?

Thyroid lobectomy if <4cm progressing to complete if malignancy detected

Bilateral thyroidectomy as initial surg if >4cm


In what circumstance would you do a lobectomy over a total/near total thyroidectomy for confirmed thyroid malignancy?

Ppillary thyroid ca >1cm in diameter under age 45 who have no hx of irradiation or mets.


When would you perform a lateral neck dissection in thyroid Ca?

- biopsy proven lateral cervical lymphadenopathy
- muscle resection is usually avoided


How do you treat thyroid ca mets to the brain?

Surgically - radiation or RAI doesn't work.


What are the features of hypoparathyroidism postoperatively after thyroidectomy?

Happens in 20%, permanent in 2%
Incidence reduced if accidentally resected parathyroids are immediately autotransplanted into neck muscles.

Watch for tetany


What is the management of pregnant women with thyroid cancer?

- delay surg until after delivery unless fast growing then after 24 weeks
- no difference in recurrence or survival if done during or after pregnancy
- higher risk comes from thyroid surg, not cancer


What is the general management of the serum TSH in thyroid cancer post thyroidectomy?

Suppress to < 0.1 with stage II disease
Suppress to <0.05 for higher stages

Risk is lower bone density but relatively minor if euthyroid


What is the treatment option for thyroid ca resistant to chemo?

Sorafenib and sunitib have partial response.


What are the reasons for treatment with I131 after thyroidectomy?

1- thyroid remnant ablation

2- tx of known or suspected thyroid ca


What is a low iodine diet and when would you use it?

- iodised salt, fish and seaweed, commercial bread, dairy, processed meats, canned/dried fruit and juice, black tea, instant coffee, red dye # 3 and MVs.

2 weeks before I131 so the radioactive form gets taken up instead

Must also avoid amiodarone and iodinated contrast


What is the role of RAI therapy in metastatic thyroid Ca?

Improves survival and reduces recurrence rates in Stage III-IV and in II with gross extension or a distant met


Which population of patients should have a prophylactic thyroidectomy?

Patients with a ret protooncogene mutation should have a prophylactic total thyroidectomy, ideally by age 6 years (MEN 2A) or at age 6 months (MEN 2B).


What is the role of recombinant TSH stimulated I131 therapy?

Thyrogen (rTSH) is given to increase the sensitive of serum thyroglobulin for residual ca and increase uptake of I131 into remant tissue or cancer.

- should NOT Be given to patients with an intact thyroid gland as will cause swelling and hyperthyroidism - and can cause this in patients with significant mets or residual normal thyroid

- Nausea and headache are SEs, can cause neurologic deterioration in CNS mets


What is the role of external radiation therapy in thyroid ca?

- anaplastic thyroid ca
- brain mets with gamma knife radiosurgery


In suppressing TSH for thyroid Ca, the serum T4 may be slightly elevated by the thyroxine dose.  How can you ensure the patient is not hyperthyroid?

Serum T3 or FT3 level


When is serum thyroglobulin a useful tumour marker?

Only after total or near-total thyroidectomy or I131 ablation and particularly when there are no serum anti-thyroglobulin antibodies.

- Detectable != recurrence

- baseline is NOT helpful, stimulated measurements should be used and always w/ neck U/S


How should neck ultrasound be used in patients with thyroid Ca? 

Supplements palpation
Perform pre-op
3 months post-op
Then as followup

Better than CT or MRI for local LN mets.


What is the role of I131 RAI scanning in thyroid Ca surveillance?

High risk
Persistant antithyrglobulin antibodies that make serum thyroglobulin determination unreliable
Must be used <2 weeks before scheduled I131 treatment to avoid stunning the mets (or can use I123 as does not stun tumors and better for SPECT)
Performed 2-4 months post op in differentiated disease
May not need repeat scanning if clear post op and low serum thyroglobulin, but continue ultrasounds


What do you do if there is persistent radioiodine uptake in the neck on diagnostic RAI scanning but no visible tumor on neck ultrasound post thyroidectomy?

No additional therapy, especially if serum thyroglobulin is very low


What is the role of PET scanning as surveillance in thyroid ca?

- useful for detecting mets when high serum thyroglobulin who have a normal whole-body RAI scan and unrevealing neck-ultrasound
- avoid sweets and in diabetics, BSL <20
- better sensitivity if done as a fusion scan with CT
- poor specificity


What can cause false positives on PET scans?

Benign hepatic tumours
Radiation therapy
Suture granulomas
Reactive LNs
Brown fat


What role does PET scanning have in prognosticating thyroid disease?

Predicts survival better than standard staging - number, location and SUV of mets are all factors.


What is the prognosis of papillary thyroid Ca?

- few mets, low SUV on PET = better
- under 40 even with mets = good

- over 45, male, bone or brain mets, >1cm, pulmonary mets or lack I131 = bad


What papillary ca histology is assoc w/ worse prognosis?

tall cell
columnar cell
diffuse sclerosing
brain mets reduce survival to 12 months but improves with resection


What increases mortality in papillary thyroid ca?

- tumor >1cm and only limited thyroid surgery (subtotal or lobectomy)
- no I131 ablation
- higher in men
- multifocal tumors


What are the prognostic features of medullary thyroid Ca?

- 90% 10 year survival when confined to the thyroid, drops to 20% with distant mets
- if LN involvement, modified radical neck dissection helps
- MEN2A associated less agressive, also women under 40
- more aggressive in MEN2B, younger in age, M918T mutation


What antigenic stain finding increases the mortality of medullary thyroid Ca x4.5?

What is associated with prolonged survival even if there are significant mets?

Myelomonocytic antigen M-1

Heavy immunoperoxidase stain for calcitonin


What is the survival rate of anaplastic thyroid ca?

1 year survival of about 10%
5 year survival of 5%
Fully localised tumor on MRI has a better prognosis


What is the prognosis of thyroid lymphoma?

100% at 5 years
Outside the thyroid, 63%
Better if MALT

Stridor, pain, palsy, mediastinal extension = worse


What are the features of iodine deficiency disorder and endemic goitre?

- low iodine diet
- high rate of congenital hypothyroidism and cretinism
- goiters may become multinodular and enlarge
- most are euthyroid


What impact does iodine deficiency have on children?

Increased risk of miscarriage and stillbirth
Congenital hypothyroidism --> deafness, short stature, lower IQ
Full blown cretinism


What aggravates iodine deficiency or can themselves, cause goiter?

Selenium, iron
Water pollution


What are the lab findings in iodine-deficient endemic goiter?

Normal serum T4 and TSH
If TSH falls and hyperthyroidism --> MNG has become autonomous in presence of sufficient amounts of iodine

- Thyroid RAI uptake usually elevated but may be normal if iodine intake has improved
- antithyroid antibodies either undetectable or low

- eleavted serum thyroglobulin


What is the treatment of endemic goiter?

- iodised table salt reduces prevalence but doesn't shrink goiter
- Concurrent vitamin A and iodine deficiency increases risk of endemic goiter, concurrent repletion reduces
- large multinodular goiter --> thyroidectomy for cosmesis, compressive sx or thyrotoxicosis
- high recurrence rate if subtotal + iodine deficient area, total is preferred


What are the complications associated with endemic goiter?

Iodine supplementation increases risk of autoimmune transformation
Excess supplementation increases risk of goiter particularly if autonomonous MNG - avoid thyroxine suppression if low TSH
Rarely - Graves post I131 in MNG


What are the essentials of diagnosis for male hypogonadism?

- diminished libido and erections
- low serum or free testosterone
- LH and FSH low/normal in hypogonadotropic hypogonadism
- increased in testicular failure (hypergonadotropic hypogonadism)


How is male hypogonadism classified?

- insufficient gonadotropin secretion by the pituitary (hypogonadotropic)

- pathology in the testes (hypergonadotropic)

- both


What are the features of hypogonadotropic hypogonadism?

- FSH and LH deficiency due to pituitary failure, either in isolation or with other hormone deficiencies

- can be primary

- main causes are functional; obesity, poor health, normal aging - spermatogenesis preserved


What is the natural history of testosterone secretion in men?

After age 40, declines by 1-2% per year
Free testosterone levels decline even faster due to increasing SHBG with age
No concomitant increase in LH until after age 70, at which point it starts to rise, suggesting primary gonadal dysfunction with age


What should the diagnosis of testosterone deficiency in older men include?

Low serum testosterone
At least 3 of the following 6:
Erectile dysfunction
Poor morning erection
Low libido
Inability to perform vigorous activity

These men are most likely to benefit from testosterone replacement


What are the general features of hypergonadotropic hypogonadism?

- failure of testicular secretion of testosterone 
- can be caused by viruses (i.e. mumps), irradiation, ca, autoimmunity, myotonic dystrophy, genetics, andropause, single testicle failure, 17-hydroxylase deficiency, 17-ketosteroid reductase deficiency


What are the features of Klinefelter syndrome?

47, XXY
Most common male chromosomal abnormality
Gynecomastia and tall stature
Dx on karyotype of RNA for X-inactive-specific transcriptase on peripheral leukocyte PCR
Azoospermia (although some produce sperm)


What are the features of XY gonadal dysgenesis?

- failure of normal testicular development
- mutation in SRY gene
- no testosterone --> sex reversal
- external female genitalia w/o uterus, have intra-abdominal gonads
- raised as girls, upon puberty, amenorrhea
- resect intrabdominal testes, risk of malignancy
- considered women, give estrogen


What are the clinical findings of hypogonadism?

Delayed puberty if congenital or acquired during childhood
Decreased libido
Decreased man hair (after years)
Low muscle mass
Weight gain


What are the lab findings in hypogonadism?

Morning serum or free testosterone (declines throughout day) will be low
- free testosterone esp important in elderly men due to high SHBG
- should be confirmed with repeat assay and low LH and FSH
- check for hyperprolactinaemia
- mild anaemia as testosterone stimulates RBC production
- BMD if longstanding as may have osteoporosis


What are the lab findings in hypogonadotropic hypogonadism?

- serum PRL may be elevated
- normal/low LH/FSH
- if gynecomastia, screen for partial 17-ketosteroid reducatse deficiency plus androstenedione and estrone which are elevated in this condition.
- serum estradiol may be elevated if cirrhotic and if rare estrogen secreting tumour


What screening test should be done in a man with hypogonatropic hypogonadism with no definite cause?

Screen for hemochromatosis and MRI the pituitary and hypothalamus looking for a lesion


What are the lab findings in hypergonadtropic hypogonadism?

- low serum testosterone with high FSH and LH
- karyotype or PCR leukocyte XIST for Klinefelters
- testicular bx in young guys if no cause found


What are the general principles of testoserone replacement?

- boys who have not start puberty by age 14
- men with hypergonadtropic hypogonadism or severe hypogonadtropic hypogonadsim
- hypogonadic symptoms (at least 3), with low serum or free testosterone


In whom is testosterone therapy contraindicated?

Active prostate or breast ca
Need DRE and PSA prior to commencing
Untreated OSA


What special considerations need to be made in testostereone replacement?

Must improve cardiac risk factors and give low-dose aspirin
If on Warfarin --> can increase INR and risk of bleeding
Will increase cyclosporine and tac levels
Hypoglycaemia in diabetic men on insulin or oral hypoglycaemics


What are the features of testosterone replacement formulations?

Topical administration is best - more stable sterum testosterone
Skin acts as reservoir of slow release - 10% gets into the blood, steady state in 1-3 days
Transdermal is inconvenient and expensive
Avoid breast or genitals

Oral forms can cause liver tumors or peliosis hepatis


Who benefits from testosterone therapy?

Low serum testosterone and at least 3 manifestations of hypogonadism


What are the risks associated with testosterone replacement therapy?

- increases risk of cardiovascular events in age over 65 with risk factors or pre-existing angina
- may be due to decrease in HDL associated with testosterone therapy

- aggravates BPH but not voiding sx

- erythrocytosis with IM but no increased risk of thromboembolic events

- aggravates sleep apnoea


- gynecomastia that resolves spontaneously, better with gel


What are the general features of male gynecomastia?

60% of pubertal boys - spontaneously resolves, common in tall oor overweight
Half of athletes who abuse
HIV on HAART - esp efavirenz of didanosine - spontaneously resolves


What are the concerning characteristics in a man with gynecomastia?

- asymmetry
- location not immediately below the areola
- unusual firmness
- nipple retraction, bleeding or discharge


What are the lab findings to consider in male gynecomastia?

B-subunit of HCG suggest a testicular tumor (germ cell or Sertoli) or other malignancy (lung or liver)
- low serum free testosterone and high LH --> primary hypogonadism
- high testosterone plus high LH --> partial androgen resistance
- estradiol increased from testicular tumours, increased B-HCG, liver disease and obesity


In a man with new gynecomastia and no clear cause - what test should be performed?

CXR for metastatic or bronchogenic ca


What is the role of selective estrogen receptor modulator therapy (SERM) in gynecomastia?

Works for lumpy 'glandular' gynecomastia rather than diffuse fatty kind.
Give raloxifene


When is surgical correction used for gynecomastia?

If persistent or severe


What is the genetic abnormality of Turner's syndrome?

Turner's syndrome is a chromosomal disorder affecting around 1 in 2,500 females. It is caused by either the presence of only one sex chromosome (X) or a deletion of the short arm of one of the X chromosomes. Turner's syndrome is denoted as 45,XO or 45,X


What are the phenotypical features of Turner syndrome?

short stature
shield chest, widely spaced nipples
webbed neck
bicuspid aortic valve (15%), coarctation of the aorta (5-10%)
primary amenorrhoea
cystic hygroma (often diagnosed prenatally)
high-arched palate
short fourth metacarpal
multiple pigmented naevi
lymphoedema in neonates (especially feet)

There is also an increased incidence of autoimmune disease (especially autoimmune thyroiditis) and Crohn's disease


What is the source, stimulus, and action of gastrin?

G cells in antrum of the stomach

Distension of stomach, vagus nerves (mediated by gastrin-releasing peptide), luminal peptides/amino acids
Inhibited by: low antral pH, somatostatin

Increase HCL, pepsinogen and IF secretion, increases gastric motility, stimulates parietal cell maturation


What is the source, stimulus, and action of CCK?

I cells in upper small intestine

Partially digested proteins and triglycerides

Increases secretion of enzyme-rich fluid from pancreas, contraction of gallbladder and relaxation of sphincter of Oddi, decreases gastric emptying, trophic effect on pancreatic acinar cells, induces satiety


What is the source, stimulus, and action of secretin?

S cells in upper small intestine

Acidic chyme, fatty acids

Increases secretion of bicarbonate-rich fluid from pancreas and hepatic duct cells, decreases gastric acid secretion, trophic effect on pancreatic acinar cells


What is the source, stimulus, and action of VIP?

Small intestine, pancreas


Stimulates secretion by pancreas and intestines, inhibits acid secretion


What is the source, stimulus, and action of somatostatin?

D cells in the pancreas & stomach

Fat, bile salts and glucose in the intestinal lumen

Decreases acid and pepsin secretion, decreases gastrin secretion, decreases pancreatic enzyme secretion, decreases insulin and glucagon secretion
inhibits trophic effects of gastrin, stimulates gastric mucous production


What are the hormones secreted by the adrenals and where?

Adrenal cortex (mnemonic GFR - ACD)
zona glomerulosa (on outside): mineralocorticoids, mainly aldosterone
zona fasciculata (middle): glucocorticoids, mainly cortisol
zona reticularis (on inside): androgens, mainly dehydroepiandrosterone (DHEA)


Where does parathyroid hormone act?

PTH acts to increase the concentration of calcium in the blood by acting upon the parathyroid hormone 1 receptor (high levels in bone and kidney) and the parathyroid hormone 2 receptor (high levels in the central nervous system, pancreas, testis, and placenta).


Describe the regulation of parathyroid hormone

Secretion of parathyroid hormone is controlled chiefly by serum [Ca2+] through negative feedback. Calcium-sensing receptors located on parathyroid cells are activated when [Ca2+] is elevated.

In the parathyroid gland, high concentrations of extracellular calcium result in activation of the Gq G-protein coupled cascade through the action of phospholipase C.

Hypermagnesemia also results in inhibition of PTH secretion.

While low levels of magnesium stimulate parathyroid hormone secretion, very low serum concentrations induce a paradoxical block.


Name the stimulators and inhibitors of parathyroid hormone release


    Decreased serum [Ca2+].
    Mild decreases in serum [Mg2+].
    An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH).


    Increased serum [Ca2+].
    Severe decreases in serum [Mg2+], which also produces symptoms of hypoparathyroidism (such as hypocalcemia).[13]


What is the cause of most hyperfunctioning thyroid nodules?

Activating TSH receptor mutations

Activating mutations in either the TSH-R or the Gs subunit genes are identified in >90% of patients with solitary hyperfunctioning nodules
Thyrotoxicosis is usually mild
Disorder is suggested by the presence of the thyroid nodule and by the absence of clinical features suggestive of Graves' disease or other causes of thyrotoxicosis
A thyroid scan provides a definitive diagnostic test, demonstrating focal uptake in the hyperfunctioning nodule and diminished uptake in the remainder of the gland, as activity of the normal thyroid is suppressed


What impact do fibrates have on blood cholesterol?

Decrease TGL
Decrease VLDL
Decrease total chol

Increase HDL


How do fibrates work?

Stimulate lipoprotein lipase by inducing PPAR-alpha receptors which induce the transcription of genes that facilitate lipid metabolism

ApoCIII (a VLDL protein) is decreased as a result which increases LPL activity

VLDL catabolism is enhanced which generates surface remnants, these are then taken up by HDL, helped by PPAR driven transcription of APoA1 and ApoA2

End result is increased HDL-mediated reverse chol transport, reduction in hepatic VLDL secretion, increased size and removal of LDL partiles, and reduced plasminogen activator inhibitor type 1 levels.


What is the role of:


 Chylomicrons carry diet-derived lipids to body cells
    VLDLs carry lipids synthesized by the liver to body cells
    LDLs carry cholesterol around the body
    HDLs carry cholesterol from the body back to the liver for breakdown and excretion.


Describe the 'non-HDL' pathway of lipid transport

1. ApoB (VLDL) secreted by liver
2.  Connects to muscle and liver via surface APO-CIII which activates lipoprotein lipase
3.  Core TGLs hydrolysed to FAs and cross capillary membrane, VLDL now ILDL (APO-B100)
4. ApO-B100 further freed of FAs by hepatic lipaseand becomes LDL (stil APO-B100) which expresses Apo CIII
5. ILDL and LDL shed APO-E and APOCIII remnants as they shrink, which get taken up by HDL
6.  LDL or remnants reuptaken by LDLr or LRP

OR - the remnants or chylomicron remnants get taken up by peripheral cells for cholesterol content or by capillary macrophages which have LDLr's --> foam cells --> atheroma.


Describe the 'HDL' or 'reverse cholesterol' pathway of lipid metabolism

1.  Poorly lipidated APoA1 secreted by liver and intestine into the plasma
2.  Cholesterol filled cell (inc macrophages) upregulate the ABCA transporter which converts cholesterol ester to free cholesterol from the lipid pool and delivers it to the cell membrane.
3.  APOA1 collects this cholesterol and forms nascent HDL.  ABCA keeps shuttling.
4.  Lecithin cholesterol athyltransferase (LCAT) esterifies cholesterol on nascet HDL surface --> chol ester moves to lipoprotein core --> HDL3 is formed.
5.  HDL collects more cholesterol from cell membranes via the FRB receptor, becomes HDL2.
6.  HDL2 via cholesterol ester transfer protein (CETP) exchanges cholesterol for triglycerides with TGL-rich lipoproteins (VLDL and LDL)
7.  HDL2 can then have it's TGLs hydrolysed by hepatic lipase and then become HDL3 again OR return to the liver where scavenger receptor SRB1 extracts cholesterol --> HDL3, or HDL2 gets catabolised by the liver.


What are the non-iatrogenic causes of hypervitaminosis-D?

Remember - excess calcitriol (aka D3)

- hyperparathyroidism --> upregulated 1-alpha hydroxylase in the kidney

- Tumor production of calcitriol:
• Predominant cause of hypercalcemia in Hodgkin’s disease and in 1/3 of patients with NHL
• Sarcoidosis and sarcoma
• Usually responds to corticosteroid administration 


What are the endocrine and exocrine features of sarcoidosis?

Increased prolactin --> amenorrhea, galactorrhoea, non peurpeural mastitis

Granuloma's secrete 1-alpha hydroxylase --> increased 1,25OHD --> hypervitaminosis D --> hypercalcemia


What is the major cause of the hypercalcemia of malignancy?

What is it's significance?

PTH-rP is the leading cause of hypercalcemia in malignancy (80% of cancer pt.’s with hypercalcemia have PTH-rP-related hypercalcemia).

Hypercalcemia in malignancy occurs abruptly, is se
vere, and portends a very poor prognosis (median
survival only six weeks). 


Which cancers are associated with hypercalcemia?

Breast, lung, and multiple myeloma


What are the threen main mechanisms of hypercalcemia in malignancy?


Osteolytic mets

Tumor production of calcitriol


What are the features of PTH related protein? (PTH-rp)

PTH-rP is the leading cause of hypercalcemia in malignancy (80% of cancer pt.’s with hypercalcemia have
PTH-rP-related hypercalcemia).

• Also known as HHM (humoral hypercalcemia of malignancy)

• PTH-rP is produced by a number of cells (neuro
endocrine, epithelial, mesoderm-derived tissues)

• Can be associated with any solid tumor (most commonly breast cancer) and occasionally humoral


Which cancers have osteolytic mets?

Remember the pneumonic BLT with a Kosher Pickle, Mustard & Mayo
Kidney, Prostate, Multiple Myeloma

• Most commonly caused by breast cancer and NSCLC 


Describe the follicular phase of the female menstrual cycle.

Beginning of menstrual cycle
Hypothalamus releases GNRH
Pituitary releases FSH
FSH stimulates follicle (1 egg, oestrogen secretion) growth and maturation
Follicle releases oestrogen
Uterine endometrium proliferates via oestrogen
Increasing GnRH results in LH secretion --> luteal phase


Describe the luteal phase of the female menstrual cycle.

Midpoint of cycle
Ever increasing GnRH acts on pituitary to spike LH secretion
Egg is released from follicle - takes 5-6 days to travel to uterus
Follicle becomes corpus luteum which secretes progesterone
Progesterone acts on endometrium to become secretory (favorable for egg)
Continues to secrete progesterone
No fertilisation --> corpus luteum dies and in presence of both falling oestrogen and progesterone --> sheds, period
Fertilisation --> corpus luteum keeps secreting progesterone for first 12 weeks of pregnancy.


Describe the gonadal production of testosterone

Hypothalamus releases GnRH
Ant pituitary releases LH & FSH
LH goes to the Leydig Cells in the interstitial space
Leydig cells secrete testosterone

Testosterone and dihydroxytestosterone negatively feedback on the anterior pituitary to reduce LH release and drop testosterone production.


Describe the hormonal control of spermatogenesis

Hypothalamus releases GnRH
GnRH stimulates LH & FSH release
LH --> Leydig cells (interstitium) --> testosterone
FSH --> Sertoli cells (seminiferous tubules) --> ABP (androgen binding protein) release

Testosterone binds ABP --> stimulates sperm growth (spermiogenesis and spermatogenesis)

Sertoli cells secrete inhibin --> negative feedback to pituitary --> reduced production of FSH.


What are the general features of the male gonads?

- approx 3 degrees cooler than body (for sperm)
- can drop away from body via spermatic cord if body gets too hot
- tunica albuginea protects teste, and extends inside to form septa --> dividing teste into lobules containing  interstitium and seminiferous tubules


What are the active areas of the male teste and what do they do?

Seminferous tubule form sperm
Interstitial cells form male hormones (androgens)


Describe the process of sperm production

FSH --> 
Spermatogonium undergo mitosis forming a daughter spermatogonium (for later) and a primary spermatocyte with 46 chromosomes.

Primary Spermatocyte undergoes meiosis 1

Secondary spermatocyte is generated in which the DNA is not replicated beforehand, leaving it with only 23 chromosomes.

Secondary spermatocyte undergoes meiosis 2, generating 4 spermatids each with 23 chromosomes.

Spermatids then differentiate to form their own heads and tails --> mature spermatozoa

In summary:  spermatogenesis forms 4 x spermatozoa (sperm cells) each with only 23 chromsomes from one primary spermatocyte (46 chromosomes).  Female ova supply the other 23 chromosomes.


Describe the components of sperm

Head --> contains nucleus and chromsomes.  Tip (acrosome) contains penetrative enzymes

Body --> mitochondria for ATP and swimming energy

Tail --> flagellum

Lives for hours to 3 days.


Describe the passage of sperm from the testes

Seminefrous tubule 
Epididymus (coiled tube) --> mature on way through here
Emptied into vas deferens then passes through the inguinal canal, loops over then down the side of the bladder to the seminal vesicle

Seminal vesicle supplies nutrition and most of the ejaculatory fluid and joins with the vas deferens to become the ejaculatory duct which passes through the prostate.

Prostate - contracts and provides the alkaline fluid to neutralise vaginal acidity, supplies more of the ejaculatory fluid

Sperm then travels through the bulbourethral glands which also provide alkali fluid to counteract urethral acidity and lubrication.

Sperm then exits the urethra.


Describe the different parts of the penis

Anterior - corpus cavernosa (does the erection)

Posterior - corpus spongiosum (has the urethra and forms the glans)

Distal end - glans

Foreskin - prepuce


What stimulates the release of human growth hormone?

GH is stimulated in response to stress, exercise, malnutrition and anorexia during the day (i.e. in response to a catabolic state - hypoglycacemia, low FFAs and high circulating amino acid concentrations).


In a normal person, which of the following is most likely to cause a decrease in circulating growth
hormone concentration?
A. Slow wave sleep.
B. Hyperglycaemia.
C. Protein meal.
D. Exercise.
E. Sepsis.


C, D, E are all potentially catabolic states which will increase circulating growth hormone concentration.  At baseline physiology, growth hormone release is highest in sleep stage III and IV (deep sleep).  B is the only option 


What are the features of human growth hormone?

Also known as 'somatotropin'.
'Stress hormone' that stimulates lipolysis, gluconeogenesis and also increases protein synthesis.

Normally pulsatile secretion, highest during sleep stages III and IV, lowest in early morning
Peaks in teenage years and declines after that, diminished further in heart failure patients.

Stimulated by slow wave sleep, ghrelin, the 'hunger' hormone released by the stomach and a catabolic state (hypoglycaemia, stress, exercise).


What are the effects of human growth hormone?

Stress hormone
Hepatic IGF-1 release (growth promoter)

Lipolysis --> FFA release
Protein synthesis
Increases T4 to T3 deoiodination
Cakcium retention and mineralisaton of bone
Stimulates internal organ growth


What is IGF-1?

Growth factor released by the liver in response to growh hormone.

Responsible for human growth in general, and growth-effects of human growth hormone.

Receptor number is regulated by GH and thyroxine.


What are the inhibitors of human growth hormone?

TRH --> somatostatin release (which suppresses TSH, in turn, hypothyroidism suppresses somastostatin)
B-agonists --> somatostatin release
Exogenous glucocorticoids (at hypothalamus)
High circulating FFAs
Leptin (released by fat cells when there's lots of fat)


Where is somastatin secreted from and what does it do?

Also known as GHIH - it's an inhibitory system

In the anterior pituitary (secreted by hypothalamus):
- inhibits GH (opposes GHRH)
- inhibits TSH
- inhibits prolactin release
- always paracrine (not in blood)

In the GI system (secreted by stomach, intestine and pancreatic delta cells)
- suppresses all the GI hormones (gastrin, CCK, secretin, VIP, GIP, secretin, motilin)
- decreases gastric emptying and reduces sm contractions in the intestine
- suppresses pancreatic hormone (endocrine and exocrine) release inc insulin and glucagon.


How is acromegaly diagnosed?

IGF-1 most sensitive, so good screening test.

If positive - GH suppression testing following oral glucose load - specific.  Failure of suppression = acromegaly)

Single GH value NOT useful.


What are the complications of acromegaly?

Arthritis and carpal tunnel
Myocardial hypertrophy
DM due to insulin resistance
Heart and renal failure
Colorectal ca


What laboratory parameter is most suggestive of psychogenic polydipsia?

Hyponatraemia - in true diapetes insipidus, the patients are dehydrated from excessive water loss


What will a water deprivation test show for

Psychogenic polydipsia

Central DI

Nephrogenic DI?

Psychogenic:  Concentrated urine both before and after desmopressin

Central DI: Dilute urine before DDAVP, concentrated after

Nephrogenic:  Dilute urine before and after DDAVP


What is desmopressin and what is it used for?

Man made vasopressin or ADH with little effect on BP as compared with vasopressin

Used to treat central DI (bind renal collecting duct V2 receptors --> aquoporin channels to apical membrane of duct)

Promotes release of vWF (also on V2 receptor) and increases factor VIII survival thanks to this --> used in VW disease, mild hemophilia A, and thrombocytopaenia.  Can also be used with uremic induced platelet dysfunction.  Not for haemophilia B or severe haemophilia A.


Describe the state of renin, aldoserone and cortisol for

Secondary hyperaldosteronism (or renovascular ht)
Addison's disease
Cushing's disease

Primary hyperaldosteronism (also known as Conn’s syndrome): high aldosterone, normal cortisol, low renin

Secondary hyperaldosteronism: high aldosterone, normal cortisol, high renin

Addison’s disease (also known as adrenal insufficiency): low aldosterone, low cortisol, high renin

Cushing’s syndrome: low-normal aldosterone, high cortisol, low renin


Which drugs should be avoided prior to perform an aldosterone:renin ratio?

Diuretics including spironolactone which raises plasma renin levels, thereby reducing the ratio.

Hypokalemia should be corrected before testing as low potassium suppresses aldosterone secretion.


What is the effect of hypothyroidism on lipid physiology?

Decreased tissue and hepatic LDL receptors

Hyperlipidaemia of LDL origin - even in subclinical hypothyroidism


What is the dyslipidemia characteristic of protease inhibitors?

Hypertriglyceridaemia (as well as increase in total chol and LDL)

Mainly Ritonavir


What are the characteristic features of a type 2 diabetic dyslipidemia?

High triglycerides
Increased small dense LDL cholesterol


What are the characteristics of atherogenic dyslipidemia?

Elevated small dense LDL
Increased TGL


What does excessive alcohol intake do to lipid levels?

Raises TGLs
Raises HDL
Minimal effect on LDL

- not recommended for prevention of coronary disease! ;)


What are the contraindications to bisphosphonates?

Delayed oesophageal emptying eg stricture, achalasia; (they can cause serious oesophageal erosions) 

inability to stand, sit upright for greater than or equal to 30 min; 


renal impairment (mainly w/ IV therapy)

recent uveitis incl bisphosphonate assoc history; pregnancy, lactation


How do you differentiate between:  
Exogenous glucocorticoids
Pseudo Cushing's
Cushing's disease
Ectopic Cushing's syndrome
Cortisol producting adrenal adenoma?

Exogenous and cortisol producing-adrenal adenoma (both are forms of primary hypercortisolism) --> ACTH suppressed (negative feedback depends on cortisol)

Pseudo Cushings - cortisol and ACTH normal

Cushing's disease (pituitary dependent) - normal/somewhat elevated (not in hundreds) ACTH (pituitary source) and high cortisol suppressed by high dexamethasone doses (tumour still sensitive somewhat)

Ectopic Cushing's syndrome (pituitary independent) - high ACTH as it is ectopic production of ACTH driving the hypercortisolaemia, wouldn't matter if pituitary productions was suppressed - elevated in hundreds. Cortisol not suppressed at all by dex suppression test.  Look in adrenals or lungs.


How do you differentiate between an adrenal crisis and a glucocorticoid insufficiency due to hypopituitarism crisis?

Hypotension / collapse
Hypothermia or hyperthermia

Hypoglycaemia (unless diabetic!)

Low T4

Adrenal only
Hyperkalemia and hyponatraemia (these are ok in hypopituitarism because renin is not affected - only production of aldosterone by the adrenals)


What are the general features of an adrenal crisis?

Severe lethargy
Hyperkalemia (elevated potassium level in the blood)
Hypercalcemia (elevated calcium level in the blood): the etiology of hypercalcemia is a combination of increased calcium input into the extracellular space and reduced calcium removal by the kidney, this last caused by decreased glomerular filtration and increased tubular calcium reabsorption. Both renal factors are secondary to volume depletion and, in fact, improve rapidly during rehydration with saline infusion.[3]
Hypoglycemia (reduced level of blood glucose)
Hyponatremia (low sodium level in the blood)
Hypotension (low blood pressure)
Hypothyroid (low T4 level)
Severe vomiting and diarrhea, resulting in dehydration


What are the clinical features of CAH?

Due to inadequate mineralocorticoids:

    vomiting due to salt-wasting leading to dehydration and death

Due to excess androgens:

    functional and average sized penis in cases involving extreme virilization (but no sperm)
    ambiguous genitalia, in some females, such that it can be initially difficult to identify external genitalia as "male" or "female".
    early pubic hair and rapid growth in childhood
    precocious puberty or failure of puberty to occur (sexual infantilism: absent or delayed puberty)
    excessive facial hair, virilization, and/or menstrual irregularity in adolescence
    infertility due to anovulation
    enlarged clitoris and shallow vagina


What is the most predictive marker of PCOS in patients who have evidence of hyperandrogenism?

Approximately three-quarters of patients with PCOS (by the diagnostic criteria of NIH/NICHD 1990) have evidence of hyperandrogenism, with free testosterone being the single most predictive marker with ~60% of patients demonstrating supranormal levels


Describe what happens to hormone levels in pregnancy

HCG - peaks in first tri then drops until birth

Progesterone and oestrogen climb consistently into third tri.


What is the mechanism and causes of SIADH?

Excessive ADH secretion and inappropriate water reabsoprtion

Caused by:

Ectopic - SCLC

Drugs - sulfonylurea

Lesion of baroreceptor pathway


What are the consequences of SIADH?

Water retention and increased ANP leading to euvolaemic hyponatraemia

Urine osmolarity greater than plasma osmolarity 
Elevated urinary sodium


What is the mechanism of sodium wasting in SIADH?

ADH activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium), causing hyponatremia; this is compounded by the fact the body responds to water retention by decreasing aldosterone, thus allowing even more sodium wasting. For this reason, a high urinary sodium excretion will be seen. 


What causes hypovolaemic hyponatraemia?



What causes euvolaemic hyponatraemia?

SIADH - brain, lung ca, pain, psych meds

Pseudo SIADH - hypothyroidism, hypoaldosteronism


Characterised by high urine osmolality


What causes hypervolaemic hyponatraemia?



How do you differentiate refractory essential hypertension from

Renal artery stenosis
Cushing's syndrome

Essential hypertension tends to have no electrolyte derangement, can have a bruit. 

Hyperaldosteronism seen in Conn's and renal artery stenosis will predispose to hypokalemia and alkalosis

Phaeo tends to present young to mid age and can be paroxysmal with tachycardias.


When do you worry about an adrenal incidentaloma?

When it's over 4cm or there's evidence of hormonal overactivation


What drug should you never give to someone with bilateral renal artery stenosis and why?


In renal artery stenosis, the afferent pressure is reduced by the narrowed vessel, hence autoregulation is almost exclusively dependent on changes in post-glomerular arteriolar tone.

Because ACE inhibitors interfere with the production of angiotensin II, autoregulation is impaired, glomerular perfusion falls, renal ischaemic nephropathy develops and renal failure ensues.

Angiotensin II forms part of the renal autoregulation of glomerular perfusion mechanism. The preglomerular arteriolar tone is reduced when renal perfusion falls, increasing glomerular blood flow and maintaining glomerular filtration.

If this response is inadequate, renin is released, activating the RAAS cascade, leading to angiotensin II mediated constriction of the post-glomerular arteriole. Pressure within the glomerulus is therefore increased and filtration restored.


What are the indications for ambulatory blood pressure recording?

• Suspected white-coat hypertension (including in
• Suspected masked hypertension (untreated subject
with normal clinic BP and elevated ABP)
• Suspected nocturnal hypertension or no night time reduction in BP (dipping)
• Hypertension despite appropriate treatment
• Patients with a high risk of future cardiovascular events (even if clinic BP is normal)
• Suspected episodic hypertension.

Ambulatory BP monitoring may also be useful for:
• titrating antihypertensive therapy
• borderline hypertension
• hypertension detected early in pregnancy
• suspected or confirmed sleep apnoea
• syncope or other symptoms suggesting orthostatic hypotension, where this cannot be demonstrated in
the clinic.


What are the most common pituitary tumors?

The common tumours secrete growth hormone (15%), prolactin (30%), ACTH (15%), gonatroophic (10% - asymptomatic) mixed secretions or no secretion at all.


What is the most common long-term side effect of radiation for pituitary tumors?



What is the role of long acting insulin in type 1 diabetes?

The aim of the basal aspect of insulin administration is to provide a constant level of insulin between meals without increasing the risk of hypoglycaemia, particularly at night (nocturnal hypoglycaemia).


Why is insulin glargine preferred over NPH insulin?

NPH activity peaks 3–5 hours after administration; its duration of action is only 14 ± 3 hours and hence it has to be injected twice daily. With NPH administered at bedtime, peak insulin activity is reached while the glucose levels are low, which increases the risk of nocturnal hypoglycaemia. Nocturnal hypoglycaemia is accepted to be an important barrier to the achievement of optimal glucose control, as users tend to lower the insulin dose to prevent hypoglycaemia.


What is the normal value for urine osmolality?

The normal 24-hour urine osmolality is, on average, 500-800 mOsm/kg of water. 

Random urine osmolality should average 300-900 mOsm/kg of water. 

After 12-14 hours of fluid intake restriction, the urine osmolality should exceed 850 mOsm/kg of water. 


What is the reference range for urine sodium?

The reference range for urine sodium is 40-220 mEq/L/24 hours


Serum osmolality should be higher than urine osmolality.



Which conditions cause low urine osmolality?

    Diabetes insipidus
    Excess fluid intake
    Acute renal insufficiency


Which conditions cause high urine osmolality?

    Syndrome Inappropriate ADH secretion (SIADH)
    Adrenal insufficiency
    High protein diet


How do you differentiate an insulinoma from exogenous insulin administration?

Insulinoma --> high c-peptide and high fasting insulin

Exogenous --> high fasting insulin, low c-peptide


What are the types of cells of the pancreas and what do they secrete?

the A cells (20%) secrete glucagon, 
the B cells (70%) secrete insulin
the D cells (5%) secrete somatostatin or gastrin.
F cells secrete "pancreatic polypeptide."


What are the general features of insulinomas?

Insulinomas are usually benign (about 90%) and secrete excessive amounts of insulin that causes hypoglyce- mia. Insulinomas also produce proinsulin and C-peptide. Insulinomas are solitary in 95% of sporadic cases but are multiple in about 90% of cases arising in MEN 1.


What are the general features of gastrinomas?

Gastrinomas secrete excessive quantities of the hor- mone gastrin (as well as "big" gastrin), which stimulates the stomach to hypersecrete acid, thereby causing hyper- plastic gastric rugae and peptic ulceration (Zollinger– Ellison syndrome). 

About 50% of gastrinomas are malignant and metastasize to the liver. 

Gastrinomas are typically found in the duodenum (49%), pancreas (24%), or lymph nodes (11%). 

Sporadic Zollinger–Ellison syn- drome is rarely suspected at the onset of symptoms; typi- cally, there is a 5-year delay in diagnosis. About 22% of patients have MEN 1. In patients with MEN 1, gastrinomas usually present at a younger age; hyperparathyroidism may occur from 14 years preceding the Zollinger–Ellison diag- nosis to 38 years afterward.


What are the general features of carcinoid tumours?

Carcinoid pancreatic neuroendocrine tumors secrete serotonin and can produce an atypical carcinoid syndrome manifested by pain, diarrhea, and weight loss; skin flushing occurs in 39% of patients. typi- cally indolent but usually metastasize to local and distant sites, particularly to other endocrine organs.


What is a VIPoma?

VIPomas are rare pancreatic neuroendocrine tumors that produce vasoactive intestinal polypeptide (VIP), a substance that causes profuse watery diarrhea and pro- found hypokalemia (Verner-Morrison syndrome).


What are the general features of 



MEN - 2B?

MEn 1: tumors of the parathyroid glands, endocrine pancreas and duodenum, pituitary, adrenal, thyroid; lipomas and facial angiofibromas.

MEn 2a: medullary thyroid cancers, pheochromo-
cytomas, Hirschsprung disease.

MEn 2B: medullary thyroid cancers, pheochromo- cytomas, Marfan-like habitus, mucosal neuromas, intestinal ganglioneuroma, delayed puberty.


What does vasoactive intestinal peptide do?

Smooth muscle relaxation (LES, stomach, GB)
Stimulates water and electrolyte secretion into pancreatic juice and bile
Inhibits gastric acid secretion and absorption
Stimulats enteric smooth muscle contraction
Overall --> increased motility
Stimulates pepsinogen secretion by chief cells


How do you differentiate Graves from thyroiditis on radioactive imaging?

During the hyperthyroid phase, iodine uptake is suppressed, while during the hypothyroid phase, uptake is increased.

This situation contrasts greatly with the elevated iodine uptake found in patients with Graves' disease


What is the most common cause of diminished tendon reflexes?

Diabetic neuropathy


What is the most affected nerve of diabetic autonomic neuropathy?

Diabetic autonomic neuropathy manifests first in longer nerves. The vagus nerve (the longest of the ANS nerves) accounts for ~75% of all parasympathetic activity; as such, even early affects of diabetic autonomic neuropathy are widespread.


What are the factors that contribute to hypoglycaemic unawareness?

a) there may be autonomic neuropathy  Since epinephrine release is a function of the autonomic nervous system, the presence of autonomic neuropathy (i.e., a damaged autonomic nervous system) will cause the epinephrine release in response to hypoglycemia to be lost or blunted. 

b) the brain may have become desensitized to hypoglycemia.   If a person has frequent episodes of hypoglycemia (even mild ones), the brain becomes "used to" the low glucose and no longer signals for epinephrine to be released during such times. More specifically, there are glucose transporters located in the brain cells (neurons). These transporters increase in number in response to repeated hypoglycemia (this permits the brain to receive a steady supply of glucose even during hypoglycemia). As a result, what was once the hypoglycemic threshold for the brain to signal epinephrine release becomes lower. Epinephrine is not released, if at all, until the blood glucose level has dropped to even lower levels. Clinically, the result is hypoglycemic unawareness.

c) the person may be using medicines which mask the hypoglycemic symptoms - i.e. beta blockers


A 30 year old woman presents with a 4cm solitary thyroid nodule - what tests would you do and why?

>1cm is a concerning feature

Start with a serum TSH - if it is a hyperfunctioning nodule it is less likely to be malignant so if TSH is suppressed and it's hot on imaging, less need to worry.

If TSH is normal, then an ultrasound to see if it's cystic or has other concerning features should be considered.


In a 53 woman with suspected pathological fractures and severe osteoporosis on dexa scan whose serum electrophoresis shows decreased Ig but no paraprotein, what should you do and why?

When hypogammaglobulinemia is observed without a coincident paraprotein in the serum, the MLT should investigate the cause of hypogammaglobulinemia. If there is no known cause (immune disorder, chemotherapy, etc) for the patient's lack of antibody production, the lab should request the collection of a urine sample. It is possible that the patient has an overproduction of free light chains that is reducing the production of normal antibodies.  The free light chains may be filtering through the kidneys and therefore, only observed in the patient's urine. The presence of free light chains is a clinically significant finding.


What is the role of demeclocycline in SIADH?

 It is widely used (though off-label in many countries) in the treatment of hyponatremia (low blood sodium concentration) due to the syndrome of inappropriate antidiuretic hormone (SIADH) when fluid restriction alone has been ineffective.[3] Physiologically, this works by reducing the responsiveness of the collecting tubule cells to ADH.


What is the first line treatment for prolactinoma?

Dopamine agonist - usually bromocriptine or cabergoline (however long T1/2, may cause difficulties if low BP as hypotension is an SE)
Dopamine antagonises prolactin and shrinks the tumor in 80% of cases.

Surgery if refractory


What are the symptoms of prolactinoma?

The symptoms due to a prolactinoma are broadly divided into those that are caused by increased prolactin levels or mass effect.

Those that are caused by increased prolactin levels are:[3]

    Galactorrhea (infrequent in men)
    Loss of axillary and pubic hair
    Hypogonadism, gynecomastia, erectile dysfunction (in males)

Those that are caused by mass effect are:

    Bitemporal hemianopsia (due to pressure on optic chiasm)
    Nausea, vomiting


What causes hyperreninaemic hypertension?

Renovascular hypertension


What HLA testing can you do in coeliac disease?

Over 99% of people affected by coeliac disease have the HLA DQ2, HLA DQ8, or parts of these genes. Therefore, a negative test for these genes effectively rules out coeliac disease. The gene test on its own cannot diagnose coeliac disease – only 1 in 30 people who have HLA DQ2 or HLA DQ8 will develop coeliac disease. A gluten free diet should only be started after confirmation of coeliac disease by small bowel biopsy.