Endocrine Flashcards
(101 cards)
1
Q
What is T4, T3, and thyroglobulin?
A
Thyroid hormone biosynthesis
- There are two biologically active thyroid hormones - Thyroxine (T4) and triiodothyronine (T3)
- Composed of a phenyl ring, attached to a tyrosine molecule.
- T4 has 4 iodine atoms attached, whereas T3 has 3 iodine atoms attached.
T4
- Solely a product of the thyroid gland.
T3
- Product of the thyroid and many other tissues.
- Produced from the deiodination of T4
Thyroglobulin
- The thyroid gland contains large quantities of T4 and T3 incorporated within thyroglobulin, a protein within which the hormones are both synthesised and stored.
- This allows for rapid secretion of T4/T3 when necessary.
- Thyroglobulin can also be used as a tumour marker
- Autoantibodies against thyroglobulin (TgAb) are made in Hashimotos disease (and sometimes Grave’s disease)
2
Q
Explain how T4 and T3 is made
A
Iodide is transported into the thyroid follicular cell
In thyroid cells, iodide binds to tyrosine to produce iodotyrosine molecules - this is catalysed by thyroid peroxidase
T4/T3 is created from coupling of iodotyrosine molecules with thyroglobulin.
Proteolysis of thyroglobulin results in release of T4/T3 into the circulation.
3
Q
How to carbimazole and PTU work?
A
Both inhibit thyroid peroxidase - which inhibits the formation of iodotyrosine molecules
PTU also reduces conversion of T4 to T3 in the peripheral tissues.
4
Q
What are the actions of thyroid hormone?
A
Act on virtually every organ system
- cardiac - increase SV, cardiac output, contractility
- muscle - stimulate growth of fast twitch muscle fivers.
- increase the basal metabolic rate
- stimulate growth during childhood.
5
Q
What are the causes of hyperthyroidism?
A
- Graves disease - 80%
- Toxic multinodular goitre - 15%
- Toxic adenoma - 5%
- Thyroiditis - 5%
6
Q
What antibodies cause Hashimoto’s disease and what antibodies cause Graves disease
A
Hashimotos - TPOAb (thyroid peroxidase antibodies) and TgAb (Thyroglobulin antibodies)
Graves - TRAb (Thyroid receptor antibodies)
7
Q
When should you obtain imaging for a patient with hyperthyroidism - and what imaging should you do?
A
In patients who Graves antibodies are not positive (i.e. TRAb) - you should obtain imaging to determine the cause. The imaging you should obtain is a thyroid uptake scan (Tc99 scan)
8
Q
What is Riedels thyroiditis?
A
Very rare autoimmune disease which relates to IgG4 disease - leads to a woody, hard thyroid due to intense fibrosis.
Associated with retroperitoneal, mediastinal and pulmonary fibrosis.
Removal can be very difficult due to the degree of fibrosis.
9
Q
What are the causes of hypothyroidism
A
- Hashimoto’s thyroiditis (80%)
- Iodine deficiency
- Treatment induced (post RAI or thyroidectomy)
- Drugs (amiodarone)
- Post-partum
De-Quervains/Subacute.
10
Q
Talk through the different options with pros and cons for the management of Graves
A
Medical
Pros
- good for Graves opthalmoplegia
- Good for patients who are not good surgical or RAI candidates.
Cons
- can cause side effects such as bone marrow suppression and liver failure.
- can’t be used in malignancy
- can fail/not control the thyrotoxicosis.
- often relapse after cessation.
RAI
Pros
- good for poor surgical candidate
- patients with mild disease/low TRAb titre have a high liklihood of remission.
- good for patients who want to avoid sugery
Cons
- contraindicated in pregnancy and malignancy
- CAN MAKE GRAVES EYE DISEASE WORST
Surgical
Pros
- good for large goitre, suspected malignancy.
- wants to be pregnant in the future
- High TRAb
Cons
- Poor surgical candidate
Avoid during first and third trimester of pregnancy.
Can result in total parathyroidectomy/post-operative hypocalcaemia
- Risk of RLN injury
11
Q
What is thyroid storm, what are the causes and what are the symptoms?
A
- Is an exaggerated form of thyrotoxicosis which can occur in people with hyperthyroidism
- More common in Graves disease
- Precipitants include thyroid surgery, recent use of iodinated contrast, RAI, acute illness, amiodarone.
- Exact pathophysiology is unclear the result is lots of release of thyroid hormone.
- Symptoms are
- Fever
- Tachycardia
- Agitation, delirium, seizures and coma.
- Nausea, vomiting, diarrhoea
Congestive heart failure with pulmonary oedema.
12
Q
What is the treatment of thyroid storm?
A
- Immediate stabilisation
- IV fluids, and Beta blockers
- Carbimazole and PTU - reduces hormone synthesis
- Lugol’s iodine solution (potassium iodide) - for some reason, high doses of iodine inhibit thyroid hormone production. This is known as the Wolf-Chaikoff effect.
- Glucocorticoids
- Cholestyramine - is a bile acid sequestrant and reduces enterohepatic recycling of thyroid hormone.
13
Q
What is a goitre?
A
- Goitre refers to pathological enlargement of the thyroid
- These can be
- Diffuse
- Nodular
- They can be associated with
- Hyperthyroidism (toxic multi-nodular goitre)
- Hypothyroidism
- Can also be
- Benign
- Malignant
- The vast majority of goitres are benign multinodular goitre (in patients which are euthyroid)
Have a female:male ratio of 5:1
14
Q
What is the pathophysiology of goitre
A
- There are two stages of goitre development
- Early stimulus is TSH-mediated hyperplasia generated by iodine deficiency or increased sensitivity to goitrogens.
The second stage is autonomous nodular proliferation due to clonal follicular cell mutations. This is associated with stromal fibrosis and cystic degneration which create structural heterogeneity
15
Q
What is the aetiology of multinodular goitre
A
- Iodine deficiency is the most common cause worldwide - results in thyroid hyperplasia due to TSH ovestimulation
- Goitrogens may also lead to growth - these include thiocyanate found in vegetables like cabbage, Brussel sprouts, cauliflower, turnip etc)
In the USA, where iodine deficiency is rare - the most common causes are multinodular goitre, Hashimoto’s thyroiditis, and Graves disease.
16
Q
What tracheal diameter results in extertional SOB and SOB at rest?
A
Exertional dyspnoea - occurs when the tracheal diameter is < 8mm.
When tracheal diameter is < 5mm - stridor or wheezing can occur at rest.
17
Q
What is the treatment of benign multinodular goitre?
A
Goals of treatment
- Treat thyroid dysfunction if present.
- Decrease size of goitre for patients with symptoms or cosmetic concerns.
- Monitor asymptomatic goitre to determine if it is growing.
Indications for surgery
- Goitre with obstructive/compressive symptoms - this is the main indication for surgery - stridor, SOB, choking sensation.
- Cosmetic swelling
- Retro-sternal goitre - if below the brachiocephalic vein needs removal pending age and fitness, if above needs monitoring.
Other indications
- Toxic multi-nodular goitre not adequately treated by medical therapy.
- Goitre with nodules suspicious for malignancy.
Surgery
- Can be either a total thyroidectomy or hemithyroidectomy (hemithyroidectomy is associated with higher recurrence rates - 20%)
Radioactive iodine
- Can be used for patients with co-morbidities which preclude surgery
Can give radioactive iodine - reduces goitre volume by 50%.
18
Q
What is the history and examination for evaulating a patient with a thyroid nodule?
A
Thyroid nodule/thyroid disorder
History
- Local symptoms and signs
- Systemic symptoms and signs.
- Thyroid status
- Family history
- Risk factors.
- Medications
- Known history of thyroid pathology/surgery
- General health/fitness for surgery.
Local Symptoms
- Solidary, multinodular, or diffuse swelling.
- Painful, painless.
- Gradual, rapidly increasing.
- Midline, lateral neck.
- Airway - SOB, stridor, choking sensation.
- Dysphagia.
- Hoarse voice.
- Symptoms of thoracic inlet obstruction.
Systemic symptoms and signs.
- Hyperthyroidism - increased appetite, weight loss, diarrhoea, palpitation, anxiety, muscle weakness, fatigue, poor sleep, dysmenorrhea, heat intolerance.
- Hypothyroidism - decreased appetite, weight gain, constipation, depression, fatigue, amenhorrhoea.
Local signs
- Goitre
- Solitary nodule, multinodular, diffuse enlargement.
- Fixation, consistency
- Movement with swallowing.
- Lack of movement with tongue protrusion.
- Tracheal deviation.
- Venous Congestion.
- Pemberton’s sign - elevate arms directly upwards. Is positive if face becomes congested and cyanosed at 1 minute. Caused by goitre “corking off” the thoracic inlet.
Systemic signs of hyperthyroidism
- Tachycardia, AF
- Sweatiness
- Facial and palmar flushing.
- Weight loss of weight gain
- Hair loss
- Hyper-reflexia
- Eyes signs - exophthalmos, lid lag, lid retraction.
Signs of hypothyroidism
- Bradycardia, hypotension.
- Myxoedema - dry, pale, cold, rough skin.
- Blunted tendon reflex.
Rough hair
19
Q
When taking a history from a patient with a thyroid nodule - what is your approach
A
- When taking a history can think of “local, systemic and malignancy”
- Ask about symptoms in the neck – lump, how long, has it grown, is it painful/tender, any voice change, difficulty swallowing, SOB and wheeze
- Ask about symptoms of hypo and hyperthyroidism
Ask about risk factors for malignancy
20
Q
What are the risk factors for malignancy of a thyroid nodule?
A
- History of head or neck radiation
- Family history of thyroid cancer – a family history of papillary thyroid cancer is associated with a 4-10x chance of developing it
- Any underlying thyroid disease process
- Low or high iodine intake.
Extremes of age - <20 or > 50
21
Q
What syndromes are associated with thyroid cancer?
A
- MEN2a and MEN2b – mutation in the RET proto-oncogene on chromosome 10 - associated with Medullary thyroid cancer
- APC mutation/Gardeners syndrome - associated with papillary thyroid cancer
- Cowden’s disease (PTEN)
Gardener’s syndrome is a “subtype” of FAP where as well as colonic polyposis, you get extra-colonic growths such as skull osteomas, thyroid cancer, desmoid tumours, epidermoid cysts, fibromas
22
Q
What is the composition of the TIRADS score?
A
Composition
- Cystic lesions are more likely to be benign.
- Solid lesions are more likely to be malignant.
Echogenicity
- Anechoic means “black” or “fluid filled” - which are obviously benign features.
- Dense tissue/tumours absorbs USS waves and doesn’t return them thus are hypo-echoic (same as breast tumours)
Shape
- Taller than wide is more likely to be malignant as it indicates the tissue is not compressible.
Margin
- Smooth margins or ill-defined are more likely to benign.
- Lobulated margins or with extra-thyroidal extension - more likely to be malignant.
Echogenic foci
- Macrocalcifications are more likely to be benign
Peripheral calcifications and punctate echogenic foci correspond with psammoma bodies - which are collections of calcium which can occur in tumours where necrosis has occurred - in particular papillary thyroid cancer
23
Q
What are the size guidelines for FNA and follow up as part of the TIRADS score
A
TIRADS 3
- FNA if >2.5
- Follow if >1.5
TIRADS 4
- FNA if >1.5
- Follow if > 1
TIRADS 5
- FNA is > 1
- Follow if >0.5
24
Q
What lymph node findings on USS are suggestive of malignancy
A
- Microcalcifications/Bright hyper-echoic spots.
- Cystic degeneration
- Round shape
- Loss of the fatty hilum
- Peripheral vascularization
- Hypoechogenicity
Lymph nodes if sampled should be tested for presence of thyroglobulin, if this is positive – the malignancy is highly likely
25
When would you do a nuclear medicine scan for a patient with a thyroid nodule? What are the two different types of scan?
- Should only be done selectively and ONLY if thyroid functions tests are abnormal with a suppressed TSH
- Options are a Tc-99 Pertechnetate scan or radioactive iodine scan - with radioactive iodine being the preferred test.
- Because 5% of thyroid cancers will take up pertechnetate making it a "hot nodule", radioactive iodine scans are preferred.
Normal thyroid tissue won't take up radio-iodide because of the suppressed TSH (where's tissue/nodules under autonomous control will take it up)
26
How should you assess a patient with multiple nodules?
Each nodule should be assessed individually and FNA'd as required
27
Describe the Bethesda classification
Look it up
28
What is the risk of malignancy for each category of the Bethesda system?
Risk of cancer based on Bethesda
1. 10%
2. 3%
3. 20%
4. 30%
5. 70%
100%
29
How should each Bethesda category be managed?
Bethesda 1
- Cytologically inadequate
- Should be repeat FNA - if this is still inadequate then consider core biopsy.
Benign nodules/Bethesda II
- Need a repeat USS - 12-24 months depending on how concerning the USS findings were.
- If the lesion grows by at least 2mm, or it still looks suspicious then repeat the FNA.
- If the second FNA is benign after follow up - can be discharged.
Indeterminate cytology - Bethesda III
- Atypia of uncertain significant/follicular lesion of uncertain significance
- These patients should undergo a repeat FNA initially. If this again shows Bethesda III
* Should proceed to mutation analysis molecular testing. If a likely malignant result is given - need diagnostic lobectomy. If likely benign - then repeat USS in 12 months.
* If mutation analysis molecular testing is not available - should have a diagnostic lobectomy.
Bethesda IV
- Follicular neoplasm/suspicious for a follicular neoplasm
- Should proceed to molecular mutation analysis testing
- Based on molecular testing - can proceed to lobectomy or observation.
Bethesda V and VI
- Should go forward for surgery - thyroidectomy or lobectomy.
NB: In New Zealand we have limited access to molecular testing thus if a FNA shows Bethesda III - repeat it - if still Bethesda III - diagnostic lobectomy.
If it is Bethesda IV - lobectomy.
30
What is the management of an autonomous nodule?
Bethesda 1
- Cytologically inadequate
- Should be repeat FNA - if this is still inadequate then consider core biopsy.
Benign nodules/Bethesda II
- Need a repeat USS - 12-24 months depending on how concerning the USS findings were.
- If the lesion grows by at least 2mm, or it still looks suspicious then repeat the FNA.
- If the second FNA is benign after follow up - can be discharged.
Indeterminate cytology - Bethesda III
- Atypia of uncertain significant/follicular lesion of uncertain significance
- These patients should undergo a repeat FNA initially. If this again shows Bethesda III
* Should proceed to mutation analysis molecular testing. If a likely malignant result is given - need diagnostic lobectomy. If likely benign - then repeat USS in 12 months.
* If mutation analysis molecular testing is not available - should have a diagnostic lobectomy.
NB: In New Zealand we have limited access to molecular testing thus if a FNA shows Bethesda III - repeat it - if still Bethesda III - diagnostic lobectomy.
If it is Bethesda IV - lobectomy.
Bethesda IV
- Follicular neoplasm/suspicious for a follicular neoplasm
- Should proceed to molecular mutation analysis testing
- Based on molecular testing - can proceed to lobectomy or observation.
Bethesda V and VI
Should go forward for surgery - thyroidectomy or lobectomy.
31
What are the histological features of papillary thyroid cancer?
- Orphan-Annie nuclei
* Nuclei with uniform staining (appear empty)
- Nuclear pseudo-inclusions and grooves
- Psammoma bodies
* Calcified remnants of tumour papillae which have infarcted
- Stain positive for thyroglobulin.
Finger like projections (papillae) - fibrovascular cores with epithelial cells on the outside
32
How does follicular thyroid cancer metastasis
Haemotogenous spread (as opposed to lymph nodes seen with papillary)
33
What mutations are seen in papillary and follicular cancer?
BRAF - 60% mutant in PTC
- not seen in follicular cancer
RAS - 15% mutant in PTC
- 40% mutant in follicular cancer
34
What is a Hurthle cell neoplasm and how is it different from a follicular cancer?
- Encapsulated tumour containing more than 75% oncocytic cells (cell with abundant eosinophilic cytoplasm due to the accumulation of mitochondria). Can be malignant or benign – 1/3 are malignant (have vascular or capsular invasion).
- Higher rates of nodal metastasis than other follicular variants thus lymph node dissection can be considered.
- Not as likely to uptake iodine thus less likely to be responsive to radioactive iodine treatment.
More likely to have local recurrence
35
What is the T-staging for differentiated thyroid cancer
T1a - <1cm
T1b - 1-2cm
T2 - 2-4cm
T3a - > 4cm limited to the thyroid
T3b - > 4cm with limited extrathyroidal extension (i.e. into strap muscles)
T4a - invasion into oesophagus, trachea, RLN, larynx
T4b - invasion in to pre-vertebral fascia, encasing carotid artery.
36
What is the N stage for differentiated thyroid cancer?
N1 - level VI or VII metastasis
N2 - lymph node met at any other level
37
What are the principles of treatment for differntiated thyroid cancer?
1. Remove the primary tumour and lymph nodes if necessary.
2. Minimize the risk of disease recurrence and metastatic spread.
3. Facilitate post-operative treatment with RAI, where appropriate.
4. Permit accurate staging and risk stratification of the disease.
5. Permit accurate long-term surveillance for disease recurrence.
Minimize treatment related morbidity.
38
In patients with a 1-4cm thyroid cancer. What factors would push you towards a total thyroidectomy versus a hemithyroidectomy
- The decision is based on three factors
* Need to consider the likelihood of there being residual disease in the other lobe i.e. the other side has to have been adequately imaged and any suspicious nodes FNA'd
* Adjuvant RAI - if this is required, you need to perform a completion thyroidectomy pre-treatment.
* Are they a high risk patient (family history of previous head and neck radiation)
39
When would you perform a completion thyroidecotomy after a hemithyroidectomy in differentiated thyroid cancer?
- Poorly differentiated high grade carcinoma
- Lymphatic or vascular invasion.
Multifocal disease
40
What cases can be considered for a prophylactic central neck dissection in differentiated thyroid cancer?
- Prophylactic neck dissection of the central nodes is recommended in the ATA guidelines (and Uptodate) but it is based on weak evidence.
- Can be considered in
* Patients with involved lateral nodes
* Large tumour (>4cm or extrathyroidal extension)
- Hx of neck radiation of fhx thyroid cancer
41
When should you perform a therapeutic neck dissection in differentiated thyroid cancer?
- Central neck dissection should be performed for patient with clinical metastatic disease.
A lateral neck dissection should be performed for patients who have biopsy proven metastatic lymph nodes.
42
What are the complications of thyroidectomy?
Hypoparathyroidism
- Transient hypoparathyroidism occurs in 20% of patients after total thyroidectomy for thyroid cancer.
- Permanent hypothyroidism occurs in 1-3%.
Recurrent or superior laryngeal nerve injury
- Unilateral paresis of the RLN occurs
* Transiently in 5% of patients
* Permanently in 0.5% of patients.
Other complications
- Horner syndrome
- Tracheal injury
- Oesophageal injury
43
How is RAI given, how does it work, what Undifferentiated thyroid cancer does it not work on, what are the CI, and what are the complications?
- Destroys all thyroid tissue and can only be given after a total thyroidectomy
- Thyroid tissue takes up the radioactive iodine (only tissue to do so), B-particles are emitted which cause cell apoptosis.
- Is not effective for Hurthle cell differentiated follicular cancer – only about 15% of these tumours will take up iodine.
- Is generally safe but is contraindicated in pregnancy, breastfeeding, or planning pregnancy in the next 6 months.
- You generally have to be isolated for a number of days after receiving radioactive iodine.
- It can cause sialoadenitis
44
How is radioactive iodine given?
- In order to do radioactive iodine treatment – you need to have the TSH level high.
- This can be done by either stopping thyroxine treatment a few weeks before OR giving thyrogen (recombinant TSH) when you give the radioactive iodine treatment.
- Using rTSH/thyrogen is easier for the patient - it can be given just before the RAI
- Patients should be put on a low iodine diet.
- Patients usually have a pre-treatment radio-iodide scan.
Usually a post treatment scan is done a 3 days after treatment to confirm there is a reduction in the thyroid tissue.
45
What is the role of a post-treatment radioactive iodine scan?
- This should occur 2-8 days after RAI is given.
- You will be able to observe WHERE the RAI has been taken up - which will thus confirm metastatic disease sites and thus help with staging.
If a metastatic site doesn't take up radio-iodide on this scan - then it is not responsive to RAI and treatment should not be repeated.
46
How do you risk stratify a patient post surgery for DTC to determine if they need RAI?
- There are a number of risk stratification tools but for the exam I will use the ATA risk calculator which looks at the below parameters
* Age
* Gender
* Size
* Invasion - any invasion or gross invasion
* Invasion into RLN, Larynx, Trachea and oesophagus
* Invasion into pre-vertebral fascia.
* Multifocality
* Complete surgical resection
* Lymph node status
* Distant metastasis
* Anaplastic.
Example of a Low risk tumour
- Tumour <4cm
- No vascular invasion.
- Not high grade
- Not a worrisome subtype.
- No lymph nodes
Example of a High risk tumour
- Gross extra-thyroidal extension
- Tumour incompletely excised with gross residual disease
- Multiple lymph nodes >3cm.
- Any evidence of distant metastatic disease.
- Follicular thyroid cancer with extensive vascular invasion (>4 foci)
- Distant metastasis.
Thyroglobulin level suggestive of metastatic disease.
47
What are the goals of RAI?
Remnant ablation
- Is typically 30mCi
- Primary goal is destruction of remnant thyroidal tissue to facilitate staging and follow up studies
- Is minimally used
- There is controversy regarding the role of remnant ablation - this is something which is generally only offered to patients with low risk tumours, which, generally don't benefit from radioactive iodine treatment anyway
Adjuvant therapy
- Is typically 75mCi
- to treat any suspected but not proven metastatic disease (i.e. in a patient with a high risk primary)
Therapeutic
- Is typically 150mCi
patients with known residual or recurrent disease (biochemically or structurally)
48
How do you follow up someone after RAI?
- This involves measurement of thyroglobulin AND imaging (radio-iodide scan for high risk groups, USS for intermediate risk)
- They can then be put into the groups below.
Excellent response to treatment
- Negative imaging (USS or radio-iodide scan)
- Non-stimulated thyroglobulin < 0.2
- Stimulated thyroglobulin level < 1.
Indeterminate response
- Non-specific signs on imaging (USS or radio-iodide scan)
- Non-stimulated thyroglobulin level which is detectable but < 1
- Stimulated thyroglobulin level which is detectable but < 10.
Biochemical incomplete response
- Negative imaging
- Non-stimulated thyroglobulin level > 1
- Stimulated thyroglobulin level > 10.
- Rising anti-thyroglobulin anti-bodies after treatment.
Structurally incomplete response
- Residual disease on USS or radio-iodide scan
With or without elevated thyroglobulin levels.
49
What is the classification of medullary thyroid cancer?
- Sporadic - 75%
- MEN2 associated - 25%
* Occurs due to RET protooncogene mutation which encodes a receptor tyrosine kinase.
MEN2a associated cancer - better prognosis.
50
Things to do when you diagnose a patient with medullary thyroid cancer which relate to MEN2
- Take a family history looking for any MEN associated cancers (i.e. medullary thyroid cancer, pheochromocytomas, parathyroid hyperplasia)
- Plasma metanephrines to look for phaeo
- Check calcium and PTH to look for parathyroid hyperplasia.
Refer for genetic testing for RET mutation.
51
What is the histopathological findings of medullary thyroid cancer and what stains are used for diagnosis?
- The histopathological appearance can be quite variable - thus staining is very important
- They usually appear as round blue cells with increased amyloid deposition (which stains with congo-red)
- Stain positive for calcitonin, CEA, chromogranin, and synaptophysin.
Will not stain for thyroglobulin (as not from follicular cells).
52
What calcitonin level means you should stage the patient
>500
53
What causes MEN1 and what problems does MEN1 result in
- Autosomally dominant inherited mutation in the MEN1 gene which encodes the menin protein– located on chromosome 11.
- Tumour suppressor gene – thus a mutation in the gene means it doesn’t suppress tumours.
Causes pituitary adenomas, parathyroid adenomas, and pancreatic tumours.
54
What are the features of MEN1 associated problems?
Hyperparathyroidism
- Usually multiglandular disease.
- Usually the first manifestation of MEN1
- 40% of patients develop disease by 20 years old. 100% by 50 years old.
- Patients with MEN1 associated hyperparathyroidism are more likely to be younger, have 4 gland disease, and have a higher recurrence rate after subtotal parathyroidectomy.
- Patients need a full neck exploration with a sub-total parathyroidectomy and a thymectomy.
- If they can’t under go surgery – need bisphosphonates and calcimimetic drugs.
Pituitary adenomas
- 50% of patients with MEN1 will develop a pituitary adenoma
- Most are prolactinoma’s – 50%
- Can also get growth hormone secreting, ACTH secreting, and non-functioning tumours.
- To screen for pituitary tumours - do a prolactin level, serum IGF-1 (screens for acromegaly), early morning cortisol, TFTs, and LH/FSH levels.
Pancreatic neuro-endocrine tumours
- 80% will be non-functional - 50% likelihood of malignancy.
- The most common functional tumour is a gastrinoma - Gastrinomas are likely to be malignant.
- Rarely they can get insulinoma’s
- If tumours are < 1cm – usually monitored/surveilled.
- Once > 2cm in size – managed with resection.
Pancreatic tumours are what these patients have the most morbidity and mortality from
55
How do you screen/surveil a patient with MEN1
- Should be offered a program of clinical, biochemical and radiological screening.
Parathyroid
- Annual plasma Ca and PTH
Pancreatic NET
- Annual gastrin, glucagon, VIP, Chromogranin A, insulin levels, and BSL.
- There hasn’t been an optimal radiological program determined – would be institution dependent.
- It would be reasonable to perform a CT or MRI pancreas every 1-2 years.
Pituitary screening
Annual plasma prolactin, IGF-1 levels, Pituitary MRI every 3-5 years.
56
What is the features of MEN2 associated medullary thyroid cancer and phaeochromoma
Phaeo
- 50% of patients will develop a phaeo and it is often bilateral
Medullary thyroid cancer
- most patients with MEN2 will develop medullary thyroid cancer but MEN2a patients develop it at a younger age and it is more aggressive.
- codon subtyping can be done to determine how aggressive the MEN2a subtype - which would determine when patients should have there thyroidectomy.
57
What is FHH? What causes it? and how do you test for it?
- Causes hyper-calaemia with low urine calcium excertion
- Autosomally dominantly inherited mutation for a gene in the calcium sensing receptor expressed in the parathyroid tissue and kidney tissue.
- Because the calcium receptors aren’t sensing calcium, there is an inappropriate amount of PTH release by the parathyroid, and an inappropriate amount of calcium is re-absorbed in the kidney.
- Typically patients are asymptomatic with a high calcium
- Rarely can get symptoms of high ca – weakness, fatigue, thirst, abdominal pain, constipation, pancreatitis, renal stones, bony pain, renal failure.
Biochemically
- High serum calcium with inappropriately normal or elevated PTH
- Low urinary calcium excretion – this is why you do a 24 hour urine
- You also need to make sure the patient isn’t Vitamin D deficient as well as ruling out the use of thiazide diuretics
Medical management of FHH
Calcimimetics – sensitizes the calcium receptor thus reducing PTH excretion and increasing renal calcium excretion
58
What is SDH?
- Genes include SDH A, SDH B, SDH C, and SDH D
- Tumour suppressor genes – thus mutant gene will stop it doing its job
- Typically autosomal dominant mutations
- Cause phaeochromocytomas and para-ganglionoma’s
- Also at risk of developing GISTs
SDH deficient GISTs are less likely to respond to imatinib.
59
What is Carny Stratakis syndrome and Carney triad?
Carney-Stratakis syndrome
- Diad of para-ganglionoma and GISTS
- Are associated with germline mutations in SDH-B, SDH-C and SDH-D.
Carney triad
- GISTS, para-ganglionoma and pulmonary chondroma
These tumours are SDH deficient - although the exact mutation which causes this hasn't been identified.
60
What is VHL?
- Autosomally dominantly inherited mutation in the VHL tumour suppressor gene
- Risk of developing various benign and malignant tumours
Tumours
- Two major endocrine manifestation - phaeochromocytomas and pancreatic NETs
- The incidence of phaeochromocytomas is 25%, of which 30% will be bilateral.
- Haemangioblastoma – can develop in the cerebrum, cerebellum, brain stem, spinal cord, and retina.
- Renal Cell cancer (clear cell RCC)
- Endolymphatic sac tumours in the inner ear
61
When should you test a patient for NF1
- >5 café au lait spots in pre-pubertal years and > 15 café au lait spots in post pubertal years.
- >2 neurofibromas
- Freckling in the axilla or inguinal regions.
- >2 lisch nodules.
- Optic gliomas.
- First degree relative with NFM-1.
62
What does NF1 cause?
- Benign neurofibromas.
- CNS tumours – astrocystomas and gliomas.
- Sarcomas
- GISTS
- Leuakaemia
- Phaeochromocytomas.
63
Explain calcium homeostasis, PTH, and Vitamin D homeostasis?
Intro
- Calcium sensing receptors are located on parathyroid chief cells
- Calcium sensing receptors are also located in the kidney and GI tract.
- PTH is released in a response to a low serum Ca level.
- PTH acts on 3 things
* Bones - osteoclasts
* Kidneys - increases calcium and phosphate reabsorption from DCT
* Gut - increases calcium reabsorption.
Vitamin D
- We get from food and also from sunlight on our skin.
- The first form of vitamin D is cholecalciferol.
- Cholecalciferol is converted by 25-hydroxylase (in the liver) to create 25-hydroxy-vitamin D.
- 25-hydroxy-vitaminD goes to the kidney where it is converted to calcitriol (1, 25, hydrovitamin D3) (by 1-alpha-hydroxylase).
Calcitriol goes to the GIT where it increases the absorption of calcium - this increased calcium uptake from the GIT results in less bone breakdown (thus calcitriol is bone protective and a good treatment for osteoporosis.
64
What are the causes of hypercalcaemia?
Redistributive
* Malignant
- Malignancy associated hypercalcaemia (release of PTHrP, release of Calcitriol, lytic bone mets)
* Non-malignant
- Hyperparathyroidism
- Sarcoidosis – activate Vitamin D
- Tuberculosis – activate Vitamin D
- Adrenal insufficiency
- Endocrine disorders – thyrotoxicosis, Acromegaly, Phaeochromocytomas.
- Prolonged immobilization
Increased intake
- Vitamin D or calcium replacement.
- TPN
Decreased output
- Thiazide diuretics
- Lithium
Familial hypocalciuric hypercalcaemia – germline mutation resulting in reduction in urinary excretion of calcium.
65
What are the symptoms and sequale of hypercalcaemia
Symptoms
- Stones – nephrolithiasis and nephrocalcinosis - as well as polyuria and polydypsia.
- Bones – osteopenia and pathological fractures.
- Abdominal moans – abdominal pain, constipation, peptic ulcers, pancreatitis.
- Psychotic groans – neurocognitive symptoms – fatigue, malaise, depression, memory loss
Calciphylaxis
- Serious but uncommon disease caused by calcium blocking the small vessels of the fat and skin.
Causes painful ulceration of the skin.
66
What is the management of severe hypercalcaemia?
Management of severe hypercalcaemia
- Fluid resuscitate aggressively - aiming for a urine output above 100mls/hour.
- Once intravascular volume has been restored - give a loop diuretic (Frusemide)
- If still hypercalcaemia add bisphosphonates or calcitonin.
* Bisphosphanates will inhibit bone re-absorption thus helping drop serum calcium.
- Glucocorticoids can also be malignancy associated hypercalcaemia. Also increased renal excretion of calcium and reduce GI absorption.
For patients with renal failure or heart failure - requires dialysis.
67
Risk factors and causes for primary hyperparathyroidism?
- Neck radiation
- MEN1 – mutation in the menin gene on chromosome 11. 3P’s – parathyroid hyperplasia, pancreatic NETS, pituitary tumours.
MEN2a – mutation in RET proto-oncogene – 2P’s 1M. Parathyroid hyperplasia , medullary thyroid cancer, phaeochromocytomas
Causes
- Single adenoma - 85% of cases
- Double adenoma - 5%
- Hyperplasia – 10% - all glands are equally abnormal. More likely in familial type.
- Carcinoma - 1% of cases.
68
What is the blood workup for a patient with hypercalcaemia and an elevated PTH
- PTH level
- Calcium level
- Electrolytes and renal function
- Vitamin D (rules out secondary hyperparathyroidism)
- Urine calcium:creatinine ratio to rule out familial hypocalciuric hypocalcaemia
* If elevated do 24 hour urine
You need to have a high PTH with a high or inappropriately normal calcium.
69
What are the indications for surgery for a patient with primary hyperparathyroidism?
- Symptomatic
- Asymptomatic – patients with life expectancy greater than 10 years, serum calcium 0.25mmol/L above upper limit or normal, eGFR < 60ml/min, T-score < 2.5 or previous osteoporotic fracture, nephrolithiasis
70
What are the requirements to perform a MIP?
- Can only be undertaken if you have pre-operatively localized an adenoma with your imaging.
- Have to have two imaging studies which confirm localisation.
71
What imaging is used for parathyroid localisation - what are the advantages and disadvantages?
Neck USS
- also allows evaluation of the thyroid to identify any lesions which need to be dealt with during surgery. Adenomas look large, hypoechoic, with peripheral vascularity and an associated feeding vessel.
- Advantages - inexpensive, fast, and allows imaging of the thyroid, also allows FNA to confirm is PTH is evident in an observed mass.
- Disadvantages - operator depended, cannot detect lesion < 5mm, difficult to image glands in the posterior mediastinum.
Sestamibi scan
- "sestamibi Tc99" is taken up by thyroid and parathyroid. Retained longer in parathyroid gland
- Is the most accurate imaging localisation study with high specificity and sensitivity.
- May not identify 4 gland hyperplasia and multiple adenomas.
- Sestamibi washout may also be delayed in thyroid nodules which can lead to false positives.
- Sestamibi can be combined with CT (SPECT) which gives excellent localisation and improves detection of ectopic glands but many centers to not have this technology available.
4D scan CT scan
- non con, arterial, venous, delayed phase. Should be hyper-enhancing on the arterial imaging and faster washout c/w thyroid gland on venous phase
- CT can also be performed with sestamibi which improves localisation.
- Advantages - allows good anatomical imaging of the neck including retroesophageal and retro-tracheal areas.
- Disadvantages - is a large dose of radiation - >50x that of a sestamibi scan.
MRI
- Not subject to artefact thus very good for re-operative cases.
- Very good at localising ectopic glands
- Not as good at detecting intra-thyroidal parathyroid glands.
- Expensive, patient compliance and issue, cannot detect lesions <5mm.
Selective venous sampling
- Is an invasive modality where the venous drainage of the thyroid is sampled.
- A 2 fold increase in PTH level when compared with serum PTH is considered abnormal
Selective venous sampling can be combined with parathyroid angiography - this examines the internal mammary, thyrocervical trunk, and superior thyroid arteries. The highly vascular parathyroids appear as an oval on angiography.
72
What defines biochemical cure when performing an ioPTH?
- Is useful for when doing a MIP
- PTH only has a short half-life of 5 minutes thus a rapid drop after removal of a gland will indicate that you have removed the adenoma.
- Dual protocol criteria - first sample taken pre incision. Second sample taken 10 mins after excision. Second PTH should be > 50% drop. If not - third sample is taken. If drop still not >50% - do a 4 gland exploration
NB: As well as a >50% drop in the PTH, it should also return to the normal range.
73
What are the reasons for operative failure in parathyroid disease?
1. Inadequate cervical exploration
2. Failure to diagnose or adequately resect multiglandular disease
3. Gland ectopia.
Wrong diagnosis (i.e. FHH)
74
What steps should you take when treating a patient with operative failure in primary hyperparathyroidism?
Steps to take after operative failure.
1. Re-confirm diagnosis - rule out FHH, sarcoidosis, pseudo-hyperparathyroidism.
2. Requirement for curative surgery re-evaluated.
3. If surgery is required - review operative notes.
4. In revision surgery - pre-operative image localisation studies are mandatory. This often includes alternate studies such as 4D-CT and selective venous sampling.
Patients must be made aware of the increased risk of RLN injury, surgical failure, or permanent hypoparathyroidism.
75
What are the causes of secondary hyperparathyoidism?
By far the most common is renal failure?
other causes
- Vitamin D deficiency
- Hypermagnaseamia.
- Osteomalacia
76
What is the pathophysiology of secondary hyperparthyoidism from renal failure?
- As renal failure progresses – impaired re-absorption of calcium in the distal convoluted tubule – low Ca
- Impaired activation of Vit D3 (calcitriol) – reduced GIT Ca absorption
- This results in lowered serum calcium - calcium sensing receptors in parathyroid gland stimulate PTH release.
Parathyroid resistance to fibroblast growth factor 23
77
What are the complications of secondary hyperparathyroidism?
- Osteoporosis and compression fractures
- Pruritis - this significantly improves after parathyroidectomy.
- Metastatic calcification causing PVD, coronary disease, and valvular disease.
Calciphylaxis.
78
What are the consequences of hyperphosphataemia?
- As renal failure progresses, renal phosphate excretion decreases.
- Phosphate binds with free calcium, which lowers the serum ionized calcium and thus stimulates PTH production.
Calcium phosphate deposits in vessel walls
79
What is the medical treatment of secondary hyperparathyroidism?
- Dietary - reduce phosphate in diet.
Treatment of hypocalcaemia - treat Vitamin D deficiency, Calcitriol (absorbs calcium from GIT), oral calcium, and calcimimetics (reduces PTH secretion by binding to parathyroid calcium sensing receptors).
80
What are the indications for surgery in secondary hyper-parathyroidism?
- Failure of medical management - Vitamin D, bisphosphonates
- Intractable bone pain.
- Intractable pruritis
- Fractures
- PTH
>100 if awaiting transplant
81
What is hungry bone syndrome?
- This can occur after surgery for secondary or tertiary hyperparathyroidism
- Occurs because after surgery, there is a sudden drop in PTH, which means bone Ca release stops, leading to severe hypocalcaemia, hypophosphatasemia and hypomagnesaemia.
- Managed with high dose IV calcium replacement
82
What are the signs of hypocalacemia?
- Numbness or tingliness in the distal extremities and around the mouth.
- Chvostek’s sign – tap at the angle of the mandible. Is positive if the facial muscles contract.
- Trousseaus sign – carpo-pedal spasm when a blood pressure cuff is inflated
Tetany, laryngospasm, arrythmias, seizures
83
What is the treatment of hypocaclaemia?
Mild hypocalcaemia (adj ca 1.7-2)
- 2 calcium carbonate tablets (1.25g tabs) TDS
- Vitamin D replacement – 1.25mg-3.75mg cholecalciferol OD or 0.25-1mcg of calcitriol per day.
Severe (adj calcium < 1.7)
- Calcium gluconate – elemental calcium (gluconate as can be given intravenously)
- 1 ampule can be given over 5 minutes into a large vein in an emergency.
- Otherwise given as an infusion over 8-12 hours.
Need to be in a monitored bed
84
What are the issues with pregnancy and hyperparathyroidism?
- Hypercalcaemia is associated with significantly elevated rates of miscarriage.
- Other complications include intra-uterine growth retardation
- Post delivery the mother can develop life-threatening hypercalcaemia because the placental calcium transfer is lost.
- Post term the fetus can develop life-threatening hypocalcaemia from parathyroid gland hypoplasia.
- The diagnosis is usually made on routine screening where hypercalcaemia then elevated PTH is picked up.
- Localisation can be difficult due to the inability to use nuclear medicine scans.
Surgery is usually performed early in the second trimester - either MIP (if able to localise lesion on USS or MRI) OR four gland exploration.
85
How should you take a history from a patient with an adnreanl incidentaloma?
History
- Should focus on:
* Functional symptoms
- Steroid – Cushings – easy bruising, fatigue, weight gain, mood swings, mental fogginess, leg swelling, moon face, central obesity, buffalo hump, thin extremities, acne, purple striations, hypertension, abnormal hair growth, osteoporosis, proximal myopathy.
- Aldosterone – primary hyperaldosteronism – muscle cramps, weakness, resistant hypertension despite multiple agents, hypokalaemia, acidosis, hypernatraemia.
- Catecholamines – phaeochromocytoma – episodes of dizziness, palpitations, headaches, diaphoresis, tremor and anxiety. Can have hypertension, orthostatic hypotension, retinopathy, CHF, elevated BSL
- Very rarely excess sex hormones can be secreted. Infertility, hirsuitism, gynecomastia, male pattern baldness.
* Local symptoms
- Abdominal or back pain, loss of appetite, vomiting.
* Malignancy symptoms
- Weight loss
* Previous history of malignancy i.e. melanoma, breast cancer, HCC.
* Should ask about any previous abdominal imaging.
Any history of MEN2a + MEN2b, VHL, NFM1, familial paraganglionomas.
86
What is the liklihood of malignancy within an adrenal adenoma based on size?
Size of an adrenal lesion and likelihood of malignancy
- < 4cm – 2% risk of malignancy
- 4-6cm – 6% risk of malignancy
>6cm – risk of malignancy is > 25%
87
For management of adrenal incidentalomas, what general rules can you use to guide management with regard to
- size
- HU
- As a rule, an adrenal incidentaloma <4cm with HU <10 and a negative biochemical workup - can be discharged.
- An adrenal incidentaloma between 4-6cm, HU < 10 - can observe.
- An adrenal incidentaloma between 4-6cm, HU > 10 - should resect (regardless of washout)
An adrenal incidentaloma >6cm should be resected as an open procedure.
88
What are the CT findings of a phaeo
- Don’t wash out.
- Have very high HU (>100)
Can have variable appearances due to necrosis, calcifications, degeneration etc.
89
What other imaging modalities can be used for diagnosing a phaeo?
Other imaging which can be used for phaeochromocytoma
* Iodine 131 MIBG scintigraphy scan
- MIBG is a structural analogue of NA which is not taken up by normal adrenal tissue
- MIBG is given and then you do whole body imaging at 24 and 72 hours.
* MRI
* FDG-PET
Dotatate-PET - can be used as it is a form of NET.
90
What is the screening, confirmatory, and localisation tests for Cushings?
Screening test - 1mg Dexamethasone suppression test
- Patient takes 1mg of dexamethasone at 11pm.
- Cortisol level at 8am.
- In general, dexamethasone should decrease the level of cortisol produced.
- If cortisol is elevated, then is positive.
- If positive – need to do a confirmatory test.
Confirm with
Confirmatory test - 24 hour urinary cortisol test
- A normal level excludes the diagnosis.
And alternative to 24 hour urinary cortisol is a late night salivary cortisol
Next steps
Localisation test
- Measure ACTH level (which is produced by the hypothalamus and ectopic tumours)
- If adrenal problem – ACTH level will be suppressed.
- Pituitary or ectopic production – ACTH will be high
High dose dexamethasone test.
- Used to differentiate between a pituitary cause of Cushing's and an ectopic.
- The principle is that high doses of dexamethasone can suppress the pituitary but not the adrenal or ectopic source.
- 8mg of dexamethasone is given
- 8am cortisol taken
- If cortisol is suppressed - likely pituitary - should proceed to MRI pituitary
If cortisol is not suppresed - likely ectopic - needs CT abdomen + chest.
91
Explain the RAAS
Renin-angiotensin-aldosterone system
- Renin release from the JGA is stimulated by
○ Low blood pressure
○ Low sodium delivery to the distal convoluted tubule.
- Action of Renin
○ Converts angiotensinogen to Ang I
○ Further cleavage by ACE in lungs to Ang II
- Angiotensin II
○ Potent vasoconstrictor.
○ Stimulates aldosterone release
- Aldosterone
○ Acts on distal tubule to increase Na+ reabsorption at the expense of K+ and H+
Increased delivery of Na+ to the distal tubule inhibits aldosterone.
92
What is the screening, confirmatory and localisation tests for phaeo?
Screening test
- Plasma metanephrine’s – these are the inactive metabolites of adrenaline and noradrenaline
- Plasma metanephrines include metanephrines, normetanephrine and 5-methoxytyramine.
* Is a highly sensitive test but lacks specificity - which is why you need the urine catecholamines.
Confirmatory test
- 24 hour urinary test – measures adrenaline, noradrenaline, and dopamine.
Localization
- CT abdomen - looking for both adrenal and extra-adrenal phaeochromocytoma. CT is highly sensitive.
- Most phaeochromocytoma are >3cm with density >10HU
- Dotatate-PET (phaeochromocytoma's are a neuroendocrine tumour thus are avid on Dotatate PET). This is rarely required because the majority of phaeo's will be diagnosed on CT.
MIBG scintigraphy - MIBG is a noradrenaline analogue - this has been superceded by Dotatate PET.
93
When you perform germline mutation in a patient with a phaeochromocytoma?
All patients looking for:
- RET
- VHL
- SDH
- NF1
94
What are the important components of per-operative management for a patient with a phaeo?
Indication for surgery
- ALL patients with phaeo due to the risk of sudden death.
Pre-operative management
- Establish on an alpha blocker – titrate up until the patient has postural hypotension and a stuffy nose.
- Tell patients to drink lots of water
- Phenoxybenzamine is generally preferred over doxazocin due to the fact it is long acting.
- If the patient has a persistent tachycardia – then start a beta blocker as well - only do this once the patient is fully alpha blocked.
- Prior to starting a beta blocker, you must be sure the patient is fully alpha blocked (i.e. has a stuffy nose with postural symptoms). The danger of having incomplete alpha blockage, is getting intra-operative adrenergic stimulation causing stroke etc OR having a hypertensive crisis/CHF.
On the day of surgery patients give high doses of IVF and Mg2+
- Intra-operatively – close communication with anesthetist – need to have noradrenaline, phentolamine (alpha blocker), an adrenergic agents for after the tumour is removed. This is because patients can have very labile blood pressures.
The vein should be secured early before manipulating the gland – potentially reduces catecholamine surges during surgery.
95
96
What is the screening, confirmatory and localisation tests for Conn's
Screening test
- Aldosterone:renin ratio – needs to be off spironolactone, ACEI, diuretics, B-blockers - will be high in patients with Conn's.
- Aldosterone:renin ratio > 20-30 - positive test
***Most patients do not need to go onto have a confirmatory test, i.e. the diagnosis can be made based on the aldosterone concentration and aldosterone:renin ratio For borderline cases, you should do a confirmatory test.
Confirmatory test
- Admission for sodium loading test. 2-3L of N saline given over a 3 hours – measure aldosterone level.
- If aldosterone isn’t suppressed – then has primary hyperaldosteronism.
- Alternative is an oral salt loading protocol
- Last alternative test – fludrocortisone suppression test. Can be done where a patient is on lots of anti-hypertensives. 5 day admission where fludrocortisone is given orally every 6 hours along with sodium chloride and potassium. If there is no suppression of aldosterone – primary hyperaldosteronism.
**Fludrocortisone is basically like oral/exogenous aldosterone**
Localisation test
- Most adenomas will be identifiable on CT or MRI.
- Adrenal venous sampling?
97
When can adrenal venous sampling be omitted?
- This can be omitted in patients < 40 years, with marked primary hyperaldosteronism, and a clear unilateral adrenal adenoma with a normal contralateral gland.
This is because young patients are unlikely to have an adrenal incidentaloma.
98
How does adrenal venous sampling work?
- Invasive test where the adrenal blood is sampled from the venous glands bilaterally.
- A catheter is passed through the femoral vein to the adrenal glands on both sides, and aldosterone and cortisol levels are measured after administration of ACTH.
- To confirm you are in the adrenal vein you look at the adrenal vein:IVC cortisol ratio - which should be > 3
- Because on the left side, the left inferior phrenic vein drains in the left renal vein, the concentration of aldosterone between each side is different.
- You thus look at the aldosterone: cortisol ratio - if it is >4 - then this is the affected side.
- Rarely - can result in adrenal infarction.
99
What are the CT findings of an adrenocortical carcinoma?
- CT shows a heterogenous, irregular tumour with area of necrosis and haemorrhage.
- >20 HU on non-con with reduced washout on delayed phase.
Vast majority are >6cm on presentation.
100
What is the T staging of adrenocortical cancer?
Staging
- T1 - tumour < 5cm.
- T2 - tumour > 5cm but confined to adrenal capsule
- T3 - tumour infiltration through adrenal capsule into surrounding tissue.
- T4 - tumour invading into other organs.
- N0 - no positive nodes.
N1 - positive nodes.
101
What score is used to differenitate between a benign adrenal adenoma and adrenal-cortical cancer?
Histopathology
- Pathological diagnosis can be difficult in many cases.
- The Weiss score is used to distinguish between benign and malignant lesions - this looks at 9 parameters.
- Tumours with 4 or more factors - usually are malignant.
Weiss score factors
- Nuclear Grade III or IV
- Mitotic rate >5/50 HPF
- Atypical mitosis.
- Clear cells comprising 25% of tumour or less.
- Diffuse architecture
- Microscopic necrosis.
- Invasion of venous structures
- Invasion of sinusoidal structures
Invasion of capsular structures
