Thyroid Flashcards
Anti-TPO ab is associated with …
Hashimoto thyroiditis
Autoimmune thyroiditis
Highly sensitive and specific
When do we measure anti-TG?
Never
Limited clinical value
TSH receptor ab is associated with …
Grave’s
Highly sensitive and specific
Hypothalamus releases …. –> stimulates anterior pituitary to release …. –> stimulates thyroid gland to release …. –> gets converted to …. –> engages in negative feedback
TRH
TSH
T4
T3
Thyroid hormone in the circulation is 99% bound to…
Carrier protein - mainly thyroxine binding globulins, also transthyridin and albumin
We measure unbound free T4
Where does T4 get converted to T3?
Mostly liver (but also in kidneys, heart, skeletal muscle)
Alemtuzumab used in MS
What’s a major side effect?
Induces autoimmune disease
34% Graves!!
Can occur even years after stopping alemtuzumab (CD52 target monoclonal ab)
How does biotin affect thyroid levels?
Causes spurious thyroid test results
Stop biotin and recheck in 3-4/52
How does amiodarone affect thyroid levels?
Can cause both hypothyroidism and thyrotoxicosis
Most common is hypothyroidism
Very long t1/2 - can take 2 years for it to be eliminated
40% amiodarone by weight is iodine
Type 1: treated with anti-thyroid medication
Type 2: treated with glucocorticoids
May not be able to tell between the two and may have to treat both initially
Thyroid scintigraphy not useful due to high circulating iodine load
Which cancer therapies can affect thyroid?
CTLA4 inhibitor e.g. ipilimumab = hypophysitis (can cause adrenal insufficiency) + central hypothyroidism
PD1 inhibitor e.g. pembrolizumab, nivolumab = primary hypo or hyperthyroidism
How does lithium affect thyroid?
Hypothyroidism + goitre
Thyroid hormone can’t be released from the thyroid colloid –> goitre formation
How does hyperthyroidism increase basal metabolic rate?
Increase synthesis of Na+ K+ ATPase
How does hyperthyroidism increase sympathetic nervous system activity?
Increase expression of B1-adrenergic receptors
Clinical features of hyperthyroidism
Weight loss Palpitations, tachycardia, arrhythmia (AF), increased CO Agitation, anxiety Insomnia Tremor Heat intolerance, sweating Staring gaze with lid lag Diarrhoea Oligomenorrhoea Bone resorption with hypercalcaemia, osteoporosis Decreased muscle mass with weakness Hypercholesterolemia Hyperglycaemia
DDx hyperthyroidism
Grave's Toxic multinodular goitre Toxic adenoma Thyroiditis Drugs (amiodarone, immune check point inhibitors, alemtuzumab) Excess iodine Excess thyroxine Pregnancy related (hyperemesis gravidarum, hydatidiform mole)
Pathophysiology of Grave’s
IgG stimulates TSH receptor –> increased synthesis of thyroid hormone
4 Clinical features of Grave’s
Diffuse goitre (constant TSH stimulation leads to thyroid hyperplasia and hypertrophy)
Thyroid eye disease - bilateral proptosis, periorbital oedema, scleral injection, lid retraction, diplopia, extraocular dysfunction, exopthalmus (most specific for Grave’s)
Pretibial myxedema
Clubbing
Mechanism behind exopthalmus and pretibial myxedema
Not due to hyperthyroidism, but due to ab stimulating TSH receptor
Fibroblasts behind the orbit and overlying the shin express TSH receptor –> TSH activation results in glycosaminoglycan build up, inflammation, fibrosis and oedema
Dough like consistency when pushing on the skin
Labs in Grave’s
High T4, T3
Low TSH
Positive TSH receptor ab
Rx Grave’s
Antithyroid medication - slowly brings down TRAb
Radioactive iodine (iodine taken up by follicle cells then these cells are destroyed by radioactivity)
Thyroidectomy - if someone is very thyrotoxic, need antithyroid medication first to reduce anaesthetic risk
What therapy is contraindicated in thyroid eye disease?
Radioactive iodine - can flare up eye disease
- Transiently release TRAb when follicle cells die which can flare up eye disease
What’s a thyroid storm?
Storm of thyroid hormone and catecholamines
Occurs during times of stress e.g. childbirth, surgery
Presents as arrhythmia, hyperthermia, vomiting, hypovolemia shock
Rx thyroid storm
PTU
B blockers
Steroids
How does PTU work?
Inhibits peroxidase-mediated oxidation, organification and coupling steps of thyroid hormone synthesis, as well as stops conversion from T4 to T3
What 2 things increase the severity of thyroid eye disease i.e. Grave’s opthalmopathy?
Radioactive iodine
Smoking
Disadvantages of radioactive iodine
Slower onset of effect 6-8 weeks Permanent hypothyroidism Can exacerbate ophthalmopathy Don't use in suspected or confirmed thyroid malignancy Don't use in pregnancy
Adverse effects of anti-thyroid medications
Usually well tolerated
Common: GI effects, rash (exclude vasculitis), arthralgia, fever, transient mild neutropenia
Rare: agranulocytosis, cholestatic hepatitis, hepatocellular liver injury, ANCA positive vasculitis, polyarthritis
Need baseline FBC, LFTs
If fever, mouth ulcers, infection then must exclude agranulocytosis
What’s a multinodular goitre?
Enlarged thyroid gland with multiple nodules due to iodine deficiency
Usually non-toxic (euthyroid)
Rarely, can be toxic (produce T4 independent of TSH)
How do differentiate between Grave’s vs thyroid multinodular goitre vs toxic adenoma?
Thyroid antibodies and thyroid uptake scan
Grave’s: positive TSH receptor ab, mildly positive TPO ab, diffuse thyroid uptake/uniform uptake on scan
TMN: negative ab, normal or elevated multifocal uptake with suppression of surrounding thyroid
Toxic adenoma: negative ab, elevated focal uptake (>3cm) with suppression of surrounding thyroid
Clinical features of hypothyroidism
Myxedema (accumulation of glycosaminoglycans in the skin and soft tissue, can deposit in the larynx and cause a deep voice, large tongue)
Weight gain
Cold intolerance
Slowing of mental activity
Muscle weakness
Bradycardia + decreased CO (SOB, fatigue)
Oligomenorrhoea
Hypercholetserolaemia
Constipation
DDx primary hypothyroidism
Hashimoto’s thyroiditis (most common)
Iodine deficiency (common)
Post-radioiodine therapy
Post thyroidectomy
Subacute thyroiditis or any form of thyroiditis
Drugs - amiodarone, lithium, immune checkpoint inhibitors, anti-thyroid medication
Neck irradiation
Riedel’s thyroiditis (rare)
Thyroid infiltration (tumour, amyloid) (rare)
Congenital hypothyroidism (rare)
Pathophysiology behind Hashimoto’s thyroiditis
Autoimmune destruction of the thyroid gland
Associated with HLA-DR5
Initial hyperthyroidism (due to follicle damage, and all the thyroid hormones leak out) –> euthyroid –> hypothyroidism with reduced T4 and increased TSH
Labs in Hashimoto’s thyroiditis
Positive TPO ab (very sensitive and specific)
Low T4, high TSH
Hashimoto’s thyroiditis is associated with what condition?
Marginal zone lymphoma
How does subacute granulomatous (De Quervain) thyroiditis present?
After a viral infection
Tender thyroid with transient hyperthyroidism
Self limiting. Rarely progresses to hypothyroidism.
How does Riedel fibrosing thyroiditis present?
Chronic inflammation with extensive fibrosis of the thyroid gland
Hypothyroidism
“hard as wood” non-tender thyroid
May extend to surrounding structures eg. airway
When to order a thyroid US?
When they have palpable abnormalities of the thyroid
What’s subclinical hyperthyroidism?
Low TSH
Normal T4, T3
Can occur when you first start antithyroid medication as TSH has a longer half life
Should you treat subclinical hyperthyroidism?
Subclinical hyperthyroidism can be associated with CV disease (AF, CCF, CAD), bone loss, fractures, dementia, particularly in persons >65 with severe disease
Data lacking but should probably treat age >65, especially if TSH <0.1. Definitely treat if both.
What’s subclinical hypothyroidism?
High TSH
Normal T4, T3
Transient - recovering from other illness, poor adherence to thyroxine, malabsorption of thyroxine, drugs (amiodarone, lithium)
Persistent - normal ageing, obesity, TSH or TRH resistance (rare), adrenal insufficiency (rare)
Should you treat subclinical hypothyroidism?
TSH increases with age
TSH <10: no treatment unless convincing signs of hypothyroidism (not just fatigue, weight gain)
TSH >10: treat but careful in those age>70 due to risk of OP, CV disease, dementia if TSH becomes too low
What’s secondary hypothyroidism?
Low TSH (<10) Low T3, T4
Central hypothyroidism - coming from the pituitary or hypothalamus
OR
Non-thyroid illness (sick euthyroidism)
What’s non-thyroid illness (euthyroidism)?
In severe illness, get functional central hypothyroidism with fall in TSH and T4
What’s secondary hyperthyroidism?
Normal/high TSH
High T4, T3
DDx secondary hyperthyroidism
TSH secreting pituitary adenoma
Resistance to thyroid hormone (reduced responsiveness of target tissue to thyroid hormone)
Thyroxine replacement
Drugs e.g. amiodarone
How to take a biopsy from a thyroid nodule?
FNA
Name the 4 types of thyroid carcinoma
Papillary carcinoma
Follicular carcinoma
Anaplastic carcinoma
Medullary carcinoma
Most common type of thyroid carcinoma?
Papillary carcinoma 80% of cases
Prognosis of papillary carcinoma
Excellent prognosis
10 year survival is >95%
Often spreads to cervical lymph nodes
Why can’t we do FNA for suspected follicular carcinoma?
Invasion through the capsule is what distinguishes follicular adenoma from follicular carcinoma
Entire capsule must be examined
FNA will only examine cells and not the capsule
How does follicular carcinoma metastasise?
Spreads haematogenously (this is an exception as carcinomas tend to spread to lymph nodes)
What is a follicular carcinoma?
Malignant proliferation of follicles surrounded by fibrous capsule with invasion through the capsule
What’s a medullary carcinoma? What biochemical changes does it typically produce?
Malignant proliferation of parafollicular C cells (sits adjacent to the follicles)
C cells secrete calcitonin –> lowers serum calcium by increasing renal calcium excretion (inactive at normal physiological levels)
What familial disorders is medullary carcinoma ssociated with?
MEN 2A and 2B
What does it mean to have a RET mutation?
Associated with MEN2 syndrome
If you inherit the mutated RET gene from an affected parent, there is almost a 100% chance of developing medullary thyroid cancer and lower probabilities of developing other features of this syndrome during his or her lifetime.
Hence you would need a prophylactic thyroidectomy
What conditions are associated with MEN2A and 2B?
MEN2 results in medullary carcinoma, pheochromocytoma, parathyroid adenoma (2A) or mucosa neuromas of the oral/GI mucosa (2B)
Which type of thyroid carcinoma has the worst prognosis?
Anaplastic carcinoma
Seen in the elderly
Often invades local structures - oesophagus (dysphagia), lungs (respiratory compromise)
Who does anaplastic carcinoma present?
Similar to Riedal thyroiditis
“hard as wood” non-tender thyroid
What is gestational transient hyperthyroidism and how does it happen?
BHCG looks similar to TSH and binds to TSH receptor –> hyperthyroidism
Occurs when BHCG is the highest (peaks 10-12 weeks). Generally resolves after 15-20 weeks.
More likely if twin or molar pregnancy with high BHCG or when there is hyperemesis gravidarum
Generally less severe than Graves with no eye signs or large goiter, and self limiting.
What is the most important reason to measure thyroid stimulating antibodies in the third trimester of pregnancy in a woman with Graves disease?
Maternal TSH receptor ab can go to the foetus and cause neonatal grave’s disease.
Neonatal hyperthyroidism is more likely when the maternal TSHR-ab activity is >500% ULN.
Warrants dose increase of anti-thyroid medication.
What corrects mortality in Graves?
Definitive treatment - Radioactive iodine only
Not anti-thyroid medication
What’s Pemberton’s sign?
Pemberton’s sign is used to evaluate venous obstruction in patients with goiters. The sign is positive when bilateral arm elevation causes facial plethora. It has been attributed to a “cork effect” resulting from the thyroid obstructing the thoracic inlet, thereby increasing pressure on the venous system.
FT3>FT4 in Graves
True or false
True
When to stop antithyroid medication in Graves?
Elevated TRAb 80-10% relapse
Low or undetectable TRAb 20-30% relapse
Which eye sign is most specific for Grave’s orbitopathy?
Exopthalmus
Which extraocular muscle is mostly commonly involved in Grave’s orbitopathy?
Inferior rectus
Treatment Grave’s orbitopathy
Mild: selenium
Moderate-severe: IV methylprednisolone, orbital radiotherapy, consider steroid sparing treatments CSA, MMF, RTX, IgG, teprotumumab, orbital decompression
Vision threatening: IV methylprednisolone –> orbital decompression
Orbital decompression is only done in inactive disease
Which thyroid condition can be cured?
Subclinical hyperthyroidism
If there is a nodule that’s releasing TSH –> wait for T3 to rise up so most of the thyroid won’t be releasing TSH –> do radioactive iodine to target nodule –> cure
Treatment hypothyroidism in pregnancy
TSH ≥4
However TABLET trial showed no difference in miscarriage and delivery outcomes
Treatment hyperthyroidism in pregnancy
Grave’s
HCG-mediated hyperthryoidism
Both PTU and Carbimazole cross placenta and may be associated with birth defect
PTU in 1st trimester then carbimazole in 2nd/3rd trimester
Is serum TG/TGab usefulin evaluating thyroid nodules?
No
Clinical and USS findings associated with an increased risk of thyroid cancer
Focal uptake of 18-FDG by the thyroid
Rapid growth of the nodule
New onset hoarseness of voice (invade into RLN and paralysis of VC)
Dysphagia (however big benign nodule can do this)
Serum calcitonin >50-100pg/ml
USS Microcalcification Nodule hypoechogenicity compared with surrounding thyroid/muscle Irregular margins Taller than wide on a transverse view
Cystic = lower risk
What’s a points system for USS findings to predict risk of malignancy in thyroid nodule?
2017 ACR TI-RADS
Thyroid cancer therapy
For metastatic differentiated thyroid cancer that are radioiodine refractory
Targeted thyroid cancer treatment
Lenvatinib
Vandetanib
Sorafenic/pazopanib/sunitinib
RET proto-oncogene
Why is it important?
Associated with more aggressive medullary thyroid cancer
Selpercatinib - at very low concentration, is 250x selective for RET proto-oncogene
This is groundbreaking treatment
