Week 3 Flashcards
What is the difference between a primary and secondary thyroid disease?
Primary thyroid disease affects the thyroid gland itself. Can occur with or without goitre, and is most commonly autoimmune in origin
Secondary thyroid disease affects the hypothalamus or the pituitary gland, without thyroid involvement.
Describe the Hypothalamic-Pituitary-Thyroid Axis
Thyrotrophin Releasing Hormone (TRH) is released from the Hypothalamus, and acts on Pituitary gland.
This causes release of Thyroid Stimulating Hormone (TSH), aka Thyrotropin, from the Anterior Pituitary, which acts on the Thyroid gland to release T4 (Thyroxin, 80% of hormone secreted) and T3 (Levothyroxine, remaining 20%)
Only T3 is active, T4 needs to be de-iodinated in the Liver to T3
T4 and T3 then have a negative feedback effect on the Pituitary and the Hypothalamus
How would TSH and T3/T4 levels appear in Primary Hypo/Hyperthyroidism?
Primary Hypothyroidism
- TSH - high
- Free T3/T4 - low
Primary Hyperthyroidism
- TSH - low
- Free T3/T4 - high
How would TSH and T3/T4 levels appear in Secondary Hypo/Hyperthyroidism?
Secondary Hypothyroidism
- TSH - Low or ‘normal’
- Free T3/T4 - Low
Secondary Hyperthyroidism
- TSH - High or ‘normal’
- Free T3/T4 - High
What is myxoedema?
In what condition is Pretibial myxoedema (rarely) seen?
Myxoedema, or myxoedema coma, is a severe hypothyroidism and is a medical emergency
Pretibial myxoedema is a rare clinical sign of Grave’s Disease (i.e. autoimmune hyperthyroidism)
What are some of the causes of Primary Hypothyroidism? Both goitrous and non-goitrous, be sure to get the most common causes!
Goitrous
- Chronic Thyroiditis (Hashimoto’s Thyroiditis)
- Iodine deficiency
- drug induced e.g. amiodarone, lithium
- maternally transmitted
Non-goitrous
- Atrophic Thyroiditis (same as Hashimoto’s but no goitre)
- Post-ablative therapy
- Post-radiation therapy
- congenital developmental defect
Self-limiting
- following the withdrawal of antithyroid drugs
- post-partum thyroiditis (weeks/months following childbirth)
Generally, what could cause Secondary Hypothyroidism?
Any disease of the Hypothalamus or Pituitary, of which there are many
- Infiltrative
- Infectious
- Malignant
- Traumatic
- Congenital
- Cranial radiotherapy
- Drug induced
What is Hashimoto’s Thyroiditis? What is it characterised by?
Most common cause of hypothyroidism in the Western World
Autoimmune destruction of the thyroid gland and reduced hormone production
Often a family history, women more affected than men
Characterised by:
- antibodies against thyroid peroxidase (TPO)
- T-cell infiltrate and inflammation
What are some of the clinical features of Hypothyroidism?
Hair and Skin
- course hair
- dull, expressionless face
- periorbital puffiness
- pale cool skin, doughy to the touch
- vitiligo
- hypercarotenaemia
Thermogenesis
- cold intolerance
Fluid retention
- pitting oedema
Cardiac
- reduced heart rate
- cardiac dilatation
- pericardial effusion
- worsening of heart failure
Metabolic
- hyperlipidaemia (xanthelasma may be seen)
- decreased appetite/weight gain
GI
- constipation
- megacolon and intestinal obstruction
Respiratory
- deep, hoarse voice
- macroglossia
- obstructive sleep apnoea
Neurological
Gynae/reproductive
What does the thyroid auto-antibody profile look like for…
- Grave’s Disease?
- Autoimmune hypothyroidism (Hashimoto’s)?
Grave’s
- Anti-TPO antibody - 70-80% are positive
- Anti-thyroiglobulin antibody - 30-50% are positive
- TSH receptor antibody - 70-100% are positive
Autoimmune Hypothyroidism
- Anti-TPO antibody - 95% are positive
- Anti-thyroiglobulin antibody - 60% are positive
- TSH receptor antibody - 10-20% are positive
Hypothyroidism - treatment
Normal metabolic rate should be restored gradually, rapid restoration could lead to cardiac arrythmias
Main treatment is levothyroxine (T4)
- younger patients are started at 50-100 micrograms daily
- in older patients with a history of IHD, start at 25-50 micrograms and review every four weeks
- check TSH 2 months after any changes in dose. Once stable, check TSH every 12-18 months
When is levothyroxine best taken?
What are the benefits of taking both T4 and T3?
How does the dosing change in pregnancy?
T4 is preferrably taken prior to breakfast.
No benefit seen in combining treatments of T4 and T3
Dose requirements may increase by 25-50% during pregnancy
(Calcium supplements and PPIs should also be avoided as these can interfere with the action of levothyroxine)
Myxoedema coma - findings and treatment
Findings
- ECG - bradycardia, low voltage complexes, varying degrees of heart block, T wave inversion, prolongation of the QT interval
- Type 2 respiratory failure
- Co-existing renal failure is seen in 10% of patients
Treatment
- Intensive care - A B C!!!
- Passively rewarm, aiming for a slow rise in body temperature
- Cardiac monitoring for arrthythmias
- Broad spec. antibiotics
- Thyroxine cautiously
What is the difference between Thyrotoxicosis and Hyperthyroidism?
Thyrotoxicosis - the clinical state of the body’s tissues being exposed to excessive amounts of thyroxin
Hyperthyroidism - refers specifically to conditions of overactivity in the thyroid, resulting in thyrotoxicosis
Thyrotoxicosis (hyperthyroidism) - signs and symptoms
Cardiac
- palpitation, AF
- very rarely, cardiac failure
Sympathetic
- tremors
- sweating
CNS
- Anxiety, nervousness, irritability etc.
GI
- frequent, loose bowel movements
Vision
- lid retraction
- double vision
- Proptosis (bulging eyes)
Hair and Skin
- brittle, thin hair
- rapid fingernail growth
Reproductive
- menstrual cycle changes
Muscles
- muscle weakness
Metabolism
- weight loss, despite an increase in appetite
Thermogenesis
- intolerance to heat
What are some of the causes of Thyrotoxicosis associated with Hyperthyroidism?
Excessive thyroid stimulation
- Grave’s disease - by far the most common
- Hashitoxicosis - initial hyperthyroidism before long term hypothyroidism
- Thyrotropinoma (THSoma, very rare)
- Thyroid cancer
Thyroid nodules with autonomous function
- Toxic solitary nodule
- Toxic multinodular goitre
What are some of the causes of Thyrotoxicosis not associated with Hyperthyroidism?
Thyroid inflammation
- Subacute (de Quervian’s) thyroiditis
- Post-partum thyroiditis
- drug induced thyroiditis (e.g. amiodarone)
Exogenous thyroid hormones
- Over-treatment with levothyroxine
- Thyrotoxicosis factitia (self-poisoning, mental health related)
Ectopic thyroid tissue
- Metastatic thyrooid carcinoma
- Struma ovarii
Who gets Graves’ disease? What are the TSH and free T3/T4 profiles like?
Women more commonly than men (2:1)
Younger people (age 20-50)
Genetic susceptibility. Sisters and children of women with Graves’ have a 5-8% risk of developing an autoimmune thyroid disease
Smokers - makes Graves’ harder to treat and the disease is a worse form
TSH is low, free T3/T4 is high
What antibody test can be done if Graves’ is suspected?
TSH Receptor Antibody (TRAb) - 70-100% are positive
No need to image thyroid if TRAb is positive
What obvious clinical signs may be seen on inspection in patients with Graves’?
And on auscultation?
What other condition is very noticeable on inspection and could feature in Graves’?
Pretibial myxoedema
Finger clubbing
Thyroid bruits (very rare), only heard in very large goitres
Graves’ Eye Disease (aka thyroid eye disease) - seen in 20% of Graves’ patients
How is Thyroid Eye Disease graded and treated?
Graded with a clinical activity score (CAS, Mourits)
Mild disease is treated with topical lubricants
More severe disease is treated with steroids or radiotherapy. Surgery to decompress can also be used
In which group does nodular thyroid disease more commonly occur? How does it present?
What tests are done to confirm the diagnosis?
Typically presents in older patients
Thyroid may feel nodular, and an asymmetric goitre may be apparent
Tests
- Free T3/T4 is raised - NB, if this is extremely high then Graves’ disease is more likely
- TSH is lowered
- Classically is TRAb negative (unlike Graves’)
- Thyroid ultrasound can be done to confirm
Thyroid storm is a medical emergency! What might you see?
How do you treat it?
Severe hyperthyroidism
Respiratory and cardiac collapse - may require mechanical ventilation
Hyperthermia
Exaggerated reflexes
Typically seen in hyperthyroid patients with an acute infection/illness, or recent thyroid surgery
Treatment
- ABC
- iodine
- glucocorticoids
- propylthiouracil (PTU) - blocks thyroid hormone production and conversion of T4 to T3
- beta blockers
- fluids and monitoring
Name some anti-thyroid drugs (ATDs).
What is their mechanism of action?
Carbimazole
- 1st line, once daily dosing
- lower rate of side effects compared to PTU
Propylthiouracil (PTU)
- 1st line if the patient is in the 1st trimester of pregnancy, twice daily dosing
- 10 times less potent than carbimazole
What are the side effects associated with ATDs?
Generally well-tolerated
1-5% develop an allergic rash
Rarely can cause cholestatic jaundice, raised liver enzymes and fulminant hepatic failure
Very rarely can cause Agranulocytosis, resulting in an increased risk of infection - 01.-0.5% of patients, and ATDs cannot be used again. Risk is highest in the first 6 weeks
Other than ATDs, what can be used to treat hyperthyroidism?
Beta blockers
- reduce the activity of the sympathetic nervous system
- Propranolol is the main one
- only used for immediate symptomatic relief of thyrotoxic symptoms
Radioiodine
- 1st choice in relapsed Graves’ disease and nodular thyroid disease
- contraindicated in pregnancy
- can cause flares in Graves’ eye disease, also high risk of hypothyroidism in Graves’
Thyroidectomy
- when radioiodine is contraindicated
- could cause RL nerve palsy/hypothyroidism/hypoparathyroidism
What are some of the possible causes of inflammation of the thyroid?
De Quervian’s (viral)
Hashimoto’s
Post-partum
Drug-induced (amiodarone, lithium)
Radiation
Acute suppurative thyroiditis (bacterial)
How can amiodarone affect the thyroid?
Amiodarone inhibits the conversion of T4 to T3 in approx. 50% of patients (raised T4, low T3, TSH normal)
Hypothyroidism occurs in 13%
Hyperthyroidism occurs in 2%
What is “Sick Euthyroid Syndrome”?
Commonly seen in the unwell, hospitalised patient
Refers to the impact of severe illness on the HPT axis
TSH is initially suppressed, and then rises on recovery
Checking TFTs in unwell patients is pointless, unless the cause of their illness is thyroid-related
What hormones are secreted by the Thyroid Gland?
What hormones are secreted by the Parathyroid Glands?
Thyroid
- T4, Thyroxine
- T3, Tri-iodothyronine
- Calcitonin
Parathyroid
- Parathyroid Hormone (PTH)
At what vertebral levels can the Thyroid be found?
5th cervical - 1st thoracic
What is found within a follicle of the Thyroid Gland?
Follicular cells - circle around the edge of the follicle
Colloid - tyrosine-containing thyroglobulin filled spheres
(Parafollicular cells - found on the outside of the follicles, secrete calcitonin)
Very briefly describe the path of T3 and T4 from their synthesis to their excretion into the bloodstream
Thyroglobulins (precursor to T3 and T4) are synthesised within the thyroid follicular cell and then exocytosed into the colloid
After some changes, the thyroglobulin then undergoes pinocytosis, meaning that it is endocytosed back into the follicular cell
Following proteolysis, T4 and T3 are liberated and are then passed into the blood.
What’s the difference between T3 and T4
T4 (thyroxine) is approx. 90% of all thyroid hormone secreted, and is converted into T3 in the Liver and Kidneys
T3 (tri-iothyronin) is the active form of the hormone and makes up the remainder
T3 is approximately 4 times more potent than T4
T4 and T3 are hydrophobic and lipophylic, so bind readily to plasma proteins. Which ones do they bind to?
Thyroxine-binding globulin (TBG) - 70%
Transthyretin (TTR) - approx 20%
Albumin - 5-10%
What are the effects of Thyroid hormone on Basal Metabolic Rate (BMR)?
The presence of thyroid hormones increases the BMR (therefore, hyperthyroidism = weight loss, hypothyroidism = weight gain)
- increases the number and size of mitochondria
- increases oxygen use and the rate of ATP hydrolysis
- increases the synthesis of respiratory chain enzymes
- increases thermogenesis
How do thryoid hormones affect the responsiveness of adrenaline and noradrenaline?
What drug class is needed as a first line in patients with hyperthyroidism as a result?
Thyroid hormones increase the number of receptors for adrenaline and noradrenaline.
Beta-blockers (Propranolol) are needed as a first line to treat initial symptoms of hyperthyroidism
What kind of receptor is the TSH receptor?
G-protein coupled receptor
What subfamily of enzymes helps to regulate the activation and deactivation of thyroid hormones?
The Deiodinase subfamily (1-3)
- Type 1 - commonly found in the liver and kidney
- Type 2 - found in the heart and skeletal muscle, CNS, fat, thyroid and pituitary. This is responsible for most of the biological effects
- Type 3 - found in fetal tissue and placenta, and brain
What are the two Thyroid Hormone Receptor Isoforms, and where are each mostly found in the body?
Will defects in these receptors affect the Thyroid feedback loop?
Thyroid hormone receptor alpha - expressed mostly in the brain
Thyroid hormone receptor beta - expressed elsewhere: heart, bone, liver, CNS etc.
Defects in the alpha receptor will lead to “central thyroid resistance” and defects in the feedback loop
Defects in the beta receptor will preserve the feedback loop, but there will be features of severe hyperthyroidism
A patient has presented to you with a lump in their neck! What are the possibilities?
95% are benign - 5% of all women will present with a neck lump within their lifetime
5% are malignant
- 80% of these are papillary thyroid carcinomas
- Follicular thyroid carcinoma
- Medullary thyroid carcinoma
- Lymphoma
- Anaplastic carcinoma
What quick clinical test can be done to determine whether or not a lump is within the thyroid?
Does it move on swallowing? If yes, then it’s in the thyroid
What are the 6 important points (2/2/2) to consider when diagnosing a lump in the neck?
History
- any history of neck irradiation?
- family history of thyroid cancer?
Examination
- any lymph node swelling? If yes, papillary carcinoma until proven otherwise
- any hoarseness? If yes, could suggest RL nerve involvement
Investigation
- test TSH - will be normal in 97% cases but if suppressed could mean solitary toxic nodule, or if raised could indicate autoimmune thyroiditis
- ultrasound-guided fine-needle aspiration (USS-FNA)
Following USS-FNA, what are the 5 possible classifications of the findings, and what does each mean?
Thy1 - inadequate, no cells just blood
Thy2 - benign
Thy3 (a/f) - atypical, 30% chance of being malignant
Thy4 - probably malignant
Thy5 - malignant
What are the treatment options for Low risk and High risk groups regarding thyroid cancers?
Low risk - thyroid lobectomy
High risk - (T3 or greater in the TNM classification) - total thyroidectomy, or consider radioactive iodine treatment
Okay, so I’ve got a lump in my neck and it’s benign, great! But what could it be?
Cyst
Colloid nodule
Benign follicular adenoma
Hyperplastic nodule
Where are T4 and T3 stored in the thyroid until they are ready to be released?
Stored in the colloid
What conditions would a loss-of-function mutation in Luteinising Hormone Receptor result in?
How is this inherited?
What kind of receptor is the Luteinising Hormone Receptor
Familial hypogonadism
Leydig cell hypoplasia (males)
Primary amenorrhoea (females)
Autosomal recessive
It is a GPCR
Why can GH not be accurately measured from a single random measurement?
What can be measured instead to give an indication of GH levels?
GH secretion is pulsatile, so both high and low levels can be considered normal
IGF-1 is continuously produced and released by the liver in response to GH, so might give an indication to the HPA axis function
Describe the release pattern of testosterone.
When is it at its highest?
Diurnal variation (like cortisol)
Highest in the morning, so if wanting to take a measurement it’s best to do so before 9am
What cells release prolactin?
What inhibits this?
Lactotroph cells of the anterior pituitary release prolactin, and this release would be constant if it weren’t for the inhibitory effects of dopamine
How does the release of prolactin differ to that of other hormone axes, with regards to inhibitory feedback?
Prolactin has an inhibitory feedback effect on the pituitary, but a positive stimulatory effect on the hypothalamus
Cortisol stimulation/inhibition tests are used to determine if a patient has either Addison’s or Cushing’s
Which test is done for each?
Addison’s - synacthen stimulation test - challenge with ACTH to see if Cortisol is produced
Cushing’s - dexamethasone suppression test - give high dose dexamethasone at night and measure Cortisol levels the next morning, should be reduced. If this is positive, confirm with a second low-dose dexamethasone test
So a patient presents with high Cortisol levels and you diagnose Cushing’s - how do you determine the cause?
Measure ACTH
ACTH low = adrenal is likely origin
ACTH high = need to distinguish if Cushing’s disease (i.e. pituitary cause) or if ectopic source. Done via CRH test - if both cortisol and ACTH rise this indicates that the pituitary is the cause
A surge in what hormone triggers ovulation?
LH
What are the following hormones produced by?
- oestradiol
- progesterone
Oestradiol - produced by the follicle (and also the placenta)
Progesterone - produced by the corpus luteum (and also the placenta)
In an expecting mother who has previously been diagnosed with hypothyroidism, how does her dose of levothyroxine change during pregnancy?
Unable to compensate for increased demand, so increase thyroxine dose by 25 mg as soon as pregnancy is suspected
How can untreated hypothyroidism affect a pregnancy?
Increased abortion
Pre-eclampsia
Abruption
Postpartum haemorrhage
Preterm labour
Negative effects on foetal neuropsychological development
How can hyperthyroidism affect a pregnancy?
Infertility
Spontaneous miscarriage
Stillbirth
Thyroid crisis in labour
How can you distinguish between hyperemesis gravidarum (prolonged vomiting) and hyperthyroidism?
Hyperemesis gravidarum will exhibit raised hCG and lowered TSH
Wait and see (with supportive management) - hyperemesis will settle by itself eventually (although Grave’s may also do so)
Only treat if persisting past week 20
Which antithyroid drugs can be used during pregnancy and when?
Propylthiouracil during the first trimester
Carbimazole during the second and third trimesters
What thryoid-associated antibodies should be checked for during pregnancy, ideally in the 3rd trimester?
Why?
TRAb - if present, alert a neonatologist
TRAb antibodies can cross the placenta and cause neonatal transient hyperthyroidism
What kind of thyroid-related pathology may develop in the mother following delivery?
Post-partum thyroiditis
Transiently thyrotoxic and hypothyroid, up to 1 year post-partum
25-50% will persist as hypothyroidism after 1 year
How common is malignancy in the thyroid?
What are the different types of thyroid malignancy and which is most common?
Quite uncommon - 95% of all thyroid lumps are benign
Papillary thyroid carcinoma - 76%
Follicular thyroid carcinoma - 17%
Medullary thyroid carcinoma - 3%
Anaplastic carcinoma - 2%
Other - 2%
What types of thyroid malignancy does “differentiated” thyroid cancer refer to?
What do they take up/secrete?
Differentiated refers to papillary and follicular carcinomas - good prognosis
Most take up iodine and secrete thyroglobulin
What is important regarding the epidemiology of thyroid cancers that a patient may find comforting to be told?
Their incidence is unrelated to diet, other cancers, lifestyle factors, smoking etc.
What type of thyroid disease are papillary thyroid carcinomas associated with?
Hashimoto’s thyroiditis
What is the investigation of choice and the gold standard of treatment for differentiated thyroid cancers?
Investigation - USS-guided FNA
Treatment - Surgical resection and radioiodine therapy
Following thyroid radioablation therapy, what can be used as a marker to assess effectiveness of treatment/activity of cancer?
Thyroglobulin
What is the cut-off in size between a microadenoma and a macroadenoma?
Micro = less than or equal to 1cm
Macro = greater than 1cm
What might a non-functioning pituitary adenoma cause?
Compression of optic chiasm - bitemporal hemianopia
Compression of nerves within cavernous sinus
Hypoadrenalism
Hypothyroidism
Hypogonadism
GH deficiency
Diabetes insipidus
What are some of the physiological causes of raised prolactin?
Breast feeding
Pregnancy
Stress
Sleep
What drugs might cause a raised prolactin?
Dopamine antagonists e.g. metoclopramide
Antipsychotics e.g. phenothiazines
What are the clinical signs of a raised prolactin level in
- men
- women
Men
- late presenation
- impotence
- visual field abnormality
- headaches
- anterior pituitary malfunction
Women
- early presentation
- Galactorrhoea (spontaneous flow of breast milk)
- Menstrual irregularities/amenorrhoea
- Infertility
What drug can be used to treat a raised prolactin level?
How effective is it?
Dopamine agonists e.g. cabergoline
PRL normalised in 96%
Menstruation regained in 94%
Pregnancy in 91%
What are some of the associated features of GH excess (acromegaly if occuring in adults)?
Thickened soft tissues
Hypertension and cardiac failure
Headaches
Snoring/sleep apnoea
Diabetes
Early CV death
Colonic polyps and colon cancer
How is acromegaly (GH excess) diagnosed?
IGF-1
Glucose tolerance test (suppression test)
How does the Oral Glucose Tolerance Test work?
Give 75g glucose and check GH levels at 30, 60, 90 and 120 mins
In normal individuals, GH is suppressed to under 0.4 micrograms/l
In someone with acromegaly, GH will either remain unchanged (i.e. no suppression) or there will be a paradoxical rise
Surgery tends to be the best treatment for acromegaly, but what drug might also be of benefit?
Somatostatin analogues e.g. Octreotide
What test is done to confirm a diagnosis of Cushing’s Syndrome?
Dexamethasone suppression test - first high dose over night, then low dose through the day to confirm if the first test was positive
The low-dose variant of the test is definitive
What is the main cause of Cushing’s syndrome?
What causes Pseudo-Cushing’s?
Pituitary cause i.e. Cushing’s Disease
Pseudo-Cushing’s is caused by either Alcohol and depression or Steroid medication
What is the main treatment for Cushing’s Syndrome?
What drugs can be used?
Main treatment is surgery to remove the source of cortisol excess
Drug treatment
-
Metyrapone
- used if other treatments fail/while waiting for post-surgery radiotherapy to work
- Ketoconazole
- hepatotoxic
- Pasireotide
What are some of the causes of pan hypopituitarism?
Pituitary tumours
Secondary metastases - lung, breast
Local brain tumours
Granulomatous disease - TB, sarcoidosis
Vascular diseases
Trauma - RTAs, skull fractures
Sheehan syndrome (autoimmune, post-pregnancy)
Meningitis (and other infections)
What are some of the risks associated with testosterone replacement therapy?
Prostate enlargement
Polycythaemia (raised haemoglobin conc in blood)
Hepatitis
What investigation is performed to test for Diabetes Insipidus?
Water Deprivation Test
