Case 9- Thyroid dysfunction Flashcards
What are the 3 main functions of the thyroid gland?
- Regulates basal metabolic rate (BMR)
- Stimulates somatic and psychic growth
- Role in calcium metabolism (with parathyroid gland)
What is the functional unit of the thyroid?
Thyroid follicles
What type of cells are follicular cells?
Simple cuboidal epithelial cells
How is are T3 and T4 synthesised?
1: PV nucleus in hypothalamus releases TRH
2: acts on thyrotrophs in AP to release TSH
3: Stimulates follicular cells to release thyroglobulin
4: Iodide moves into the FC with Na+ and then via pendrin proteins
5: iodide is oxidised to iodine via thyroid peroxidase (TPO)
6: TPO catalyses the iodination of tyrosine AA in thyroglobulin -> T3 and T4
How are T3 and T4 isolated and transported?
1: After synthesis = endocytosis of thyroglobulin with T3 and T4
2: lyosozyme enzymes split the thyroglobulin colloid to isolate T3 and T4
3: liver produces thyroxine-binding globulin (TBG), which binds to T3 and T4 to transport them in blood
What are the full names of T3 and T4? Which is the active form?
T4 (thyroxine) and T3 (triodothyronine)
T3= active form
How does T4 get converted into T3?
Crosses over the lipid bilayer to enter the cell, then 5’ deiodinase (also known as type 1 selenodeiodinase [D1]), enzyme removes iodine off T4 –> T3
How does thyroid hormone increase basal metabolic rate?
Retinoic acid and T3 bind to a transcription factor, activating it so it can stimulate genes. Overall result = protein synthesis of Na/K+ ATPase pumps. These pumps utilise ATP therefore leads to decreased cellular ATP, increased O2 usage = metabolic rate increases.
How does thyroid hormone cause increased BP?
Effects the heart - increases B1 adrenergic receptors (R for Adr/NA) so contractility, SV and Q goes up, acts on SAN/AVN to increase B1aR’s too, so HR increases [overall increases BP]
How does thyroid hormone affect the CNS?
Increases dendrites, myelination, synapses
How is the HPA axis altered in depression?
- Increased corticotrophin-releasing hormone (CRH)
- Enlarged pituitary and/or adrenal
- Increased ACTH and/or cortisol during depressive periods
What is Cushing’s syndrome? What psychological symptoms may it present with?
Cortisol hypersecretion, often associated with depression and irritability. May also suffer:
- Fatigue
- Decreased libido
- Poor concentration
- Impaired memory and poor problem solving
What is Addison’s syndrome? What psychological symptoms may it present with?
Cortisol hyposecretion, often associated with lethargy and apathy. Other behaviours:
- Irritability
- Crying
- Insomnia/ impaired sleep
- Problems with memory and concentration
- Tachycardia
What are the differential diagnoses of Addison’s and Cushing’s syndrome?
Cushings - depression,
Addisons- anxiety, as the symptoms are non-specific and come and go (esp during periods of stress)
How can hyperthyroidism influence behavioural states?
Intense dysphoria, usually pronounced anxiety. May also include:
- Nervousness
- Emotional instability
- Restlessness
- Impaired concentration
- Insomnia and fatigue
How can hypothyroidism influence behavioural states?
Cognitive dysfunction = impaired memory, concentration, inattentiveness, slowness, poor problem solving
Mood= depressed mood, anxiety, irritability, confusion (if severe can = psychosis)
What is the 2-pattern response of stressors on endocrine response?
1: stress promotes adaptive changes in the endocrine system to help the person deal with the threat, i.e. mobilisation of fuel, increased resistance to infection
2: prolonged/ repeated stress= adaptive changes such as enlarged adrenal glands
What is an allostatic load? What can it lead to?
Cumulative burden of chronic stress and life events
Prolonged stress can lead to dysregulation of endocrine function.
What is thyrotoxicosis and what can it be caused by?
Excess circulating thyroid hormone. Causes:
- Pharmacological: i.e. taking too much thyroid hormone
- Transient: viral infection (e.g. coxsackie), inflammation of the thyroid (transient wave of overactivity then leads to underactivity)
What can cause hyperthyroidism?
- Graves disease
- Toxic nodule - single or multiple, benign follicular adenomas
- TSH-secreting pituitary adenoma: rare tumour secreting high TSH so T3/T4 are elevated. Doesnt respond to the negative feedback loops
- Pituitary thyroid hormone resistance syndrome: genetic mutations in beta gene, usually euthyroid but thyrotoxic symptoms
What are some symptoms of hyperthyroidism?
- Irritability, nervousness
- Hyperactivity
- Heat intolerance & sweating
- Weight loss
- Increased appetite
- Dyspnoea
- Palpitations
- Diarrhoea
- Hair loss
How does hyperthyroidism lead to heat intolerance and sweating?
Thyroid hormone causes vasodilation of blood vessels to lose excess heat from the high metabolism, also Adr/NA stimulate sweat glands to produce more sweat for evaporative cooling
How does hyperthyroidism lead to dyspnoea?
tracheal compression from a large goitre
What finding may be present in a patient with hyperthyroidism for:
- Percussion
- Auscultation
- Percussion of the sternum may = dull, indicates the thyroid may have extended below and behind (retrosternal goitre)
- Auscultation: bruit (constant noise), i.e. increased BF to the thyroid gland
What might the results of thyroid function tests be for a patient with hyperthyroidism? i.e. overt primary, subclinical primary, and secondary
Overt = T3 and T4 high, TSH low
Subclinical = T3 and T4 normal, TSH low - indicates the thyroid hormones have been compensated for
Secondary = T3 and T4 high, TSH high
What is a differential for hyperthyroidism? What would indicate this?
Grave’s disease = thyroid auto-antibodies (for TSH receptor), positive clinical picture and TFTs, positive family history
What 3 investigations may be done if you suspect hyperthyroidism? What might they show?
- Ultrasound of the neck: may show increased inflammation or increased vasculature (accounting for the bruit), can show if there’s nodules or not
- Radioiodine uptake scan: also shows if there’s nodules
- 24hr urinary iodine excretion: can confirm if its due to excessive iodine intake
What are some risk factors for Grave’s disease?
- Female sex: 10x more likely
- Family history
- Smoking
- Low iodine intake: may cause MNG or SNG
- Autoimmune disease
- People with psychiatric disorders?
Whilst waiting for an endocrinologist’s referral, what may you prescribe to a patient with suspected hyperthyroidism?
Beta blockers for adrenergic symptoms (i.e. palpitations, tremor, tachycardia, anxiety)
What would you treat hyperthyroidism with?
Anti-thyroid drugs: thionamides, such as carbimazole (1st line) or propylthioruacil (2nd line)
What is carbimazole contraindicated in?
Pregnancy - use PTU
What is the MOA of thionamides?
Act as a preferred substrate for iodination by TPO - the key step in thyroid hormone production
After euthyroidism is achieved, what two drug regimens may be used?
- Titration-block regimen: dose is adjusted depending on free T4 levels - titrate to lowest dose possible to maintain euthyroid state
- Block and replace: give thionamide and then when free T4 is normal, add levothyroxine
What is radioactive iodine treatment?
What patients might this be used for?
Induces damage of DNA leading to death of thyroid cells = decreases thyroid function and/or reduction in thyroid size.
- First line definitive treatment for Grave’s and toxic MNG
Who is radioactive iodine treatment contraindicated in?
People with Grave’s and has active or severe orbitopathy
Patients with Grave’s but are pregnant
What are some complications of untreated hyperthyroidism?
- Graves orbitopathy
- Thyrotoxic crisis (thyroid storm) - leads to fever, tachycardia, hyperthermia
- Compression symptoms - dysphagia or breathlessness
- Cardiac problems
- Osteoporosis
- Psychosis
Where is hyperthyroidism more prevalent?
In iodine-deficient areas, such as Denmark
What is Grave’s disease?
Systemic autoimmune disorder - characterised by TSH-receptor auto- antibodies, leading to thyroid hyperplasia and excessive secretion of thyroid hormone. Has waves of inflammatory stimulation
Who is at increased risk for Grave’s disease?
- Women
- People with a personal or family history of autoimmune disorders (i.e. T1DM, Addison’s vitiligo, pernicious anaemia, myasthenia gravis, coeliac disease)
Other than the typical hyperthyroidism symptoms, what signs may be present in Graves disease?
- Orbitopathy: bulging of the eyes forwards
- Pretibial myoxedema: thickening of the skin
- Vitiligo: white patches
What is Grave’s orbitopathy?
Inflammation of extra-ocular muscles, causing increased retro-orbital pressure leading to proptosis = eye(s) pushed forward.
When would you be concerned about a patient with Graves Orbitopathy?
If the eyes don’t get pushed forward, the pressure can damage the optic nerve, leading to inability of the eyes to function (= diplopia, corneal ulceration, blindness).
How might you treat Grave’s disease?
- Carbimazole
- Carbimazole + thyroxine (block and replace)
- Beta-blockers - symptom relief
How might Grave’s disease be affected by pregnancy?
- Exacerbated early in pregnancy, as hCG stimulates the thyroid so low TSH is normal (reduces it further)
- Ameloriated later in pregnancy
Why is radioiodine treatment for Grave’s contraindicated in pregnancy?
Fetal thyroid is present at 8-10 weeks - risk of damaging it
What is the half life of T3 and T4 in circulation?
T3= 1-3 days
T4= 5-7 days
How might TFT results differ for overt, subclinical and secondary hypothyroidism?
Overt: high TSH but low free T4
Subclinical: high TSH but normal T4 and T3
Secondary: inappropriately low or normal TSH, but free T4 is low
What can cause primary hypothyroidism?
- Drugs, such as amiodarone and lithium
- Iodine deficiency
- Autoimmune thyroiditis (Hashimoto’s)
- Post-ablative surgery or therapy
- Transient thyroiditis
- Genetics
What can cause secondary hypothyroidism?
Pituitary or hypothalamic disorder
What is the most common cause of primary hypothyroidism in the UK?
Hashiomoto disease
Which genes may be implicated in hypothyroidism? What do they lead to?
- TTF1, PAX8 = gland never forms properly
- Pendren syndrome = can’t handle degradation of thyroglobulin and subsequent release of T3 and T4
What causes pernicious anaemia?
Autoimmune destruction of the parietal cell, loss of intrinsic factor secretion and consequently vitamin B12 defiency
What are some signs and symptoms of hypothyroidism?
- Fatigue and lethargy
- Cold intolerance
- Weight gain: eating the same but metabolism is slowed (low levels of lipolysis in adipose tissue)
- Constipation
- Depression
- Mentally slowed, dull: lack of synpases/ myelination/ dendrities in CNS
- Dry, brittle thinning hair
- Hoarse voice – more advanced
How can you distinguish primary and secondary hypothyroidism from the signs/symptoms?
Secondary would have the same symptoms as primary hypo, but would may also have:
- Recurrent headaches
- Diplopia and/or visual field defects
Also, abnormal pituitary hormone production can lead to sex hormone dysfunction (atrophic breasts, galactorrhoea, amenorrhoea, erectile dysfunction).
What might you look at in the blood when assessing a patient for hypothyroidism?
- Thyroid function test
- Mixed dyslipidaemia: reduced LDL uptake from the liver
- Normochromic normocytic anaemia or macrocytosis (latter= B12 deficiency)
How else might you investigate for hypothyroidism?
Detailed family history - likely autoimmune cause
Drug history
What are some potential complications of untreated hypothyroidism?
- Cardiovascular: HF, stroke, CHD
- Reproductive: infertility, miscarriage, stillbirth, pre-eclampsia
- Neuro: impaired concentration, memory, decreased vision and hearing
- Myxyoedema coma: fatal but rare = bradycardia, lethargy, seizures
How would you manage/treat a patient with overt hypothyroidism? Why?
Levothyroxine - give life-long at usually 100 mcg/d. Repeat blood tests after 4-6 weeks!
Patient has low T3 and T4 so there’s low negative feedback at the pituitary = high TSH. As you restore T3 and T4, TSH returns to normal range.
How would you manage/treat a patient with normal T3 and T4 but high TSH (compensated response)?
- If seen with symptoms = give levothyroxine to see if you can normalise TSH levels and symptoms improve
- If no symptoms = may repeat the test
If the T3, T4 and TSH were all low, what should be considered?
Pituitary disease
sick euthyroid syndrome
What are the 3 zones of the adrenal cortex? What does the zonation depend on?
Zonation depends on the enzymes within it
- Zona glomerulosa: cells in outer most part, produce mineralocoticoids
- Zona fasiculata: main producers of cortisol (glucocorticoids)
- Zona reticularis: responsible for producing sex steroid precursors
What enzymes are responsible for conversion of cortisol to cortisone and vice versa (in peripheral tissues)?
HSD11B1: Cortisone –> cortisol
HSD11B2: Cortisol –> cortisone
What enzyme is present in the zona glomerulosa and is responsible for production of progesterone from pregnenolone?
3B-hydroxysteroid dehydrogenase (type 2)
i.e. HSD3B2
Which adrenal zones does the HPA axis regulate?
Zone fascicularis and zona reticularis
What syndromes may occur if there was hormone excess in the zona glomerulosa or zona fasciculata?
Glomerulosa: Conns syndrome (mineralocortoid excess)
Fasiculata: Cushing’s (glucocorticoid excess)
What is Cushing’s syndrome?
Excessive, inappropriate endogenous cortisol secretion characterised by:
- Features of glucocorticoid excess
- Loss of circadian rhythm to control secretion
- Disruption of negative feedback loop
What signs/ symptoms may be present in Cushing’s syndrome?
- Rounded face with purplish discoloration
- Fat deposition on back of neck
- Central obesity- buffalo hump
- Weight gain
- Hypertension
- Easy bruising
- Proximal myopathy: may find it difficult to stand up out of the chair
- Purplish stretch marks on abdomen
How might Cushing’s syndrome be diagnosed?
- Assess cortisol levels over 24hr, would see a loss of circadian rhythm (usually falls at night and increases in the morning)
- Dexamethasone suppression test: then reassess cortisol response in morning (24h monitoring)
- Exclude pseudo-Cushings, i.e. from alcohol or depression
What findings would indicate Cushing’s syndrome from a dexamethasone suppression test?
Cortisol should be supressed due to the negative feedback with dexamethasone [should be <50nmol/L]
therefore, if >50nmol/L = diagnose with excess
What are some causes of Cushing’s syndrome?
- Taking endogenous cortisone, i.e. prednisolone in asthma or RA
- Ectopic ACTH-secreting tumour: in the lung, i.e. late stage lung cancer
- Corticotroph tumour (Cushing’s disease): secretes excess ACTH
- Adrenocortical tumour: in the adrenal gland itself
How can you distinguish whether Cushing’s syndrome is caused by an adrenal tumour?
Due to negative feedback, adrenal tumour would have very low ACTH
What tests might you do to distinguish ACTH-dependent causes of Cushing’s syndrom?
- low dose dexamethasone suppression test
- Inferior petrosal sinus sampling
- high dose dexamethasone suppression test = localises Cushing’s
Explain how inferior petrosal sinus sampling would indicate the cause of Cushing’s
Canulate veins/ sinuses going into the pituitary, then compare ACTH from here to blood in the periphery (can do baseline test or give CRH)
- If levels of ACTH are high in a sinus then indicates tumour in the gland
Explain how the high dose dexamethasone suppression test would indicate the cause of Cushing’s
- If cortisol is driven by ACTH then the pituitary tumour will retain some elements of negative feedback, so cortisol should fall after high doses of dexamethasone supplementation
- Ectopic ACTH will not have the negative feedback so cortisol will stay high
What drugs may be given to treat Cushing’s?
Can block production of cortisol, i.e. metyrapone, ketoconazole, mitotane.
How might you treat a pituitary tumour causing Cushing’s?
- Trans-sphenoidal hypophysectomy: through the nose, can remove some bone and take away the tumour from pituitary gland.
- Radiotherapy
However, 20-50% may not be permenantly cured, and may require bilateral adrenalectomy. would need to replace hormones
What is Addison’s disease?
Primary hypoaldosteronism = reduction in all steroids (glucocorticoids and/or mineralocorticoids) that are normally secreted by the 3 layers of adrenal cortex. Usually reduction in cortisol, aldosterone and DHEA.
Other than Addison’s disease, what can cause of hypoadrenalism?
- Autoimmune disorders, i.e. T1DM, thyroid disease, PA, vitiligo
- Tuberculosis / AIDS
- Metastatic tumour
- Lymphoma
- Intra-adrenal haemorrhage or infarction
What are some symptoms of hypoadrenalism?
-Weakness and tiredness
- Nausea and vomiting, GI disturbance
- Postural hypotension: take BP lying down and standing up – will see it drop when they stand up
- Abdominal pain
- Weight loss
- Hypoglycaemia
- Hypotensive, hyperkalaemia patient (think primary hypoadrenalism!!)
What 2 signs strongly indicate primary hypoadrenalism?
Hypotension and hyperkalaemia
What test may you do if you suspect a patient has hypoadrenalism? What is a diagnostic result?
Short synacthen test: give ACTH IV or IM and measure cortisol 30 minutes later.
If cortisol <400 nmol/L = inadequate
How do you treat hypoaldosteronism?
Hydrocortisone lifelong: 10mg on waking, 5mg mid afternoon. Double in significant illness (e.g. ‘flu’). Patient should also have a steroid alert bracelet and card.
Other than hydrocortisone, what else might you treat a patient with Addison’s disease with?
A mineralocorticoid replacement – fludrocortisone (100 mcg). Helps sustain BP and potassium levels.
What is Conns syndrome? What zone is affected?
Primary mineralocorticoid (i.e. aldosterone) excess = over production in zona glomerulosa
What are some symptoms of Conns syndrome?
Hypokalaemia, weakness and lethargy. Headaches due to hypertension
What can cause hypokalaemia?
➢ Vomiting: metabolic alkalosis
➢ Diarrhoea: fluid loss from the bowel
➢ Insulin therapy
➢ Diuretic use
➢ Rare causes = renal tubular acidosis and Barter syndrome
What is the typical presentation of Conns syndrome?
young person, severe HTN, high sodium, low potassium
How would you treat Conns syndrome?
If unilateral cause= remove adrenal gland
If bilateral tumour = Spironolactone and eplerenone
What is the MOA of spironolactone and eplerenone?
Aldosterone acts on the mineralocorticoid receptor (MR) in the DCT. Spironolactone and eplerenone are MR antagonists, so block aldosterone effect
What is a phaemochromocytoma?
Tumour in the adrenal medulla, where you make catecholamines
What is the classic triad of symptoms of phaemochromocytoma?
- Hypertension
- Throbbing, bilateral headaches
- Palpitation
What is the MOA of hydrocortisone?
binds to glucocorticoid receptor, leading to downstream effects such as inhibition of inflammatory transcription factors and promotes anti-inflammatory genes.
What is the MOA of fludrocortisone?
inactive pro-drug. Synthetic adrenal steroid with high mineralocorticoid activity. It acts on the kidneys to increase Na+ resorption and K+ excretion.
What is sensitivity?
measure of the probability of correctly diagnosing a condition
= True positives / number of those with the disease
i.e. TP / TP + FN
What is specificity?
measure of the probability of correctly identifying a non-diseased person
= True negatives/ those without the disease
i.e. TN / TN + FP
On a frequency polygon, what happens if the axis of cut off goes to the left? I.e. the cut off value for the disease gets lower
= less FN but also less TP
On a frequency polygon, what happens if the axis of cut off goes to the right? I.e. the cut off value for the disease gets higher
More TP but more FP
What is positive predictive value (PPV)?
probability disease is present when the test is positive
TP / TP + FP
What is Negative predictive value (PPV)?
probability disease is not present when the test is negative
TN / TN + FN
What is false negative rate? How can it be calculated?
Divide number of false negatives by (true positive + false negative)
Also equal to 1- sensitivity
What is false positive rate and how can it be calculated?
divide number of false positives by (FP + TN)
Also equal to 1-specificity
What curve is used to determine accuracy of tests? What does it assess?
ROC curve = Plot sensitivity (y axis) against 1-specificity (x axis)
Looks at the ability of the test to detect true positive, compared with the proportion of false positives detected
What is determined as a good plot line on an ROC curve?
As close to 1 as possible
What are the five main factors to consider when considering the most appropriate diagnostic test and cut off point?
- Serious of the disease – if fatal then want most number of TP
- Prevalence of disorder
- Cost of the test
- Invasiveness of procedure, usually more accurate but not well tolerated
- Stress on those who are false positive
