hypothyroidism/hyperthyroidism Flashcards
what does the hypothalamus release in the hypothalamus-pituitary-thyroid (HPT) axis? what does it act on?
releases TRH (thyrotropin releasing hormone) — acts on thyrotrophs in the anterior pituitary
what does the anterior pituitary release in the HPT axis and what does it act on?
releases TSH (thyroid stimulating hormone) — acts on thyroid
what do T4 and T3 do in the HPT axis?
provide -ve feedback to further regulate the production of TRH and TSH
what happens when TSH binds to its receptor on the basal membrane?
- increases levels of cAMP —> triggers various intracellular effects
various processes occur:
- thyroglobulin synthesised
- iodide is actively recruited via an active transport process —> results in iodisation of thyroglobulin to create iodinated thyroglobulin
- thyroid peroxidase enzyme activity stimulated as part of intracellular effects
where is active thyroid peroxidase enzyme (TPO) located?
apical membrane (microvilli surface) of thyroid epithelial cells where it is secreted into colloid
how does I- enter the thyroid epithelial cell?
Na+/I- symporter on the basal membrane
what is active TPO enzyme stimulated by?
TSH
what does active TPO enzyme do?
assists the chemical reaction that adds I- to thyroglobulin to form thyroid hormone (thyroglobulin in complex with iodide)
what is TH stored as?
colloid
how is TH recycled?
- thyroglobulin degradation —> active hormone is released into circulation (T3 and T4) and I- is recycled through pendrin across apical membrane
what is the active thyroid hormone name?
T3 = triiodothyronine
the critical I is on what carbon of T3?
5
what is T4 name?
thyroxine
what are the 2 inactive forms of T3 and T4?
T2 = diiodothyronine
reverse-T3 = triiodothyronine
80% vs 20% of hormone release by thyroid
80% = T4
20% = T3
where and how is T4 converted to T3?
in circulation of peripheral tissues
enzyme = type 1 selenodeiodinase (D1)
what enzyme converts T3 and T4 to their inactive counterparts?
D3 deiodinase
what are the inactive counterparts to T3 vs T4?
T3 —> T2
T4 —> rT3
what does T3 do when it enters the nucleus?
- binds to thyroid hormone receptor (TR is in complex with RXR)
- turns on/off gene expression to alter cell function
- mRNA forms and enters cytoplasm
- protein formation = what accounts for TH action
thyroid hormone action is therefore a SLOW process
what is the essential precursor to thyroid hormone?
tyrosine — (sequential iodination of tyrosine)
thyroid hormone is stored as ______ in gland
colloid
T4 vs T3
- T4 is produced entirely by thyroid
- T3 - peripheral T4 mono-deiodination (liver and kidney)
- T3 is metabolically active
- half life of T4 is longer (5-7 days vs 1-3 days) — therefore in treatment T3 has to be given 3 x a day vs once a day for T4
serum what is a long term and best indicator of thyroid?
serum TSH
what is the name of an enlarged thyroid gland?
goitre
what is hashimoto disease?
an autoimmune disorder that can cause hypothyroidism, or underactive thyroid
is hypothyroidism more common in men or women?
women
classic hashimoto vs atrophic thyroiditis
- classic = goitrous
- atrophic = non-goitrous (in relality, a mix of antibody mediated/T cell-mediated. TPO, TSHR, Tg auto-antibodies)
what causes goitre?
iodide deficiency
what drugs can induce hypothyroidism?
amiodarone, iodides, lithium
what antibody is most specific to autoimmune thyroid disease?
TSH receptor antibody — binds to receptor and blocks its function
what can cause genetic/developmental hypothyroidism?
Thyroid Transcription Factor 1 (TTF1), PAX8, Pendred syndrome, NIS (Na I Symporter)
what is pendred syndrome?
a disorder typically associated with hearing loss and a thyroid condition called a goiter in children
what else can cause hypothyroidism?
post-ablative radioiodine/post-operative
what are secondary/tertiary causes of hypothyroidism?
- hypopituitarism and hypothalamic
- pituitary adenoma, congenital deficiency, irradiation of pituitary gland
(- sarcoid, infection)
what are signs and symptoms of hypothyroidism?
METABOLISM SLOWED
why can the skin thicken in hypothyroidism? what can this lead to?
get deposition of glycosaminoglycans
—> can get compression of median nerve causing carpal tunnel syndrome
what are examples of organ-specific autoimmune diseases? (must think about these if hypothyroidism diagnosed)
- Graves’ disease
- autoimmune hypothyroidism
- pernicious anaemia
- Addison disease
- Autoimmune atrophic gastritis
- type 1 diabetes mellitus
what is addison disease?
autoimmune destruction of adrenal gland
what is pernicious anaemia?
arises from autoimmune destruction of the parietal cell —> loss of intrinsic factor secretion and consequently vitamin B12 deficiency
what would someone with congenital hypothyroidism look like?
what can triglyceride and cholesterol levels be like in hypothyroidism?
elevated — hypothyroidism predisposes an individual to dyslipidaemia
what investigations are carried out for hypothyroidism?
- blood test (TFTs)
- normochromic normocytic anaemia
- macrocytosis, mixed dyslipidaemia
no need for ultrasound scan (or autoantibody measurement in UK)
consider other autoimmune endocrinopathies eg. adrenal, ovary, T1DM, (pernicious anaemia, vitiligo)
what are RBCs like in pernicious anaemia?
large —> macrocytosis
how is hypothyroidism treated?
REPLACE THYROXINE
- once daily thyroxine, lifelong
- usually 100mcg a day
- rapid start in young, gentle increment in elderly
- repeat blood tests after 4-6 weeks
what is the goal of treatment in hypothyroidism?
normalise TSH
what are the levels of T4/T3/TSH like in hypothyroidism?
- T4 and T3 levels are low
- TSH levels are raised due to lack of -ve feedback
what happens in treatment if there are normal levels of T4 and T3 but TSH is raised?
compensated response
- if symptoms, treat with thyroxine
- if no symptoms, could wait and repeat test, subclinical hypothyroidism
what would you consider if T4 and T3 levels are low but TSH are also low or normal?
consider potential pituitary disease/sick euthyroid syndrome
what is sick euthyroid syndrome?
abnormal findings on thyroid function tests that occur in the setting of a nonthyroidal illness (NTI), without preexisting hypothalamic-pituitary and thyroid gland dysfunction
what is vitiligo?
autoimmunity against melanocytes
why does iodine deficiency cause a goitre?
the thyroid gland increases in size to attempt to capture as much iodide as possible
what is thyrotoxicosis?
excess circulation thyroid hormone (NOT THE SAME AS HYPERTHYROIDISM)
what is hyperthyroidism
an overactive thyroid gland
what can cause hyperthyroidism?
- graves’ disease (autoimmune, other associated features)
- toxic nodule (possibly part of multi nodular goitre, no other features)
(- pituitary adenoma or thyroid hormone resistance syndrome) - transient (viral eg. coxsackie, ECHO)
- pharmacological (thyroid hormone - take too much levothyroxine)
what is De Quervian subacute thyroditis?
a painful swelling of the thyroid gland thought to be triggered by a viral infection, such as mumps or flu
Subacute thyroiditis (also known as De Quervain’s thyroiditis, granulomatous thyroiditis, or giant cell thyroiditis) is inflammation of the thyroid characterised by a triphasic course of transient thyrotoxicosis, followed by hypothyroidism, followed by a return to euthyroidism
subacute thyroditis:
The thyrotoxic phase is due to thyroid _______ damage and release of preformed thyroid hormone. This phase is characterised by ______ thyroid uptake on nuclear scan and _______ serum ___ or ___ levels
The thyrotoxic phase is due to thyroid follicular damage and release of preformed thyroid hormone. This phase is characterised by low thyroid uptake on nuclear scan and elevated serum ESR or CRP levels
symptoms of hyperthyroidism
examination for hyperthyroidism
describe thyroid orbitopathy
autoimmune affecting muscles behind eyes — eyes pushed forwards
what is pretivial myxoedema?
thickening of skin on shins
a skin condition that causes plaques of thick, scaly skin and swelling of your lower legs. This condition is a form of Graves’ disease and can affect people diagnosed with thyroid conditions
describe bruit
- very increased blood flow
- only hear it in autoimmune graves’ disease affecting all of the gland
what are the differential diagnoses of primary hyperthyroidism/thyroiditis?
- transient thyroiditis — viral infections
- Graves’ disease
- toxic nodule (part of MNG)
- pituitary adenoma
- thyroid hormone resistance syndrome
what are T4,T3,TSH levels like in primary hyperthyroidism?
- T4 and T3 are elevated
- TSH is slow
what are T3,T4,TSH levels in subclinical (compensated) hyperthyroidism?
T4 + T3 are normal
TSH is low
what are thyroid autoantibodies like in hyperthyroidism?
TSH receptor antibodies — stimulate receptor
graves vs toxic multi nodular goitre
what does an ultrasound scan show in hyperthyroidism? Graves vs MNG
increased echogenicity: homogenous (Graves) or heterogenous (MNG)
uptake scan (low dose radioiodine or other radionuclide) : graves vs MNG
graves - homogenous
single/MNG - isolated ‘hot nodule’
treatment of hyperthyroidism
block thyroid hormonogensis
- Thionamide: Carbimazole (most common) or proprylthiouracil
- goal = restore normal thyroid hormone levels. in time TSH should normalise
- definitive treatment options (radioiodine or surgery)
how does carbimazole work?
Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from iodinating and coupling the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine).
they are thionamides
when is propylthiouracil preferred over carbimazole in hyperthyroidism treatment?
if trying for pregnancy or pregnant
carbimazole can (albeit rarely) have adverse effects on the skin of a developing baby
what is Graves’ disease associated with? (autoimmune characteristics)
T1DM, Addison’s disease, vitiligo, pernicious anaemia, alopecia areata, myasthenia gravis, coeliac disease
what is the major auto antigen in Graves’ disease?
TSH receptor
is graves’ disease more commin in men or women?
women
0.8/1000 vs <0.1/1000
characteristics of graves’ disease
- waxing and waning inflammatory autoimmune stimulation of the thyroid (not constant — wavers)
- 20-40 years old
- more aggressive in children and males
symptoms and signs of graves’ disease
same as for primary hyperthyroidism
plus
- thyroid bruit
- thyroid eye disease/Graves orbitopathy
- pretivial myxoedema
treatment of Graves’ disease
- carbimazole
- high dose carbimazole + thyroxine (block and replace)
- beta blockers for symptomatic relief
- monitor thyroid function test
- trial off treatment
- 1/3 cure, 1/3 relapse sometime, 1/3 relapse soon
possible adverse blood effect of carbimazole?
agranulocytosis
it is immunosuppressive
what is proptosis?
eye further forward than it should be = not as bad as eye being pushed back (could press on optic nerve)
describe graves orbitopathy/thyroid eye disease
- inflammation of the extraocular muscles, causing increased retro-orbital pressure
- proptosis or optic enrve damage, diplopia, corneal ulceration
- usually associated weight thyroid upset, but can be entirely separate
- higher frequency and worse outcome with cigarette smoking
- radioiodine aggravates — choose surgery over this
- treated with artificial tears, immunosuppression, debatable effects of radiotherapy
- ultimately ‘burns itself out’
how does graves’ disease change throughout pregnancy?
exacerbated in early pregnancy, but ameliorated in later pregnancy
how can graves’ disease affect pregnancy/foetus?
- spontaneous abortion rates increase
- premature labour
- small birth weight
- congestive cardiac failure
- pre-eclampsia
why is graves’ disease worse at the start of pregnancy?
hCG also simulates the thyroid
T3/4, TSH levels in pregnancy
normal T4/3, low TSH is normal in pregnancy
how is graves’ disease treated/not treated in pregnancy?
- not radioiodine — foetal thyroid present at 8-10 weeks gestation
- not beta blockers — foetal bradycardia, hypoglycaemia, respiratory depression, IUGR (intrauterine growth restriction)
- surgery if intolerant of thionamide/agranulocytosis
what do 1% of Graves’ pregnancies generate?
foetal hyperthyroidism — get placental crossing of TSHR stimulating Abs
- foetal HR >160 bpm, goitre, advanced neonatal bone age, craniosynostosis
- even if maternal thyroidectomy, might still have lots of antibodies, measure at start of 2nd trimester? (if >5 fold normal, significant risk of foetal hyperthyroidism, can be treated by maternal thionamide)
what are the 3 thionamides?
carbimazole, methimazole, propylthiouracil
