ENDOCRONOLOGY WK 2 Flashcards
what cells in the thyroid produce what
Follicles produce thyroxine
C-cells produce calcitonin
how is thyroid hormone made
- Trap iodide ions into the epithelial cell through the apical membrane
- Converted to iodine inside
- Iodine molecules added onto protein skelenton (thyroglobulin) to create diff. types of thyroid hormone
o Catalysed by enzyme thyroid peroxidase
o And hydrogen peroxide
Different amounts of iodine added onto thyroglobulin skelenton - Add 1 = monolodotyrosine
- Add 2 = dilodotyrosine
- Add 3 = trilodotyrosine (T3)
- Add 4 = tetralodotyrosine (T4)
T3 and T4 - “active” status and relationship to each other
- T4 is an inactive prohormone
- Is converted to T3 by removal of one iodine
- By deiodinase enzymes
- T3 is the active hormone
T4 is bound to albumin so exists in a bound state as inactive, only the free hormone is active
thyroid hormone - where is T3 produced and what is it’s mechanism of action
- 20% T3 produced from thyroid gland
- The thyroid produces T4:T3 in a 14:1 ratio
- 80% T3 produced from peripheral conversion of T4 in liver, kidney and muscle
- Thyroid hormone acts on nuclear receptors – transported into the cell and binds to receptors in the nucleus
what would you expect to happen to TSH levels if T4 levels are low - why is this important clinically
If someone has low T4 you’d expect them to be producing more than normal TSH
- If TSH is in normal reference range this would actually be inapropriate in this context
actions of thyroid hormone
- Growth development
- Basal metabolic rate
- Activate mental processes
- Thermogenesis in brown adipose tissue
Graves - hyperthryoidism
Graves (~75%)
- Autoimmune disease
- Antibodies attack thyroid to make it overactive
- Can be associated with eye disease
toxic multinodular Goitre (MNG) - hyperthyroidism
- Mulitple lumps (nodules) or enlarged thyroid (goitre)
- Often one or more lumps will be overeactive
- Can get lid lag or lid retraction (starey look to their eyes), but no other features of thyroid eye disease
o Caused by thyrpoid hormones over activating SNS
what is seen in scan if a patient has MNG
- Discrete areas of the gland light up (the nodules)
- Nodules over produce thyroid hormone which will feedback on the pituitary and switch off production of TSH
- Normal bits of gland between nodules will switch off because there’s no TSH information
singular toxic nodule - hyperthyroidism
- Single overactive lump
- Only one part lights up as rest of the gland is producing no hormones
thyroiditis - hyperthyroidism
- Temp. overeactivity of thyroid (isn’t technically overeactive)
- Gland is damaged which releases all the stored preformed hormones
- Can be followed by period of underactivity
- Truggered by pregnancy, infection or some drugs (eg amiodarone)
symptoms of primary hyperthyroidism
- Weight loss
- Tiredness
- Tremor
- Hot,sweaty
- Palpitations
- Diarrhoea
- Light/absent menses
- Mood – irritabel, anxiety
- Eyes (change in appearance, red, gritty, painful, double vision)
- Muscle weakness
what can be seen in an examination for primary hyperthyroidism
- agitated, talk fast
- warm, sweaty
- tremor
- inc. HR, atrial fibrillation
- smooh giotre (Graves) vs MNG vs single nodules vs no goitre (thyroiditis)
- bruit heard over goitre almost diagnostic of Graves
- Eye
o Lid retraction and lid lag in any casue of overactive thyroid
o Any other eye signs indicates Graves disease
eye symptoms in hyperthyroidism
lid retraction and lid lag - Associated with any cause of thyrotoxicosis. All other eye signs are specific to Graves Graves… - Redness - Gritty sensation - Dry or watery eyes - Pain on eye movement - Swelling around the eyes - Proprosis (pushed forward appearance of eyes) - Double vision - Loss of colour vision
diagnosis of P. hyperthyroidism
- TRAbs (TSH Receptor Antibodies) significantly positive indicates Graves
- TPO (thyroid peroxidase) antibodies less specific
- If TRAbs are neg, so scintigraphy (often technetium rather than radio-iodine uptake because lower dose of radioactivity)
what would you expect to see in a technetium scan for the different causes of hyperthyroidism
thyroiditis - thyroid hardly seen at all
Graves disease - whole thyroid lights up more than usual
Toxic MNG - multiple areas light up more than normal and rest of the thyroid is barely seen
toxic adenoma - one area lights up more than normal with other areas not lighting up
what’s the time course for destructive thyroiditis in terms of TSH, T3 and T4 levels
0-2 months (thyrotoxic
- TSH decreases due to massive increase in T3 and T4 as thyroid gland is destroyed releasing stores of these molecules
2-2.5 months (euthyroid)
- TSH rapidly inc. and T3 and T4 rapidly dec. but are within reference ranges
- 5-5 months (hypothyroid)
- TSH is very high due to drop in T3 and T4 as thyroid is damaged and can’t produce these hormones
> 5 months - recovery
management of primary hyperthyroidism
Antithyroid drugs (ATDs):
- Carbimazole and propylthiouracil (PTU)
- Decrease production of thyroid hormone (block TPO)
- Not thyroiditis (high T4 levels are due to release of hormone stores from damaged gland, but gland is not actually overactive)
- Rare side effect of agranulocytosis (<1/500)
o Signs of this are high fever, bad sore throat, bad mouth ulcers = stop meds
Propranolol good for tremor and inc. HR
- Not used in asthmatics
Radioactive Iodine (I ^131)
- Taken up by bits of gland that are overreactive
- Risk of longterm hypothyroidism
- Avoid pregnancy for 6 months
- Restrict contact with children under age 12 and pregnant womedon’t share bed with partner for 4 days
Surgery
- Risk of longterm hypothyroidism or damager to recurrent laryngeal nerve and parathyroid glands (control calcium)
treatment for Grave’s specifically
- Treated with ATDs first time around
o 12-18 month course of tablets
o 60-70% chance of relapse (since autoimmune) - I^131 fro recurrent Graves
o Once it returns it will keep coming back
using Iodine^131 as treatment for MNG or singular toxic nodule
- I^131 for TMNG or toxic nodule
o No chance of long term remission with a course of tablets - Risk of hypothyroidism after I^131
o Lower with TMNG and toxic nodule than Graves - Risk of thyroid eye disease flaring up after I^131 so av oid in thyroid eye disease
mechanism of thyroid eye disease
TRab Antibodies also bind to receptors in connective tissue in and behind the orbit
Effecting…
Adipocytes
- Adipogenesis – creation of new fat cells
- More tissue behind the eyes pushes them forward
Fibroblasts
- Increased amount of glycosaminoglycans
- These retain fluid leads to increase bulkiness of ECM
- Swelling behind the eyes – increase in pressur ebehind the eyes
how to take a history of thyroid eye disease
- Change in appearance of eyes or periorbital tissues
- Corneal symptoms (grittiness, photophobia, watering)
- Extra-ocular muscle (EOM) restirction (eg diplopia/ double vision)
- Symptoms of EOM inflammation (pain at extreme gaze)
- Orbital ache unrelated to gaze
- Synptoms of optic neuropathy (Dec. colour vision, blurred vision)
- “popping” of eye – inability to close lids (globe subluxation)
examination of thyroid eye disease
- Redness
- Eyelids
o Thickening/ oedema
o Lid retration - Chemosis
- Proptosis
- Test eye movements (H)
- Lagophthalmos (inability to close eyelids without forcing)
- Optic nerve
o Visual acuity (snellen chart)
o Fundoscopy or slot lamp to visualise head of optic nerve
management of Graves eye disease
- Unless mild, should be managed in joint thyroid eye clinic
- Achieve euthyroidism
o Both hyper and hypothyroidism are bad
o Can have active eye disease without throid being overactive
o Thyroid eye disease can even present many months nefore thyroid disease develops
conservative measures for management of graves eye disease
- Smoking cessation (smokers have 9x inc. risk of developing severer and respond less well to treatment)
- Topical lubricants
- Selenium 200mcg daily (antioxidant)
- Steroids (oral or iv if active eye disease)
- Other immunosuppresion (eg cyclosporine)
what is seen an an xray of graves eye disease
- 50% of eyes should sit behind the red line so you can see they are vv swollen
- Extraocular muscles (medial and inferior rectus muscles) are swollen
- Optic nerve very compressed by swollen muscles – concern for sight
primary hypothyroidism, hormone levels, prevelance and symptoms
TSH increased, FT4 decreased, TT3 decreased/normal
- Prevelance depends on age and gender o 0.3-2% women and <0.15% men - Symptoms o Tired (slowed down, lethargic) o Weight gain, puffy eyes and skin o Feeling cold o Slow hr o Constipation o Dry hair and skin o Heavy periods (menorrhagia) o Hyperlipidaemia o (enlarged thyroid = goitre) - No evidence to support giving thyroxine to people with symptoms but normal TFTs o A lot of people can present with these symptoms and no physiological changes
causes of primary hypothyroidism
Hashimoto’s thyroiditis
- Antibodies attack thyroid and make it undereactive
- Permanent
- Tendency can run in families
Iatrogenic (post surgery or radioactive iodine)
Spontaneous atrophic
Temporary thyroiditis
- Eg viral thyroiditis, postpartum thyroiditis
Other (congenital (screening programme), iodine deficiency (not UK), drug-induced (eg lithium)
- Babies screened after birth for TSH levels
- Because it’s key for growth and cognitive developm ent
treatment of primary hypothyroidism
Thyroid hormone replacement
Ideal replacemnet
- Need to know normal fluctuations of thyroid an dpituitary hormones are
- Free T4
o stable throughout day, drifts down inmorning then rises slowly
- TSH and free T3
o dips down in afternoon and rises in evening so it’s highest overnight and dips down in the morning again
thyroid replacement therapy - levothyroxine - aim of treatment and general info
- up to 3% of the UK population are on thyroid hormone replacement
- the vast majority of patients are treated with (and feel fine on) once daily levothyroxine (T4)
- a small proportion of patients feel considerably less well on levothyroxine than when they had a normally functioning thyroid
- half life lvothyroxine approx. 7 days
- once daily dosing results in stable fT4 and fT3 levles
- commonly around 100mcg thyroxine (1.6mcg/kg/day)
- aim to normalise TSH
- usually managed by GPs
- no further Inx needed for hypothyroidism if inc. TSH (scans do not change Mx)
levothyroxine - timing of dose, monitoring and what medications to avoid
LEVOTHYROXINE – TIMING OF DOSE - aim of treatment is to normalise TSH - taking on an empty stomach before breakfast is preferable to with breakfast or before bed Monitorung therapy - annual TFTs once stable - if dose change, wait at leadt 6 wks before rpt TFTs Some OTC meds impair T4 absorption - PPIs eg omeprazole/iansoprazole - H2 antagonists eg ranitidine - Iron, calcium, aluminium - Don’t take T4 <4h after these Increased T4 requirement if start oestrogen (OCP, HRT) or anticonvulsants
T4 and T3 combination therapy
- Levothyroxine is not the perfect thyroid hormone replacement but current alt. do not have strong evidence of greater effectiveness (eg combinaton T3/T4, dessicated thyroid extract)
- T3 (liothyronine) peaks at 2-4 hrs and has a half-life of 1 day
- At least 3x daily dosing is required to achieve stable levels
- Concerns around effects of rapid peaks of highly active thyroid hormone
- What dose? What ratio of T3:T4?
- Difficult to achieve ‘blinding’ in studies
- No clear benefit of combination on quality of life
desiccated thyroid extract (DTE)
- Names > DTE, “natural thyroid”, armour thyroid
- Contains T3 and T4
- Human thyroid T4:T3 is 14:1 (unusual ratio for humans as it’s in 4:1 ratio instead)
- Contains pig thyroid extract with T3, T4 and a bunch of other thyroid products that are unecessary
- One grain (60mg) contains 38ug T4 and 9ug T3
in what case may levothyroxine not be adequate treatment
- Hypothyroid patients with less active deiodinase 2 had slightly better response to combination of T3 and T4 than T4 alone
- In the future, genetic markers may help guide therapy
subclinical hypothyroidism - hormone levels and why TSH is important
TT3 and FT4 normal, TSH elevated
- TSH more sensitive marker of thyroid hormone status than T4
- If T4 normally sits in upper end of normal range then drops to the lower end of the range it’s technically still normal but for them specifically thyroid is becoming underactive
Before T4 drops down below the normal reference range TSH detects this and pushes up the TSH
- For this reason TSH is most valuable bc/ it’s the earliest indicator of something going wrong
- So if TSH is above normal this is known as compensated hypothyroidism/ sub-clinical hypothyroidism
Same with hyperthyroidism
- As T4 rises to high in the normal range
- The TSH becomes supressed and is an ear;y sign of hyperthyroidism
subclinical hypothyroidism - prevalence, cause, adverse effects
- Prevelance 4-10%
- Main cause is autoimmune chronic thyroiditis
- Some (weak) evidence of adverse effects
o Lipids
o BP
o Other CV risks eg CRP, arterial stiffness
o No hard end-points evidence (ie no evidence that it increases heart attacks or strokes) - No convincing evidence that it causes symtpoms
- However, TFTs often checked because of symptoms that MAY relate to thyroid so patients often convinced that the 2 are linked
conclusions of study into if subclinical thyroidism is likely to progress to hypothyroidism
- Having a raised TSH >2mU/l increases risk of hypothyroidism (independent of age)
- People with TPO antibodies increases risk also
- Treat if TSH> 10 on 2 occasions and/or if TPO strongly positive
secondary hypothyroidism - hormone levels, a clinical example of if it were misdiagnosed as P. hypothyroidism
TSH is low or nomal, low FT4 and low/normal TT3
- patient presents with low T4 and normal TSH
- diagnosed as hypothyroidism and patient given T4 replacement
- in follow up TSH is suppressed and so patient is given lower dose of T4
- emergency admission with bitemporal hamaenopia as has adenoma of pituitary gland
what is an important rule to remember when diagnosing hypothyroidism
IN ORDER TO DIAGNOSE PRIMARY HYPOTHYROIDISM YOU MUST HAVE A HIGH TSH
IF TSH IS INNAPROPRIATELY NORMAL/LOW THINK ABOUT PITUITARY DISEASE
non-thyroidal illness effect on thyroid hormones
- TSH – can be supressed acutely then rise on recovery
o can be misinterpreted as primary hyperthyroidism - tT3 falls (imparied hepatic uptake and T4 to T3 conversion dec.)
- illnesses affects thyroid binding proteins, which reduces total hormone and raises free hormone fraction
- fT4 usually stays within references range or is modestly raised
- severity and duration of illness often correlated with the degree of abnormality observed in TFTs
- low T3 found in NTI may be an adaptive response (diminish basal rate, conserve essential body protein stores)
