Endocrinology - Week 2 Flashcards
what percentage of the population has thyroid disease?
2-5%
more common in women - autoimmune
what are follicles filled with?
colloid (T3 and T4)
what do interfollicular cells produce
aka parafollicular cells or “c” cells produce calcitonin
how is thyroid hormone created?
• Iodide ions trapped within the cell and converted into iodine
• Creation begins with thyroglobulin and iodine is added onto this skeleton to create different types of thyroid hormone.
o This reaction is catalysed by thyroid peroxidase and hydrogen peroxide is also involved in the reaction
o One added iodine makes mono-iodothyronine
o Two = di-iodothyronine
o 3 = tri-iodothyronine (T3)
o 4 = tetra-iodothyronine (T4)
- Colloid is reabsorbed into the cell and broken down by lysosomes.
- T3 and T4 are then secreted
- T4 is a pro-hormone and is turned into active T3 by the removal of one iodine which is catalysed by deiodinase enzymes
how do thyroid hormones circulate
circulate in blood mainly bound to proteins • Thyroxine binding globulin (TBG) – 70% • Transthyretin – 20% • Albumin – 10% • 99.95% of T4 bound to protein
what proportions of thyroid hormones are produced where
- 20% of T3 produced from thyroid gland
- 80% produced from peripheral conversion of T4 in liver, muscle and kidney
- The thyroid produces hormones at a ratio of 14 T4:T3 1
- The pituitary and hypothalamus control the thyroid – e.g. TSH from pituitary
- Controlled by negative feedback – T3 and T4 inhibit the production of TSH from the pituitary and TRH from the hypothalamus
what are the actions of thyroid hormone?
- Growth development
- Basal metabolic rate
- Thermogenesis in brown adipose tissue
- Activate mental processes
what are some causes of primary hyperthyroidism?
• Graves disease – 75%
o Autoimmune disease
o Antibodies attack thyroid to make it overactive
o Can be associated with eye disease
• Toxic multinodular goitre – 15%
o Multiple nodules on an enlarged thyroid (goitre)
o Often one or more lumps will be overactive
o Can get lid lag or lid retraction, but no other features of thyroid eye disease
• Toxic nodule
o Single overactive lump
• Thyroiditis
o Temporary overactivity of thyroid due to damage releasing stored hormone
o Can be followed by a period of underactivity
o Triggered by pregnancy, some drugs or infection
what are some symptoms of hyperthyroidism
- Weight loss despite good appetite (often very hungry
- Tiredness
- Tremor
- Hot, sweaty
- Eyes: change in appearance, red gritty, painful, double vision)
- Muscle weakness
- Palpitations
- Diarrhoea
- Light/absent menses (periods)
- Mood: irritable, anxiety
whats important to ask about in a patient with hyperthyroidism?
- Check about asthma an heart disease (relevant to use of propranolol and risk of tachycardia respectively)
- FHx – autoimmune disease
- SHx – smoking (eyes), job and family (radio-iodine)
what could be evident in an examination of a patient with hyperthyroidism
• Agitated, talk fast
• Warm, sweaty
• Tremor
• Increased heart rate, may be atrial fibrillation
• Smooth goitre (graves) vs nodular thyroid disease
• Bruit heard over goitre almost diagnostic of graves
• Eyes
o Lid retraction and lid lag in any cause of overactive thyroid
o Any other eye signs indicate graves disease
what eye symptoms may a graves disease patient have
Redness Gritty sensation Dry or watery eyes Pain on eye movement Swelling around the eyes Proptosis – bulging eyes Double vision Loss of colour vision
how do you diagnose hyperthyroidism
- TRAbs – (TSH receptor antibodies) – significantly positive indicates graves
- TPO (thyroid peroxidase) – antibodies less specific
- If TRAbs are negative, do scintigraphy (often technetium rather than radio-iodine uptake)
what are some anti-thyroid drugs, what do they do and some side effects
- Carbimazole and propylthiouracil (PTU)
- Decrease production of thyroid hormone
- Not for thyroiditis as gland isn’t actually overactive
- Rare side effect of agranulocytosis
- Propranolol good for tremor and high HR – not in asthama
describe radioactive iodine risks
- Risk of long term hypothyroidism
- Avoid pregnancy for 6 months
- Restrict contact with children under 12 and pregnant women
- Don’t share bed with partner for 4 days
what is the risk of thyroid surgery
• Risk of long term hypothyroidism or damage to recurrent laryngeal nerve and parathyroid glands – hypocalcaemia
what is graves disease treated with first
Graves often treated with tablets first - carbimazole, block and replace, beta blockers
Radio-iodine for reccurent graves or nodular disease
how does the risk of I131 different for different thyroid disease
Risk of hypothyroidism after I131 is lower for nodular disease than graves
Risk of thyroid eye disease flaring up after I131
why do eyes pop out in thyroid eye disease
• B cell antibodies that trigger release of hormone from the thyroid also attach to TSH receptor in connective tissue behind the orbit
o Adipocytes which stimulates adipogenesis which pushes eyes forward
o Fibroblasts which stimulates production of glycosaminoglycans which retain fluid and their bulk pushes eyes forward
what might turn up in a history for thyroid eye disease
- Change in appearance of eyes or periorbital tissues
- Corneal symptoms (grittiness, photophobia, watering)
- Extra-Ocular Muscle (EOM) restriction (eg diplopia/double vision)
- Symptoms of EOM inflammation (pain at extreme gaze)
- Orbital ache unrelated to gaze
- Symptoms of optic neuropathy* (colour vision, blurred vision)
- “Popping” of eye; inability to close lids (globe subluxation*)
what is the examination for eye disease
• Redness
o (either eyes themselves or eyelids)
• Eyelids:
o thickening or oedema,
o lid retraction
- Chemosis
- Proptosis (eyes pushed forward)
- Test eye movements (“H”)
- Lagophthalmos (inability to close eyelids without forcing)
• Optic nerve
o Visual Acuity (Snellen chart)
o Fundoscopy or slit lamp to visualise head of optic nerve
whats important to remember with eye disease
- Need to differentiate between active and inactive
- Only active disease responds to steroids
- Severe but inactive disease is treated with corrective surgery
- There are scoring systems to help us
- Eg Clinical Activity Score (looks at pain, redness, swelling and change in function)
- Different classifications for severity, none of which are perfect
what is the management of Graves eye disease
• Unless mild, should manage in joint thyroid eye clinic
• Achieve euthyroidism
– Both hyper and hypothyroidism are bad
– Can have active eye disease without thyroid being overactive
– Thyroid eye disease can even present many months before thyroid disease develops
– Smoking cessation (smokers have 9x increased risk of developing severe disease and respond less well to treatment)
• Topical lubricants
• Selenium 200mcg daily (antioxidant)
• Steroids (oral or iv if active eye disease)
• Other immunosuppression (eg cyclosporine)
• If these measures do not work
– Consider orbital radiotherapy
– Consider immunosuppressant treatment (eg cyclosporine) as it is TRAbs that drive the eye disease
– Surgical decompression if evidence of optic neuropathy and raised intraocular pressure
• Once active eye disease settles may need:
– Elective decompression to resolve residual proptosis
– Squint surgery if EOM restriction
– Eyelid surgery if residual swelling or retraction
(In that order)
describe primary hypothyroidism
• Prevalence age and gender dependent • 0.3-2% women and <0.15% men • Symptoms o Tired o Weight gain, puffy eyes and skin o Feeling cold o Slow heart rate 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
what are some causes of hypothyroidism
• Hashimoto’s thyroiditis
o Antibodies attack thyroid and make it underactive
o Permanent
o Tendency can run in families
- Iatrogenic (post surgery or radioactive iodine)
- Spontaneous atrophic
These first three account for 90% of cases
• Temporary thyroiditis
o Eg Viral thyroiditis, Postpartum thyroiditis
• Other [Congenital (screening programme), Iodine deficiency (not UK), Drug-induced (e.g lithium)]
what happens in iodine deficiency
aka Derbyshire neck
very rare in UK
• Cannot manufacture enough thyroid hormone without iodine
• TSH rises in response to fall in T4
• High TSH stimulates hypertrophy (growth) of the thyroid gland
what are the fluctuations of HPT axis hormones
- T4 remains fairly constant throughout the day but drops in the early hours of the morning and rises between about 7 and 10am
- TSH dips down in the course of the afternoon and rises in the late evening so it is highest overnight and falls again in the early hours of the morning
- T3 also follows this pattern of TSH
We give synthetic T4 for hypothyroidism as it is easiest to replace for this reason (levothyroxine)
describe treatment of hypothyroidism
Up to 3% of 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 levothyroxine approximately 7 days
Once daily dosing results in stable fT4 and fT3 levels
Commonly around 100 mcg thyroxine (1.6 mcg/kg/day)
Aim to normalise TSH
Usually managed by GPs
No further Inx needed for hypothyroidism if TSH (scans do not change Mx)
Large body of evidence on safety and effectiveness of thyroxine
Taking levothyroxine on an empty stomach before breakfast is preferable than in the evening or with food
• Monitoring of therapy – Annual TFTs once stable – If dose change, wait at least 6/52 before rpt TFTs • Some OTC meds impair T4 absorption – PPIs eg omeprazole/lansoprazole – H2 antagonists eg ranitidine – Iron, calcium, aluminium – Don’t take T4 <4h after these • Increased T4 requirement if start oestrogen (OCP, HRT) or anticonvulsants
describe T3 and T4 combination
- Levothyroxine is not the perfect thyroid hormone replacement but current alternatives do not have strong evidence of greater effectiveness (eg combination T3/T4, dessicated thyroid extract)
- T3 (liothyronine) peaks at 2 – 4 hours 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 therapy
describe DTE: Dessicated Thyroid Extract
- DTE, “Natural thyroid”, Armour thyroid
- Contains T3 and T4
- Human thyroid T4:T3 is 14:1
- One ‘grain’ (60mg) contains 38μg T4 and 9μg T3 (4:1 ratio)
- Pork thyroid extract is clearly not natural for humans
- Pig thyroid extract contains other substances beyond T3 and T4
- A short-term study (16 weeks) compared DTE with levothyroxine
- 48.6% preferred DTE, 18.6% preferred levothyroxine and 32.9% expressed no preference
- DTE group was 3lb lighter but HDL (“good”) cholesterol was worse. No other clinically significant differences between groups
- No long-term studies so safety has not been established
- Potential placebo effect.
which thyroid medication is best?
- Hypothyroid patients with less active deiodinase 2 had slightly better response to combination T3 and T4 than T4 alone
- In the future, genetic markers may help guide therapy
- Levothyroxine alone is adequate for most hypothyroid patients
- Research needed to identify patients who may benefit from T3
- Beware potential placebo effect of less evidence-based treatments
- TSH suppression should be avoided wherever possible
- Safety of T3 and DTE is not well established
what is important about TSH
TSH is the most sensitive indicator of thyroid hormone status – earliest indicator of something going wrong
If T4 and T3 are normal but TSH is elevated it is called subclinical hypothyroidism
describe clinical hypothyroidism
- Prevalence 4-10%
- Main cause is autoimmune chronic thyroiditis
• Some (weak) evidence of adverse effects
– Lipids
– BP
– Other CV risks eg CRP, arterial stiffness
– No hard end-points evidence (ie no evidence that it increases heart attacks or strokes)
– No convincing evidence that it causes symptoms
• However, TFTs often checked because of symptoms that MAY relate to thyroid so patients often convinced that the two are linked
what can low levels of TSH, T3 and T4 be due to?
an indicator of non-thyroidal illness
what are the levels of hormones in primary hypothyroidism?
high TSH, low T4, low or normal T3
what are the levels of hormones in subclinical hypothyroidism
high TSH, normal T4, normal T3
what are the levels of hormones in secondary hypothyroidism
low or normal TSH, low T4, low or normal T3
describe non-thyroidal illness
– TSH: can be suppressed acutely then rise on recovery.
– tT3 falls (impaired T4 hepatic uptake and T4 to T3 conversion).
– Illnesses affects thyroid hormone binding proteins, which reduces total hormone and raises free hormone fraction.
– fT4 usually stays within reference 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 metabolic rate; conserve essential body protein stores).
– Many hormones and substances raised in acute illness supress TSH
what are the mechanism of TSH supression in NTI
– TRH release suppressed by cytokines and glucocorticoids
– Some drugs e.g dopamine may also inhibit TSH release.
– Carbohydrate residues on TSH dictate its biological activity and plasma half-life. In NTI, the carbohydrate moieties on TSH are modified, leading to diminished bioactivity.
– In illness, thyroid hormone uptake by the liver is impaired, resulting in low circulating tT3.
– Conversion of T3 to T4 by deiodinases is impaired in NTI so T3 levels fall.
– Deiodinases may be affected by oxidative stress, altered redox state of the cell and cytokine release
whats important to remember about NTI
- Illness can mimic TFTs seen in patients with thyroid disease.
- For example, acute illness may produce elevated Free T4 and suppressed TSH (similar to primary hyperthyroidism) but low T3 points to NTI
- In patients recovering from illness a raised TSH may be misinterpreted as hypothyroidism.
- No evidence that giving thyroxine helps in this situation
- TFTs should not be performed in patients with chronic or acute illness unless thyroid disease is considered to be the cause of their presenting complaint.
