Thyrotoxicosis

Symptoms and signs

• Anxiety, palpitations, tremor
• Heat intolerance
• Increased appetite
• Pruritus, acropatchy, pretibial myxoedema (in Grave’s)
• Weight loss (a few have weight gain)
• Diarrhoea
• Amenorrhoea
• Fatigue
• Visual problems, eye signs (see below)
• Goitre, neck pain (in thyroiditis)
• Compression symptoms – a large goitre may cause dysphagia or breathlessness due to oesophageal or tracheal compression
• CV consequences – hypertension, atrial fibrillation, heart failure
• Proximal myopathy
• Osteoporosis, hypercalcaemia
• Can be mistaken for anxiety, or the menopause
• Ask about recent pregnancy, iodine contrast media, autoimmunity/family history, drugs, cerebral disease (to help understand the cause)

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Common causes (90% of cases)

• Graves’ disease
  • • The most common cause of hyperthyroidism in iodine-sufficient areas, accounting for about 75% of cases
    • Peak incidence is at 30–50 years of age, and it is 10 times more common in women
    • Often a family history
    • Large spectrum – some mildly thyrotoxic, others extremely
    • The thyroid gland is usually diffusely symmetrically enlarged without nodules, and there may be a bruit (but not always a goitre)
    • Smoking is a dose‐dependent risk factor
    • Progression is independent of thyroid status
    • Eye signs
      • • Proptosis, ophthalmoplegia, chemosis, periorbital oedema in one third
        • People report puffiness, redness, watering, diplopia, grittiness. Not usually itchy/sticky
        • Occurs in both Graves and Hashimotos, and patients can be hypothyroid, hyperthyroid or euthyroid. More likely in smokers
        • Treat with drops, selenium supplement, antithyroid drugs, steroids, surgery
        • Refer same day if severe pain, loss of acuity/colour vision, corneal opacification, inability to close eyes
    • Investigations – check for other autoimmune disease and check TSH-receptor antibodies. Don’t need to image thyroid routinely if diagnosis clear
• Toxic multinodular goitre (TMG)
  • • The second most common cause of hyperthyroidism in the UK, and is more common in older adults
    • Usually not extremely thyrotoxic
    • Condition never remits so needs surgery or radioiodine after anti-thyroid drugs
• Toxic thyroid nodule (adenoma) – accounts for up to 5% of cases of hyperthyroidism, also more common in older adults

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Uncommon causes (10%)

• Thyroiditis
  • • Causes thyrotoxicosis without hyperthyroidism
    • Due to release of stored T3/4 into circulation (can be very thyrotoxic)
    • Treat with betablockers rather than antithyroid drugs
    • Can use thyroxine if hypothyroid phase is prolonged but trial off thyroxine later
    • Postpartum thyroiditis (PPT)
      • • A painless, inflammatory autoimmune condition which typically occurs within 2–6 months after delivery or miscarriage.
        • There’s a thyrotoxic phase and then a hypothyroid phase
        • 20% are permanently hypothyroid
        • Monitor TFTs every 4 weeks
    • Subacute (de Quervain’s) thyroiditis
      • • Typically presents with thyroid pain and fever, and is thought to be due to a viral infection or a post viral inflammatory process
        • There’s a tender, firm, irregular, diffusely enlarged thyroid gland which may be asymmetrical
        • Hyperthyroid phase of around 4 weeks, then euthyroid or hypothyroid, then recovery in most
        • Normal thyroid antibodies
        • Give analgesia and sometimes steroids. Can recur
• Secondary hyperthyroidism
  • • High/normal TSH and high T4
    • May be due
      • • TSH-secreting pituitary adenoma
        • Struma ovarii
        • Hydatidiform mole
        • Other tumours
• Drugs
  • • Amiodarone-induced thyrotoxicosis
    • Iodine exposure (seaweed)
    • Interferons
    • Immunotherapies
• Pregnancy – Gestational Transient Thyrotoxicosis (GTT) – high concentrations of human chorionic gonadotrophin (hCG) can stimulate TSH receptors and suppress TSH
• Thyroxine – excess use of levothyroxine may be intentional (factitious) or unintentional (iatrogenic)
• Follicular thyroid cancer – although note that TSH is suppressed as part of the treatment for thyroid cancer… so don’t lower their levothyroxine dose!
• Thyrotoxic periodic paralysis
  • • More common in Asian males, especially after vigorous exercise or high carbohydrate meals
    • Flaccid ascending paralysis, proximal>distal, which spares facial and respiratory muscles
    • Depressed or absent deep tendon reflexes
    • Causes hypokalaemia
    • Management involves oral propranolol 60mg orally every 6 hours, replacing potassium, treating hyperthyroidism and avoiding IV glucose

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 Investigations

• TFTs
• TSH-receptor antibodies (TRAbs) – If a diagnosis of Graves’ disease is suspected or the person is pregnant
• Thyroid peroxidase antibodies (TPOAbs) – If a woman is postpartum and a diagnosis of postpartum thyroiditis is suspected
• Consider an ultrasound of the neck
  • • If malignancy suspected (though note that TFTs are usually normal in people with thyroid cancer)
    • USS can’t always reliably distinguish between benign and malignant lesions. Sometimes a biopsy required – see thyroid lumps and nodules. A cold nodule has < 20% chance of being malignant
• Radionuclide thyroid scan
  • • If thyroid-stimulating hormone (TSH)-receptor antibodies TRAbs are not present, a scan of radionuclide thyroid uptake (with radioiodine or technetium) can help distinguish different causes of hyperthyroidism while awaiting specialist endocrinology assessment
    • Uniform uptake typical of Graves
    • Patchy uptake in toxic multinodular goitre
    • Localised uptake in adenoma
    • Low uptake in thyroiditis (antithyroid drugs not required)
    • Contraindicated in pregnancy
• Consider DEXA scan, echo or holter for some

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Subclinical hyperthyroidism

• Low TSH and normal T4
• Iodine deficiency and factitious use of thyroxine are differentials
• If TSH undetectable – more likely to develop overt hyperthyroidism
• Check T3 – patient may have T3 toxicosis (usually due to multinodular goitre or single adenoma, treat this straight away)
• If low TSH, normal T3 and T4 – repeat TFTs in 2 months
• If TSH remains low – can repeat in another 2 months, then refer endocrinology at 6 months (consider a Holter or DEXA scan to look for complications of hyperthyroidism like osteoporosis or AF)
• Usually treat if aged > 65 and TSH < 0.1 (as increased risk of AF, CVA, death), and have a lower threshold if goitre, symptoms or positive thyroid antibodies

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Management of thyrotoxicosis

• Consider prescribing a beta-blocker (propranolol used most often)
  • • Can titrate the dose depending on clinical response
    • If intolerant or asthmatic, can try a rate limiting calcium channel blocker instead
    • Often need a relatively large dose (such as propranolol 40mg QDS) as lots removed in first pass metabolism (but not in thyroid storm – fill them first, then betablock)
    • May be the only treatment needed in transient thyrotoxicosis without hyperthyroidism (eg thyroiditis)
• Graves’
  • • Offer a choice between radioiodine and antithyroid drugs (if drugs likely to induce remission)
    • If persistent or relapsed hyperthyroidism – go for radioiodine or surgery
    • Total thyroidectomy is first line in Graves’ if concerns around compression, malignancy or if other treatments unsuitable

• Antithyroid drugs
  • • Usually best for mild, uncomplicated Graves’
    • Usually use for 12-18 months
    • Monitor TFTs every 6 weeks until TSH in range, then every 3 months
    • Carbimazole usually first line for Graves (unless allergic, pregnant or planning pregnancy in next 12 months)
      • • Dose depends on T4 level
          • • T4 20-30 – 10mg OD
            • T4 30-40 – 20mg OD (some would give 30mg)
            • T4 40-60 – 20mg BD
            • T4 > 60 – 20mg TDS
        • Then reduce dose, or increase dose and add thyroxine
        • Max dose 25mg/day if breastfeeding
        • Side effects include rashes, agranulocytosis, pancreatitis/liver dysfunction
        • Rash is common – treat with antihistamine (warn patients prior)
        • Follow up
          • • Check FBC and LFTs only if unwell
            • It takes 2-4 weeks to start to feel better
            • See in clinic in 6 weeks
            • Recheck TFTs in 4-6 weeks after dose changes
            • Will convert most to euthyroid in one month
            • TSH receptor antibody will fall. Check at end of treatment (usually 12 or 18 months)
            • If relapse (50% do) – usually needs definitive treatment (ie surgery or radioiodine), but restart carbimazole in meantime. Long term treatment with 5-10 mg carbimazole is safe and sometimes used
        • Counsel for Agranulocytosis (and document that you explained risk)
          • • Warn patients to stop if sore throat, flu-like illness, mouth ulcers, fever and seek urgent blood tests (agranulocytosis).
            • If normal WCC – can restart it.
            • Diagnosed if neutrophils < 0.5
            • Occurs in first 3 months
            • Prevalence <0.5%
            • Treat with antibiotics and sometimes GCFS
            • Note if neutropenia mild and asymptomatic – this could be normal for the patient not related to treatment
            • Can’t have any antithyroid drugs after this – often have emergency thyroidectomy
            • Risk is dose-related
    • Propylthiouracil (PTU)
      • • 2^nd line due to a small risk of severe liver injury, except in certain circumstances such as pre-pregnancy or the first trimester of pregnancy, or for specialist treatment of thyrotoxic crisis. Also used if history of pancreatitis.
        • Dose of PTU is 100-600mg BD (dose equivalents: 5mg carbimazole = 50mg PTU, but the latter needs to be split dose)
        • Again titrate against T4 concentrations at 4-6 weeks, follow up every 3 months
        • Monitor LFTs (although ALP often raised in hyperthyroidism, and alone it doesn’t usually mean discontinuation)
    • Pregnancy
      • • Some say must be on contraception as carbimazole teratogenic
        • Some say both drugs probably safe. Possible association between carbimazole and foetal aplasia cutis, so generally PTU preferred (but can stay on carbimazole if on 20mg or less per day). PTU is excreted less in breast milk

• After euthyroidism is achieved with drugs, two different treatment regimens may be used
  • • Titration-block regime, or
    • Block and replace regime
• Relapse
  • • Remission long term seen in 55%
    • Risk factors for relapse include
      • • High TRAb level
        • Large goitre
        • Very high T3/4
        • Male
        • Family history
        • Ophthalmopathy
        • Smokers

• Radioactive iodine
  • • First-line definitive treatment for adults with Graves’ disease and those with toxic multinodular goitre – unless antithyroid drugs are likely to achieve remission or it is contraindicated
    • Especially useful if previous surgery, cardiorespiratory disease, elderly
    • Contraindications
      • • Graves’ disease with active or severe orbitopathy as it may cause an exacerbation of orbitopathy or de novo development
        • Pregnancy and breastfeeding women (don’t conceive or father a child for at least 6 months afterwards)
        • Concerns about compression
        • Malignancy suspected
    • Risks
      • • High risk of hypothyroidism (20% in first year, then 2% per year)
        • Worsening eye disease (use prophylactic steroids)
        • Sialadensitis
    • Must restrict personal contact initially due to radiation exposure (so not good if your patient has caring responsibilities)
    • Stop antithyroid drugs for 1 week before starting it
    • Treat for 3 months
    • Check TFTs every 6 weeks for the first 6 months until TSH in range
    • Can repeat if hyperthyroidism persists after 6 months of treatment

• Surgery
  • • Partial thyroidectomy (sometimes total)
    • Patients should be euthyroid first
    • Afterwards monitor TFTs long term
    • Risks
      • • Recurrent laryngeal nerve palsy 0.5%
        • Hypoparathyroidism 5%
        • Hypothyroidism 20%
        • Recurrent hyperthyroidism 5%
        • Carotid or jugular damage 0.5%

• Refer to ophthalmology for Graves’ eye disease

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Thyrotoxic crisis / thyroid storm

• A rare and potentially life-threatening complication
• 30% mortality (although 90% if undiagnosed)
• Tends to occur in long standing thyrotoxicosis
• May occur after a trigger such as 
  • • Acute infection
    • Trauma
    • Pregnancy
    • Surgery including thyroidectomy
    • Stroke
    • Iodine load from CT contrast / radioiodine treatment
• Features
  • • Agitation and confusion – this is the most important diagnostic feature and makes diagnosis much more likely
    • Hyperthermia (also a key feature especially if >40°C), sweating, dehydrated
    • Tachycardia out of proportion to fever
    • CV complications – arrhythmias, heart failure, AF
    • Gastrointestinal symptoms – abdominal pain, jaundice, diarrhoea, vomiting
    • Seizures
    • Multiorgan failure
    • Can cause a myopathy, swallowing problems and profound muscle weakness (can be confused with neuromuscular disorders)
• Do Burch-Wartofsky Point Scale (BWPS) for Thyrotoxicosis
  • • You need to know the temperature, heart rate, ECG
    • Score > 45 = thyroid storm. 25-45 – impending storm. < 25 – storm unlikely
• Investiagations
  • • TFTs
      • • T4 always high (>45) and TSH 0
        • But the severity does not correlate to numbers (and TFTs irrelevant to the scoring). It’s more about sensitivity to thyroid hormones (eg due to surgery, infection, iodine load)
    • Check usual bloods plus calcium, LFTs, CBG. Typically – High WCC, raised alk phos, mildly raised calcium
    • ECG
    • Consider thyroid uptake scan later
    • Send antibodies but don’t delay treatment waiting for results
• Management
  • • HDU setting best
    • Cooling and IV fluids (caution in heart failure)
    • Might need high doses of antiarrhythmics like digoxin
    • Antithyroid medication – Propylthiouracil works fastest (consider 200mg TDS or QDS, PO/NG/PR)
    • Then > one hour after PTU, can give potassium iodide / Lugols iodine (5 drops QDS PO in milk or orange juice). It blocks TH release/production
    • Give IV fluids before betablockers – Can try propranolol 80mg TDS PO (a big dose!), or 2 mg IV, or as an infusion 2-5 mg /hour
    • Consider calcium channel blocker if betablocker contraindicated
    • Steroids – hydrocortisone 200mg IV, or dexamethasone 2mg every 6 hours (reduces conversion of T3 to T4), then prednisolone 20mg TDS
    • Chlorpromazine is useful for both hyperpyrexia and agitation. Can try 50-100mg IM for sedation
    • Lithium can be used an alternative antithyroid drug if you can’t use the standard ones
    • Cholestyramine 4g QDS – reduces enterohepatic circulation of thyroid hormones
    • Consider antibiotics – low threshold
    • Avoid aspirin – releases thyroid hormone from binding globulin
    • Give thiamine
    • Check CBGs four hourly
    • If the patient is resistant to antithyroid drugs – can use plasmapheresis and dialysis (otherwise giving general anaesthesia for thyroidectomy poses big risks)
    • Can use radioiodine later or thyroidectomy