Hyperthyroidism: Causes, Antithyroid Drugs and Thyroid Storm

Introduction

Thyrotoxicosis is the clinical and biochemical syndrome resulting from excess circulating thyroid hormone. Hyperthyroidism is the subset in which the thyroid gland itself is overproducing hormone. The distinction is not pedantry: thyrotoxicosis caused by a destructive thyroiditis or by exogenous thyroxine will not respond to antithyroid drugs, because there is no excess synthesis to block.

Thyrotoxicosis affects around 2% of women and 0.2% of men, and is around ten times more common in women overall.

Clinical features

Symptoms

• Weight loss despite an increased appetite - a highly suggestive combination
• Heat intolerance and excessive sweating
• Palpitations
• Anxiety, irritability, restlessness and emotional lability
• Tremor
• Insomnia and fatigue - patients are exhausted but unable to rest
• Diarrhoea or increased bowel frequency
• Oligomenorrhoea or amenorrhoea, and reduced libido
• Proximal muscle weakness - difficulty rising from a chair or climbing stairs
• Itch and thinning hair

Signs

• Tachycardia, and atrial fibrillation in around 10 to 15%, rising steeply with age
• Fine tremor of the outstretched hands
• Warm, moist skin and palmar erythema
• Lid retraction and lid lag - caused by sympathetic overactivity of the levator palpebrae and occurring in thyrotoxicosis of any cause. Distinguish these from proptosis, which is specific to Graves' orbitopathy.
• Goitre - diffuse and smooth with a bruit in Graves', nodular in toxic multinodular goitre, solitary in toxic adenoma, and tender in subacute thyroiditis
• Proximal myopathy and brisk reflexes
• Onycholysis (Plummer's nails) - separation of the nail from the nail bed
• Signs specific to Graves' disease - proptosis, ophthalmoplegia, pretibial myxoedema and thyroid acropachy. Their presence makes the diagnosis without further testing.

Investigations

Determining the cause

• TSH receptor antibodies (TRAb) - positive in around 95% of Graves' disease and effectively diagnostic. NICE recommends measuring TRAb to confirm Graves' rather than proceeding straight to imaging in most patients.¹
• Anti-TPO antibodies - positive in Graves' and in Hashimoto's, so less discriminating
• Technetium or radioiodine uptake scan - where TRAb is negative or the picture is unclear. It separates the high-uptake causes from thyroiditis and exogenous hormone (see figure above).
• Thyroid ultrasound - for nodules and to assess vascularity, which helps distinguish type 1 from type 2 amiodarone-induced thyrotoxicosis
• ESR and CRP - markedly raised in subacute thyroiditis, which is also painful
• Thyroglobulin - low or suppressed in exogenous thyrotoxicosis, and raised in thyroiditis. This is how factitious thyrotoxicosis is detected.

Other tests

• ECG - for atrial fibrillation
• Full blood count - a baseline before starting a thionamide is essential, as is a baseline for comparison if agranulocytosis is later suspected
• Liver function tests - deranged in thyrotoxicosis itself, and a necessary baseline before antithyroid drugs
• Bone profile - calcium and alkaline phosphatase are often raised from increased bone turnover
• Glucose, since thyrotoxicosis worsens glycaemic control
• Pregnancy test in women of childbearing age - it changes drug choice entirely

Management

Symptom control

• Propranolol - typically 40 mg three times daily, or a longer-acting alternative. It controls tremor, palpitations, anxiety and sweating within days, and additionally inhibits peripheral conversion of T4 to T3.
• Diltiazem or verapamil where beta-blockade is contraindicated, most commonly in asthma
• Continue until the patient is biochemically euthyroid, then withdraw

Antithyroid drugs (thionamides)

These inhibit thyroid peroxidase and therefore hormone synthesis. They take 4 to 6 weeks to produce clinical improvement, because the gland's existing hormone stores must be depleted first - which is why a beta-blocker is given alongside.

• Carbimazole is first line in the UK, given as either a titration (dose-reduction) regimen or a block-and-replace regimen in which a fixed high dose is combined with levothyroxine
• Propylthiouracil is reserved for the first trimester of pregnancy, for thyroid storm, and where carbimazole cannot be used - because it carries a risk of severe hepatotoxicity and acute liver failure
• Duration in Graves' disease is typically 12 to 18 months, after which the drug is stopped and the patient monitored. Around half relapse, most within the first year.
• Toxic nodular disease does not remit - a drug course will control it but will not cure it, so definitive treatment with radioiodine or surgery is required

Definitive treatment

Cause-specific management

• Thyroiditis (low uptake) - antithyroid drugs have no role. Treat symptomatically with a beta-blocker, and NSAIDs or corticosteroids for the pain of subacute thyroiditis. Expect a thyrotoxic phase, then a hypothyroid phase, then usually recovery - and monitor rather than treating each swing.
• Amiodarone-induced thyrotoxicosis - type 1 occurs in an abnormal gland from iodine excess, shows increased vascularity on Doppler and responds to carbimazole, sometimes with potassium perchlorate; type 2 is a destructive thyroiditis with absent vascularity and responds to corticosteroids. Mixed pictures are common, and management should be joint with endocrinology and cardiology. Whether to stop the amiodarone depends on the cardiac indication and it has a half-life of many weeks.
• Subclinical hyperthyroidism - consider treating if TSH is persistently below 0.1 mU/L on two occasions 3 months apart, particularly in those over 65, or with atrial fibrillation, osteoporosis or cardiac disease, because of the risk of fracture and arrhythmia
• Pregnancy - distinguish gestational thyrotoxicosis (hCG-mediated, associated with hyperemesis, self-limiting, no TRAb) from Graves' disease. Use propylthiouracil in the first trimester and switch to carbimazole thereafter, at the lowest effective dose. TRAb crosses the placenta and can cause fetal and neonatal thyrotoxicosis, so measure it and involve fetal medicine.

Thyroid storm

A rare, life-threatening decompensation of thyrotoxicosis with a mortality of 10 to 30%. It is a clinical diagnosis - the thyroid hormone levels are no higher than in uncomplicated thyrotoxicosis, and waiting for them delays treatment.

Complications

• Atrial fibrillation - occurring in 10 to 15%, with associated thromboembolic risk. It frequently reverts to sinus rhythm once the patient is euthyroid, so anticoagulation and rhythm decisions should account for that.
• Heart failure - high-output failure, and thyrotoxic cardiomyopathy
• Osteoporosis and fragility fracture - from accelerated bone turnover, and a particular concern in postmenopausal women and in subclinical disease
• Thyroid storm
• Thyroid eye disease - specific to Graves', and covered separately
• Thyrotoxic periodic paralysis - episodic profound hypokalaemic weakness, classically in young men of East Asian descent, precipitated by carbohydrate loads and exercise. Treat the thyrotoxicosis and replace potassium cautiously, as rebound hyperkalaemia can occur.
• Proximal myopathy
• Subfertility, miscarriage, pre-eclampsia and preterm birth
• Anxiety, psychosis and cognitive impairment
• Treatment complications - agranulocytosis and hepatotoxicity from thionamides, permanent hypothyroidism after radioiodine or surgery, and recurrent laryngeal nerve or parathyroid injury after thyroidectomy

Red flags

Prognosis

Outcome depends heavily on the cause. Thyroiditis is self-limiting in most cases - the thyrotoxic phase lasts weeks, is followed by a hypothyroid phase, and the majority recover normal function, although around a quarter of women with postpartum thyroiditis develop permanent hypothyroidism.

Graves' disease remits after a 12 to 18 month course of antithyroid drugs in around half of patients, with relapse most likely in the first year. Predictors of relapse include a large goitre, high initial T4 and T3 levels, persistently high TRAb titres, young age and smoking. Definitive treatment with radioiodine or surgery is highly effective, at the near-certain cost of lifelong levothyroxine - which is a trade most patients accept readily once it is framed as exchanging an unpredictable disease for a predictable tablet.

Toxic nodular disease does not remit spontaneously and requires definitive treatment.

Two points deserve emphasis. Untreated thyrotoxicosis carries real cardiovascular and skeletal cost - atrial fibrillation, thromboembolism, heart failure and fragility fracture - and this applies to persistent subclinical disease in older people too, which is why a suppressed TSH should not simply be observed indefinitely. And smoking cessation matters specifically here: smoking increases the risk of relapse after drug treatment and is the strongest modifiable risk factor for thyroid eye disease, making it one of the few interventions that alters the natural history of the condition.