Hyperthyroidism

Hyperthyroidism is a common endocrine condition caused by an overactive thyroid gland causing an excess of thyroid hormone.

Hyperthyroidism affects around 1-2% of the population. It more commonly affects women than men (5:1) and may be associated with a number of autoimmune and endocrine conditions.

Hyperthyroidism and thyrotoxicosis are not interchangeable terms (though they are often used this way). Thyrotoxicosis refers to an excess of thyroid hormone, having an overactive thyroid gland is not a prerequisite.

Thyroid hormone release is controlled by the hypothalamic-pituitary-thyroid axis.

1. Thyrotropin releasing hormone

TRH is secreted from the paraventricular nucleus of the hypothalamus. As the name suggests it is a tropic hormone i.e one that acts upon another endocrine gland. 

It reaches the anterior pituitary via the hypophyseal portal system. Here it causes the release of thyroid stimulating hormone. 

2. Thyroid stimulating hormone

TSH, produced by the thyrotrophs of the anterior pituitary, is released following stimulation by TRH.

Transported in the blood, TSH acts upon the thyroid gland promoting the synthesis and release of thyroid hormone.

3. Triiodothyronine and thyroxine

The thyroid is stimulated to synthesise and release thyroid hormone by TSH. The thyroid produces two hormones, thyroxine (T4) and triiodothyronine (T3). 

These thyroid hormones complete a negative feedback loop through the suppression of TRH and TSH release.

Though T3 is more biologically active than its counterpart T4, secreted thyroid hormone is 90% T4. Peripherally much of T4 is converted to T3.

Both are highly lipophilic, act on intracellular receptors and bind to thyroxine-binding globulin (TBG) in the blood. Only the ‘free pool’ is active: <0.1% T4 and <1% of T3.

The effects to T3/T4 are numerous:

• BMR: increases the basal metabolic rate.
• Metabolism: it has anabolic effects at low serum levels and catabolic effects at higher levels.
• Growth: increases release and effect of GH and IGF-1.
• Cardiovascular: increases the heart rate and contractility through increasing sensitivity to catecholamines. 

Hyperthyroidism is an excess of thyroid hormone caused by overactivity of the thyroid gland.

Graves’ disease

Graves’ disease is a common autoimmune condition and is the most common cause of hyperthyroidism (60-80% of cases) in the UK.

It is caused by IgG antibodies to the TSH receptors found within the thyroid. Termed TSHR-Ab, these antibodies mimic the action of TSH causing excessive stimulation of the gland.

Graves’ ophthalmopathy affects up to 30% of patients.

Toxic multinodular goitre

Toxic multinodular goitre is the second most common cause of hyperthyroidism in the UK.

In this condition multiple autonomous nodules develop that are capable of secreting thyroid hormones.

Solitary toxic adenoma

In this condition, a single adenoma develops and produces thyroid hormones.

Amiodarone-induced thyrotoxicosis type 1

Amiodarone is a lipophilic class III anti-arrhythmic drug with a high iodine content. Its effects on the thyroid can be alarming and may cause both hypothyroidism and hyperthyroidism.

In type 1 the Jod-Basedow phenomenon, in which excess iodine intake causes excess thyroid hormone synthesis, occurs. It is seen in patients with pre-existing thyroid disease.

Beta-HCG related

Beta-HCG is thought to mimic the action of TSH causing thyroid hormone synthesis and release. It occurs in states of elevated Beta-HCG:

• Pregnancy 
• Hydatidiform mole 
• Choriocarcinoma 
• Testicular germ cell tumour

Pituitary adenoma

In rare cases, a TSH-secreting pituitary adenoma causes excess stimulation of the thyroid gland and resultant hyperthyroidism.

Thyrotoxicosis may occur without hyperthyroidism (i.e. an overactive thyroid gland), these conditions are described as thyrotoxicosis without hyperthyroidism.

These conditions do not feature overactivity of the thyroid gland. This may be demonstrated by reduced or absent radioiodine uptake. It can result from:

• Thyroiditis: inflammation of the thyroid gland resulting in the release of stored thyroid hormone. 
• Exogenous ingestion: a person ingests thyroid hormone.
• Ectopic production: tissue outside the thyroid gland itself produces thyroid hormone.

Anti-thyroid drugs will have little effect in the majority of these conditions as increased synthesis of thyroid hormone is not always part of the aetiology.

Levothyroxine

When taken at supra-therapeutic doses levothyroxine may cause thyrotoxicosis without hyperthyroidism. Patients may abuse levothyroxine for weight-loss purposes.

De Quervain’s (subacute granulomatous) thyroiditis

This is a self-limiting condition, thought to be viral in origin. It results in inflammation of the thyroid gland and release of thyroid hormone.

It features three phases:

• Thyrotoxicosis
• Hypothyroidism
• Resolution

It characteristically causes a painful goitre.

Amiodarone-induced thyrotoxicosis type II

Amiodarone is a lipophilic class III anti-arrhythmic drug with a high iodine content. Its effects on the thyroid can be alarming and may cause both hypothyroidism and hyperthyroidism.

Type 2 is caused by a destructive thyroiditis with resultant release of thyroid hormone. 

Follicular thyroid cancer

In metastatic follicular thyroid cancer, malignant tissue may remain functional. The increased amounts of tissue can lead to an overproduction of thyroid hormone. 

Struma ovarii

This is a rare but interesting condition. Hyperthyroidism is caused by thyroid hormone release from ectopic thyroid tissue related to:

• Ovarian teratomas
• Dermoid tumours

The majority of these tumours are benign.

Symptoms

• Goitre
• Palpitations
• Heat intolerance
• Weight loss
• Diarrhoea 
• Amenorrhoea 
• Reduced libido
• Gynaecomastia (in men)
• Fatigue

Signs

• Goitre
• Sinus tachycardia/arrhythmias
• Myxoedema - deposition of mucopolysaccharides in the skin leading to swelling.
• Hair loss
• Palmar erythema
• Tremor
• Thyroid bruit (Graves’)

Graves' disease has a number of unique features.

Graves’ ophthalmopathy

This condition affects up to 50% of patients with Graves', threatening sight in 5-10% of these cases. It is more commonly seen in smokers.

The pathogenesis of Graves’ ophthalmopathy is not fully understood, it is known that TSHR-Abs are involved. Inflammation and accumulation of mucopolysaccharides occur in the retro-orbital adipose tissue and extra-ocular muscles.

It may be classified with the American Thyroid Association system (using the mnemonic 'NOSPECS'). 

Onset may precede the presentation of hyperthyroidism or follow its treatment. Radioiodine is thought to increase the chances of developing Graves’ ophthalmopathy.

Features include proptosis, periorbital oedema, lid retraction, eye pain and visual loss.

Thyroid dermopathy

The most common manifestation is pretibial myxoedema. This is an infiltrative dermopathy resulting from deposition of mucopolysaccharides in the dermis.

Thyroid acropachy

This is characterised by periostitis, nail clubbing and soft tissue swelling of the extremities. It's most commonly seen in smokers with co-concomitant Graves’ ophthalmopathy.

Measurement of TSH and fT4/fT3 are necessary to diagnose hyperthyroidism.

Hypothalamic-pituitary-thyroid axis

Primary hyperthyroidism: low TSH, raised fT4 and fT3

Subclinical hyperthyroidism: low TSH, normal fT4 and fT3

Pituitary adenoma: high TSH, raised fT4 and fT3

Autoantibodies

Thyroid stimulating hormone receptor antibodies (TSH-Ab) are seen in >90% of those with Graves’ disease, measurement not typically indicated.

Imaging

May be used if aetiology uncertain or malignancy suspected:

• Ultrasonography
• Thyroid uptake scan

Anti-thyroid drugs (thioamides), radioactive iodine (RAI) and surgery are all viable management options.

Thioamides

The thioamides carbimazole and propylthiouracil are the mainstays of treatment. These drugs reduce thyroid synthesis working over a number of weeks.

A beta-blocker or calcium channel blocker may be prescribed to treat adrenergic symptoms whilst the thioamides take effect.

In the UK carbimazole is used first-line. Propylthiouracil may be used first-line if the patient is intolerant to carbimazole, in the first trimester of pregnancy or if in thyroid storm (for acute thyrotoxic crisis see below).

Baseline FBC and LFTs are obtained prior to the commencement of thioamides. Neutropaenia or severely deranged transaminases are a contraindication to treatment.

Agranulocytosis is a severe side effect associated with both thioamides.

Two regimes available:

• Block and replace: Thioamides given at a level sufficient to block endogenous T3/T4 production alongside levothyroxine. This regime must not be used in pregnancy.
• Dose titration: Thioamides are given alone, dose adjusted to give normal levels of T3/T4.

In Graves' disease remission may be seen after 18-24 months of treatment, demonstrated by a trial without therapy.

NOTE: The decision about whether to treat subclinical hyperthyroidism is complex. Some 5% of patients with subclinical disease will develop overt features each year. Decisions about treatment should take the underlying aetiology, severity and associated comorbidities into account. ​

Radioactive iodine

RAI is taken up by the thyroid causing destruction and reduced thyroid hormone release. It is contraindicated in pregnant women and those breastfeeding.

In Graves, RAI may exacerbate or cause ophthalmopathy. 

Thyroidectomy

A thyroidectomy may be used as definitive therapy in the malignant or treatment resistant setting.

Complications of the surgery include:

• Hypocalcaemia: affects 10%, typically transient, may be permanent in a minority of cases. Due to the proximity of parathyroid gland to the thyroid gland.
• Recurrent laryngeal nerve injury: presents with hoarse voice post-operatively.

Management of Graves’ ophthalmopathy is dependent on disease severity.

In mild disease ('NO') artificial tears, elevation of the head during sleep and sunglasses may help symptoms. Smoking cessation is always advised.

In more severe disease ('SPECS') further management is necessary. Referral to an ophthalmologist is required if there is evidence of optic nerve compression, corneal opacity or inability to close an eye.

Treatment may include:

• Steroids
• Irradiation
• Surgical decompression

A thyrotoxic crisis is rare but potentially fatal result of untreated/undertreated hyperthyroidism. 

It is a medical emergency that requires admission to hospital that may result from decompensation during an intercurrent illness.

It presents with hyperthermia, tachycardia, arrhythmias, nausea, vomiting, seizures and cognitive decline. 

Management involves:

• Beta-blockers
• Thionamides: typically propylthiouracil, which in addition to its anti-thyroid effect also reduces the conversion of T4 to T3.
• Corticosteroids: reduce the conversion of T4 to T3.

Electrolyte imbalances, heart failure and hyperthermia should be addressed. Dialysis or plasma exchange may be required.