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 is important to first define the terminology:
Hyperthyroidism more commonly affects women than men (5-10 times more common) and may be associated with a number of autoimmune and endocrine conditions.
Thyroid hormone release is controlled by the hypothalamic-pituitary-thyroid axis.
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.
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.
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:
Hyperthyroidism is an excess of thyroid hormone caused by overactivity of the thyroid gland.
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 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.
In this condition, a single adenoma develops and produces thyroid hormones.
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 is thought to mimic the action of TSH causing thyroid hormone synthesis and release. It occurs in states of elevated Beta-HCG:
In rare cases, a TSH-secreting pituitary adenoma causes excess stimulation of the thyroid gland and resultant hyperthyroidism.
In metastatic follicular thyroid cancer, malignant tissue may remain functional. The increased amounts of tissue can lead to an overproduction of thyroid hormone.
This is a rare but interesting condition. Hyperthyroidism is caused by thyroid hormone release from ectopic thyroid tissue related to:
The majority of these tumours are benign.
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:
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.
When taken at supra-therapeutic doses levothyroxine may cause thyrotoxicosis without hyperthyroidism. Patients may abuse levothyroxine for weight-loss purposes.
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 (though does not always follow this pattern):
It characteristically causes a painful goitre.
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.
Hyperthyroidism may be asymptomatic or present with non-specific malaise or signs of thyroid hormone excess.
Graves disease has a number of unique features that may be present which we discuss in the chapter below.
Graves' disease has a number of unique features.
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.
The most common manifestation is pretibial myxoedema. This is an infiltrative dermopathy resulting from deposition of mucopolysaccharides in the dermis.
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.
Primary hyperthyroidism: low TSH, raised fT4 and fT3
Subclinical hyperthyroidism: low TSH, normal fT4 and fT3
Pituitary adenoma: high TSH, raised fT4 and fT3
Thyroid stimulating hormone receptor antibodies (TSHR-Ab) are seen in >90% of those with Graves’ disease.
May be used if aetiology uncertain or malignancy suspected:
Anti-thyroid drugs (thioamides), radioactive iodine (RAI) and surgery are all viable management options.
Management is complex! Here we will outline the three main modalities, discussing in particular the management of Graves', toxic multinodular goitre and solitary toxic adenoma.
Following diagnosis, patients are normally offered thioamides (carbimazole or propylthiouracil) whilst a decision on definitive therapy is being made. Definitive therapy may be radioactive iodine, ongoing thioamide therapy or surgery.
A beta-blocker or calcium channel blocker may be prescribed to treat adrenergic symptoms whilst the thioamides take effect.
RAI is taken up by the thyroid causing destruction and reduced thyroid hormone release. Contraindications include in pregnant women and those breastfeeding.
It is typically offered first-line in Graves' in those suitable and not likely to enter remission. It is often offered as first line definitive management for toxic multinodular goitre.
In Graves, RAI may exacerbate or cause ophthalmopathy.
The thioamides carbimazole or propylthiouracil may be used. These drugs reduce thyroid synthesis working over a number of weeks. May be offered first line in Graves' disease, particularly if likely to have remission (mild, uncomplicated disease). Remission may be seen after 18-24 months of treatment, demonstrated by a trial without therapy.
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:
In those with toxic nodules, treatment is likely life-long if chosen as definitive management (hence surgery or RAI is often preferred).
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.
A thyroidectomy may be used as definitive therapy if malignancy is suspected, there is a compressive goitre or RAI/ anti-thyroid medications are unsuitable.
Hemithyroidectomy may be offered to patients with a solitary toxic nodule.
Complications of the surgery include:
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:
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:
Electrolyte imbalances, heart failure and hyperthermia should be addressed. Blood sugar must be monitored. Dialysis or plasma exchange may be required.
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