Hyperthyroidism

• Hyperthyroidism is an endocrine condition from an overactive thyroid gland producing excess thyroid hormone.
• It affects 1-2% of the population.

Terminology

• Hyperthyroidism: overactive thyroid gland, increased thyroid hormone production, causing excess thyroid hormone and thyrotoxicosis.
• Thyrotoxicosis: excess of thyroid hormone, overactive thyroid gland is not required.

Thyroid Physiology

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

Thyrotropin Releasing Hormone

• TRH is secreted from the paraventricular nucleus of the hypothalamus.
• It is a tropic hormone that acts on another endocrine gland.
• It reaches the anterior pituitary via the hypophyseal portal system, causing the release of thyroid stimulating hormone.

Thyroid Stimulating Hormone

• TSH is produced by the thyrotrophs of the anterior pituitary and released following TRH stimulation.
• Transported in the blood, TSH acts on the thyroid gland, promoting the synthesis and release of thyroid hormone.

Triiodothyronine and Thyroxine

• The thyroid is stimulated by TSH to synthesize and release thyroid hormones, producing thyroxine (T4) and triiodothyronine (T3).
• These hormones complete a negative feedback loop by suppressing TRH and TSH release.
• Secreted thyroid hormone is 90% T4, though T3 is biologically more active.
• Peripherally, much of T4 is converted to T3.
• The effects to T3/T4 are numerous.
• Both are 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

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

Thyrotoxicosis with Hyperthyroidism

• Thyrotoxicosis with hyperthyroidism is an excess of thyroid hormone caused by overactivity of the thyroid gland.

Graves' Disease

• Graves' disease is an autoimmune condition, the most common cause of hyperthyroidism (60-80% of cases) in the UK.
• IgG antibodies to TSH receptors in the thyroid cause it.
• Termed thyroid-stimulating hormone receptor antibodies (TSHR-Ab), they mimic TSH action, causing excessive gland stimulation.
• 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.
• Multiple autonomous nodules develop, producing and secreting thyroid hormones.

Solitary Toxic Adenoma

• A single adenoma develops and produces/releases excess thyroid hormones.

Amiodarone-Induced Thyrotoxicosis Type 1

• Amiodarone is a lipophilic class III anti-arrhythmic drug with 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, excess iodine intake causes excess thyroid hormone synthesis, seen in patients with pre-existing thyroid disease.

Follicular Thyroid Cancer

• In metastatic follicular thyroid cancer, malignant tissue remains functional.
• Increased tissue amounts may lead to thyroid hormone overproduction.

Struma Ovarii

• Hyperthyroidism is caused by thyroid hormone release from ectopic thyroid tissue related to ovarian teratomas and dermoid tumours.
• The majority of these tumours are benign.

Beta-HCG Related

• Beta-HCG is thought to mimic TSH action, causing thyroid hormone synthesis and release, occurring in states of elevated Beta-HCG.
• Elevated Beta-HCG: pregnancy, hydatidiform mole, choriocarcinoma, testicular germ cell tumour.

Secondary Hyperthyroidism

• Secondary hyperthyroidism: excess TSH production stimulates increased T3/T4 production/release; very rare, typically caused by a TSH-secreting pituitary adenoma.

Thyrotoxicosis Without Hyperthyroidism

• These conditions do not feature overactivity of the thyroid gland.
• May be demonstrated by reduced or absent radioiodine uptake.
• Can result from thyroiditis (inflammation of the thyroid gland resulting in hormone release) and exogenous ingestion (a person ingests thyroid hormone).
• Anti-thyroid drugs have little effect in these conditions, as increased hormone synthesis is not always part of the aetiology.

Levothyroxine

• At supra-therapeutic doses it 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, resulting in thyroid gland inflammation and hormone release.
• It features three phases: thyrotoxicosis, hypothyroidism and resolution.
• It typically causes a painful goitre.

Amiodarone-Induced Thyrotoxicosis Type II

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

Clinical Features of Hyperthyroidism

• Hyperthyroidism may be asymptomatic or present with non-specific malaise or signs of thyroid hormone excess.
• Graves' disease has unique features.

Symptoms

• Goitre
• Palpitations
• Heat intolerance and sweating
• Weight loss and increased appetite
• Diarrhoea
• Amenorrhoea
• Reduced libido
• Gynaecomastia (in men)
• Fatigue and weakness
• Hyperactivity, irritability, insomnia
• Change in mood
• Tremor

Signs

• Goitre
• Sinus tachycardia/arrhythmias (AF >50y)
• Hair loss
• Palmar erythema
• Tremor
• Thyroid bruit (Graves')
• Hyper-reflexia
• Myxoedema (deposition of mucopolysaccharides in the skin leading to swelling)
• Warm and clammy

Features of Graves' Disease

• Graves' ophthalmopathy
• Thyroid Dermopathy
• Thyroid Acropachy

Graves' Ophthalmopathy

• Affects up to 50% of patients with Graves', threatening sight in 5-10% of these cases, more common in smokers.
• Inflammation and accumulation of mucopolysaccharides in retro-orbital adipose tissue and extra-ocular muscles occur.
• Classified with the American Thyroid Association system (NOSPECS).
• Onset may precede or follow hyperthyroidism treatment.
• Radioiodine may increase chances of this.
• Features include proptosis, periorbital oedema, lid retraction, eye pain, and visual loss.

Thyroid Dermopathy

• The most common manifestation is pretibial myxoedema, an infiltrative dermopathy resulting from mucopolysaccharide deposition in the dermis.

Thyroid Acropachy

• Characterized by periostitis, nail clubbing, and soft tissue swelling of the extremities.
• Most seen in smokers with co-concomitant Graves' ophthalmopathy.

Investigations & Diagnosis

• TSH and fT4/fT3 measurement is necessary to diagnose hyperthyroidism.
• Hyperthyroidism should be suspected in anyone presenting with the suggestive features described.
• Clinicians should have a low threshold for ordering a thyroid profile as the symptoms are often non-specific.
• NICE guidance (NG 145) advises testing for thyroid dysfunction in those with type 1 diabetes, other autoimmune diseases, and new-onset atrial fibrillation.

Thyroid Profile

• TSH levels are the single most important diagnostic test.
• A thyroid profile distinguishes between subclinical, primary, and secondary disease.
• Primary hyperthyroidism: low TSH, raised fT4/fT3.
• Secondary hyperthyroidism: high TSH, raised fT4/fT3.

Autoantibodies

• Thyroid-stimulating hormone receptor antibodies (TSHR-Ab) are seen in > 90% of those with Graves' disease.
• Check the following bloods FBC & LFT, ESR, CRP (thyroiditis) and TSH-receptor antibodies

Imaging

• May be used if the aetiology is uncertain or malignancy suspected.
• Ultrasonography
• Thyroid uptake scan:
• Thyrotoxicosis with increased uptake: indicates increased hormone synthesis.
• Thyrotoxicosis with decreased uptake: indicates inflammation/destruction of the thyroid gland with hormone release.

Management

• Anti-thyroid drugs (thioamides), radioactive iodine (RAI) and surgery are management options.
• NICE guideline (NG145) provides a comprehensive overview of management.

Initial Therapy

• Patients are normally offered thioamides (carbimazole or propylthiouracil) while a decision on definitive therapy is 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.

Radioactive Iodine

• Iodine is key to thyroid hormone synthesis.
• Radioactive iodine (RAI) is taken up by the thyroid, causing destruction and reduced hormone release.
• Contraindications include current pregnancy, falling pregnant within 6 months, breastfeeding, fathering a child within 4-6 months.
• Patients emit radiation for a short time, advised to avoid close contact, especially with children or pregnant women.

Thioamides

• Carbimazole or propylthiouracil reduce thyroid synthesis over weeks.
• May be offered first line in Graves', particularly if likely have remission (mild, uncomplicated disease).
• Remission may be seen after 18-24 months of treatment, demonstrated by trial without therapy.
• In the UK carbimazole is used first-line, however is teratogenic and subject to Medicines and Healthcare products Regulatory Agency guidance on safety in those with childbearing potential.
• Propylthiouracil can be considered in adults where the patient is/has: Intolerant/allergic to carbimazole, pregnant or planning on pregnancy in the next 6 months and a history of pancreatitis

Two Thioamides Regimes

• Block and replace: thioamides are given at a level sufficient to block endogenous T3/T4 production alongside levothyroxine; regime restricted in pregnancy.
• Dose titration: thioamides are given alone, dose adjusted to give normal TSH levels.
• In those with toxic nodules, treatment is likely life-long if chosen as definitive management (surgery or RAI often preferred).

Thyroidectomy

• Removal of the thyroid gland, may be used as definitive therapy if malignancy is suspected, there is a compressive goitre or RAI/ anti-thyroid medications are unsuitable.
• Hemithyroidectomy (removal of half the thyroid gland) may be offered to patients with a solitary toxic nodule.
• Baseline FBC and LFTs are obtained prior to thioamide commencement.
• Neutropenia or severely deranged transaminases are a contraindication to treatment.
• Agranulocytosis is a severe side effect of thioamides, referring to an absence/reduction of granulocytes particularly neutrophils, putting patients at risk of severe infection/sepsis.

Complications of Surgery

• Hypocalcaemia affects 10%, typically transient, and may be permanent in a minority of cases.
• Recurrent laryngeal nerve injury may present with hoarse voice post-operatively.

Graves' Ophthalmopathy Management

• Dependent on disease severity.
• For mild disease using artificial tears, elevating head during sleep, and wearing sunglasses may help; smoking cessation is advised.
• More severe disease requires referral to an ophthalmologist if there is optic nerve compression, corneal opacity, or inability to close an eye.
• Treatment may include steroids, irradiation, and surgical decompression.

Thyrotoxic Crisis

• A rare but potentially fatal result of untreated/undertreated hyperthyroidism.
• It is a medical emergency requiring admission to the hospital, resulting from decompensation during an intercurrent illness.
• Presents with hyperthermia, tachycardia, arrhythmias, nausea, vomiting, seizures and cognitive decline.

Management Involves:

• Managing electrolyte imbalances, heart failure, and hyperthermia.
• Monitor blood sugar.
• Dialysis or plasma exchange may be required. • Beta-blockers • Thionamides: typically propylthiouracil, which reduces the conversion of T4 to T3. • Corticosteroids reduce the conversion of T4 to T3. • Lugol's iodine