Endocrinology: Thyroid disorders
Thyroid function
Anatomy
Embryology
The thyroid gland has its embryological origin at the back of the tongue, migrating downwards to the midline, sitting anteriorly to the thyroid cartilage in the neck (Figure 9.1a). This embryological origin can lead to remnant tissue, which presents as a lingual thyroid or thyroglossal cyst.
Anatomical relations
The thyroid gland has a left and right lobe joined by a central isthmus (Figure 9.1a). Thyroid lesions can be distinguished from other neck lumps by their movement on swallowing. The anatomical relations of the thyroid are important in clinical practice. The recurrent laryngeal nerve lies laterally on each side and the parathyroid glands lie posteriorly (Figure 9.1a) – both may be damaged during thyroid surgery. The thyroid gland has a rich vascular supply from the inferior and superior thyroid arteries.
Histology
Thyroid tissue is made up of colloid (Figure 9.1b), which contains iodinated thyroglobulin. Thyroglobulin is synthesised by the surrounding follicular cells and is the large molecule from which thyroxine is made and stored in colloid. The thyroid is also made up of neuroendocrine cells (parafollicular or C cells), which are situated between the follicular cells, and secrete calcitonin, a physiologically active peptide. Calcitonin is relevant clinically as a biomarker for medullary thyroid cancer.
Physiology
Thyroid hormones have a profound effect on metabolism.
Iodination of the amino acid tyrosine forms thyroxine (T4) and triiodothyronine (T3). T4 is the main circulating hormone,
which is converted peripherally to the more potent and shorter acting T3 (Figure 9.1c). Thyroid hormones are bound tightly to proteins in the circulation: thyroxine binding globulin (TBG), transthyretin and albumin. Only the free hormone acts on intracellular thyroid receptors (TR). There are two main types of thyroid receptor (TRα and TRβ), which are variably expressed in different tissues. Mutations in TRβ lead to the rare condition of thyroid hormone resistance. The local action of thyroid hormones on tissues is determined by a series of activating and de-activating enzymes (de-iodinase enzymes; DIO 1, 2 and 3).
Actions of thyroid hormones
Thyroid hormones increase basal metabolic rate and affect growth and development. They act on the cardiovascular system to increase heart rate and stroke volume, and receptors are widely expressed in the CNS and reproductive system (Figure 9.1d).
Because of the widespread role of thyroid hormones in metabolism, patients with disorders of thyroid function can present to any specialty in clinical practice.
Interpreting thyroid function tests
Thyroid function tests (TFTs) are readily available and commonly requested in clinical practice. Understanding the feedback axis is the key to correct interpretation of thyroid results. The thyroid has a classic negative feedback system (Figure 9.1e). TRH stimulates pituitary TSH secretion, which acts on G-protein coupled receptors in the thyroid to stimulate T3 and T4 secretion. T3 and T4 exert their peripheral effects via TRα and TRβ. Thyroid hormones have minimal circadian rhythmicity and are not pulsatile, therefore basal levels are sufficient for interpretation, and dynamic tests are not needed.
Primary and secondary hypothyroidism
Primary hypothyroidism is caused by thyroid disease, commonly autoimmune in origin. It is characterised by reduced circulating T3 and T4 and compensatory elevation in TSH. Secondary hypothyroidism is caused by TSH deficiency, usually as a result of pituitary disease, and is characterised by low T3/T4 levels and non-elevated TSH – often TSH is normal rather than low.
Hyperthyroidism
Primary hyperthyroidism is characterised by increased circulating T3 and T4, and suppressed TSH due to negative feedback. If TSH is not suppressed in the context of hyperthyroidism, rare conditions or assay interference should be considered. In this situation, the clinical picture is important to guide whether diagnosis is likely to be an assay problem or a genuinely rare pathology.
Factors affecting thyroid results
TFTs can be affected by non-thyroidal illness (‘sick euthyroid syndrome’), typically causing central TSH suppression, although any pattern of results can be seen. TFTs are therefore best measured in the outpatient setting when patients are relatively well, rather than during acute illness or hospitalisation.
Medication (e.g. lithium and amiodarone) and pregnancy can also affect thyroid function results.
Hyperthyroidism: clinical presentation
and investigation
Hyperthyroidism, also known as thyrotoxicosis, is a common condition. It most commonly affects young women but can also develop in men and occur at any age.
Causes
Graves’ disease (autoimmune thyroid disease)
Graves’ disease is the most common cause of hyperthyroidism, and results from the production of TSH receptor stimulating antibodies (Figure 10.1a). It typically affects young women and usually follows a relapsing–remitting course.
Nodular thyroid disease
The second most common cause of hyperthyroidism, which typically presents at an older age than Graves’ disease, nodular hyperthyroidism is caused by autonomous secretion of T3 and/or T4, either from a solitary toxic nodule or, more commonly, numerous nodules situated within a multinodular goitre (toxic multinodular goitre; Chapter 14).
Thyroiditis
This is less common, and refers to inflammation of the thyroid gland causing a destructive release of thyroxine. Thyroiditis is caused by viral infection, medication (commonly amiodarone) or follows childbirth (post-partum thyroiditis). A hypothyroid phase may follow the initial hyperthyroidism.
Clinical presentation
Symptoms
Hyperthyroidism manifests with a range of symptoms caused by increased activation of the sympathetic nervous system (Figure 10.1b). Classic features include weight loss (often with increased appetite), insomnia and irritability, anxiety, heat intolerance, palpitations and resting tremor. Other common symptoms of hyperthyroidism include pruritus, increased bowel frequency and loose motions, menstrual disturbance and reduced fertility.
Elderly patients can present atypically with reduced energy levels (termed apathetic thyrotoxicosis). Hyperthyroidism is less common in children than adults. Patients can present with classic symptoms, or with accelerated growth and behavioural disturbance.
Signs
General signs of hyperthyroidism include a resting tachycardia (sinus rhythm or atrial fibrillation), warm peripheries, resting tremor, hyper-reflexia and lid lag. Lid lag can be seen in any cause of hyperthyroidism, because of increased sympathetic tone of the upper eyelid. Lid retraction and proptosis are only seen in Graves’ disease. Patients may have a hyperdynamic circulation, causing hypertension and a flow murmur. Patients with hyperthyroidism often appear agitated and hyperkinetic (‘thyroid affect’).
Graves’ disease
Specific clinical signs of Graves’ disease include thyroid eye disease (Chapter 11), and rarer extra-thyroidal manifestations, including skin changes (dermopathy) characterised by pre-tibial myxoedema as well as nail changes similar to clubbing (thyroid acropachy). These are a result of cross-reactivity with TSH receptors in the back of the orbit and skin.
Goitre
Goitre refers to enlargement of the thyroid gland (Chapter 14).
Goitres in Graves’ disease are typically smooth, symmetrical and vascular, often with a thrill and bruit on palpation and auscultation.
Nodular goitres are less vascular, and dominant nodules may be clinically palpable. Nodules can be single or multiple.
Thyroid disease and the heart
Hyperthyroidism can present as an acute cardiovascular emergency (Figure 10.1c). The most common acute presentation is supraventricular tachycardia (SVT) or fast atrial fibrillation (AF). Patients more rarely present with a thyrotoxic cardiomyopathy, which is more common in Graves’ disease.
Thyroid storm is a rare medical emergency that presents with high output cardiac failure and extreme agitation. It has a high mortality and requires high dependency care (Chapter 38).
Investigation
T3, T4 and TSH
The hallmark of hyperthyroidism is an elevated free T4 (fT4) and free T3 (fT3) with undetectable TSH (Figure 10.1d). Elevated fT3 alone with suppressed TSH is termed T3 toxicosis. Patients with a normal fT4/fT3 and suppressed TSH have subclinical hyperthyroidism, suggesting autonomous thyroid activity. The presence of elevated fT4 and fT3 with non-suppressed TSH is unusual and requires further investigation.
Thyroid antibodies
Graves’ disease may be clinically obvious on examination, but can be confirmed by measuring thyroid antibodies. Thyroid peroxidase antibodies (TPO) are non-specific markers of autoimmune thyroid disease. TSH receptor stimulating antibodies are more specific and can be helpful in particular clinical situations such as pregnancy, in addition to supporting a clinical diagnosis of Graves’ disease.
Imaging
Thyroid ultrasound (US) can help to confirm nodular thyroid disease but does not assess gland activity. Nuclear imaging (technetium or iodine uptake isotope scan) helps determine functionality and therefore the cause of hyperthyroidism. In Graves’ disease there is uniform increase uptake, whereas in nodular disease there is increased uptake only in the autonomous nodule(s). In thyroiditis there is absent uptake on isotope scan (Figure 10.1e).
Hyperthyroidism: management and
ophthalmopathy
Management options for hyperthyroidism include anti-thyroid medication, surgery and radioactive iodine (RAI)
(Figure 11.1). Medical treatment is usually the first line approach, especially in Graves’ disease, with definitive options (surgery or RAI) chosen later on.
Medical treatment
Thionamides (carbimazole and propylthiouracil) block thyroid peroxidase enzymes, thereby reducing the synthesis of T3 and T4. It takes 4–6 weeks for patients to become euthyroid after initiation of anti-thyroid drugs. Beta-blockers can be used to control symptoms until thyroid function returns to normal.
Thionamides can cause agranulocyotisis (bone marrow suppression) and patients should be warned of this potential rare side effect before commencing treatment. If unexplained fever or sore throat occur, an urgent full blood count is required to exclude pancytopaenia, and the drug should be stopped if bone marrow suppression is confirmed. A more common side effect is generalised rash, which disappears after cessation of the drug.
Anti-thyroid treatment regimes
Graves’ disease has a relapsing–remitting natural history, whereas nodular thyroid disease does not tend to go into remission. Definitive options are therefore used earlier in nodular thyroid disease. A 12- to 18-month course of carbimazole or propylthiouracil is generally used first line in Graves’ disease.
The relapse rate is approximately 50% upon treatment cessation.
Relapse is more likely in patients with high thyroid hormone levels and antibody titres at presentation.
‘Titration’ versus ‘block and replace’
The two approaches to medical treatment with thionamides include the ‘titration’ and ‘block and replace’ regimens. There are advantages and disadvantages to each. Dose titration involves altering the thionamide dose in response to thyroid hormone response. The ‘block and replace’ approach uses high dose thionamide in combination with thyroxine (e.g. 40 mg carbimazole + 100 µg thyroxine). The ‘block and replace’ regimen should not be used in pregnancy as thyroxine crosses the placenta less well than anti-thyroid medication, putting the fetus potentially at risk of hypothyroidism.
Definitive treatments
Treatment includes RAI and surgery. Both therapies have advantages and disadvantages and are usually driven by patient choice (Figure 11.1).
Radioactive iodine
RAI is a straightforward treatment, and involves the administration of a single dose of 131I. It is contraindicated in pregnancy and can lead to a flare of eye disease in patients with pre-existing ophthalmopathy.
It commonly causes hypothyroidism, which requires lifelong thyroxine replacement. Patients emit a small amount of radiation after administration of 131I and are therefore advised to avoid close contact with young children and pregnant women for a few weeks after treatment.
Surgery
Thyroidectomy is an effective definitive treatment for hyperthyroidism, particularly when patients cannot easily comply with radiation restriction guidance (e.g. mothers with young children).
Thyroid function should be optimally controlled pre-operatively to avoid anaesthetic problems. This is usually achieved by thionamides alone, but lithium or iodine can be used in refractory cases. Beta-blockade can be used during anaesthetic induction if thyroid function is not optimal, to prevent peri-operative AF.
Complications of thyroid surgery include bleeding, infection, damage to the recurrent laryngeal nerve and temporary or permanent hypocalcaemia, but these risks are low if the procedure is undertaken by an experienced surgeon.
Thyroid ophthalmopathy
Thyroid eye disease (ophthalmopathy) can occur at the same time as, or within several years either side of thyroid dysfunction in patients with Graves’ disease. It can be mild, moderate or severe.
Mild ophthalmopathy
Many patients with Graves’ disease have subtle eye disease, reporting dryness or grittiness of the eyes when asked directly.
Moderate ophthalmopathy
Patients can present with significant inflammatory changes, including eyelid swelling, chemosis and peri-orbital oedema.
Proptosis and lid retraction can lead to a ‘staring’ appearance (Figure 11.2), which may be socially debilitating.
Severe ophthalmopathy
Severe proptosis can lead to exposure keratopathy and compressive optic neuropathy, which may be sight-threatening.
Diplopia is caused by inflammation of the extraocular muscles.
Management of ophthalmopathy
Thyroid ophthalmopathy is most commonly mild and improves with time (Figure 11.2). Management of mild disease involves simple measures such as sitting up in bed, lubricant eye drops and cessation of smoking (an independent risk factor for ophthalmopathy), in addition to maintenance of euthyroidism.
Selenium supplementation can also have a role.
In moderate and severe eye disease, patients may need high dose pulsed intravenous methylprednisolone. Surgical orbital decompression is performed for sight-threatening disease. If diplopia is severe, squint surgery to the retro-ocular muscles may be needed after orbital decompression. Patients with severe lid retraction may need lid-lengthening surgery. Orbital radiotherapy and immunosuppressant agents can be used if other measures fail to improve symptoms.
Hyperthyroidism: special
circumstances
Hyperthyroidism and pregnancy
Hyperemesis gravidarum
Pregnancy affects thyroid status in numerous ways (Figure 12.1a). TSH has a similar molecular structure to β human chorionic gonadotrophin (β-HCG), therefore the hyperemesis of pregnancy (which is characterised by raised β-HCG) can be associated with mild biochemical hyperthyroidism. This usually resolves spontaneously in the second trimester of pregnancy.
Graves’ disease in pregnancy
Patients with Graves’ disease require observation during pregnancy every 4–6 weeks, because of the increased risk of maternal complications as well as reduced fetal growth (Figure 12.1b). Pregnancy usually has a beneficial effect on autoimmune disease, including Graves’ disease, such that the dose of anti-thyroid medication can usually be reduced or even stopped. Propylthiouracil (PTU) is preferred to carbimazole in the first trimester because congenital malformations (notably choanal atresia and aplasia cutis) have not been described with PTU. Carbimazole is preferred during the second and third trimesters, because of the increased risk of PTU-associated hepatitis later in pregnancy. Placental transfer of TSH receptor stimulating antibodies can affect the fetus so additional scans are performed during pregnancy to ensure there is no evidence of tachycardia, goitre or growth restriction, which are signs of fetal hyperthyroidism.
Patients with Graves’ disease who have had previous surgery or RAI require fetal monitoring during pregnancy. In this situation, although the mother has had her thyroid removed or ablated, there is still a risk of placental antibody transfer to the fetus and neonatal thyrotoxicosis. Signs of this include irritability and failure to thrive during the first 3 weeks of life.
Breastfeeding is safe on anti-thyroid medication, as long as doses are not excessive. Hyperthyroidism often becomes worse after delivery, because the immunosuppressive effect of pregnancy is removed, demanding an appropriate dosage increase in thionamide therapy.
Subclinical hyperthyroidism
Subclinical hyperthyroidism refers to a suppressed TSH with normal fT4 and fT3, often in the upper part of the normal range.
Subclinical hyperthyroidism suggests a degree of autonomous thyroid hormone production. This is often due to the presence of nodular thyroid disease. Patients may not be symptomatic, but are at risk of the same long-term complications as frank hyperthyroidism (notably AF and osteoporosis), especially if the TSH is completely unmeasurable. Treatment is indicated to control symptoms, and can also be considered on a case-by-case basis in asymptomatic patients, dependent on comorbidities (e.g. AF) and extent of TSH suppression. Surveillance alone, until the development of frank hyperthyroidism, is an alternative.
Elevated fT4 with unsuppressed TSH
Thyroid results are usually easy to interpret. A high fT4 with a suppressed TSH is the norm in hyperthyroidism. It is unusual in clinical practice to see a high fT4 with non-suppressed TSH.
In this situation it is important to consider assay interference, TSHoma and thyroid hormone resistance (Figure 12.1c).
Assay interference
If the thyroid results do not fit with the clinical presentation, blood should be sent to another laboratory for confirmation by another method. Equilibrium dialysis is the most accurate way to measure fT4, and eliminates the possibility of interfering antibodies affecting the result. Antibodies to TSH (heterophile antibodies) can make the TSH look falsely high or low, and these can be detected. Familial dysalbuminaemic hyperthyroxinaemia (FDH) should also be considered in the context of high fT4 and normal TSH. FDH leads to falsely elevated T4 due to an abnormal albumin, which has a higher affinity for thyroxine than TBG.
TSHoma and thyroid hormone resistance
If the high fT4 and non-suppressed TSH is not due to assay interference, the differential diagnosis lies between TSHoma and thyroid hormone resistance.
TSHoma
TSHoma is a rare TSH-secreting pituitary tumour, which drives fT3 and fT4 production from the thyroid. Patients present with symptoms of hyperthyroidism, or mass effect from the pituitary tumour if it is a macroadenoma. If MRI confirms a pituitary tumour, trans-sphenoidal surgery is indicated, although somatostatin analogues are also effective in achieving biochemical control.
Thyroid hormone resistance
Thyroid hormone resistance causes high fT3/fT4 and non-suppressed TSH due to reduced end-organ unresponsiveness to thyroxine. This is caused by an inactivating mutation in the thyroid hormone receptor β (TR-β) gene. This condition is autosomal dominant and there is usually a family history of unusual thyroid function results. There may be variable sensitivity to thyroid hormones in different tissues. A diagnosis of thyroid hormone resistance can be confirmed by genetic testing.
Distinuishing TSHoma from thyroid hormone resistance
SHBG is produced by the liver, and is elevated in hyperthyroid states. In TSHoma, patients are truly hyperthyroid and therefore typically have high SHBG levels, while thyroid hormone resistance is associated with low or normal SHBG. TRH injection (the TRH test) typically leads to a flat TSH response in TSHoma, with an exaggerated rise seen in thyroid hormone resistance. Patients with TSHoma will usually also display a raised α-subunit, have evidence of a pituitary tumour on MRI (or 11C-methionine PET) and normalise thyroid function in response to somatostatin analogues.
Hypothyroidism
Primary hypothyroidism affects 2–5% of the UK population. It affects six times more women than men, and prevalence
increases with age.