Hypothyroidism is the underproduction of thyroid hormones by an underactive thyroid gland. These hormones are important in metabolism and a deficiency therefore causes many of the body’ s functions to slow down. Most cases are caused by an autoimmune disorder such as Hashimoto’s thyroiditis. More rarely, however, hypothyroidism results from the removal of part of the thyroid gland to treat hyperthyroidism (overactivity of the thyroid).

Symptoms and signs 

Symptoms of hypothyroidism include tiredness, lethargy. and cold intolerance. There may also be muscle weakness, cramps, a slow heart rate, dry skin, hair loss, constipation, a husky voice, and weight gain. Women may experience heavy menstrual periods. A syndrome called myxoedema, in which the skin and other tissues thicken, may develop. Enlargement of the thyroid gland may also occur (goitre). If the condition occurs in childhood, it may retard growth and normal development.

Diagnosis and treatment 

The disorder is diagnosed by measuring the level of thyroid hormones in the blood. Treatment consists of replacement therapy with the thyroid hormone thyroxine, usually for life. In adults, the symptoms usually improve about three weeks after the start of treatment. Hormone treatment is monitored regularly so that the correct dosage is maintained.

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Hypothyroidism in detail - non-technical

Hypothyroidism in detail - technical

Essentials

Aetiology—iodine deficiency and neonatal hypothyroidism remain major challenges for public health in many countries, but the most frequent cause of thyroid dysfunction in iodine-sufficient areas is autoimmunity, where the follicular gland structure is destroyed by autoreactive T cells.

Clinical features—manifests in the adult with the gradual onset of a constellation of symptoms and signs including tiredness, feeling cold, weight gain, hoarseness of the voice, and slow-relaxing tendon reflexes. A goitre may (Hashimoto’s thyroiditis) or may not (atrophic thyroiditis/primary myxoedema) be present. Biochemical diagnosis of primary hypothyroidism is confirmed by a high serum TSH and a low free T₄, with autoimmune hypothyroidism associated with the presence of thyroid peroxidase autoantibodies (against the ‘microsomal’ antigen). Treatment is with thyroxine (100–150 µg/day, but beginning with a low dose in older people or those with heart disease).

Myxoedema coma—this is the most dramatic presentation of hypothyroidism and a medical emergency with high mortality: management requires (1) supportive treatment; (2) identification and treatment of any precipitating condition, often infective; (3) parenteral thyroid hormone replacement.

Introduction

Impaired production of thyroid hormones is usually due to a primary abnormality of thyroid gland or iodine deficiency; occasionally it is secondary to pituitary or hypothalamic disorders. The onset of primary hypothyroidism is gradual and may be detected when the TSH is elevated (to compensate for impaired thyroid output) but the free thyroid hormone levels are normal. This state is subclinical hypothyroidism. As thyroid damage continues, TSH levels rise further but free T₄ levels fall. The TSH level at this stage is usually above 10 mU/litre, symptoms become apparent, and the patient is said to have overt or clinical hypothyroidism.

Aetiology

The causes of hypothyroidism are listed in Bullet list 1 (below). The commonest cause worldwide is iodine deficiency, discussed above. In iodine-sufficient areas, autoimmune hypothyroidism and thyroid damage after radio-iodine or surgical treatment for hyperthyroidism are the major causes.

Epidemiology

The prevalence of overt hypothyroidism in white populations is around 2% in women and 0.2% in men, with a mean age of 60 at diagnosis. Subclinical hypothyroidism is even more common (6–8% of women and 3% of men). Around 4% of these individuals progress to overt hypothyroidism annually if thyroid peroxidase antibodies accompany the elevated TSH. Half this number progress in the absence of thyroid peroxidase antibodies. Focal lymphocytic infiltration of thyroid associated with thyroid autoantibody positivity occurs in up to 15% of healthy women and 2% of men without an elevated TSH level, representing the earliest manifestation of thyroid autoimmunity; 2% of these people progress to overt hypothyroidism annually. Congenital hypothyroidism occurs in about 1 in 4000 births and this high frequency has led to the widespread introduction of neonatal screening.

Pathogenesis

Autoimmune hypothyroidism is primarily the result of autoreactive T-cell-mediated cytotoxicity directed against thyroid follicular cells. Cytokines derived from the locally infiltrating T cells, macrophages, and dendritic cells impair thyroid cell function and enhance T-cell-mediated cytotoxicity. The role of thyroid autoantibodies in thyroid cell destruction is unclear, but thyroid peroxidase antibodies fix complement and may cause secondary damage. In 10 to 20% of patients, antibodies which block the TSH receptor are partially or wholly responsible for hypothyroidism, and transplacental passage of these antibodies (but not thyroid peroxidase antibodies) occasionally causes transient neonatal hypothyroidism. Genetic and environmental factors are involved in the aetiology but, as with most autoimmune disorders, the complex interaction of these factors has so far prevented a full understanding. Polymorphisms in the HLA-DR and CTLA4 genes are associated with autoimmune hypothyroidism, and a high iodine intake may be an important environmental factor in some cases.

Bullet list 1 Causes of hypothyroidism

Congenital hypothyroidism is caused by thyroid aplasia or hypoplasia in 60% of cases and in 30% there is an ectopic gland. Mutations in thyroid-specific transcription factors have been found in some of these cases. In the remaining 10%, hypothyroidism is due to dyshormonogenesis (see Bullet list 3).

Clinical features

The cardinal features in adults with hypothyroidism are shown in Bullet list 2. However, the ready availability of reliable screening tests for hypothyroidism, especially TSH assays, has led to the recognition of many patients in whom there are only vague or nonspecific symptoms, such as tiredness, weight gain, and poor concentration. The differential diagnosis is accordingly vast but the high frequency of hypothyroidism should prompt its exclusion when any suggestive features are present, particular in middle-aged women with chronic fatigue or depression.

Autoimmune hypothyroidism may present with a goitre (Hashimoto’s thyroiditis) or without (atrophic thyroiditis or primary myxoedema). When present, the goitre is of variable size but is often hard and irregular, sometimes giving rise to suspicion of a malignancy, which then requires exclusion by fine needle aspiration biopsy. Primary lymphoma of the thyroid is a rare but important association. Thyroid pain due to autoimmune thyroiditis is also a rare complication. Patients may notice a Hashimoto goitre before any thyroid dysfunction has developed and annual follow-up is then needed.

The most dramatic presentation of hypothyroidism is myxoedema coma, which is fortunately rare. In addition to the usual features, there is hypothermia (as low as 23 °C) and coma, sometimes with seizures. Mortality is 50% even with intensive treatment. Patients are typically older and either previously undiagnosed or poorly compliant with medication. There is generally an additional precipitant, such as respiratory depression due to drugs, chest infection, heart failure, stroke, blood loss, or exposure to cold.

Autoimmune hypothyroidism is frequently associated with other autoimmune conditions. In the type 2 autoimmune polyglandular syndrome, autoimmune thyroid disease (hypothyroidism or Graves’ disease) is associated with type 1 diabetes and/or Addison’s disease. This syndrome is autosomal dominant with variable penetrance. In the rare, autosomal recessive type 1 autoimmune polyglandular syndrome (chronic mucocutaneous candidiasis, Addison’s disease, and hypoparathyroidism), autoimmune hypothyroidism is found in 5 to 10% of patients. Other common associations include pernicious anaemia, vitiligo, and alopecia areata and there is a significant excess of autoimmune hypothyroidism in coeliac disease, dermatitis herpetiformis, chronic active hepatitis, premature ovarian failure, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome. Breast cancer patients and individuals with Down’s and Turner’s syndromes have a higher than expected frequency of thyroid autoimmunity. Around 5% of patients with thyroid-associated ophthalmopathy, discussed later in this chapter, have autoimmune hypothyroidism and 15% of patients with Graves’ disease successfully treated with antithyroid drugs develop hypothyroidism 10 to 20 years later. This relationship with Graves’ disease is further emphasized by rare patients who oscillate between hyperthyroidism and hypothyroidism over a period of months. The likely explanation is fluctuation in the relative levels of TSH receptor stimulating and blocking antibodies, but the cause of these changes is unknown.

Bullet list 2  Clinical features of hypothyroidism

Juvenile hypothyroidism is uncommon. The features of adult hypothyroidism (Bullet list 2) may be present, but the diagnosis is usually suggested by retarded growth and dentition, and an infantile face. Myopathy with muscle enlargement is common. Puberty is usually delayed, although sometimes it is precocious. Congenital hypothyroidism is typically unrecognizable at birth but, if not identified by screening, gives rise to prolonged jaundice, failure to thrive, impaired growth, feeding difficulties, constipation, and hypotonia. Left untreated, even for a few weeks after birth, there is permanent neurological damage resulting in intellectual impairment.

Pathology

In Hashimoto’s thyroiditis there is a prominent diffuse and focal lymphocytic infiltrate with germinal centre formation. The thyroid follicles show varying degrees of destruction and little or no colloid. The remaining thyroid follicular cells have an increased number of mitochondria, giving rise to oxyphil metaplasia (Askanazy or Hürthle cells). There is a variable degree of fibrosis. In atrophic thyroiditis, fibrosis is the most prominent feature, with a less obvious lymphocytic infiltrate than in Hashimoto’s thyroiditis. Thyroid follicles are usually sparse, reflecting the later stage at which this form of autoimmune hypothyroidism is diagnosed. Whether there is a natural progression from Hashimoto’s to atrophic thyroiditis is unclear, although the goitre usually decreases with T₄ replacement.

Laboratory diagnosis

Measuring serum TSH is the first step in diagnosing hypothyroidism, with the important caveat that this approach will miss most cases of secondary hypothyroidism in which the serum TSH measured by immunoassays may be low, normal, or even slightly raised, due to the secretion of bioinactive forms of the hormone. If secondary hypothyroidism is suspected, for instance in the follow-up of a patient with treated pituitary disease, it is essential to check the free T₄ level. The TSH is elevated in other settings besides primary overt hypothyroidism (Table 1 below). It is therefore important to confirm the diagnosis by measuring the free T₄ in all samples in which the TSH is elevated. Measurement of free T₃ adds nothing to the diagnosis, especially as values may be within the reference range in a quarter of hypothyroid patients due to extrathyroidal conversion of T₄.

If myxoedema coma is expected, it is essential that treatment is initiated immediately without awaiting confirmation of the diagnosis. These patients often have dilutional hyponatraemia, hypoglycaemia, and electrocardiography changes (low voltage, prolonged QT interval, flat or inverted T waves, and heart block). Other nonspecific features which may be found in any patient with hypothyroidism are elevation in serum liver and muscle enzymes (the raised creatine phosphokinase particularly may cause unnecessary concern), raised cholesterol, and anaemia. The anaemia is usually normocytic or macrocytic, but microcytosis occurs when hypothyroidism is accompanied by menorrhagia.

The aetiology is usually easily established. In the absence of a history of treated hyperthyroidism or iodine exposure, the majority of juvenile or adult onset primary hypothyroidism in iodine-sufficient countries is due to autoimmune hypothyroidism. Transient hypothyroidism due to destructive thyroiditis is considered later. The diagnosis of autoimmune hypothyroidism is confirmed by the presence of thyroid peroxidase antibodies, usually at high levels, although occasionally these antibodies are absent. Cytological diagnosis of Hashimoto’s thyroiditis is possible using fine needle aspiration biopsy, but is only necessary if there is uncertainty over the cause of a nodular goitre.

Once congenital hypothyroidism is diagnosed by routine testing after birth, it is usual to initiate T₄ immediately. Treatment can then be stopped without neurological consequences at age 3 to 4 years to establish whether life-long T₄ replacement is necessary. At this time, the aetiology can be established by scintiscanning and/or ultrasound. Dyshormonogenesis, suspected when there is detectable thyroid tissue and a family history, requires specialized investigation to establish the diagnosis and increasingly this is possible by direct analysis of gene mutations. The commonest of these defects is Pendred’s syndrome in which there are mutations in the pendrin gene (SLC26A4) encoding a chloride/iodide transporter present in the thyroid and cochlea, leading to goitre, mild hypothyroidism, and deafness. The thyroid abnormalities usually appear in the second or third decade, rather than at birth. The diagnosis can be made easily by the perchlorate discharge test, which shows an excessive decline of radioactivity in the thyroid when potassium perchlorate is given 2 to 3 h after allowing the thyroid to take up a tracer dose of radio-iodine.

Treatment

In adult patients without heart disease and below the age of 60, treatment can begin with the estimated replacement dose of T₄. If there is no remaining thyroid tissue (indicated by a very high TSH level and very low or undetectable free T₄), the daily replacement dose is 1.6 µg T₄/kg body weight, which is around 100 to 150 µg/day. In practice, the typical starting dose is 50 to 100 µg T₄ daily, the lower dose being reserved for patients with mild to moderate biochemical abnormalities. Dosage changes should be based on TSH levels measured 2 to 3 months after starting treatment, the main goal of treatment being to normalize the TSH. A similar period is required to assess the effect of any change to the dosage, made as 25 or 50 µg increments or decrements depending on the degree of abnormality of the TSH. Treatment is usually straightforward, although if there is only partial thyroid failure when treatment is begun, the dose of T₄ may require adjustment over many months.

Once on a full replacement dose, TSH levels should be checked annually. Fluctuating or elevated TSH levels in a previously stable patient, or T₄ requirements in excess of 200 µg/day, usually indicate adherence problems. It is important to rule out malabsorption, including Helicobacter pylori infection, excessive soya intake, or drugs: cholestyramine, ferrous sulphate, lovastatin, aluminium hydroxide, rifampicin, amiodarone, carbamazepine, and phenytoin all alter the absorption or clearance of T₄. A common cause for poor adherence is worsening angina. Optimization of antianginal treatment is then required, although some patients may simply prove intolerant of full T₄ replacement if their coronary artery disease is extensive and irremediable. It is important to remind poorly adherent patients that, because of the long half-life of T₄, missed tablets should always be taken and that this is safe. It should be emphasized that, in the absence of coronary artery disease, T₄ has no adverse effects when given at doses that return TSH levels to normal.

In older patients or in individuals with heart disease, the usual starting dose is 25 µg T₄ daily (or on alternate days when there is severe angina). Dosage should be increased slowly with increments of 12.5 to 25 µg T₄. Proportionately higher doses of T₄ are needed during the first year of life than in adults, and the starting daily dose of T₄ for congenital hypothyroidism is 10 µg/kg body weight. There is a continuing debate on the benefit of T₄ in subclinical hypothyroidism. It is reasonable to commence T₄ when subclinical hypothyroidism is coupled with the presence of thyroid peroxidase antibodies, as there is a high risk of progression to overt hypothyroidism. Modest improvements in mental function and lipid levels occur when T₄ is given to some patients with subclinical hypothyroidism, but long-term studies on the benefits of treatment have not been conducted. At present, it seems reasonable to offer a 3-month trial of T₄ to thyroid peroxidase antibody-negative patients with subclinical hypothyroidism. If the patient notices an improvement in the symptoms which prompted thyroid function testing, T₄ is continued, but is stopped if there is no benefit. All patients with subclinical hypothyroidism or positive thyroid peroxidase antibodies should be offered annual testing for the development of overt hypothyroidism.

Another problem is posed by the occasional patient with overt hypothyroidism who continues to feel unwell or who fails to lose weight after the TSH is normalized with T₄ replacement. It can take around 3 months from achieving full replacement for all symptoms to disappear, and weight gained during hypothyroidism will generally only be lost by following an appropriate diet. It is sensible to ensure that the TSH level is in the lower half of the reference range and sometimes a small increment of T₄ can achieve this, improving symptoms but not suppressing the TSH. Higher doses of T₄ that suppress the TSH should be avoided, as there is an increased risk of atrial fibrillation due to subclinical thyrotoxicosis. The other recognized adverse effect of excessive T₄ is a decrease in bone mineral density, particularly in postmenopausal women who have previously had hyperthyroidism and therefore already have a low skeletal mass. However, the changes in bone mineral density are modest and no increase in fracture rate has been reported as a result of T₄ given at supraphysiological doses. There has been a revival of the concept that thyroid hormone replacement should consist of both T₄ and T₃, based on the observation that deiodinase activity varies between tissues, suggesting that in some organs the level of the active thyroid hormone, T₃, is insufficient when only T₄ is given. The short half-life of T₃ makes it alone unsuitable for replacement and a recent meta-analysis of all trials to date has shown no evidence of any benefit from combined T₄ and T₃ treatment.

Treatment of myxoedema coma is a medical emergency (see Bullet list 3).

Prognosis

T₄ treatment is usually life-long and, properly taken, restores normal health and lifespan. Occasional patients may discontinue T₄ and remain euthyroid. Errors in initial diagnosis account for some of these; in others, a spontaneous decline in TSH receptor blocking antibody levels may be responsible. There is no easy means of ascertaining whether a patient continues to need T₄, short of stopping it and measuring the TSH 6 weeks later. Because remission is uncommon and of uncertain duration, few endocrinologists attempt T₄ withdrawal once started.

Bullet list 3  Treatment of myxoedema coma

Special problems in pregnant women

Untreated hypothyroidism impairs fertility and increases the risk of miscarriage. Children born to such mothers have varying degrees of intellectual impairment. It is therefore essential that T₄ replacement is monitored closely in women with hypothyroidism who intend to become or who are pregnant. Ideally TSH and free T₄ should be checked prior to conception, once pregnancy is confirmed, and at the beginning of the second and third trimesters. The requirement for T₄ can increase by 50 to 100% during pregnancy but reverts to normal after delivery. There are no implications for breastfeeding.

Areas of uncertainty or needing further research

Although present preparations of T₃ and T₄ have shown no additional benefit compared to T₄ alone, development of a sustained release preparation of T₃ could be worth assessment. Because hypothyroidism is frequent, routine screening of certain groups or even the entire population has been advocated (Bullet list 4), but the cost–benefit of setting up new screening programmes is unclear. 

• Congenital hypothyroidism
• Previous treatment for hyperthyroidism
• Previous neck irradiation (e.g. for lymphoma)
• Pituitary tumours, including follow-up after surgery or irradiation
• Treatment with lithium or amiodarone
• Subclinical hypothyroidism

• Antepartum^a in type 1 diabetes
• Three months postpartum after a prior episode of postpartum thyroiditis
• Unexplained infertility
• Nonspecific symptoms in women over 40 years of age
• Refractory depression or bipolar affective disorder with rapid cycling
• Turner’s syndrome
• Down’s syndrome
• Autoimmune Addison’s disease

• Patients with a family history of thyroid autoimmunity
• Dementia or obesity without other evidence of thyroid disease
• Antepartum to detect unsuspected hypothyroidism^b
• Breast cancer

a Also measure thyroid peroxidase antibodies; screen euthyroid antibody-positive women 3 months postpartum for postpartum thyroiditis.

b It is also uncertain whether all pregnant women should be checked for thyroid peroxidase antibodies as predictors of postpartum thyroiditis.

If widely adopted, screening will turn up many individuals with subclinical hypothyroidism for whom the benefits of early treatment with T₄ have not yet been fully established. Recent data show that there is an increased risk of miscarriage in thyroid peroxidase antibody-positive women who are euthyroid and this may be reduced by T₄ treatment, but more work is needed to confirm this.