Contributed by Dr Sudesna Chatterjee, consultant physician and specialist in diabetes and endocrinology, Stoke Mandeville Hospital, Buckinghamshire.

Section 1: Epidemiology and aetiology
Hypothyroidism is a relatively common condition occurring in 1-2 per cent of the population with 10 times greater frequency in older women compared with other hypothyroid patients. In the Whickham survey, prevalence of overt hypothyroidism was three per 1,000 women.1

Painful thyroid swelling

Land-locked geographical areas lead to iodine deficiency resulting in hypothyroidism. For example, the term 'Derbyshire neck' comes from a description of patients with goitres.

Iodination of table salt has lessened the incidence of this form of hypothyroidism.

Primary hypothyroidism
The most common cause of primary hypothyroidism is autoimmune or Hashimoto's thyroiditis, where circulating autoantibodies destroy thyroid tissue.

There is a tendency for hypothyroidism to cluster in families, especially in female relatives, with increased incidence of other autoimmune disorders such as type-1 diabetes.

Hypothyroidism often occurs as a consequence of treatment for hyperthyroidism, either temporarily due to excess antithyroid medication, or permanently after radioactive iodine therapy or total thyroidectomy.

Amiodarone-induced hypothyroidism is more likely to occur in iodine-deficient areas or in patients with an underlying tendency to autoimmune diseases. Lithium induces hypothyroidism in up to 15 per cent of patients and may even cause the condition several years after discontinuation.

Hypothyroidism may result from radiotherapy for cancers of the neck.

Viral thyroiditis is usually characterised by a painful thyroid swelling associated with transient hyperthyroidism followed by a period of hypothyroidism and then spontaneous normalisation of thyroid function.

Congenital hypothyroidism due to either abnormal fetal thyroid development or genetic defects in thyroid function can lead to cretinism but is now very rare in the UK due to neonatal screening as part of the Guthrie test.

Secondary hypothyroidism
Secondary hypothyroidism may occur with generalised anterior pituitary failure, or more rarely from isolated TSH deficiency. As with other pituitary disease, patients should be referred to an endocrinologist for further management.

Section 2: Diagnosis

The onset of hypothyroidism is often insidious, due to symptoms that are non-specific and multisystemic.

Clinical features
Typical symptoms include excessive fatigue, intolerance to cold, weight gain, poor appetite and constipation.

Patients may also report coarse skin, dry hair and brittle nails. Reduced concentration and memory are especially common in the elderly.

A hoarse voice, deafness and carpal tunnel syndrome are less common features.

Women may experience heavy or absent menstruation with associated subfertility.

On examination, there is often a typical coarse facies with a peaches-and-cream complexion and loss of the outer third of the eyebrows. A large goitre may be present if the aetiology is autoimmune whereas goitre is absent with thyroid atrophy.

Subcutaneous oedema leads to a puffy appearance. Bradycardia, hypothermia and slow tendon reflexes may be evident. In severe cases, patients present with a life-threatening emergency known as myxoedema coma.

The diagnosis is confirmed with TFTs. TSH is elevated in hypothyroidism with low concentrations of free thyroxine and triiodothyronine (fT4, fT3).

Nearly all T4 and T3 is transported bound to serum proteins such as thyroxine-binding globulin and albumin.

It is more useful to measure free concentrations of thyroid hormones as total concentrations can be affected by changes in serum binding proteins caused by illness and drug interactions.

Biological activity is determined by free hormone concentrations.

Serum TSH has a sensitivity of 89-95 per cent and specificity of 90-96 per cent for overt thyroid dysfunction. Autoimmune hypothyroidism or Hashimoto's disease is indicated by thyroid peroxidase autoantibodies (TPO), which are nearly always highly positive.

Subclinical hypothyroidism is characterised by low TSH associated with normal fT4 and fT3 concentrations. If TPO is positive in subclinical hypothyroidism, the risk to progression of overt hypothyroidism is increased.

Radioactive iodine isotope scans are not routinely indicated but would reveal generalised reduced uptake.

Section 3: Management
The aim of hypothyroidism treatment is to restore and maintain TSH within the reference range. Once the diagnosis is confirmed, levothyroxine therapy is indicated.

Patients are exempt from prescription charges as this is physiological life-long hormone replacement.

The optimal dosage varies widely. In older patients or in those with ischaemic heart disease, an initial low dosage, for example 25 micrograms daily, is advisable to avoid precipitating anginal symptoms and coronary ischaemia.

In younger patients, or those who have had a total thyroidectomy, a dosage of levothyroxine 50-100 micrograms daily would be reasonable.

The half-life of levothyroxine is seven days and it is converted easily to the active form of tri-iodothyronine within tissues. Further dosage titration should be carried out on repeating TFT after four weeks.

Usually TSH alone is sufficient for monitoring replacement. If patients omit tablets for a while and then recommence treatment, which sometimes occurs prior to medical consultations, fT4 and fT3 levels can be normal although TSH rises.

This is because the recent thyroxine ingestion normalises serum thyroid hormone levels but TSH is increased due to negative feedback as a consequence of chronic under-replacement.

A full TFT profile may be necessary if variable compliance is suspected. It is important to remember, however, that in hypothyroidism secondary to TSH deficiency, measurement of fT4 is required to guide replacement.

Clinical improvement is often fairly rapid with the introduction of thyroxine. A few patients appear to be sensitive to the excipients of different thyroxine preparations and may benefit from obtaining thyroxine from the same manufacturer.

Triiodothyronine replacement
The indication for T3 or triiodothyronine replacement is more controversial. Eighty per cent of circulating thyroid hormone is thyroxine and only 20 per cent of triiodothyronine is secreted directly by the thyroid gland with conversion of T4 to T3 in peripheral tissues.

Some patients appear to respond better to the active form of thyroxine and may require the addition of this to thyroxine replacement. However, as triiodothyronine has a short half-life of 24 hours, twice or three times daily dosing is usually required.

A recent meta-analysis of combination treatment with T4 and T3 replacement did not show significant benefit in symptoms such as depression, weight loss, fatigue or quality of life, or in physiological markers such as lipid profile.2

There are concerns that T3 treatment can cause osteoporosis and arrhythmias and therefore it should only be prescribed by GMC accredited endocrinologists. In particular, desiccated animal thyroid extract (available commercially from Armour, for example), which contains excess T3 in relation to T4 and is not consistent with physiological thyroid function, should not be used.

The treatment of euthyroid individuals with thyroxine has been discouraged in a joint statement by the British Thyroid Association and Society for Endocrinology.3 Seriously unwell or hospitalised patients may have slightly low TSH, fT4 and fT3 levels consistent with non-thyroidal illness, which does not require treatment.

Section 4: Prognosis
Once thyroxine replacement is optimised, patients are unlikely to need to adjust the dosage further. TFTs should be performed on an annual basis.

Hypothyroidism in pregnancy
A special circumstance occurs during pregnancy. Studies have shown that inadequate thyroxine replacement in early pregnancy can cause mild reductions in a child's intellectual ability. Therefore, on confirmation of pregnancy, women should be advised to increase thyroxine dosage by around 30 per cent to ensure optimal fetal neurodevelopment and to meet metabolic demands.

TSH should be less than 2.5mU/L in the first trimester and less than 3mU/L in the second and third trimesters with TFT monitoring four weeks after dosage adjustments and six weeks once stable. The thyroxine dosage should be reduced to pre-pregnancy levels within four weeks of delivery.

Post-partum thyroiditis increases the risk of subsequent hypothyroidism. All women with a history of postpartum thyroiditis should be offered an annual check of thyroid function and should also be screened prior to and at six to eight weeks after future pregnancies.

Subclinical hypothyroidism
Subclinical hypothyroidism may be a precursor to overt hypothyroidism. Whether this condition results in significant symptoms and should be treated remains controversial.

If TPO levels are strongly positive according to laboratory assay (varies according to labs), annual TFT monitoring is recommended (or sooner if symptoms develop) but no treatment per se. The current guidance is that subclinical hypothyroidism should only be treated with thyroxine replacement if TSH is greater than 10mU/L.4,5.

TFT monitoring
Patients taking amiodarone or lithium should have TFT monitoring prior to initiation of therapy. Those taking amiodarone should have a TFT every six months thereafter and 12 months after discontinuation. Those taking lithiums should have TFT every six to 12 months while taking treatment.

Patients with type-1 diabetes should have a TFT annually. In type-2 diabetes, the recommendation is to check at diagnosis with no need for subsequent screening.

There should be annual TFT screening in patients with Down's and Turner's syndromes due to the increased association with hypothyroidism.


1. Tunbridge W M, Evered C D, Hall R et al. The spectrum of thyroid disease in the community: the Whickham Survey. Clin Endocrinol (Oxf) 1977; 7: 481-93.

2. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2006; 91: 2,592-9

3. The Clinical Committee of the Society for Endocrinology and the British Thyroid Association. Statement on the appropriate management of thyroid disease. http://www.british-thyroid- association.org/news/Docs/thyroid_statement.pdf

4. Surks M I, Ortiz E, Daniels G H et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004; 291: 228-38.

5. Gharib H, Tuttle R M, Baskin HJ et al. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab 2005; 90: 581-5.

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