Clinical review: Hypothyroidism

An overview of the diagnosis and management of hypothyroidism, including causes, investigations, the effect of pregnancy on thyroid function and treatment with levothyroxine.

Goitre in Hashimoto's thyroiditis (SPL)
Goitre in Hashimoto's thyroiditis (SPL)

Section 1: Epidemiology and aetiology
Section 2: Making the diagnosis
Section 3: Managing the condition
Section 4: Prognosis
Section 5: Case study
Section 6: Evidence base


Section 1: Epidemiology and aetiology

Thyroid hormones play a major part in regulating metabolism. The thyroid gland produces mainly thyroxine (T4), the precursor, and small amounts of the active hormone, triiodothyronine (T3).

Hypothyroidism develops when the thyroid gland does not produce enough hormones.

In iodine-replete communities, the prevalence of spontaneous hypothyroidism is 1-2%, and it is more common in older women and 10 times more common in women than in men.

Studies in northern Europe, Japan and the US have found prevalence between 0.6 and 12 per 1,000 in women and 1.3-4 per 1,000 in men investigated. It is higher in surveys of the elderly in the community. Overt hypothyroidism was found in 7% of 558 subjects aged 85-89 years in Leiden, in the Netherlands.1

Subclinical hypothyroidism, a milder form, is much more common, with a prevalence of 2-16%, and higher frequency in women and the elderly.

In one study, the mean annual incidence of spontaneous hypothyroidism during the 20-year follow-up was 3.5 per 1,000 and 0.6 per 1,000 in surviving women and men, respectively.1

Raised serum TSH or positive thyroid auto-antibodies alone or in combination were associated with a significantly increased risk of developing hypothyroidism. In the surviving women, annual risk of spontaneous overt hypothyroidism was 4% in those who had high serum TSH and positive thyroid auto-antibody concentrations, 3% if only their serum TSH concentration was high, and 2% if only their serum thyroid antibody concentration was high.

Aetiology
The most common cause of hypothyroidism is autoimmune destruction of the thyroid gland. Autoimmune hypothyroidism is more common in those with a family history of the disease, other autoimmune conditions, those who have recently quit smoking, those with Down's or Turner syndrome and those who may have had Graves' disease or postpartum thyroiditis. Causes are listed in box 1.

Box 1: Causes of hypothyroidism
  • Autoimmune thyroid disease
    Most common cause in the UK (mainly Hashimoto's thyroiditis)
  • Previous treatment of thyroid/neck
    Thyroid surgery, radioiodine therapy, neck radiotherapy
  • Iodine deficiency
    Common cause in other parts of the workd
  • Drugs
    Amiodarone, lithium, interferon alfa, sunitinib
  • Central hypothyroidism
    Hypothalamic and/or pituatary pathologies (characterised by low serum TSH and thyroid hormone levels)
  • Congenital hypothroidism
    Detected by newborn screening

Section 2: Making the diagnosis

Hypothyroidism should be suspected in any patient who reports symptoms that suggest a slowdown of their metabolism. Typical symptoms are tiredness, weight gain, feeling cold, dry skin, constipation, and poor concentration and memory.

However, the presence of any one or a collection of these symptoms is not by itself sensitive enough to be diagnostic of hypothyroidism.2

Examination of a patient with overt hypothyroidism may reveal loss of the outer third of the eyebrow, dry skin, pale skin and slow relaxing ankle reflexes.

Investigations
The pituitary gland produces TSH under the control of TSH regulating hormone from the hypothalamus and negative feedback from circulating thyroid hormones. TSH levels are sensitive to changes in circulating thyroid hormone concentrations.

Serum TSH levels rise before circulating thyroid hormones fall, so for most patients who do not have underlying pituitary disease, a serum TSH test is a very sensitive marker of thyroid hormone status. Therefore, in the vast majority of patients, a TSH first screening policy is adequate in detecting thyroid function abnormality – a serum TSH value within the reference range makes underlying thyroid dysfunction extremely unlikely. Measurement of thyroid hormones (FT4 and/or FT3) is only needed if the TSH level is abnormal. However, a TSH only screening policy is inappropriate in patients with suspected pituitary disease. These patients need both TSH and FT4/FT3 measurement.

The reference range for serum TSH is 0.4-4.5mU/L and higher values are consistent with hypothyroidism. In addition, tests to check underlying thyroid autoimmunity may be useful. When serum TSH is found to be elevated, testing for antibody to thyroid peroxidase (anti-TPO) is useful.

Apart from providing a clue to the aetiology of the thyroid dysfunction, positive TPO antibody status flags up a higher risk of progression to overt thyroid dysfunction.

Pregnancy has a significant effect on thyroid function, which changes over the course of gestation and makes assessment more difficult. This is mostly due to the weak stimulatory effect of beta hCG on the thyroid gland.

Generally, the reference range for serum TSH is lower in pregnancy. Guidelines for diagnosing and managing thyroid disease during pregnancy, issued by the American Thyroid Association, recommend trimester-specific reference intervals for TSH, as well as TSH targets for diagnosing and treating hypothyroidism during pregnancy.3

Diagnosis
The signs and symptoms of hypothyroidism are non-specific and widely prevalent, so it is very difficult to diagnose on clinical grounds.

Some signs or symptoms may raise the suspicion of hypothyroidism and this is then confirmed by the measurement of serum TSH.

Owing to the high frequency of symptoms that raise suspicion of hypothyroidism, TFTs are one of the most commonly requested tests.

In any given year, one in four patients in the UK will have their thyroid function measured.2


Section 3: Managing the condition

Treatment of hypothyroidism is with levothyroxine (LT4), an oral synthetic analogue of thyroxine that can be taken once daily.

The aim of treatment is to render the patient euthyroid. This is best achieved by LT4 and by regular monitoring to ensure serum TSH levels are within the reference range.

Most patients can be started on a full replacement dose of 1.6 microgram per kg per day, although a lower starting dose (usually 25 or 50 microgram per day) is advisable in the elderly or those with existing IHD.

The dose can be titrated in two to three months until serum TSH levels are within the reference range and any symptoms of hypothyroidism have improved. However, some patients may require a slightly higher dose of LT4 to aim for serum TSH levels towards the lower limit of the reference range.

Over-replacement with LT4, as evidenced by suppressed serum TSH levels, is not advisable because this has been associated with increased risk of osteoporosis and AF.4

Pregnancy
Because of the reported impact of hypothyroidism during pregnancy, with adverse neurodevelopmental outcomes in offspring,5 it may be safest to increase the dose of LT4 by 25% as soon as pregnancy is confirmed in women with hypothyroidism.

Other treatment options
Despite treatment with LT4, some patients (approximately 10%) may have continuing symptoms.

Such patients should be investigated for other conditions, such as other autoimmune disease (Addison's disease, primary biliary cirrhosis, pernicious anaemia) and obstructive sleep apnoea.

There is no clinical evidence that T3 therapy in addition to LT4 is of any benefit in primary hypothyroidism.6

Figure 1 outlines a possible algorithm for the management of hypothyroidism (both overt and subclinical), dividing patients into two groups based on their age.


Section 4: Prognosis

The prognosis for patients who are being treated for hypothyroidism is generally excellent.

However, regular checks for thyroid function measurement are required, to exclude under or over-replacement and minimise the risk of side-effects such as osteoporosis and AF.4

This means that annual clinical and biochemical assessment should be performed for patients who are stable on LT4 treatment.

If any adjustment is required to the patient's dose of LT4, a repeat TFT should be carried out three months after the adjustment has been made.


Section 5: Case study

A 56-year-old woman was admitted to the coronary care unit with chest pain. Her clinical presentation, ECG and troponins were consistent with acute coronary syndrome. She was treated accordingly.

The cardiologist noted that the patient looked pale and had lost the outer third of her eyebrows. She also admitted to feeling extremely tired over the past three years.

On examination, she had slow relaxing ankle jerks and a smooth soft goitre. A TFT revealed profound hypothyroidism, with serum TSH 91mU/L (normal range 0.4-4mU/L) and free T4 levels of 3.2pmol/L (normal range 10-25pmol/L). A TPO antibody test was strongly positive.

A coronary angiogram showed diffuse atheromatous disease in all three major coronary arteries. She was commenced on alternate day LT4 25 microgram per day, due to concerns of precipitating further cardiac ischaemia. She tolerated this well.

The dose was gradually titrated up at intervals of six weeks. However, four months after the original presentation, when she was taking 50 microgram per day of LT4, she complained of angina on exertion.

Despite maximum medical therapy, her symptoms did not improve and she was referred to the cardiothoracic surgeons for a coronary bypass graft procedure.

The patient is now well, free of chest pain and established on 100 microgram per day of LT4. Her tiredness has disappeared.

This case highlights several important points. First, patients can sometimes present after a significant delay, so hypothyroidism can become severe and may lead to other complications, such as coronary artery disease and dyslipidaemia.

Second, treating hypothyroidism in patients with unstable coronary artery disease can be challenging and can occasionally trigger a worsening of cardiac ischaemia.

Finally, nearly all patients, when adequately treated with LT4, report disappearance of their symptoms of hypothyroidism.


Section 6: Evidence base

Clinical trials

  • Rodondi N, den Elzen WP, Bauer DC et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010; 304: 1365-74.

This large, individual patient-level data analysis showed that patients who have advanced hypothyroidism (TSH >10mU/L) are more likely to have CHD and CHD-related mortality.

  • Razvi S, Ingoe L, Keeka G et al. The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function and quality of life. JCEM 2007; 92: 1715-23.

This large (n=100) randomised double-blind crossover trial showed that several cardiovascular risk factors, including LDL cholesterol and endothelial function, improved with treatment of subclinical hypothyroidism, the most common form of the condition. In addition, tiredness improved in a significant number of patients.

Reviews

Online resources

Dr Salman Razvi is consultant endocrinologist and honorary senior lecturer, Queen Elizabeth Hospital, Newcastle University.

Thanks to Dr Jackie Gilbert, consultant endocrinologist, King's College Hospital NHS Foundation Trust for helping to organise this article.

Take a test on this article and claim your certificate on MIMS Learning

This is an updated version of an article that was first published in September 2014.

References

  1. Vanderpump MPJ, Tunbridge WMG et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol 1995; 43: 55-68.
  2. Allahabadia A, Razvi S, Abraham P et al. Diagnosis and treatment of primary hypothyroidism. BMJ 2009; 338: b725.
  3. Stagnaro-Green A, Abalovich M, Alexander E et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Thyroid 2011; 21: 1081-125.
  4. Flynn RW, Bonellie SR, Jung RT et al. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab 2010; 95: 186-93.
  5. Haddow JE, Palomaki GE, Allan WC et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549-55.
  6. Grozinsky-Glasberg S, Fraser A, Nahshoni E et al. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2006; 91: 2592-9.

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