Clinical Review: Hyperthyroidism

Hyperthyroidism is a common endocrine disorder in which the thyroid gland produces too much thyroid hormone.

Section 1: Epidemiology and aetiology

Hyperthyroidism is a disorder of excess synthesis and secretion of thyroid hormones, resulting in typical clinical manifestations of thyrotoxicosis.1

The population prevalence of hyperthyroidism is 2% in women and 0.2% in men in the UK,2 with higher incidence in white populations, areas of iodine deficiency and older people.3

Hyperthyroidism is usually primarily a disorder of the thyroid gland, but in rare cases, it may be secondary to increased secretion of pituitary TSH or hypothalamic TSH releasing hormone (TSHR).

The most common cause of overt hyperthyroidism, accounting for 80% of cases in the UK, is Graves' disease, an autoimmune condition in which auto-antibodies bind to the TSH receptors on thyroid follicular cells, resulting in increased secretion of thyroxine (T4) and triiodothyronine (T3).

Graves' disease is the most prevalent autoimmune disorder in the UK and may be associated with other autoimmune conditions, such as rheumatoid arthritis, suggesting a shared pathogenesis. A low threshold for screening for associated autoimmune disorders is advisable.4

Graves' hyperthyroidism is caused by an interplay between genetic (80% of susceptibility) and environmental (20% of susceptibility) factors, including smoking, infection, stress and pregnancy. Almost 50% of patients will report a family history.5

Other causes include toxic nodular hyperthyroidism (15% of cases in the UK, with 50% of cases in iodine-deficient areas)6 when one (toxic adenoma) or more nodules (toxic multinodular goitre) cause autonomous overproduction of thyroid hormones.

Thyroiditis or inflammation of the thyroid represents a condition of thyroid cell destruction, resulting in the release of excess thyroid hormones in the circulation, thereby causing thyrotoxicosis.

Subclinical hyperthyroidism is a biochemical diagnosis, in which serum TSH concentrations are low or undetectable, with normal concentrations of circulating thyroid hormones. This may be endogenous or exogenous (due to excessive doses of levothyroxine replacement).

Classification
Table 1 lists common and less common causes of hyperthyroidism and thyrotoxicosis.

Section 2: Making the diagnosis

Excess thyroid hormone concentrations affect nearly every physiological system, but symptoms and signs relating to the cardiovascular system often predominate.1

Patients often report palpitations and sinus tachycardia is usually evident on clinical examination.

Development of AF is one of the most serious consequences of hyperthyroidism and is an independent predictor of mortality.7

Signs and symptoms
Weight loss despite increased appetite, fatigue, heat intolerance, nervousness, irritability, muscle weakness and increased frequency of bowel movement are common symptoms of thyrotoxicosis.

SOB and reduced exercise capacity are caused by a combination of cardiovascular abnormalities and respiratory muscle weakness.8

Clinical signs include the presence of a smooth goitre in Graves' disease and a single nodule or multinodular goitre in toxic nodular disease. A fine tremor, sinus tachycardia, warm moist skin and hyperreflexia are also common signs of hyperthyroidism.

About 50% of patients with Graves' disease have ophthalmopathy, characterised by eyelid retraction and lag, proptosis, conjunctival injection and periorbital oedema; in severe cases, this may result in ophthalmoplegia.

It is estimated that about 5% of patients with Graves' disease develop severe ophthalmopathy.9 Other extrathyroidal manifestations of Graves' disease include pretibial myxoedema and thyroid acropachy.

Overall, the frequency and severity of symptoms are related to the degree of circulating thyroid hormone abnormality.

Older patients have fewer symptoms and signs, with the exception of weight loss, SOB and AF.10

Investigations
Measurement of serum TSH is the most sensitive screening test to exclude thyrotoxicosis. This is usually undetectable in overt hyperthyroidism because of negative feedback of high levels of circulating thyroid hormones on the anterior pituitary.

Thyroid hormones circulate bound to proteins in the blood, but current assays measure free thyroid hormone concentrations.

Free T4 is usually raised in patients with overt hyperthyroidism, except in more rare cases of T3 toxicosis.

The patient's history and clinical features often identify Graves'

hyperthyroidism, especially if extrathyroidal manifestations are present. Current sensitive assays can accurately measure TSH-receptor antibodies, confirming the diagnosis of Graves' disease.11

Anti-thyroid peroxidase (TPO) antibodies are also present in 75% of patients with this condition.

Isotope imaging (with technetium or radioactive iodine) may help to distinguish Graves' disease from other causes of thyrotoxicosis.

The investigations required to establish a differential diagnosis of thyrotoxicosis are listed in table 2.

Section 3: Managing the condition

Treatment with beta-adenoceptor blockers is effective in controlling symptoms of tremor, palpitation and anxiety.

Once a diagnosis of hyperthyroidism has been confirmed, there is a choice of three treatment options: antithyroid drugs, radioiodine administration or surgery.

Table 3 summarises the indications, advantages and disadvantages of therapeutic strategies for
hyperthyroidism.

The American Thyroid Association guidelines on hyperthyroidism recommend discussion of all three options with the patient.12

Antithyroid drugs
Thioamides, carbimazole and propylthiouracil (mainly in early pregnancy) are the drugs of choice.

If a dose titration regimen is used, the dose of antithyroid drugs is reduced as serum free T4 concentrations normalise, aiming for completion of 12-18 months of therapy.

Some clinicians prefer a block- replace regimen, in which high doses of antithyroid drugs are used to block thyroid function in combination with levothyroxine replacement. This approach does not improve remission rates and is associated with more side-effects.13

Minor and often transient side-effects occur in about 3% of patients on antithyroid drugs. These include rashes, arthralgia, fever and GI upset.14 The most severe side-effect of carbimazole and propylthiouracil is agranulocytosis, which occurs in 0.2-0.5% of patients taking these drugs. Propylthiouracil is associated with antineutrophil cytoplasmic antibody-positive vasculitis15 and acute liver failure.16

Radioiodine
Radioiodine is the treatment of choice in relapsed Graves' disease and is increasingly used as first-line therapy. It is also the treatment of choice in patients with toxic nodular hyperthyroidism.

This is a safe and effective treatment option, with cure rates of up to 85% after a single dose.17

The aim of treatment is to restore a euthyroid state with or without hypothyroidism. Contraindications include pregnancy or lactation, desire for pregnancy within six months of treatment and inability to comply with radiation protection regulations.18

Most clinicians use a single fixed dose and the use of calculated doses has not proved cost-effective.19

Graves' ophthalmopathy is a relative contraindication and many clinicians will administer radioactive iodine in patients with inactive thyroid eye disease, under steroid prophylaxis.20

Surgery
Surgery is used infrequently to treat hyperthyroidism. Total thyroidectomy is advised and complication rates are low in the hands of experienced surgeons.

Relative indications include large goitres (especially if thyroid cancer is suspected), pregnancy and pronounced ophthalmopathy.1

New developments
Efforts to better understand the genetic basis of autoimmune disease should ultimately provide novel approaches to treat the underlying disease process, rather than inhibition or destruction of the thyroid.

Promising developments include the use of rituximab, a CD20 antibody,21 and selective TSH-receptor antagonists22 in preclinical trials.

Section 4: Prognosis

A prolonged course of antithyroid drugs induces lasting remission in 30-50% of patients.13 Factors predicting poor response include severe biochemical disease, male gender, younger age, smoking, presence of a large goitre and high concentrations of TSHR antibodies.23

The other modalities result in permanent hypothyroidism, usually requiring levothyroxine. Treatment of toxic nodular hyperthyroidism is preferentially with radioiodine, or surgery if the goitre is large. Annual TFTs are required in patients who have radioiodine, regardless of the induction of hypothyroidism.

A long-term increase in all cause and vascular mortality after treatment of hyperthyroidism has been described. Induction of hypothyroidism after radioiodine treatment reduced the risk, possibly because hypothyroidism is the best marker of reversal of adverse tissue effects.24,25

Section 5: Case study

A 34-year-old woman presented with symptoms of heat intolerance and irritability.

She admitted to losing 5kg in the past three months, despite eating more than usual. She had no diarrhoea or palpitations. Her mother had an underactive thyroid.

The patient was married, with two children aged 12 and 10. She worked as a primary school teacher.

The GP considered hyperthyroidism and this was confirmed by TFTs. The patient was referred to the thyroid clinic.

Clinical examination revealed a fine tremor and a small diffuse goitre. Eye examination identified bilateral lid retraction, but no active thyroid eye disease.

A clinical diagnosis of Graves' hyperthyroidism was made and measurement of auto-antibodies was arranged.

Treatment options - antithyroid drugs, surgery or radioiodine - were discussed. In view of the age of her children, the radiation protection requirements for radioiodine would be difficult (she would need to have minimum contact with her children for nearly four weeks).

The patient chose carbimazole and was warned in writing about the risk of agranulocytosis.

She was treated using a titration regimen and completed 15 months of treatment.

She returned eight months later with relapsed Graves' disease and because her youngest child was still only 13 years old, she opted for a further course of carbimazole.

Unfortunately, she developed agranulocytosis, which was picked up when she developed symptoms of fever and pharyngitis.

The carbimazole was discontinued and arrangements were made for her to receive radioiodine.

The patient's children went to stay with their grandparents for two weeks and because she received the treatment during the summer holidays, she was able to avoid school for four weeks without needing to miss any of the term time.

She was made aware of the nearly 80-90% chance of hypothyroidism developing after radioiodine.

Hypothyroidism was picked up on blood tests three months following radioiodine administration, before she developed symptoms, and she was put on lifelong levothyroxine.

Section 6: Evidence base

Clinical trials

  • Torring O, Tallstedt L, Wallin G et al. Graves' hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine - a prospective, randomized study.Thyroid Study Group. J Clin Endocrinol Metab 1996; 81: 2986-93.

This is the only RCT comparing all three treatment modalities in the management of hyperthyroidism.

Reviews

  • Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet 2012; 379: 1155-66.

A Lancet seminar on the management of hyperthyroidism.

  • Abraham P, Avenell A, McGeoch SC et al. Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev 2010(1): CD003420

A systematic review of block replacement versus the titration regimen for treating Graves' hyperthyroidism. Similar relapse rates, but more side-effects and withdrawal of treatment were reported on the block replacement regimen.

Guidelines

  • Bahn RS, Burch HB, Cooper DS et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. www.thyroid.org/thyroid-guidelines/hyperthyroidism

Online resources

References

1. Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet 2012; 379: 1155-66.

2. Tunbridge WM, Evered DC, Hall R et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977; 7: 481-93.

3. Golden SH, Robinson KA, Saldanha I et al. Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab 2009; 94: 1853-78.

4. Boelaert K, Newby PR, Simmonds MJ et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Amer J Med 2010; 123: 183-9.

5. Manji N, Carr-Smith JD, Boelaert K et al. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J Clin Endocrinol Metab 2006; 91: 4873-80.

6. Laurberg P, Bulow PI, Knudsen N et al. Environmental iodine intake affects the type of nonmalignant thyroid disease. Thyroid 2001; 11: 457-69.

7. Osman F, Franklyn JA, Holder RL et al. Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study. J Amer Coll Cardiol 2007; 49: 71-81.

8. Norrelund H, Hove KY, Brems-Dalgaard E et al. Muscle mass and function in thyrotoxic patients before and during medical treatment. Clin Endocrinol (Oxf) 1999; 51: 693-9.

9. Weetman AP. Graves’ disease. N Engl J Med 2000; 343: 1236-48.

10. Boelaert K, Torlinska B, Holder RL et al. Older subjects with hyperthyroidism present with a paucity of symptoms and signs: a large cross-sectional study. J Clin Endocrinol Metab 2010; 95: 2715-26.

11. Winter WE, Jialal I, Devaraj S. Thyrotropin receptor antibody assays: clinical utility. Am J Clin Pathol 2013; 139: 140-2.

12. Bahn RS, Burch HB, Cooper DS et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011; 21: 593-646.

13. Abraham P, Avenell A, Park CM et al. A systematic review of drug therapy for Graves’ hyperthyroidism. Eur J Endocrinol 2005; 153: 489-98.

14. Cooper DS. Antithyroid drugs. N Engl J Med 2005; 352: 905-17.

15. Noh JY, Yasuda S, Sato S et al. Clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis caused by antithyroid drugs. J Clin Endocrinol Metab 2009; 94: 2806-11.

16. Rivkees SA, Mattison DR. Ending propylthiouracil-induced liver failure in children. N Engl J Med 2009; 360: 1574-5.

17. Boelaert K, Syed AA, Manji N et al. Prediction of cure and risk of hypothyroidism in patients receiving 131I for hyperthyroidism. Clin Endocrinol (Oxf) 2009; 70: 129-38.

18. Royal College of Physicians. Radioiodine in the management of benign thyroid disease. London, RCP, June 2007. www.rcplondon.ac.uk/publications/radioiodine-management-benign-thyroid-disease

19. De Rooij A, Vandenbroucke JP, Smit JW et al. Clinical outcomes after estimated versus calculated activity of radioiodine for the treatment of hyperthyroidism: systematic review and meta-analysis. Eur J Endocrinol 2009; 161: 771-7.

20. Vaidya B, Williams GR, Abraham P et al. Radioiodine treatment for benign thyroid disorders: results of a nationwide survey of UK endocrinologists. Clin Endocrinol (Oxf) 2008; 68: 814-20.

21. El FD, Nielsen CH, Bonnema SJ et al. B lymphocyte depletion with the monoclonal antibody rituximab in Graves’ disease: a controlled pilot study. J Clin Endocrinol Metab 2007; 92: 1769-72.

22. Neumann S, Eliseeva E, McCoy JG et al. A new small-molecule antagonist inhibits Graves’ disease antibody activation of the TSH receptor. J Clin Endocrinol Metab 2011; 96: 548-54.

23. Allahabadia A, Daykin J, Holder RL et al. Age and gender predict the outcome of treatment for Graves’ hyperthyroidism. J Clin Endocrinol Metab 2000; 85: 1038-42.

24. Boelaert K, Maisonneuve P, Torlinska B et al. Comparison of mortality in hyperthyroidism during periods of treatment with thionamides and after radioiodine. J Clin Endocrinol Metab 2013; 98: 1869-82.

25. Franklyn JA, Sheppard MC, Maisonneuve P. Thyroid function and mortality in patients treated for hyperthyroidism. JAMA 2005; 294: 71-80.

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  • Thanks to Dr Jackie Gilbert, consultant endocrinologist, King's College Hospital NHS Foundation Trust, and secretary of the British Thyroid Association, for helping to organise this article
  • Contributed by Dr Prakash Abraham, consultant endocrinologist, Aberdeen Royal Infirmary, and Dr Kristien Boelaert, reader in endocrinology, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham.
CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Reacquaint yourself with the clinical features of Graves' disease.
  • Organise an audit of patients in your practice who have Graves' disease and review their access to radioiodine therapy or surgery.
  • Arrange a meeting with the consultant endocrinologist to discuss a protocol for referring patients with Graves' disease.

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