Thyroid disorders: clinical features and diagnosis

The thyroid is a small gland that weighs less than 30g and is located at the front of the neck, just below the larynx. It has two lobes, which lie along the trachea and are joined by the isthmus, a band of thyroid tissue.

Thyroid cells are the only cells in the body that absorb iodine. The function of the thyroid gland is to convert dietary iodine into thyroid hormones. When released into the bloodstream, thyroid hormones regulate the metabolism of carbohydrates, fats and proteins (this is mediated through other hormones such as insulin).

Normally, about 80% of the thyroid hormone produced is thyroxine (T4), a pre-hormone. T4 is activated to triiodothyronine (T3) in the liver, predominantly, but also in peripheral tissues. T3 is about four times more potent than T4 and is the active hormone used by the body.¹ About 10% of the hormone produced by the thyroid is T3. Small amounts of minor hormones, such as 3,3′-diiodothyronine (T2) and reverse-T3, are also released by the thyroid gland.

The thyroid gland is regulated by the anterior pituitary, which, in turn, is regulated by the hypothalamus. Negative feedback ensures that, when circulating T3 and T4 levels drop too low, the hypothalamus increases secretion of thyrotrophinreleasing hormone (TRH). This acts on the anterior pituitary, which, in turn, releases thyroid stimulating hormone (TSH). TSH stimulates the thyroid gland to release T3 and T4. This feedback loop ensures appropriate production of thyroid hormones (see Figure 1).

Assessing thyroid function

Thyroid function tests — blood tests measuring serum TSH, free T4 (FT4) and free T3 (FT3) levels — are used to diagnose thyroid disorders and to assess response to therapy. In certain patient groups periodic thyroid monitoring should be undertaken (see Box 1). Most circulating T3 and T4 is bound to thyroid binding globulin (TBG). Free (unbound) thyroid hormones are the biologically active fraction of the total circulating thyroid hormone pool. Therefore, measuring the amounts of free hormones provides a more accurate means of diagnosing thyroid dysfunction than measuring total hormone concentrations.

In the first instance TSH and FT4 are measured since results of these tests should identify most cases of thyroid dysfunction. Additional tests, such as FT3, may be required in certain situations (eg, hyperthyroidism caused by amiodarone treatment, or where hyperthyroidism is suspected clinically and TSH is suppressed but FT4 is not elevated). Measurement of FT3 is not required for diagnosing hypothyroidism.

A TSH value within the reference range (0.4–4.5mU/L) excludes most cases of primary overt thyroid dysfunction. The normal reference range for FT4 is 9–25pmol/L and for FT3 is 3.5–7.8pmol/L.

Other tests that may be required include:

• TBG — this can be measured in cases where the cause of hyper- or hypothyroidism is unclear
  
• TRH test —in healthy people, an injection of TRH will stimulate the production of TSH (the normal baseline level of 0.4–4.5mU/L will increase to 10–20mU/L); hyperthyroid patients will not show an increase in TSH, hypothyroid patients will show an increase of greater than 40mU/L
  
• Thyroid antibodies — these are present in the serum of patients with immune-mediated thyroid disorders, such as Hashimoto’s disease and Graves’ disease
  
• Thyroid scans —can be used to assess iodine uptake by the thyroid, detect benign or malignant nodules, measure the size of goitres (see Box 2), monitor patients after thyroid surgery or locate thyroid tissue outside the neck; radioactive iodine is administered orally and images are obtained subsequently using a gamma camera or computerised rectilinear thyroid scanner

Certain medicines can interfere with the synthesis, secretion, binding and metabolism of TSH and thyroid hormones. Some drugs can alter thyroid function and others can cause abnormal thyroid function test results in otherwise euthyroid people. In general, medicines are more likely to affect levels of thyroid hormones than they are to affect levels of TSH (although corticosteroids and high dose dopamine inhibit TSH release).² The effects of specific drugs on thyroid hormones are summarised in Box 3.

Hypothyroidism

Hypothyroidism refers to any state in which thyroid hormone production is inadequate. In the UK the annual incidence of hypothyroidism is approximately 1–2%, with the incidence for women (particularly older women) around six times greater than that for men.³

Typically the onset of hypothyroidism is insidious. Patients will often experience several non-specific symptoms, which can vary depending on the severity and duration of the deficiency. This often results in a delayed diagnosis. The most common signs and symptoms are shown in Box 4. Hypothyroidism can often be reversed by the administration of levothyroxine (see accompanying article).

Hypothyroidism can be categorised as primary or secondary, depending on the cause.

Primary hypothyroidism

Primary hypothyroidism is caused by failure of the thyroid gland to produce thyroid hormones. Usually, the condition has an autoimmune origin (eg, Hashimoto’s disease), but it can also be caused by dietary deficiency of iodine, antithyroid medicines, thyroidectomy or adverse drug reactions (see Box 3).⁴ Up to a third of cases arise from removal or destruction of the thyroid gland (see accompanying article).

A low FT4 and high TSH indicates primary hypothyroidism, since the pituitary is compensating by overproducing TSH in an attempt to increase thyroid hormone levels.

Secondary hypothyroidism

Secondary hypothyroidism occurs due to pituitary or hypothalamic dysfunction, which results in inadequate release of TRH and TSH.⁵ This reduces the stimulation of the thyroid gland to produce thyroid hormones.

Although not every case of secondary hypothyroidism has a clear cause, it is usually due to damage to the pituitary gland caused by radiation, surgery or the presence of a tumour. FT4 and TSH levels are low in secondary hypothyroidism.⁴

Hyperthyroidism

Hyperthyroidism occurs when the thyroid gland produces excessive amounts of thyroid hormones. The annual incidence is 0.8 per 1,000 for females and less than 0.1 per 1,000 for males. The most common cause of hyperthyroidism is Graves’ disease (also termed “diffuse toxic goitre”). Less common causes include subacute thyroiditis, excessive doses of levothyroxine or liothyronine, high iodine intake, postpartum thyroiditis and malignancy. Hyperthyroidism can also be induced by amiodarone treatment.

Common signs and symptoms of hyperthyroidism are listed in Box 5. In overt hyperthyroidism, TSH is low and FT4 and/or FT3 are raised. In sub-clinical hyperthyroidism, TSH is persistently low, with normal FT3 and FT4 concentrations. Thyroid scans can help diagnose the underlying cause.

Graves’ disease

Graves’ disease is the most common form of hyperthyroidism. It is an autoimmune condition, in which TSH receptor-stimulating antibodies (TRAb) cause local tissue inflammation and fluid accumulation, resulting in excessive levels of thyroid hormones. The same immune reaction can occur in the skin and orbital tissues, resulting in exophthalmos (protrusion of the eyes) and, sometimes, ocular dysfunction. Exophthalmos occurs in 25–50% of patients with Graves’ disease and affects an estimated 400,000 patients in the UK.⁶ Most signs and symptoms of Graves’ disease result from the direct and indirect effects of hyperthyroidism, involving most body systems (Box 5). The severity is related to the duration of the disease and the magnitude of the thyroid hormone excess.

Thyroiditis

The term “thyroiditis” describes inflammation of the thyroid gland. This inflammation can damage thyroid cells, leaving them incapable of meeting the body’s demand for thyroid hormones. Initially symptoms can be subclinical and go unnoticed. However, excessive amounts of thyroid hormone can pass into the bloodstream from the inflamed thyroid gland causing temporary hyperthyroidism, followed by hypothyroidism. The most common cause of thyroiditis is Hashimoto’s disease (also known as chronic lymphocytic thyroiditis) — an autoimmune condition in which lymphocytes produce antibodies that damage thyroid cells. It is usually diagnosed in patients who are over 40 years of age. Other types of thyroiditis include postpartum thyroiditis and de Quervain’s disease (a subacute or “silent” thyroiditis that shows microscopic changes). Rarely, thyroiditis can develop into a bacterial infection termed acute suppurative thyroiditis. Thyroiditis can be self-limiting, resolving in two to six months with no adverse effect on thyroid function, but more commonly it is a chronic condition.

Thyroid emergencies

Myxoedema crisis

Myxoedema crisis is a state of decompensated hypothyroidism characterised by:⁷

• Altered mental state — patients can be entirely unconscious or may be roused by stimuli; usually lethargy and drowsiness have been present for many months
  
• Defective thermoregulation —hypothermia (as low as 23C) or the absence of fever despite infection
  
• Presence of a precipitating event — such as infection, drugs (eg, diuretics, sedatives, analgesics), trauma, stroke, heart failure, gastrointestinal bleeding, cold exposure

It is a rare but life-threatening condition that requires immediate treatment. Despite optimum treatment, mortality rates of up to 50% have been reported; mortality is higher if myxoedema crisis progresses to coma and multi-organ failure.⁷ Persistent hypothermia and bradycardia have been associated with poorer prognosis. Higher age and cardiac complications are also significantly associated with a fatal outcome within one month of treatment.⁸ Generally, myxoedema crisis occurs in elderly women and is rarely seen in patients aged under 60 years.

A diagnosis of myxoedema crisis should be considered for all unconscious patients with hypothermia, especially if chronic renal insufficiency and hypoglycaemia can be excluded as causes. Most patients have reduced responsiveness of the respiratory system to hypoxia and hypercapnia.⁹ Bradycardia, hypotension and electrocardiographic changes are also common. Biochemical abnormalities include hyponatraemia and anaemia (normocytic or macrocytic).

Markedly increased TSH and low total T4 and FT4 confirm the diagnosis of myxoedema crisis (although TSH levels can be normal or low for patients with secondary hypothyroidism).^{7, 9}

Thyroid storm

The terms “thyroid storm” or “thyrotoxic crisis” describe an acute, life-threatening, hypermetabolic state that affects multiple systems and results from excessive release of thyroid hormones in people with hyperthyroidism.¹⁰ This is a rare condition and early diagnosis is essential since it has a mortality rate over 90% if left untreated. With early treatment the adult mortality rate declines to less than 20%.

Because no specific diagnostic tests are available, the diagnosis of thyroid storm is largely clinical. The clinical picture reflects severely exaggerated effects of thyroid hormones. Heat intolerance and sweating are commonly associated with simple hyperthyroidism. However, in thyroid storm this manifests as hyperpyrexia — temperature can exceed 41C. Hypermetabolism also increases oxygen and energy demands.

Cardiac findings range from mild-to-moderate sinus tachycardia in hyperthyroidism to accelerated tachycardia, hypertension, arrhythmias and high-output cardiac failure in thyroid storm. Similarly, irritability and restlessness in hyperthyroidism progress to severe agitation, delirium, seizures and coma in thyroid storm.

Several factors may precipitate the progression of hyperthyroidism to thyroid storm. These include:¹⁰

• Infection/sepsis
  
• Radioactive iodine therapy
  
• Surgery
  
• Diabetic ketoacidosis
  
• Direct trauma to the thyroid gland
  
• Medication (eg, treatment with amiodarone, cessation of antithyroid drugs)

With regard to biochemical tests, hyperglycaemia, leucocytosis, mild hypercalcaemia and abnormal liver function tests can be present. Impairment of adrenal reserve may also occur.

References

1. Ball SG, Sokolov J, Chin WW. 3,5-diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro. Journal of Molecular Endocrinology 1997;19:137–47.
2. Association for Clinical Biochemistry, British Thyroid Foundation, British Thyroid Association. UK guidelines for thyroid function tests. July 2006. www.acb.org.uk/site/guidelines.asp (accessed 20 May 2011).
3. Vanderpump MP, Tunbrldge WMG, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clinical Endocrinology 1995;43:55–68.
4. American Thyroid Association. Hypothyroidism. 2003. www.thyroid.org (accessed 20 May 2011).
5. Vaidya B, Pearce SHS. Clinical review: management of hypothyroidism in adults. BMJ 2008;337:a801.
6. Cawood T, Moriarty P, O’Shea D. Recent developments in thyroid eye disease. BMJ 2004;329:385–90.
7. Wall CR. Myxedema coma: diagnosis and treatment. American Family Physician. 2000;62:2485–90.
8. Fliers E, Wiersinga WM. Myxedema coma: diagnosis and treatment. Reviews in Endocrine and Metabolic Disorders 2003;4:137–41.
9. Sarlis NJ, Gourgiotis L. Thyroid emergencies. Reviews in Endocrine and Metabolic Disorders 2003;4:129–36.
10. Savage MJ, Mah PM, Weetman AP, et al. Endocrine emergencies.