Answers

Short answers

1 This patient presented with mild triiodothyronine thyrotoxicosis (thyroid stimulating hormone suppressed, free thyroxine normal, and free triiodothyronine raised to just above the upper limit of the reference range).

2 At subsequent follow-up appointments, the patient’s thyroid function varied slightly from triiodothyronine thyrotoxicosis to subclinical hyperthyroidism (thyroid stimulating hormone suppressed, free thyroxine and free triiodothyronine within reference range).

3 Triiodothyronine thyrotoxicosis is almost always owing to endogenous hyperthyroidism, whereas potential causes of subclinical hyperthyroidism can be either endogenous or exogenous (see box).

4 The risks associated with triiodothyronine thyrotoxicosis and subclinical hyperthyroidism include: atrial fibrillation; stroke; cardiovascular disease; fracture; and premature death.

5 Triiodothyronine thyrotoxicosis represents the earliest or mildest form of overt hyperthyroidism and should generally be treated in the same way as full blown thyrotoxicosis. Treatment options for subclinical hyperthyroidism range from observation to specific therapies for thyrotoxicosis.

Long answers
1 Biochemical abnormalities
This woman presented with mild triiodothyronine thyrotoxicosis, as demonstrated by her low concentration of thyroid stimulating hormone, normal concentration of free thyroxine, and raised concentration of free triiodothyronine (elevated to just above the upper limit of the reference range).

2 Abnormalities in thyroid function test
Over the 18 months following presentation, the thyroid function tests showed persistent triiodothyronine thyrotoxicosis. On one measurement, the patient’s triiodothyronine fell transiently into the reference range (subclinical hyperthyroidism), although this drop did not persist.

Triiodothyronine thyrotoxicosis can be considered the mildest form of overt hyperthyroidism and patients often complain of mild symptoms of thyrotoxicosis; for example, palpitations, sweating, anxiety, and change in bowel habit. The diagnosis of subclinical hyperthyroidism is based on the results of laboratory tests—specifically low or undetectable serum thyroid stimulating hormone with circulating thyroxine and triiodothyronine levels within the reference range; in addition, patients often have little in the way of symptoms.

3 Causes of thyroid hormone abnormalities
Both triiodothyronine thyrotoxicosis and subclinical hyperthyroidism can result from endogenous overproduction of thyroid hormones (owing to Graves’ disease, an autonomously functioning thyroid adenoma, or a toxic multinodular goitre, for example). Subclinical hyperthyroidism, however, can also be caused by intentional or unintentional overadministration of thyroid hormones. The pattern of thyroid function tests seen in subclinical hyperthyroidism is also seen in normal pregnancy¹ in euthyroid sick syndrome;² in patients taking glucocorticoids,³ amiodarone,⁴ levodopa,⁵ or opiates;⁶ and following injection of intravenous contrast agents that contain iodine.⁷

Triiodothyronine thyrotoxicosis and subclinical hyperthyroidism are more frequent in women than in men (female:male ratio 1.5:1). Triiodothyronine thyrotoxicosis is less common than subclinical hyperthyroidism, which affects between 1% and 2% of women over the age of 60^{8 9} and up to 3% of people over 80 years of age.¹⁰

4 Risks to health
Triiodothyronine thyrotoxicosis is associated with the complications of thyrotoxicosis, including increased mortality due to cardiovascular and cerebrovascular disease; cardiac dysrhythmias, particularly atrial fibrillation; and osteoporosis.

Subclinical hyperthyroidism was once considered a benign biochemical abnormality. In recent years, however, evidence has accrued to suggest that persistent subclinical hyperthyroidism is also associated with significant morbidity and mortality, just like triiodothyronine thyrotoxicosis and full blown thyrotoxicosis.

The morbidity and mortality associated with subclinical hyperthyroidism are owing to cardiovascular and cerebrovascular disease. In a study of community dwelling individuals over 60 year of age, the circulatory mortality at the 5 year follow-up point was 25% in study participants with a thyroid stimulating hormone concentration of less than 0.5 mIU/l compared with 15% in participants with a thyroid stimulating hormone concentration within the reference range. These values represent a 10% difference in survival between patients with subclinical hyperthyroidism and those with normal thyroid function.¹¹ This finding has been replicated across a cohort of the "oldest old" in the Leiden 85-plus study.¹²

Subclinical hyperthyroidism can progress to triiodothyronine thyrotoxicosis or full blown overt hyperthyroidism, the incidence of progression to overt thyrotoxicosis being approximately 5% per year.^{13 14} In addition, the probability of atrial fibrillation, a long established risk factor for cerebrovascular disease, is increased three fold in patients with subclinical hyperthyroidism.¹⁵ One study found that the risk of atrial fibrillation risk was little different between patients with subclinical hyperthyroidism and those with overt thyrotoxicosis.¹⁶

Finally, just as overt hyperthyroidism is a risk factor for reduced bone mineral density and bone fracture, a number of studies have shown that subclinical hyperthyroidism is also associated with these two problems. A prospective cohort study clearly demonstrated that women over 65 years of age with low serum thyroid stimulating hormone levels have a three fold increased risk of sustaining a new hip fracture and a four fold increased risk of sustaining a new vertebral fracture compared with women who have normal levels of thyroid stimulating hormone.¹⁷ This finding might not be applicable to premenopausal women, however, and data is conflicting in groups of patients whose subclinical hyperthyroidism has an exogenous cause.

5 Treating triiodothyronine thyrotoxicosis and subclinical hyperthyroidism
Both radioiodine therapy and antithyroid drugs are effective treatment options for patients with triiodothyronine thyrotoxicosis. In addition, these therapeutic approaches are effective in correcting the biochemical abnormalities in subclinical hyperthyroidism. No robust evidence exists, however, to suggest that these strategies lead to a reduction in the morbidity and mortality associated with subclinical hypothyroidism, or an improvement in quality of life and survival. These treatments both have drawbacks. For example, carbimazole, the most commonly used antithyroid drug, is in rare cases associated with agranulocytosis, which has a mortality of 10% in the elderly.¹⁸ In addition, patients with triiodothyronine thyrotoxicosis or subclinical hyperthyroidism are often elderly and, therefore, take multiple medications. Adding further medications can result in confusion and compliance problems, and increases the risk of drug interactions. In contrast, radioiodine therapy is a convenient one-off treatment; however, this approach may render the recipient hypothyroid and, therefore, dependent upon thyroid replacement therapy for life, again increasing the patient’s tablet burden. Following radioiodine therapy, recipients should be advised to avoid close contact (within a metre) with adults for 10-14 days and with children and pregnant women for 3-4 weeks.

Most endocrinologists agree that triiodothyronine thyrotoxicosis should be treated and offer one of the above two treatments. In contrast, there is little robust evidence to demonstrate that treating subclinical hyperthyroidism is beneficial. Nevertheless, many endocrinologists do offer treatment to patients with subclinical hyperthyroidism. A recent survey of UK endocrinologists showed that one third of respondents would generally treat an elderly individual who had subclinical hyperthyroidism, particularly if the patient was in atrial fibrillation or had osteoporosis. Of those respondents offering treatment, two thirds recommended radioiodine, whereas most of the remainder favoured thionamides.¹⁹ Given this uncertainty, options for treatment should be discussed with the patient and the pros and cons of each possibility explored.

Outcome
The patient’s investigations were completed by gastroenterologists and no sinister cause for her diarrhoea was found. Dosulepin hydrochloride was restarted, the diarrhoea improved, and her weight increased. The gastroenterologists discharged her from their care after referring her to the endocrine department for investigation of her abnormal thyroid function tests. The patient was investigated and found to have a solitary toxic thyroid nodule. She felt well in herself and, therefore, declined the offer of radioiodine therapy and opted instead for careful monitoring.

In October 2007, the patient began to feel very short of breath and complained of palpitations and dizzy spells. A 12-lead electrocardiogram showed atrial fibrillation and thyroid function showed worsening triiodothyronine thyrotoxicosis (thyroid stimulating hormone <0.05 mIU/l, free thyroxine 23 pmol/l, free triiodothyronine 6.9 pmol/l). She was given digoxin to control her heart rate and anticoagulation therapy with warfarin. She was treated with radioiodine therapy in November 2007.

In January 2008, the patient was clinically euthyroid; however, her levels of thyroid stimulating hormone were increasing. She was, therefore, started on a low dose of thyroxine (25 µg/day) in anticipation of her becoming hypothyroid. She remained in atrial fibrillation so was referred for direct current cardioversion.

In April 2008, the patient was successfully cardioverted back into sinus rhythm and reported considerable improvement in her symptoms. Immediately after cardioversion, digoxin was stopped and her atenolol dose was reduced to 50 mg once daily. She continued with warfarin for a further 6 months after cardioversion. Having confirmed that she remained in sinus rhythm, this treatment was stopped in June 2008. She is currently well, remains in sinus rhythm, and is maintained on 25 µg of thyroxine daily.

Cite this as: BMJ 2009;338:b1721