Raised TSH, normal free T4 or T3
This is the pattern of thyroid function normally seen with mild thyroid failure (subclinical hypothyroidism) (panel 6). It is common in the population, affecting 5–10% of all women, and in most cases is associated with positive anti-TPO antibodies. Subclinical hypothyroidism is caused by autoimmune hypothyroidism that has not yet progressed to severe thyroid impairment,46 although it can also follow radioiodine treatment or thyroidectomy.
Although subclinical autoimmune hypothyroidism is by far the most common cause of this pattern of thyroid function tests, alternative diagnoses should be considered under certain circumstances. If the TSH concentration is raised to a value usually associated with a low free T4 or T3—eg, over 20 mU/L—or does not return to normal with T4 therapy, the presence of a heterophile—eg, anti- mouse immunoglobulin—interfering with the TSH assay is likely.47 Repeat estimation, with a different assay, or the addition of blocking agents such as mouse serum, can rapidly provide confirmation. Such interfering antibodies persist for years, so the patient should be made aware and the medical records marked to ensure only assays in which interference does not occur are used. Individuals with heterophile antibodies could have completely normal thyroid function, but are often prescribed thyroxine and then accused of poor compliance because intermittent T4 therapy in true hypothyroidism can generate this same pattern of thyroid function tests.
In patients taking thyroxine, an apparent increase in thyroxine requirement, signalled by an increase in TSH in a previously stable patient, could be caused by malabsorption of thyroxine.48 Poor absorption can be caused by small bowel disease or, iatrogenically by cholestyramine or iron therapy.48 A similar change in thyroid function tests has been noted in some individuals on sertraline, but the exact mechanism remains unclear. Amiodarone therapy frequently results in mildly raised TSH values in the first 3 months of therapy, caused by inhibition of T4 or T3 conversion in the pituitary. Affected individuals have normal free hormone concentrations (or slightly raised free T4), and this situation should be distinguished from true amiodarone induced hypothyroidism.14 Recovery from severe non- thyroidal illness, during which thyroid hormones were depressed, can be associated with a transient overshoot of TSH, resulting in a similar pattern of thyroid function.9
In individuals who are negative for thyroid antibodies, an isolated raised TSH could be a result of subclinical defects in thyroid gland function caused by congenital abnormalities. Some individuals with Pendred’s syndrome fall into this category, although most have a goitre but a TSH within the normal range.49 The prevalence of this condition could be as high as 1 in 10 000, accounting for as many as 10% of all cases of hereditary sensineural deafness. The abnormality has been located to a gene on chromosome 7, and Pendrin was cloned in 1997. This gene codes for a putative sulphate transporter. However, the connection with impaired organification of iodine in the thyroid (and therefore a positive perchlorate discharge test) remains unclear.49
Additionally, as mentioned above, syndromes of TSH resistance,42 some with TSH receptor defects,43 and some cases of thyroglobulin synthetic defects,41 might be detected for the first time in adulthood and can be associated with an isolated raised TSH and normal-sized thyroid gland. No doubt further congenital abnormalities will be identified.
