Improvement of Laboratory Diagnostics in Hypothyroid Patients Using Levothyroxine

Hypothyroidism is a thyroid disorder and one of the most common endocrine disorders. Hypothyroid patients have a thyroid hormone deficiency characterized by a shortage of thyroid hormone (TH) in the circulation and at the organ level and are normally treated with a synthetic form of thyroid hormone (L-T4 or levothyroxine). Thyroxine (T4) is a prohormone, produced by the thyroid gland and converted into the active hormone triiodothyronine (T3) in peripheral tissues. A minor percentage (20%) of circulating T3 is directly produced by the thyroid gland. Although L-T4 treatment accounts for all patients with hypothyroidism, the pathogenesis of hypothyroidism differs. Most patients suffer from primary hypothyroidism (Hashimoto's disease), which is an auto-immune disorder, but also central hypothyroidism, hypothyroidism after total thyroidectomy due to thyroid carcinoma or hypothyroidism due to therapy of Graves' disease are commonly seen.

Currently, thyroid-stimulating hormone (TSH) and/or free T4 (fT4) are measured in serum to monitor the treatment efficacy of L-T4. TSH is produced by the pituitary to stimulate the production of thyroid hormones by the thyroid gland and due to the negative feedback loop considered as a good reflection of thyroid hormone status. Target concentrations of TSH and fT4 differ depending on the cause of hypothyroidism. In patients with Hashimoto's hypothyroidism, TSH concentrations are measured to monitor treatment and TSH levels within the reference intervals are pursued. TSH is measured to monitor treatment in patients with hypothyroidism after total thyroidectomy due to thyroid carcinoma as well, although a suppressed TSH is warranted in this group. The extent of TSH suppression is determined based on the type and stage of the carcinoma. In patients who are hypothyroid due to therapy of Graves' disease, other target values apply. Patients who are just diagnosed with Graves' disease start with thyroid suppressive therapy together with thyroid hormone supplementation (L-T4) and show a prolonged suppressed TSH; therefore, fT4 is initially used to monitor therapy. TSH is used to monitor treatment again when TSH starts to normalize. Nevertheless, TSH shall always be slightly suppressed due to the TSH receptor antibodies produced during Graves' disease, which means fT4 concentration is still taken into account during follow-up. Finally, it is not possible to monitor treatment by using TSH concentrations in patients with central hypothyroidism, which means fT4 concentrations are leading in this group. In conclusion, TSH cannot always be used to assess thyroid function in which cases fT4 is assessed as well.

It is known that patients using L-T4 can show a combination of fT4 values above the upper reference limit and non-suppressed or only slightly suppressed TSH levels. The most likely explanation for this is twofold. First, thyroid hormones are supplemented by L-T4, which only replaces T4, whereas the production of the active thyroid hormone T3 by the thyroid gland is lacking and the patients depend on peripheral conversion of T4. Literature showed that these patients need a higher L-T4 dosage to obtain a normal, or even somewhat lower, concentration of T3. TSH is regulated by changes in T3 rather than T4, clarifying the lack of pituitary feedback to increased fT4 concentrations if fT3 concentrations are not increased simultaneously. Second, previous studies showed that fT4 levels peak two until four hours after L-T4 intake and gradually decline until the next dosage is taken. Sometimes, this peak increases above the upper limit of the reference interval. This pattern is not seen for TSH levels. Looking at aforementioned outcomes, it seems that fT4 levels are higher in patients using L-T4 compared to healthy controls, thus not reflecting thyroid hormone status adequately.

In clinical practice, the largest group of hypothyroid patients are monitored by measuring TSH as mentioned above. Therefore, these high fT4 levels will only rarely cause problems. However, these high fT4 levels can have treatment consequences in patient groups wherein therapy is monitored via fT4 levels (e.g. central hypothyroidism), which could lead to unwarranted dose adjustments (leading to a too low dose of L-T4).

Free T3 (fT3) concentrations can be measured but are used only rarely in clinical practice. Previously, the fT3 measurement using immunoassay techniques was troublesome and, therefore, considered as unreliable. However, the quality of the currently used immunoassay has been substantially improved resulting in the availability of reliable fT3 immunoassays. Furthermore, in contrast to fT4, fT3 is not subject to change after L-T4 intake. Consequently, fT3 might be an interesting parameter to assess thyroid hormone status in L-T4 users along with TSH. In addition, literature suggested that the ratio between fT3 and fT4 might be worthwhile investigating as an indicator of peripheral conversion. The fT3/fT4 ratio is thought to be lower in L-T4 users compared to euthyroid controls and could, therefore, be used to evaluate to what extent T4 is converted to T3. A decline might represent insufficient availability of thyroid hormone throughout the body.