Levothyroxine is a commonly prescribed medication for hypothyroidism, and many cases of acute ingestion of excess levothyroxine have been reported, such as young children ingesting tablets by accident [3], adults attempting to commit suicide [5] [6] [7]. Edmundo K et al. described an adult case of accidental intoxication with 50 mg/day instead of 50 µg/day of levothyroxine over 9 days, due to pharmacist error in the preparation of the capsules, leading to an FT4 level of 74.1 ng/dL (955.90 pmol/L) measured by an automated chemiluminescence system. The patient presented with a stuporous mental state, atrial fibrillation and acute respiratory failure, but treatment with charcoal hemoperfusion was successful [8]. In most of the cases mentioned above, the patients did not have severe clinical courses in spite of the excessive intake of levothyroxine, ranging from 2 mg to 720 mg. These reports suggested that clinical course severity did not always depend on the amount of levothyroxine ingested or on the patient’s free thyroid hormone level, though pre-hospital deaths were not included.
In terms of thyroid hormone action, more than 99% of T4 and T3 are pooled in serum in binding forms with thyroxine binding globulin, prealbumin and albumin [9]. Thyroid hormone activity is produced by FT3. Serum FT3 enters cytoplasm through thyroid hormone transporters, specific transporters for T3 or T4. Next, T3 is pooled in cytoplasm following conversion of T4 to T3 by iodothyronine deiodinase [10]. Finally, T3 binds to nuclear T3 receptors to initiate transactivation. Thus, there are various binding sites in serum and cytoplasm which are capable of storing T3 and T4. In the present case, the patient had a benign clinical course despite temporal toxic exposure to levothyroxine. As she had thyroid dyshormonogenesis, it was indicated that the prior discontinuation of levothyroxine for a month caused severe hypothyroidism before massive ingestion, which increased the potential thyroid hormone binding capacity as a buffer to prevent toxic T3 effect.
Ishihara T et al. reported an athyreotic patient having taken 2 mg of levothyroxine at one time, with serum concentrations of T4, FT4 and reverse T3 (rT3) that reached a peak on the second day, while the serum T3 level peaked one day later [7]. FT3 level in the present case also peaked later, indicating that the toxic dose of levothyroxine partly changed to T3 during the two days. Ishihara T et al. also pointed out that the maximum concentrations of T4, FT4 and rT3 were very high, while the peak T3 level did not exceed the upper limit of the normal range. No signs or symptoms of thyroid toxicity other than mild tachycardia were noted. The patient exhibited a low T3/T4 ratio, and it was speculated that the thyroid type 1 deiodinase activity in the thyroid was one of the major determinants in the metabolic clearance of serum T4. Furthermore, there was a report that the mean FT3/FT4 ratios in Graves’ disease and destruction induced thyrotoxicosis were 0.395 and 0.287, respectively [11]. Compared to that study, the FT3/FT4 ratios in the present case, 0.11 on the first day and 0.15 on the third day (Table 1), were obviously low. Another group reported that the FT3/FT4 ratios after total thyroidectomy were lower than those before the surgery in patients with papillary thyroid carcinoma, demonstrating that the median ratio was 0.31 (0.28–0.34; 25th to 75th percentiles) on pre-thyroidectomy and 0.25 (0.22–0.28) on post-thyroidectomy [12]. It is known that almost 80% of T3 is derived peripherally from T4, and about 20% of T3 is secreted directly from the thyroid in healthy subjects. The half-life of T3 is about one day, which is much shorter than that of T4, which is about seven days. Therefore, it is considered that T3 level in thyroid dyshormonogenesis could be increased remarkably only if there is a continuous, sufficient supply of T4. All T3 in our patient was considered to be derived from T4; thus, her FT3 level, which represented thyroid hormone activity, would had been lower than that of people with normal thyroid function in the same situation.
Concerning methodology for measurement of thyroid hormone, various immunoassays are commercially available. Thirteen in vitro diagnostic manufacturers participated in the Phase IV methods comparison study of standardization of free thyroxine measurements, and the upper limits of measurement intervals for FT4 by those immunoassays were listed as 77–155 pmol/L [13]. Not only by levothyroxine overdose, but also in daily medical practice, we sometimes see a patient, typically one with Grave’s disease, whose FT4 or FT3 levels exceed the upper measurement limit. It is generally impossible by immunoassay to accurately determine real concentration when it is over the measurement range. Using LC-MS/MS, however, higher concentrations are able to be determined: the measurement ranges of FT4 and FT3 by the ultrafiltration LC-MS/MS used in this case were 3.1–1225 pmol/L and 1.8-731.1 pmol/L, respectively. As a result of measuring FT4 by LC-MS/MS in the present case, it was revealed that FT4 level was tremendously increased compared to FT3 level on the first day, and was decreased on the third day. It should be noted that ultrafiltration is distinct from the standard method, which is equilibrium dialysis. Nevertheless, a previous comparison study evaluated an ultrafiltration plus LC-MS/MS assay for FT4, and reported that the correlation between the ultrafiltration LC-MS/MS and the gold standard equilibrium dialysis methods was excellent (r = 0.954) [14].
While there is a consensus about the management of ordinary thyrotoxicosis, standards for treatment of patients with acute intake of excess levothyroxine have not been established. Therefore, it is possible that patients with a large amount of ingested levothyroxine may undergo unnecessary treatment. Lessons from this case suggest that patients’ symptoms and condition may not totally depend on the amount of levothyroxine, and that the trend of both FT4 and FT3 level is helpful to understand the patient’s clinical course. It is essential that clinicians assess each patient’s condition appropriately not to provide overtreatment but rather sufficient treatment. To that end, accurate and rapid measurement of extreme high level of free thyroid hormone, which is impossible by conventional immunoassays, is desirable. Soldin OP et al. reported that LC-MS/MS had great potential to be applied in the routine clinical assessment of FT4 and FT3 in the near future [15]. When the measurement of high concentrations of free thyroid hormone by LC-MS/MS becomes common in the future, more beneficial data for the management of thyrotoxicosis can be obtained.
In conclusion, the serum level of FT4 after the ingestion of 5 mg of levothyroxine in the present case with hypothyroidism increased above the measurable range of immunoassay. More specific FT4 concentrations were determined using ultrafiltration LC-MS/MS, which revealed that the value of FT4 was extremely high compared to that of FT3. These results indicate that LC-MS/MS is worth utilizing for measuring free thyroid hormone levels in thyrotoxic cases when the level is over immunoassay’s upper measurement limit. Though LC-MS/MS is currently a time-consuming technique, it is expected to be developed into a routine method in clinical laboratories in the near future, which will lead to more appropriate management of extreme thyrotoxicosis.