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In vivo evidence for a direct ultra‐fast negative feedback of thyroxine on TSH secretion in humans: a case of L‐thyroxine pseudomalabsorption

Pseudomalabsorption of levothyroxine is a factitious disorder suggesting malabsorption of levothyroxine. One of the therapeutic possibilities for treating hypothyroidism is the once weekly supervised administration of a large dose of thyroxine. 1 We describe such a patient with whom we had the opportunity to follow hormonal concentrations after each dose of thyroxine. A 55-year-old man ( weight 60 kg ) was referred because of persistent hypothyroidism (TSH 200 mU/l, N = 0·15–4·5) despite relatively high doses of levothyroxine (200 μ g/day). He had undergone thyroidectomy for ‘uncontrolled hyperthyroidism’ in another hospital two years before. The retrospective review of his chart led us to suspect noncompliance with his thyroxine replacement therapy. Clinical examination was unremarkable; pulse was regular at 60 beats/min; the patient had no complaint and reported taking his levothyroxine regularly every morning. Pseudomalabsorption was diagnosed and advice given to the patient. He was admitted 6 months later at the emergency unit with a spontaneous cutaneous haematoma. This episode was probably related to the surreptitious taking of warfarin but again the patient denied taking any drug other than levothyroxine. At the time of the hospitalization, TSH was about 200 mU/l. There were no clinical or biological signs of malabsorption and upper endoscopy with duodenal biopsies was normal. To verify thyroxine absorption, we administered a large dose of thyroxine under medical supervision and then took blood samples to assess TSH and thyroid hormone concentrations. As the first procedure confirmed the efficacy of this modality of treatment and excellent tolerance, he was then asked to return once a week to continue his treatment. Once per week, at 08·00 h as he was fasting, he was orally administered 1000 μ g of levothyroxine under the supervision of a nurse. During the first 10 weeks of thyroxine charge, TSH decreased by 39 ± 6% of the initial values 2 h after oral thyroxine administration, with great consistency each week, whatever the initial TSH levels (ranging from 178 to 2·53 mU/l). The decrease continued more slowly during the subsequent 6 h to about 60% of the initial values after 8 h. At the same time, free T4 (FT4) increased by twoto threefold the initial values, peaked between the second to third hour and then declined very slowly. As expected, there was no significant variation in free T3 (FT3) levels after 2 h and then a very slight increase 4 h and 6 h after the charge. After analysing the first results, the patient agreed to one session with blood sampling every 15 min for the first 2 h to allow us more detailed kinetics studies (Fig. 1). TSH decreased from 108 mU/l to 95·8 mU/l after 15 min and to 87·5 mU/l after 30 min. At the same time, FT4 increased from 8·44 pmol/l to 11·67 pmol/l and then to 19·6 pmol/l, whereas FT3 increased slightly from 3·67 pmol/l to 3·78 pmol/l and then to 3·93 pmol/l. The peak of FT4 levels was observed 1 h after thyroxine ingestion, whereas that of FT3 appeared biphasic with the first maximum 1 h after ingestion and a second peak 2 h after ingestion. Alpha subunit was at relatively high levels before treatment and exhibited large fluctuations after thyroxine administration without a clear pattern. Several months after the beginning of the weekly thyroxine treatment, TSH on the day of dosing varies between 2 mU/l and 10 mU/l and the patient remains asymptomatic. The inhibitory effect of thyroxine on TSH secretion is classically due to the pituitary conversion of T4 to T3 by type 2 deiodinase (DT2), with subsequent repression of TSH synthesis by the genomic effects of T3. In thyroidectomized rats, the administration of T4 or of T3 is rapidly associated with an increase in T3 nuclear receptor occupancy and a decrease in TSH levels. 2 In this model, TSH suppression is dependent upon nuclear T3 content and serum T3 concentration. 3 When iopanoic acid (an inhibitor of T4 to T3 conversion) is given to rats, it prevents the decrease of TSH provoked by the administration of T4. However, in none of these papers, was plasma TSH measured as early after T4 administration as in our study. Several authors have studied the kinetics of the negative feedback of thyroid hormone on TSH in man but most have used T3, either orally or intravenously, and the beginning of the decrease of TSH was not always precisely mentioned. Spencer et al . have studied in detail the kinetics of plasma TSH after a single oral or intravenous dose of T3 both in euthyroid and in hypothyroid subjects. 4 They defined a two-phase response beginning 1–4 h after thyroid hormone administration with a fall of 25–50% in TSH levels, a decrease of the same amplitude as that observed in our patient. This effect likely relies on the release of preformed TSH stores, because the effect on TSH synthesis requires several hours. This hypothesis is also sustained in our patient by the absence of inhibition of subunit α release, which is known to be controlled in a different way than that of mature TSH. In other studies using oral thyroxine administration, the peak of serum T4 was observed 2–3 h after the administration, and TSH responses during the first 10 h were not generally mentioned. Recent papers have shown the complexity of the regulation of DT2. 5 Briefly, DT2 is up-regulated in hypothyroidism but is also stimulated by T4. This could partly explain the rapidity of the TSH decrease at the beginning of treatment of hypothyroidism, a situation