Santini F, Giannetti M, Ricco I, Querci G, Saponati G, Bokor D, Rivolta G, Bussi S, Braverman LE, Vitti P, Pinchera A. steady state serum T3 concentrations for 48 hours following the oral administration of a single dose of 3,5,3’-triiodothyronine sulfate (T3S). Endocr Pract. February 14, 2014 [Epub ahead of print].
Athyreotic patients who are given levothyroxine (L-T4) usually have a slightly low serum T3 level (about 80% of normal). Peripheral tissues typically deiodinate the outer ring of T4 to meet each tissue's particular needs for T3 and are presumed to be able to adjust to this slight decrease in the circulating T3 level. However, we need to keep in mind the occasional patient who “doesn't feel normal” even though the dose of T4 she is taking has normalized her serum TSH level, because our understanding of the mechanisms involved in the metabolism of thyroid hormones has improved. To try to mimic thyroid physiology more closely, desiccated thyroid or combinations of L-T3 plus T4 have been tried, but the outcomes of clinical trials have not been very convincing. Furthermore, if T3 is given only once a day, its serum level rises well above normal: even if T3 is given several times a day, the serum level still undergoes unphysiologically wide excursions. Although triiodothyronine sulfate (T3SO4) is often regarded as being a waste product of thyroid hormone metabolism, it clearly can be reactivated by hepatic and intestinal sulfatases (1). This report of a novel investigation shows the effects of a giving single oral dose of unlabeled T3SO4 on serum levels of TSH, T3SO4, T3, and T4 to patients with severe hypothyroidism.
When patients with thyroid cancer are being prepared for 131I treatment in Pisa, Italy, they are routinely given L-T4 for 6 weeks, which is then discontinued for a week. Next, 20 µg of L-T3 is given twice a day for 3 weeks, and then it too is stopped for 2 weeks. An earlier study indicated that patients receiving 20 µg of T3 orally 2 days before undergoing 131I therapy did not have depressed TSH levels or 131I efficacy. Based on those data, an initial oral dose of 20 µg of T3SO4 was given to 4 patients and blood samples were collected for the next 48 hours, until 131I was administered. Serum levels of TSH, T3SO4, T4, and T3 were measured; the rise in serum T3 did not exceed 197 ng/dl, the level previously shown not to affect TSH levels or 131I efficacy. The same tests were performed in 4 patients give 40 µg of T3SO4 orally 48 hours before undergoing treatment with 131I, then in 4 patients given 80 µg, and finally in 16 patients given 160 µg.
Serum T3SO4 levels peaked between 2 and 4 hours and returned to basal levels in 8 to 24 hours. The peak T3SO4 level, the area under the T3SO4 curve, and the time to return to baseline levels were directly related to the dose. Serum T3 levels rose significantly by 1 hour and peaked at 4 hours; however, in distinct contrast to the T3SO4 levels, T3 levels remained persistently elevated for at least 48 hours. The peak T3 level correlated with the dose of T3SO4, but the area under the T3 curve over the 48-hour period did not correlate with the dose of T3SO4. Reportedly, free T4 levels did not change, while serum TSH levels rose slightly (no data provided).
The serum level of T3SO4 rises quickly and remains elevated for a few hours when patients with hypothyroidism are given a single oral dose of T3SO4. The serum level of T3 also rises quickly, but it remains elevated for at least 2 days. The authors hypothesize that the persistent increase in T3 levels despite a fall in T3SO4 levels indicates that pools of T3SO4 that are sequestered from the bloodstream continue to generate T3, which could be a manifestation of the well-established enterohepatic cycle for T3SO4. If conversion of T3SO4 to T3 also occurs in patients taking T4, T3SO4 could represent a new agent to use in combination with T4 for treating patients whose symptoms do not seem to respond completely to treatment with T4 alone.
ANALYSIS AND COMMENTARY
Previous studies of euthyroid patients given excessive oral doses of T3 or T4 found serum T3SO4 levels to be high (2, 3), and in patients with hyperthyroidism, the basal level of T3SO4 is high (4). The high T3SO4 levels in thyrotoxic conditions may indicate an autoregulatory response: T3SO4 is more water-soluble, promoting its excretion, and it is also a much better substrate for deiodinase I, which deiodinates the outer ring of T3SO4 much more rapidly than it deiodinates T3 (5, 6).
On the other hand, there are sulfatases in intestinal bacteria and in liver, kidney, cerebral cortex, and muscle that can reactivate T3SO4 to form T3. When 125I-labeled T3SO4 was injected intravenously into euthyroid iodine-blocked subjects, 125I and T3 levels in the urine rose progressively from about 7% at 1 hour to over 20% at 8 hours (7). In euthyroid rats, T3SO4 has about one-fifth the molar activity of T3 (5). When thyroidectomized rats were injected with unlabeled T3SO4, serum T3SO4 levels rose rapidly, then fell by 4 hours, whereas serum T3 levels rose rapidly into the normal range and remained there for the entire study period (6), findings that resemble the results reported in the current study.
Thyroid hormone–responsive tissues can express different levels of thyroid hormone/metabolite transporters, intracellular binding proteins, enzymes involved in thyroid hormone metabolism, thyroid hormone receptors, and finally the myriad proteins involved with each of these activities. A relatively minor abnormality in any of these proteins might well affect the ability of specific tissues to adjust to a lower level of circulating T3 or to sequester thyroid hormone metabolic products. A patient's spectrum of intestinal bacteria doubtless also can influence thyroid hormone metabolism; will fecal transplantation become part of endocrinology in the future?
Details provided about the high-performance liquid chromatography method and the T3SO4 immunoassay are scanty. Although cross-reactivity of their antibody with T3 was low (<0.01%), the antibody's cross-reactivity with thyroxine sulfate (T4SO4) and rT3SO4 receptor seems greater than reported in an early assay (4). No data on percent recovery or sensitivity are provided, although apparently the assay is sensitive to T3SO4 levels below 1 ng/dl. Several of the authors are named on patents filed for clinical uses of T3SO4 and on improvements in the T3SO4 immunoassay, but the assay does not appear to be generally available to thyroid researchers.
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