Thyroid hormone is one of the most important substances affecting the entire body, essential for brain development, body growth and metabolism. Its crucial role is defined by the extreme changes seen in patients with hormone abnormalities. Abnormally high hormone levels in adults (hyperthyroidism) commonly cause weight loss, mood changes, fatigue and rapid heartbeat, and the reverse (hypothyroidism) can produce depression, weakness, sluggishness and increased sensitivity to cold. Unrecognized lack of sufficient thyroid hormone levels in early life can result in permanent mental retardation, which prompted routine screening of all newborns for thyroid hormone deficiency in the United States and around the world.
For decades scientists have used errors of nature to identify the normal stages of thyroid hormone synthesis, transport and action. Dr. Samuel Refetoff, professor at the University of Chicago Departments of Medicine, Pediatrics and the Committee on Genetics, has successfully employed this approach in his many discoveries over the past four decades. However, precisely how thyroid hormone is released from the gland into the bloodstream remained unknown. The prevailing theory of scientific experts speculated that thyroid hormone was sufficiently small to diffuse across the cell membrane. But a curious type of genetic defect, found in fewer than 200 individuals worldwide thus far, has led Dr. Refetoff’s laboratory team to a different conclusion, published today in the Journal of Clinical Investigation.
In 2004 Dr. Alexandra Dumitrescu, then a graduate student of Human Genetics in Dr. Refetoff’s laboratory, identified mutations in the MCT8 gene of children born with developmental disabilities and abnormal thyroid tests. The MCT8 gene is the code for a transporter that enables thyroid hormone to enter into cells and into brain cells in particular. It therefore came as no surprise that children with mutated, non-functional MCT8 suffered from brain hypothyroidism and later exhibited speech and motor disabilities with inability to walk.
“In these instances, although the mother has normal levels of thyroid hormone, the hormone cannot get to the embryonic tissue,” Refetoff said. “Consequently we believe that the lack of thyroid hormone during embryonic life prompts delayed development of the nervous system.”
But there remained an ambiguity in explaining some of the thyroid test results – specifically, the low blood level of the thyroid hormone precursor thyroxine (T4) secreted from the thyroid gland. To study the defect, Dr. Refetoff’s laboratory created a mouse model devoid of MCT8. Experiments in this mouse exposed further information – a reduced supply of thyroid hormone, potentially due to defective release.
The new paper, authored by postdoctoral scholar Dr. Caterina Di Cosmo, describes experiments devised to test this hypothesis, utilizing what Refetoff called “old physiology.” Mice lacking the MCT8 gene were administered a small amount of radioactive iodine, which was taken up by their thyroid glands and biologically incorporated into thyroid hormone. Researchers later measured the amount of radioactivity released from the gland which appeared in the bloodstream. As suspected, mutant mice retained more radioactivity in their thyroid glands with less detectable in their blood, suggesting reduced release of the hormone when MCT8 was not present.
Refetoff cautioned that MCT8 is clearly not the only transporter responsible for thyroid hormone release – if it was, no thyroid hormone would be released at all. But the important gatekeeper role of MCT8 could nevertheless be exploited for potential clinical use, he said. Currently, hyperthyroidism is treated with drugs that block the synthesis rather than the release of thyroid hormone, a treatment that can take weeks to take effect, and in extreme cases the thyroid is radioactively destroyed or surgically removed. These irreversible treatments could be rendered obsolete if an effective thyroid cell-selective MCT8 inhibitor was developed.
“The interest will be to manipulate the secretion,” Refetoff said. “If we know how thyroid hormone is secreted we can work to identify drugs to inhibit secretion, which will be more effective than blocking the synthesis.”
For the rare, unlucky child with an MCT8 mutation, the news is not so good. Hypothyroid patients are typically treated by merely supplementing thyroid hormone. But in the absence of MCT8 the hormone is unable to enter cells that require this transporter, and the lack of hormone signaling inhibits correct development. Refetoff and colleagues are currently testing an analog of thyroid hormone that can enter a cell without the use of MCT8, but whether such a treatment could be delivered to an embryo with an MCT8 mutation early enough remains in question.
This newly identified factor involved in thyroid hormone release greatly increases the possibilities for more refined treatments than the blunt addition or subtraction of thyroid hormone. Though more research will be required to fully understand the release process and capitalize on it for clinical use, Refetoff said he welcomes the challenge.
“My view of advances in science is that every time you find something new, you create more questions,” Refetoff said. “It is for this reason that scientists remain in business!”