Weizmann Institute team proposes model to explain thyroid disease dynamics
About 5% of the world population suffers from thyroid disease with often severe symptoms, yet treatment is not a simple adjustment of thyroid hormone levels.
About 5% of the world population suffers from thyroid disease with often severe symptoms, yet treatment is not a simple adjustment of thyroid hormone levels.
Whether an individual has too much thyroid hormone (such as in Graves' disease) or too little (Hashimoto's disease), it can take weeks after hormone treatment before the body's thyroid hormones stop fluctuating and normalize.
Why this delay--called hysteresis-- takes place is not fully understood. But new research by a team of Israeli scientists has developed a mathematical model that helps explain the mechanism of the delay and provides some guidelines to help doctors treat individuals who have too much or too little thyroid hormone.
The model adds a crucial component to the calculation of hysteresis, which is the thyroid-axis gland mass, a measure of the amount of hormone-secreting cells in the pituitary gland, known as thyrotrophs.
Their work appears in the journal Molecular Systems Biology, Aug. 1.
Lead author Yael Korem Kohanim, a Ph.D. who worked at the Weizmann Institute of Science in Israel, in the molecular cell biology lab of professor Uri Alon, led the research team. Korem Kohanim, currently a post-doctural candidate at Yale, described the problem in an interview with Current Science Daily.
The treatment puzzle
"In order to diagnose thyroid diseases, doctors often measure the levels of a hormone called TSH---thyroid stimulating hormone," Kohanim said. "This hormone is very sensitive to deviations of thyroid hormones from their healthy set point.
"When thyroid hormones are too high--a state called hyperthyroidism--TSH is abnormally low," she added. "When they are too low--hypothyroidism--TSH is abnormally high. Even small deviations of thyroid hormones from their set point induce large deviations in TSH, making it a very good indicator for thyroid problems."
It's not simply a matter of supplementing the too high or too low thyroid hormone.
"After diagnosing thyroid diseases and treating them with medications, there is a peculiar phenomena: TSH stays abnormal long after thyroid hormone levels are normalized," Kohanim said. "It takes many weeks or even months for TSH to go back to its normal levels, even though thyroid hormones can be normalized much faster. This phenomena of long TSH delays can make it difficult for clinicians to determine drug doses to treat thyroid disorders. In addition, from a scientific point of view, the source of these delays is not well understood."
The missing piece of the puzzle
Korem Kohanim described the additional piece of the diagnosis and treatment puzzle that the research team developed.
"We add to the textbook model of the thyroid axis an additional layer of regulation: The effect of hormones on cell proliferation and growth," she said. "TSH causes the thyroid gland to grow, while thyroid hormones suppress the growth of TSH-secreting cells in the pituitary.
"This is how we explain the delays in TSH normalization," she added."During hypothyroidism, in which thyroid hormone levels are low, the pituitary TSH-secreting cells, called thyrotrophs, grows into a mass. After starting treatment it takes time for the pituitary thyrotroph mass to shrink back, and this is why TSH stays high.
"In hyperthyroidism, the opposite thing happens," she concluded. "The high thyroid hormone levels lead to thyrotroph mass shrinkage. When starting treatment, it takes time for thyrotroph mass to grow, and therefore TSH levels stay low."
A large-scale study
The researchers used a large population sample of Israelis who had thyroid disease, with data covering 18 years and 46 million person-years. They analyzed data from people who had Hashimoto's disease and Graves' disease, looking at blood tests taken before diagnosis, after diagnosis, and during treatment.
From the data they developed a mathematical model, and identified changes in the thyrotroph mass as crucial for determining hysteresis. The model also clarified the dynamics and interactions of thyroid hormones and helps explain other thyroid disorders.
Thyroid disease is complex, and varies greatly by individual, Korem Kohanim noted. For some the adjustment period may take six weeks, for others months or longer.
For Hashimoto's disease, the normalization time is typically 6 weeks, she said. For Graves' disease, the normalization time is more variable, between a few months to a year, and sometimes TSH never normalize at all.
"The set point is the healthy levels of thyroid hormones and TSH for each individual," Korem Kohanim said. "It depends on environmental conditions, such as temperature and nutrition, and on different parameters that vary between individuals such as the production and clearance rates of the hormones."
A hopeful advance
Using the mathematical model, along with other measurements, to aid in diagnosis and treatment will shed some light on the complexity of returning to each thyroid disease individual's set point.
"Knowing the reason for TSH delays may help doctors to better plan and adjust their treatment strategies," Korem Kohanim said. "They can assess how far the patient is from stabilization by calculating his/her thyrotroph mass."
-------
Yael Korem Kohanim et al. Dynamics of thyroid diseases and thyroid-axis gland masses. Molecular Systems Biology, Aug. 1, 2022.
Alerts Sign-up