How long does it take for the final dose of synthetic LT3 (Liothyronine) hormone to clear from blood, and how much suffering might a withdrawal cause?
This is an important question for many people who dose LT3. They want to know what would happen if they unexpectedly ran out of supply due to a pharmaceutical shortage, a health care system breakdown, or if they were unable to access their medicine cabinet for a few weeks.
The answer is that it depends. It could be between 72 hours and 10 days, depending on the individual’s T3 clearance rate, prior length of time on therapy with T3, whether T4 hormone is present in blood at the time of withdrawal, and whether a person’s own thyroid can produce any hormone.
In this post, I present some graphs and half-life calculations for T3 clearance rate, discussing the various factors that make clearance faster or slower.
I then conclude with data from a survey showing the harm to “quality of life” of even a short-term LT3 withdrawal, and a discussion of the serious health risks of withdrawal.
What is the half-life of LT3?
According to Wikipedia,
“Biological half-life (also known as Elimination half-life, pharmacologic half-life) of a biological substance such as medication is the time it takes from its maximum concentration (Cmax) to half maximum concentration in human body.”
If you look online, some publications will estimate 24 hours, and others say as long as 2.5 days. But as you will see below, it depends on
- The duration of LT3 monotherapy prior to withdrawal,
- the size of the final dose,
- how much thyroid hormone supply you have before the final dose,
- whether or not you have T4 in bloodstream, and how much T4, that is converting to T3 while the LT3 dose clears from blood.
When is a “half life” deceptive?
A half life can be misleading when the clearance rate is skewed, as it is in LT3 dosing.
As shown below, the Cmax T3 level achieved after a dose is absorbed is extremely transient. The peak clears from blood within a few hours, followed by a very long tail. The first half of the half life describes a steep crash; the decline past the half-life takes a much longer time.
The half life can also be deceptive because a single number (an average) or a range do not specify important contextual factors.
In thyroid therapy, one must ask, “half life in what kind of patient?”
Studies of T3 half life are often performed in thyroid-healthy subjects on a short-term basis after taking a single large dose. Such half-life estimates are easily misapplied to the severely thyroid-disabled people most likely to be taking LT3 in smaller doses several times a day over weeks, months, or years.
The half life is also deceptive because it does not map onto a single symptom or health impact, such as slower heart rate. Different symptoms and health impacts appear at different points on the way to thyroid hormone depletion.
At peak levels, a properly dosed LT3 patient with healthy adrenals will not experience any thyrotoxic symptoms.
Hypothyroid symptoms do not appear at the same rate as clearance from blood. One of my first symptoms of LT3 withdrawal is slower cognition, followed by cold intolerance and slower heart rate. But symptoms may differ in another person with different concurrent health conditions.
Symptoms that impair complex and demanding tasks may appear long before the half life of the dose if one starts from a position of LT3-dependent euthyroidism (Busnardo et al, 1983) and then progresses all the way to depletion of T3 without any T4 support.
Finally, the half life is deceptive because some people may mistake that the Cmax of a single dose achieves the maximal effect, and that complete clearance removes all the effects of the medication.
However, after beginning LT3, the medication can take weeks to achieve euthyroid stability and full effect after being on a different medication or no medication at all.
After withdrawal, some symptoms do not appear until after the medication has disappeared from circulation, due to the long-term and cumulative nature of thyroid hormone signalling.
LT3 withdrawal post-thyroidectomy
It has been a common practice for many decades to treat thyroid cancer patients after a total thyroidectomy with either LT4 or LT3 monotherapy, and then completely withdraw thyroid hormone prior to radioioidine (RAI) ablation of any thyroid remnants left behind after surgery.
Studies of LT3 withdrawal have usually waited 2 weeks post-withdrawal. Their goal is not clearance of T3, but a target TSH that will strongly stimulate the thyroid remnant to take up the radioactive iodine.
Here are the most recent graphs of LT3 clearance rate over 75 hours in 14 patients post-thyroidectomy after being treated with LT4 alone for 30 days, and “terminal elimination was assessed over 11 days.” (VanTassell et al, 2019.)
In all but one patient who had a functional thyroid remnant, Total T3 levels fell below the assay’s limit of detection [LOD]. Van Tassell does not quantify the limit of detection in units, but it seems to be 10 ng/dL.
To put that in context, the reference range of total triiodothyronine (T3) is approximately 80-220 ng/dL in adults.
LT3 clearance in healthy people
Compare the rates above to the pharmacokinetics of a 50 mcg single dose of LT3 in healthy euthyroid subjects over the same time period.
(It seems quite ridiculous to give people large single doses of thyroid hormone when they don’t need it. However, the recruitment of healthy subjects is standard in most pharmaceutical testing, and a single tablet rarely causes adverse effects in a healthy person.)
In people with healthy thyroid glands, the rise and fall in Free T3 and Total T3 is parallel over time.
Individuals vary slightly in their rate of absorption and clearance, as shown in the TT3 graph.
In Jonklaas’ study, the average half life was 22.04 hours. However, with this skewed curve, the “half life” in numbers is very deceptive given the long, low tail. Baseline levels were reached at approximately 50 hours on average, but at 22 hours, most of the transient peak was long gone.
These healthy people’s baseline T3 levels were not as high as they would be in a person maintained on LT3 alone without thyroid function, because up to twice as much T3 as normal is required in bloodstream to maintain euthyroid status when T4 is completely absent (Busnardo, 1983).
These people didn’t fall below 100 ng/dL TT3 because they had T4 in circulation, which did not have time to clear out, and some of which continues to convert to T3 every minute of every day.
Very few studies measure LT3 withdrawal in both types of patients at the same time on the same laboratory tests.
Lum et al 1984 (over)dosed euthyroid people on LT3 for 4 weeks to compare their clearance with hypothyroid people.
(The study did not mention any adverse side effects experienced by the euthyroid people who ended up dosing 100 mcg/day under supervision. This is because LT3 dosing will lower TSH stimulation and therefore lower the T4 level to make room for a higher average T3 level).
- “The normal subjects were placed on T3 doses of 50 mcg daily the 1st wk, 75 mcg daily the 2nd wk; and 100 mcg daily for the last 10 d.”
- “The athyreotic patients were switched from oral thyroxine replacement to oral T3 (Cytomel), 75 mcg daily.”
- There was only one dose per day. (This is not common. LT3 monotherapy is often taken in several divided doses per day.)
The peak T3 levels shown in the graph were the transient maximum. They were “a reflection of the daily morning oral T3 dose” because “blood samples were drawn daily at 0800-1200 h or 2-4 h after the daily T3 dose.”
The T3 remaining by day 8 was buoyed up by T4-T3 conversion:
“The mean serum T4 values in the athyreotic group were 0.4±0.1 mcg/dl, indicating that residual T4 was present from previous T4 therapy. ”
In contrast, the T3 values fall faster and fall lower after 12 weeks of LT3 therapy, after all the prior LT4 has cleared from blood:
“In one athyreotic subject placed on oral T3 for 12 wk [not shown in the graph], the serum T4 value was below the assay limit of 0.1 mcg/dL,” and “Serum T3 levels fell below the assay limit of 10 ng/dl by day 4 after T3 withdrawal.”
As T3 falls, clearance rate slows.
The less thyroid hormone you have in circulation, the more the body hangs on to it, as verified by Bianchi et al, 1978.
A high MCR (metabolic clearance rate) means it is cleared faster.
Clearly, the persons with the least amount of T3 in circulation had the slowest clearance rate, and those with a higher T3 cleared it faster.
This is a compensatory mechanism by which the body reduces the effect of hypothyroidism on the one hand, and can clear out short term excess on the other hand.
Nicoloff et al’s 1972 report showed the following graph for clearance rates of an injection of T3 that was tagged by radioactive iodine.
The lines for “serum” are almost straight. None of the lines follow the “spike-crash-tail” shape seen in Jonklaas or Van Tassell, above.
This straight line of serum clearance reflects the fact that these calculations were for injected, iodine-marked T3 only, rather than absorbing a tablet over a few hours, followed by full clearance of all T3 in serum post-withdrawal down to the point of utter depletion.
The mean half-life in this study must be interpreted as the half-life of I-125 radioactive iodine tagged T3 in three different situations:
- I-125-T3: Half-life 0.63 days in 7 hyperthyroid patients,
- I-125-T3: Half-life 1.0 day in 8 euthyroid individuals, and
- I-125-T3: Half-life 1.38 days in 9 hypothyroid patients.
Nicoloff and co-authors found that the clearance rate also depended on the amount of TBG (thyroxine binding globulin) in blood. People with a TBG deficiency had a T3 clearance rate similar to that of thyrotoxic people.
Clearly, we do not all metabolize or clear T3 at the same rate.
How do people survive 2 weeks post LT3 withdrawal?
The answer is, not without some extreme suffering.
Our suffering is often underestimated by scientists and doctors. But the amazing thing is that we do survive.
Lee’s study in 2010 compared 1) LT4 withdrawal, 2) LT3 withdrawal, and 3) supplementation with recombinant human TSH (rhTSH), to achieve a “very good” TSH stimulation averaging 82 mU/L.
Those words “very good” are from the doctor’s point of view. That’s also a “very severe” level of hypothyroidism.
Nevertheless, the hypothyroidism could have been worse. Lee et al’s patients given LT3 had been treated with LT4 prior to only 2 weeks of LT3 monotherapy, so they still likely had LT4 in bloodstream 2 weeks post-withdrawal. This prevented their TSH from rising higher and their T3 from falling lower by the end of 2 weeks’ withdrawal.
Unsurprisingly, patients’ quality of life (QoL) suffered.
The QoL survey items focused on physical symptoms, signs, problem duration, impact on social life, mood changes, and medical resource utilization. The quantitative results were as follows:
The Quality of Life scores were equally poor for LT4 and LT3 withdrawal, the maximum score for the poorest quality of life being 31.
Biases in Lee’s [reduced] Quality of Life survey
First of all, the survey was not co-designed by patients who had a long experience with hypothyroidism or who had already undergone this withdrawal.
It was a “modified version of the self-rating Kellner symptoms questionnaire, the Hamilton depression scale, and Luster’s 13-item scale for measurement of hypothyroidism.” They cherry-picked from these 3 sources, and then they did not adapt it to the situation very well at all.
It was cobbled together by doctors who did not want to make it seem like they were harming their patients. Therefore, the survey was designed so as to make it nearly impossible to come near to the maximum score of 31 for a severely reduced quality of life.
Insignificant symptoms and unlikely events were often given equal or more weight than significant and likely ones.
It was especially difficult for the LT3 withdrawal patients to answer with maximums for their 2 weeks of withdrawal alone, since the maximum scores often required an answer of “always,” or a duration lasting more than 2 weeks, or an event occurring more than 2 times.
For example, one of the questions was simply “Duration of symptoms: For how long did you experience symptoms” and the maximum score of 3 was only permitted for “more than 2 weeks.”
The survey minimized several debilitating symptoms such as fatigue, insomnia, cold intolerance, and weight gain. In answer to Question 1, the following were only permitted a maximum score of 0.5 each, simply by answering yes/no:
- weight gain,
- edema of extremities,
- facial edema,
- dry skin,
- bowel habit change, and
- cold intolerance.
It is hard to imagine weight gain or dry skin occurring within only 2 weeks of withdrawal. How did clinical experience suggest this?
In contrast with these minimized symptoms, psychological symptoms were given up to 9 points total. Depression (0-3), Anxiety (0-3), Retardation “Slowness of thought or speech, impaired concentration, decreased motor activity” (0-3). The score of 3 was reserved for “always,” which would not be likely for the LT4 patients on 4 weeks of withdrawal given the slow clearance rate of LT4.
“Genital symptoms” (0-3) were also overemphasized compared to “fatigue.” Perhaps men designed this survey? They considered this to be “Loss of libido, impaired sexual performance, menstrual disturbances,” and “more than 1 week” was given a maximum score of 3. Obviously, symptoms such as a “menstrual disturbance” would have less chance of appearing within only 2 weeks post LT3-withdrawal, or if the patient was male or a woman in menopause.
“Medical resource utilization” (0-6) included questions about how many times 1) “did you consult your physician,” or 2) “were you treated in a hospital for relief of your symptoms.” Illogically, the only options were “Not at all,” and “one time” (1), but no option was offered for “two times.” The maximum score of 2 was only given to “more than two times.”
Consider that such “medical resource utilizations” were less likely to occur 3 times within 2 weeks of LT3 withdrawal compared to 3 times within 4 weeks of LT4 withdrawal.
I’m not sure about Korea (where the study was done), but in our culture, it would require serious symptoms as neurological, cardiovascular or pulmonary distress go to a hospital, and such symptoms were not listed, though even ONE visit to a hospital would likely be for a very severe reason.
Overall, the survey revealed an average of severe suffering, given that an LT3 withdrawal patient with extremely severe symptoms (but no minor “genital” symptoms or weight gain or dry skin) may have answered with a score of 20 or less.
The benefit of LT3 withdrawal in comparison to LT4 was that LT3 cut the post-withdrawal suffering time in half (2 weeks) by speeding up the rise of TSH. It takes much longer for TSH to rise after LT4 withdrawal (Lee et al, 2010).
It is obvious why the alternative to withdrawal — supplementation with recombinant human TSH (rhTSH) often sold under the brand name Thyrogen — was given an average Quality of Life reduction score of 4.2 (pretty good!).
Why don’t people suffer more from withdrawal?
For obvious reasons, no one does studies testing the limits of human hypothyroidism beyond rare case studies and retrospective observational studies.
Too many studies of Low T3 syndrome (nonthyroidal illness, NTIS) have shown that low T3 is an independent predictor of mortality and morbidity (Rhee et al, 2016), and the outcome worsens when serum T4 levels also fall below normal range.
The delay in TSH rise post-withdrawal, and also delay in developing the cognitive symptoms of myxedema coma, is partly due to two factors:
1. T3 receptor signaling can have longer-term effects in the body than the T3 hormone itself.
T3-driven DNA transcription in every organ and tissue throughout the body causes diverse signalling cascades. It often results in the construction of new proteins. Proteins triggered by T3 remain in the body and have their own life cycle beyond T3’s clearance.
Therefore, signalling effects linger on even after the T3 is no longer bound to the receptor and is depleted from blood.
It is believed that the health emergency of myxedema crisis is found in “long term” untreated hypothyroidism, and that only the “chronic” phase of Low T3 syndrome is pathological (Fliers et al, 2015).
Even maintaining a thyroid patient with very low-normal FT3 and FT4 can cause myxedema crisis, given enough time (Mallipehdi et al, 2011).
2. Biology will temporarily compensate for a hypothyroid state, if the patient is healthy enough.
- Thyroid hormone receptors may become more sensitive to T3, since the opposite is true (temporary receptor insensitivity) in persons with higher T3 levels.
- A high TSH can stimulate a rise in cortisol, at first. (Walter et al, 2012)
- Cardiac compensations occur:
“Low intracellular T3 secondary to hypothyroidism is the basic underlying pathology in myxedema crisis which leads to hypothermia and suppression of cardiac activity. The body tries to compensate by neurovascular adaptations including chronic peripheral vasoconstriction, mild diastolic hypertension, and diminished blood volume.” (Mathew et al, 2011)
However, compensatory mechanisms may only be short term.
An accident or severe infection can upregulate DIO3 enzyme, thereby deactivating T3 at a higher rate, which may precipitate the dangerous crisis of myxedema coma.
The pathological state of Myxedema Coma, in which 50% of patients die (Dutta et al, 2008), is defined as “decompensated hypothyroidism” — because the compensatory mechanisms have failed and thyroid hormone supplementation arrives too late.
The most severe and deadly cases, according to Dutta et al, are not among those who were previously undiagnosed, but rather among the people who stopped their thyroid therapy.
Lessons to learn
Withdrawal of thyroid hormone, but especially of LT3 monotherapy, can be severely harmful to one’s quality of life in the short term.
It does not take long for T3 to fall to harmful and then to dangerous levels in persons who do not have concurrent T4 supply. Don’t walk on thin ice.
Patients, do not do this at home! Don’t experiment with LT3 thyroid therapy withdrawal unless you already know you have a healthy enough thyroid gland or you are building up T4 while your T3 is depleting at the rates you see here.
Doctors, never, ever, force LT3 monotherapy withdrawal on a patient who may have no thyroid function. Obtain ethical informed consent from the patient first, and offer alternatives.
- Do not treat LT3 as if it is the same as LT4. It is not. Learn from the experts how to dose LT3 monotherapy to euthyroidism. Instead of withdrawing it, understand it (Busnardo, 1980, 1983).
- If you want to raise their TSH before RAI ablation, you can now offer people Thyrogen. Be truly compassionate.
- If you want to see how well their thyroid gland functions, order an ultrasound and learn how to recognize autoimmune fibrosis and atrophy.
- If you want to check for central hypothyroidism, try a TRH-TSH stimulation test, or reduce the dose to achieve mid-range FT3, which is often enough to elevate the TSH to a certain level (see Celi et al, 2010).
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