By Alan B. McDaniel, MD
Part 1 of this three-part article (published May 2021) presented the complex physiology of thyroid function and discussed symptoms and diagnosis of hypothyroidism.
Start T4 Treatment: Dose and Timing
Despite optimistic declarations in the medical literature that starting with a “full dose” of T4 is safe in all but the elderly or infirm,100 I never do that. Whether treating with T4, “natural” thyroid or T3, all my patients receive gradually increasing doses. This is a good idea with T4 and imperative when treating with T3. I prescribe levothyroxine 25 mcg tablets, which can be divided to give the smallest accurate increment.
Typical T4-doses vary from 50-200 mcg/d daily.113 What daily dose will a particular patient probably need? It is wise to anticipate a safe maximum before writing the prescription. Lean body mass is proven to be the best initial indicator of the ultimate levothyroxine dosage.114 Age and gender differences mainly reflect different proportions of lean mass vs. total body weight.
Guidelines state the usual maximum daily-T4 is 0.73 mcg per pound of body weight (1.6 mcg/kg) when TSH is markedly elevated.100 With experience and attention to situational clues and lab values, you will learn to modify the dose for frail or overweight people (hunters call such adjustments “Kentucky windage”). For safety, always bring patients back for follow-up before increasing their dose to reach the estimated “maximum.”
My patients start taking 25 mcg T4-daily. Although remaining vigilant, I expect no problem, particularly as all have begun taking nutritional support for their adrenals and other steroid-forming tissues. I give written directions for the patient to increase the dose by 25 mcg weekly—as tolerated—and put it in writing on a fill-in MS Word form (free upon request).38 Figure 3 shows typical instructions for a person who may need as much as 125 mcg T4 daily:
Let me challenge you: If our goal is to restore normal hormone levels, why do we give thyroid treatment once daily? This is so not physiological! The healthy gland releases steady amounts of hormones throughout the day. Thus, circulating thyroid hormones remain quite stable all day.115 Yes, TSH varies a bit, rising from about 1.5 in the day to 2.2 at night—that’s +/- 0.35 …no big deal.116 Healthy bodies do best with blood levels close to the “normal physiology.”
Once-daily levothyroxine doses were suggested as a marketing strategy in the 1950s. Using tests that weren’t available back then, we find this creates abnormal blood levels: A big peak of T4 occurs around three hours after the pill is swallowed,117 then the level drops steadily until the next dose. Because levothyroxine was approved long before good assays were available, no proper pharmacokinetic studies were, or ever have been published.
In their place, data for other drugs can represent the likely levothyroxine kinetics. Graphic representations of blood levels for topirimate118 and methadone119 in once- and twice-daily doses are available online. They clearly show that divided doses maintain therapeutic blood levels and avoid the supra- and sub-therapeutic values seen with once-daily doses.
If a patient asks, “What is the best way to take thyroid?” I may tell him the ideal would be to take a tiny tablet every minute; that impossible schedule would best-mimic normal physiology. Yes, most people can tolerate once daily-doses – but dividing it every 12 hours often works better. Osler, acclaimed as the greatest physician of the last century, prescribed desiccated “natural” thyroid every eight hours.120
Similarly, when someone asks me, “What is the best time to take thyroid?” I usually answer, “three hours before you wake up.” People get out of bed a lot more easily with peak blood levels of thyroid than at trough. Although some practitioners endorse once-daily T4 doses at bedtime,121 taking divided thyroid doses, on waking and about 12 hours later, seems better for most patients. Caution: Avoid taking take the PM dose less than four hours before bedtime, as peak levels make it harder to fall asleep.
I am an agnostic regarding the stickers that pharmacies place on prescription bottles, advising that T4 should not be taken with food (especially soy) or supplements (particularly calcium and iron).122 The studies proved malabsorption is statistically significant,123 but experience shows it is rarely clinically significant in adults—except in this way: Patients’ efforts to follow this instruction commonly disrupt their doses.
So, my patients take thyroid every 12 hours, regardless of meals—though I ask them to avoid a bolus of soy.124,125 The patient should always have a few doses with them. My wife has a little pillbox in her purse; men can put a small pill-cylinder on their keychain. Also, reminders are helpful: Set an alarm on the cell phone to ring when the PM dose is due (that’s the one most likely to be missed).
Dose Escalation: The Initial Phase of Treatment
While lean body mass predicts the maximum dose, the patient’s symptomatic response to treatment helps to define the “optimal.” From any dose adjustment, there are only three possible outcomes: The patient feels better, the same or worse. It takes up to a week before this can be determined with any certainty; each step results in many changes and protein-bound hormones are slow to reach their new equilibrium.
At the end of each week, the patient assesses her response to the current dose and decides upon the next step. Caution her that if any dose increase feels worse, she should reduce it: Drop back just one step and contact me (I’m emphatic about this!). If it seems unlikely that her dose would be too high, take a careful history for the use of stimulants and seek clues to any other, unexpected problem. If none can be found, ask her to continue the new, lower dose and after two weeks, check blood levels.
When Your Patient Unexpectedly Feels Worse
The most common reason people feel “worse” during the dose-escalation phase is simply over-stimulation from caffeine. I know this from my personal experience. People with hypothyroidism need something to give them energy and caffeine is the most available legal solution – I had a two pot-daily coffee habit.
As thyroid hormone levels rise towards normal, the high caffeine intake begins to produce the jitters and naturally, the thyroid replacement is blamed. Be pro-active: Their former “best-friend” caffeine must be tapered-off during build-up and temporarily discontinued (Figure 3) – even decaf products, which still have too much. The prohibition can be relaxed after the safe, effective thyroid dose is established.
Thyroid replacement can also reveal symptoms of low blood sugar and estrogen deficiency. However, it is unusual to get any such call using levothyroxine. People rarely feel worse during T4-escalation.
Schedule your first follow-up visit at the end of the planned build-up time—four weeks in the illustration given in Figure 3. By design, she will be taking less than the estimated “maximum.” Her clinical response will then guide the next steps.
The First Follow-Up Visit
Inventory symptoms: If your patient feels 100% well, maintain the current dose and check blood levels to ensure safety and efficiency. This can be done after two weeks on a stable dose. Some writers prefer to wait four weeks or more.126
When symptoms persist – with no evidence of over-replacement—I recommend cautious increments of just 12.5 mcg T4/week until reaching the estimated maximum dose. Laboratory tests are then needed. When symptoms are resolved, the lab should validate the dose. If symptoms persist, your blood tests should show you the problem.
Daniel Boone was once asked if he had ever gotten lost. He replied no, but he had once been bewildered for three days. If you are ever “bewildered” about how to proceed, it is always appropriate to check blood levels on an equilibrated dose – the way a modern Boone checks her location by GPS.
Pathology 201: The First Laboratory Follow-Up
Let’s re-visit “pre-analytical error”: When a patient regularly takes levothyroxine, at what time should her blood be drawn? Graphs of peak and trough therapeutic values indicate random tests are imprecise. Accuracy requires specimens to be drawn in relation to doses…but when? It was written that free hormone values can vary by 30% following a dose (in an article I can’t find, alas!). The best pharmacokinetic data I can find state thyroid hormones peak “some 3 or 4 hours” after a dose.127
Internists usually test at trough, just before the AM dose. This most sensitively detects insufficient treatment. However, excessive dosing can be missed – for example, among 25,862 health fair-attendees, 40% of all people taking thyroid hormone had out-of-range TSH values – 90% of which were low, suggesting over-treatment.2
Followers of the Belgian endocrinologist Thierry Hertoghe128 draw blood specimens three hours after the thyroid dose (at peak), which best reveals high levels. As the converse of the internists’ method, it may be expected to miss under-treated patients—and it will (see Patients 4 and 5, following).
Given such uncertainty, I prefer to test my patients’ blood levels exactly mid-way between evenly spaced doses, which are divided as evenly as possible. This tactic gives me an average: Half of the day, therapeutic levels are higher, and they’re lower the other half (Figure 4). Admittedly, therapeutic values may be high when tested at peak or low if tested at trough – even with Q 12 hour divided doses.
Patient 1 provides a good example. Her endocrinologist tested her at “trough,” 24 hours after her last AM dose of T4 125 mcg. Her values were TSH=5.2 H; freeT4=0.8 and freeT3=2.9. The Doc increased the T4 dose by 25 mcg, but she felt no better and consulted me.
I suggested dividing her T4 to 75 mcg Q 12hrs., then testing in two weeks. But she was in a hurry: Late that afternoon, we checked her levels as close to mid-dose as possible – just before the lab closed. These values were typical of excessive levothyroxine treatment: TSH 0.488; freeT4=1.96 H, freeT3=2.7 …and RT3=39.6 H.
Testing at mid-dose is successful in my practice. I have no objection when other physicians adhere to a different strategy they like better, as long as they are consistent, minimize pre-analytical error before performing their tests, and are aware of relative drawbacks of their choice. However, I cannot endorse random testing.
However, you prefer to test, keep good records to both facilitate your therapeutic choices and validate them. On receiving a lab report, I send the following form to my patient by e-mail (Figure 5). I ask her to copy it and paste it into an e-mail to me; then fill-in the blanks and return it for her records. I review many files from other physicians, and it is disappointing how little value reports offer without the dose and timing information.
Confirm Treatment Results with “All 5” Thyroid Hormones
The “ideal” therapeutic TSH-level is a matter of opinion. The 2014 American Thyroid Association (ATA) guidelines simply recommend “a value within the reference range” for adults (0.4-4.0 µIU/L) and no higher than 2.0 for children, lest their development lack support.100 Online, the ATA suggests 0.5 to 2.0 for all patients,129 which I and practitioners around me prefer. A Norwegian writer has suggested 0.5-1.5.130
If your goals include suppressing TSH, first be sure that the patient feels well on her levothyroxine. If not, taking more T4 will probably make her feel worse. Only after all other aspects of her therapy are satisfactory will I increase the replacement dose to suppress TSH.
In addition to TSH, it is important to check freeT4, freeT3, totalT3 and RT3. This is especially true when a patient’s symptoms have not responded to treatment – yours or that of other physicians for whose failures you were consulted. If you are not yet inspired by the metaphor of the basketball coach, keep reading….
Subsequently, it is wise to follow your patient with an office visit and mid-dose labs at around three months and again at some six months after proving the “optimal dose.” Then, schedule annual check-ups. As reviewed just below, thyroid function can be unstable, and adherence may be undisciplined. In the first year, it is prudent to metaphorically keep a finger on the pulse.
Therapeutics 102: Problems with Levothyroxine Treatment
Levothyroxine treatment should be sufficient – so we’ve been taught for 60 years. However, there are a number of potential problems. Among them is our dependency on the patient’s (diseased) gland to keep producing.
It is not unusual to find patients taking T4 have undesirable TSH values,2,131,132 whether due to patient non-adherence, prescriber technique, or progressive disease. However, unless the T4 dose suppresses the patient’s TSH, her gland will still contribute to the total amount of circulating thyroid hormone. With ongoing thyroiditis (e.g. Hashimoto’s), the progressive failure of the patient’s residual function is predictable—and she will need increasingly large replacement doses. For this reason, lab values must be followed at least annually and any time the patient seems to take a down-turn.
Pharmacies participate too: My patients have received incorrect prescriptions on occasion. Once dispensed, the pills can be damaged: A patient left her 90 days-supply of T4 on the dashboard in July, where the heat inactivated them and sparked great perplexity. Other, undiagnosed conditions also can prevent a good response.133
Autonomous function is unfortunately common, especially among “difficult” patients. You will hear from them during the escalation phase, earlier than you would expect. Because of this autonomy—whether undiagnosed Graves, “toxic” multinodular goiter, functioning adenoma, or even Hashitoxicosis—your calculated replacement dose will give them more than they can tolerate. Tests of “all-5” hormones should reveal this.
Spuriously elevated TSH can be deceiving. If you’ve correctly calculated the replacement dose, this patient won’t be hyperthyroid at her first follow-up: As she increased the T4 dose, her (normal) hypothalamic-pituitary-thyroid (HP-T) axis will have reduced its production to maintain normal thyroid hormone levels. If she takes too much T4, though, she will feel worse and “5 tests” show the mismatch between the bogus TSH value and high thyroid hormone levels.
Up to 16% of patients report poor results using T4, despite normal test values for TSH and freeT4.134,135,136,137 That is one of every six people! The voices of this unfortunate minority have become increasingly angry.138,139
Lately, they have been given proper academic attention: Multiple centers sent a survey to their hypothyroid patients asking them to grade their satisfaction with thyroid replacement treatment on a scale of 1-10. They received 2,146 responses: Satisfaction with levothyroxine treatment was “5.” Combined T4 and T3 treatment (as given) was better (“6”) and best of all was “natural” thyroid, scored “7.”134
Correct the Failure of T4 Treatment
Patient 2 was a 31-year-old woman on her arrival for consultation. She had been hypothyroid for 14 years due to Hashimoto’s disease. She was unhappy with her results on once-daily levothyroxine 112 mcg Q AM: In the previous two years, she had three confirmed 1st-trimester miscarriages (ICD-10: N96) and a fourth had been likely.
Despite normal TSH and freeT4 on treatment, she had many symptoms suggesting low thyroid, including fatigue, feeling cold, cold hands and feet, tired on waking, gas and bloating, constipation, reduced libido, and dry skin. Adrenal issues were suggested by symptoms such as orthostatic lightheadedness and craving salt. She had 28-day cycles; no PMS; menstrual flow lasted three days with clots and pain for one day. Her diet had long been gluten-free (Dad has celiac). Her BMI was 19.6.
She began taking neonatal bovine “adrenal glandular” and divided her T4 dose to 56 mcg q 12h. After two weeks, she had blood drawn six hours after her AM dose; it showed: TSH= 0.663; fT4= 1.66, fT3= 2.9; tT3= 87, RT3= 36.1 H. Ratio tT3/ RT3= 2.4 (L)
We agreed to replace some of her T4 with T3. I used the common semi-equivalency that 25 mcg T4 ≈ 5 mcg T3 (5 to 1), though a few studies have used 3:1.140 Figure 6 shows her instructions38 for the four weeks of transition.
After two weeks on T4 25+12.5 mcg and T3 10+10 mcg, she felt much better. Blood was drawn 6 hrs. after her AM dose: TSH= 0.463; fT4= 0.59 L, fT3= 4.2; tT3= 152, RT3= 10.3 and tT3/RT3 ratio= 14.8 (a more complete discussion of the ratio will follow).
We had to increase T4 – which was lower than anticipated because she was again pregnant! Binding proteins are greatly increased with pregnancy, and like most women, she now needed a larger dose: T4 37.5+37.5 and T3 10+10. She delivered a healthy boy at term and after six weeks, she required less T4.
A year later, during her second pregnancy, she once again needed the same greater thyroid dose. She delivered her second healthy baby and in the postpartum, again reduced her T4 dose. Years later, her latest test results at mid-dose, taking T4 25+25 mcg and T3 12.5+ 10 mcg (divided Q 12 hours) were: TSH= 0.711; fT4= 0.80 “L” (0.82-1.77), fT3=4.1; tT3=151, RT3=13.3 and tT3/RT3 ratio= 11.4 (“10-14”).
Physiology 201: Why Does T4 “Fail” So Many People?
Patient 2 raises important issues. Although the pre-hormone levothyroxine restored TSH and freeT4 to their normal ranges, the initial set of “5-labs” proved that her body could not efficiently activate T4 to T3; she made RT3 instead. The first therapeutic move was to divide her dose. Let’s examine the reasons for this:
The healthy hypothalamic-pituitary-thyroid (HP-T) axis continually “trickles” hormones into the bloodstream. In contrast, once-daily thyroid hormone floods the body with a bolus of T4 sufficient to last 24 hours. This rush of T4 signals “hyperthyroidism!” during the hepatic “first pass” and with supra-physiological free T4 blood levels peaking in three hours.117
Excessive T4 redirects deiodinase enzymes from producing T3 to instead make RT3141—and deactivate T3 to T2 (Figure 2). An elevated T4/TSH ratio exerts the same effect.80 This has been reported in Graves’ disease,142,143 for which it is considered adaptive and protective. When T4 is taken for hypothyroidism, it is neither.
Some patients treated with levothyroxine have frankly low values of T3,100 which can correlate with symptoms.144 In such cases, increasing the T4 dose can ultimately produce T3 levels somewhere in the “normal” range (there was no mention of symptom improvement).145 However, higher than normal RT3 levels consistently accompany once-daily oral levothyroxine, in both humans146,147,148,149 and beasts.150,151 I find no report to the contrary.
Like most patients whose activation of T4 is somehow dysfunctional, Patient 2 had hypothyroid symptoms and signs (miscarriages); normal TSH; normal T4 levels but a low ratio of tT3/ RT3. Unfortunately, even though taking divided T4 doses, Patient 2 continued to have both symptoms and excessive RT3 relative to T3.
Dysfunctional Deiodination and Low tT3/ RT3 Ratio
Prescribing T4 without testing the patient’s ability to activate it might be compared to charitably sending cans of food to starving Third-World children without ensuring they have a can-opener. The thyroid “can-opener” is a 5’-deiodinase enzyme (there are two isoforms).
While 80% of the T3 we humans need daily is derived from T4,152 not everyone is able to efficiently perform this conversion. For some, the enzyme responsible for making 50-70% of our T3 (type-2 deiodinase, 2-DI)153 is faulty. A 2009 report showed that 16% of Britons carry loss-of-function mutations of the gene (DIO2) encoding this enzyme.136 The “mutated” patients responded significantly better to combined-therapy with T4 and T3 than to T4-alone. Patient 2 has Northwestern European ancestry.
Patient 2 also has hypothyroidism due to Hashimoto’s disease (AIT). Research has strongly associated AIT with the excessive production of RT3 (p<0.00002).147 Many other factors can direct deiodination of T4 away from T3 to RT3, including drugs (particularly epinephrine,154 steroids,155,156 beta-blockers,157,158 and amiodarone159); iron-deficiency160; inflammatory cytokines161,162; bacterial endotoxin163,164; mold mycotoxins165; elements of metabolic syndrome166; and even some tumors.167,168
The effects of stress are also important: The acute stress response to severe illness reduces both TSH-release and peripheral T3 production. Thus, the metabolism slows to a low energy-consuming, conservative state.72,73,74 This can be adaptive in cases of serious injury, illness and starvation.169 However, it becomes maladaptive when inappropriately prolonged170,171,172 and is called “euthyroid sick syndrome” (ESS) or “non-thyroidal illness” (NTI).161,173,174
Emotional stress can also initiate this response, to the detriment of the patient. ReverseT3 can rise rapidly as patients enter a surgical suite175 or simply experience pre-operative anxiety.176,177 This has also been reported among medical students taking examinations.178
But the Problem Is Not “Low” T3
The alert reader may now ask: How can I say Patient 2 had dysfunctional deiodination? Her freeT3 and totalT3 values were normal all along! This question perplexes scientists studying ESS/ NTI.161,173 At first, it was called “low T3-syndrome”—until it became evident that indeed, low T3 was not the hallmark of the problem.
Harvard researchers wrote that altered deiodination may cause physiological hypothyroidism—“disruption of thyroid hormone signaling”—while T3 levels remain within the normal range.171 If not low T3, what test result identifies this physiological aberration—and what causes the severe ill-effects of ESS/NTI?
Elevated RT3 is characteristic of ESS/NTI, and it predicts a bad clinical outcome.172,179,180 However, a far more accurate diagnosis of this problem is established by a low tT3/RT3 ratio, which has a ten times-greater prognostic significance than elevated RT3 alone.77 This ratio is our best indicator of thyroid hormone signaling; to some, it seems even a better marker of euthyroid status than TSH.78
Inhibitory Thyroid Hormones: The Actions of RT3
Many ideas are proposed to explain ESS/NTI. “Occam’s razor” states the simplest of these is the most likely to be valid: ReverseT3 inhibits the effects of thyroid hormone. Lying buried in the medical literature is a surprising amount of evidence supporting this hypothesis.
The existence of an inhibitory thyroid hormone-metabolite was recently proven with the discovery that 3-iodothyronamine (3-T1AM) can rapidly and reversibly cause tissue-hypothyroidism.181,182 The validity of these observations is generally accepted. Reverse T3 is a parent molecule of 3-T1AM, but the accumulated evidence that RT3 also is thyroid-inhibitory has not been reviewed in a publication. Here’s a brief summary.
Inhibitory effects of RT3 were reported in some of its earliest studies.183,184,185,186 Its hypometabolic effect comes partly from antagonizing the actions of T3.187 Perfused RT3 blocks the genomic effects of T3 at a number of hepatic thyroid-response (T3-stimulated) genes.188 Studies show T3 cannot displace RT3 that is bound to the nuclear thyroid-receptor—and vice-versa.189,190 Thus, RT3 and T3 have the same relationship with the thyroid-receptor as do antihistamine and histamine at the histamine-receptor.
Reverse T3 exerts various non-genomic effects independently of T3.191,192,193 Acting at critical regulatory effectors, RT3 deactivates both 5’-deoidinase enzymes that convert T4 to T3: Type-2194,195,196,197,198 and type-1.199,200,201 An active role for RT3 was indicated in a well-designed study by the administration of RT3 to volume-depleted dogs, which resulted in significantly elevated death rates.202
Intriguing evidence for the inhibitory role of RT3 comes from AIDS patients, whose infections almost uniquely lead to pathologically low values of RT3.203,204 Low-RT3 and not high T3 correlated with their hyper-metabolic state and weight loss—apparently because their metabolism is disinhibited by the lack of RT3.205 Conversely, greater RT3 has been associated with increased whole-body fat mass and decreased lean mass in healthy men.206
Pathology 202: Laboratory Tests for Dysfunctional Deiodination
Well, this is news to nearly everyone. How can we use the laboratory to validate complaints of patients who are dissatisfied with their response to levothyroxine—who may have, in effect, ambulatory ESS/NTI?207 If so, the problem may be corrected.
Measuring ReverseT3 alone is insufficient, either to diagnose ESS/ NTI208 or to monitor therapeutic response209; it is just the denominator. We rely upon the tT3/ RT3 ratio: It quantitates hormone effect at the thyroid receptor, comparing the binary and competitively antagonistic products of T4 deiodination. The ratio also minimizes some common concerns about thyroid testing, including observed non-Gaussian distribution206 and vagaries of binding proteins (as long as we compare the total values of both!).
As an indicator of thyroid function, the tT3/RT3 ratio is as significant to the body as the annual profit/loss statement is to your practice. Think of T4 as representing billing, a necessary potential; consider T3 your collections, essential cash—and RT3 represents your operating costs. You live off the surplus!
Neither totalT3 nor RT3 is part of “standard thyroid panels”; they must be ordered separately. The tT3/ RT3 ratio is calculated with the values expressed in the same units. On request, LabCorp USA reports both tests (in ng/dL) and provides the ratio with a single order code: 002193. Your Rep can activate it for use in your online portal. The ICD-10 code for dysfunctional deiodination is E07.81. If you prefer to use Quest or any other lab, just contact them and ask.
“Normal” tT3/ tRT3 Ratio
What value is desirable? First, thyroid hormones are released from the thyroid gland in a 10:1 ratio: 90% T4, 9% T3 and 0.9% RT3.65,66,67 Thus, the “baseline” ratio of T3/RT3 is 10. A lower value implies deactivation. But what is “good?”
Three studies measured and reported tT3/ RT3 in their healthy control groups: The average values ranged from 11.03 to 12.5 with narrow variation (+/- 0.5).210,211,212 In contrast, groups of unhealthy people with metabolic syndrome and their age, BMI and TSH matched-controls had tT3/ RT3 of 8.8 and 7.3, respectively.213 Following treatment results, I find my patients feel well in the 10 to 14 range and I believe it can or should be a bit higher in adolescents. In comparison, Patient 2 had a ratio of only 2.4 while taking only T4—that is unusually poor.
Therapeutics 201: Options for Patients Who Fail to Benefit from T4
For years, my efforts to remove or remediate the above-listed causes of dysfunctional deiodination without using T3 were unsuccessful. Importantly, a 2012 review reported that most comparison trials indicate replacement with both T4 and T3 is superior to T4-only.214 Now, responsible voices of endocrine experts have stated that combined T4 and T3 therapy can improve results for at least some hypothyroid patients.215,216,217 The long-term safety of combined treatment has been demonstrated.218
The simplest and most generally acceptable method of adding T3 is demonstrated by Patient 2. Let’s examine a few issues before moving to our next treatment option.
Replace Some T4 with T3: What Happens?
First, please understand that when TSH has been restored to “normal,” adding T3 while maintaining the same T4—even divided Q 12H—will fail. T4 must be reduced as T3 is added. This is why:
Continuing the same T4 that had “normalized” TSH as you add T3 will predictably suppress TSH. Abundant T4 and suppressed TSH can be expected to maintain so much RT3 production that even robust T3 cannot restore a good tT3/ RT3 ratio…that’s “no joy.”
Adding T3 to the treatment increases blood T3 values. Reducing the T4 dose decreases RT3 levels, because 95% of circulating RT3 comes from T4-deiodination.65 After replacing some T4 with T3, your patient has more T3 and less RT3, which improves and ultimately, can restore normal tT3/ RT3.219
How Much T4 Should We Replace?
Physiology informs us: People need some T4. It is the precursor of T3 and of RT3. In addition, T4 (like RT3) has many non-genomic functions.220 Results of an ill-planned trial disregarding this fact validate the statement: People taking T3 with immeasurably low T4 do badly.221
The variable determining the amount of T4 we need to prescribe is the patient’s own thyroid hormone production, which is 90% T4. If her gland is surgically absent or otherwise ablated, T4 replacement is essential – in my experience, at least 75 mcg daily. When hypothyroidism is mild, a person might need little added T4; she’ll make some of her own if your T3 dose doesn’t suppress TSH.
Patient 2 is a typical case: She arrived with normal TSH and robustly normal freeT4. It was safe to use the 5 mcg T4=1mcg T3 replacement. It was wise to make small steps as tolerated. I recommend reducing the T4 dose to no less than 70% of the total thyroid replacement until blood test results prove that ratio should be altered.
The “70% T4/ T3 30%” suggestion may surprise some readers. The healthy human thyroid produces only 10% T3. The PDR informs us that “natural” thyroid (desiccated thyroid extract, porcine USP—currently in medical literature “DTE”) is only 20% T3. In fact, some endocrinologists advise giving no more than 5% T3 in combined T4 and T3 treatment.222 Compared to healthy human thyroid or DTE thyroid, why give patients so much T3?
These people have dysfunctional deiodination; they need more T3 than “normal.” Also, they are taking hormones orally and about 20% will not be absorbed.223 Furthermore, some of the oral T3 is destroyed in the hepatic “first pass,” for all of which we accommodate by following clinical indicators and blood values (discussed below). Reviewers have recommended individualized treatment for each patient,214 and I certainly agree. Patient 2 is quite well now, currently taking 70% T4 and 30% T3.
Repeat for emphasis: For optimal T3 treatment results, WE MUST DIVIDE T3 DOSES. T3 has a short half-life.224 In healthy people, a single T3 dose peaks at 2½ hours and reaches its nadir at 12 hours.225,226 Our more-sensitive patients often prefer taking doses every 8 hours, as advocated by Osler in 1901.120 Interestingly, I find that after switching from Q 12 hours to Q 8 hours, patients may require slightly less T3 daily.
Problems During T3 Escalation Are More Noticeable
The instructions given to Patient 2 (Figure 6) demonstrate a cautious T3 dose escalation, as though the patient were being given her initial thyroid replacement. Predictably, the problems associated with restoring thyroid function are more frequently and emphatically reported by patients taking active hormone. Some of these were discussed above, including issues of adrenal support, estrogen replacement, and interacting caffeine and stimulants.
Unlike Patient 2, some patients who fail T4 treatment would rather not become pregnant. Therefore, warning of increased fertility is an important part of informed consent-talk before adding T3. Everything seems to work better with good thyroid replacement, including every aspect of reproduction. Women can discover they were not menopausal, just amenorrheic due to poor thyroid function.
With correctly prescribed T3 treatment, two issues in particular can be remarkable. First, the potency and short half-life of T3 makes missed doses more consequential; people can feel the lack of it!
Patients also complain more often of anxiety, jitters, and tremulousness. Against expectation, it rarely occurs from too much T3—their thyroid blood tests are usually fine. Before ordering labs, ask when the symptoms occur: If neither at peak nor trough—and the adrenals are supported—then reactive hypoglycemia is the probable cause, via the adrenergic counter-regulatory response. When excessive RT3 slows the metabolism, the glycemic and insulinemic responses are blunted. T3 “frees” the glucose to swing up and down, so it gets blamed; but the real problem is a sugary/starchy diet. I recommend a Mediterranean, Paleo, or ketogenic diet for most of my patients.
Other problems will be encountered: Even the best verbal and written instructions may be forgotten or ignored. Patients may not consider the dose-response curve when building T3. If too much makes one feel tired again, he can choose to take more—and upon feeling worse, still more!
People may build their T3 dose to greater than optimal—or ignore your directions and take more than you had recommended. Mildly high T3 may feel stimulating for a few people but it is risky; don’t consent to it.
When patients get “too busy” to come back for follow-up, it implies they feel well but it bodes ill. The lack of follow-up is never desirable – especially when taking T3.
For these reasons, schedule a timely follow-up appointment for your patients, preferably before they leave your office with the Rx for T3. Hold them to keeping it! It is wise to prescribe no more tablets than will be sufficient to allow for a couple of goofs and one reschedule; limit their refills to ensure safety. A test to validate the dose is needed before authorizing multiple Rx refills is sensible. A final caution: Low tT3/RT3 ratio is adaptive in some circumstances.227 A rare patient “needs” low tT3/RT3 and if so, T3-treatment can “dis-inhibit” protective adaptation. Two patients have been intolerant of even tiny doses of T3: One had received multiple courses of cancer chemotherapy; the other took four mitochondria-toxic psychoactive medications. I believe their elevated RT3 was adaptive, and my efforts were misdirected.
