{"slug":"free-t4-t3","name":"Free T4 and free T3","aliases":["Free thyroxine","Free triiodothyronine","FT4","FT3"],"kind":"biomarker","system":"metabolomics","unit":"ng/dL (FT4) and pg/mL (FT3)","unitNote":"Some reports print pmol/L: multiply free T4 in ng/dL by about 12.9, and free T3 in pg/mL by about 1.54.","answer":"Free T4 and free T3 are the unbound fractions of the two thyroid hormones, and about four fifths of the T3 in blood is made from T4 outside the thyroid by deiodinase enzymes. In 134,346 adults pooled from 26 cohorts, cardiovascular and mortality risk was lowest with free T4 in the 20th to 40th percentiles of the range (about 1.05 to 1.15 ng/dL) and rose in the top fifth, where atrial fibrillation, sudden cardiac death and about three fewer years of life were also seen; a low T3 marks illness and calorie restriction and was the pattern in offspring of long-lived families, so no study supports aiming high in either range, and no trial has targeted a position inside it.","summary":"T4 is the thyroid's main product and T3 is the active hormone; most T3 is made from T4 in the tissues, so free T3 reads the conversion step as much as the gland. Laboratories call about 0.8 to 1.8 ng/dL normal for free T4 and about 2.0 to 4.4 pg/mL for free T3. The large cohorts put the lowest risk in the lower-middle of the free T4 range and find more atrial fibrillation and shorter life at the high-normal end; low T3 marks illness and calorie restriction, and the trials of adding T3 to levothyroxine have shown no consistent benefit.","whatItIs":[{"text":"On a metabolomic panel these two numbers are read as one network, not two levels. The thyroid secretes mostly T4, a prohormone with four iodine atoms; the active hormone T3 is made when one iodine is removed, and that step is done by the deiodinases, a family of three selenium-containing enzymes. D1 and D2 activate T4 to T3, D3 inactivates T4 to reverse T3 and T3 to T2, and D2 and D3 can raise or lower thyroid hormone signaling inside a tissue, independent of the blood level, in response to signals as varied as hypoxia, bile acids, nuclear factor-kappaB and a growing list of foreign chemicals. The free T4 reports the supply; the free T3 reports, in part, what the conversion machinery did with it.","cites":["bianco2002","bianco2019"],"grade":"A"},{"text":"The split between gland and tissues has been measured. In 14 healthy people studied with labeled hormone and a six-pool kinetic model, the thyroid contributed 3.3 micrograms of T3 per day per square meter and the periphery 12.7, which is about 80 percent from conversion; a Lancet seminar puts it the same way, with about 20 percent of circulating T3 coming from direct thyroidal secretion in people with a working gland, and all of it coming from conversion in anyone on levothyroxine alone. That is why a free T3 on levothyroxine is a different measurement from a free T3 in an untreated person.","cites":["pilo1990","chaker2017"],"grade":"B"},{"text":"The word free is an estimate, not a measurement. Nearly all of both hormones travel bound to proteins, and the assays that report a free fraction have to allow for the amount and the binding capacity of those proteins; a standardization review states that none of the methods developed so far measures the actual unbound hormone in serum, and that the indirect methods approximate it while the direct ones estimate it in the presence of the bound hormone. Competitors that displace hormone from protein in the body, including many medications, are underestimated by assays that dilute the sample, and fatty acids generated in a stored sample, especially after heparin, can spuriously raise the free T4 estimate.","cites":["thienpont2013","stockigt2009"],"grade":"B"},{"text":"Guidelines treat TSH and free T4 as the diagnostic pair. The 2017 Lancet seminar on hypothyroidism states that no indications exist for routine measurement of total T3, total T4 or free T3, and the American Thyroid Association task force that reaffirmed levothyroxine as the standard treatment listed mechanistic research on serum T3 levels, including the effects of age and disease and the relationship with tissue concentrations, as a research need rather than a settled tool. A free T3 is therefore a question-driven test: useful when the TSH and free T4 disagree, when hyperthyroidism is suspected, during serious illness, and in the specific debate about people who feel unwell on levothyroxine.","cites":["chaker2017","jonklaas2014"],"grade":"A"}],"origins":[{"text":"The conversion step is older than the gland that feeds it. All three vertebrate deiodinases carry a selenocysteine in their catalytic center and are present from fish to mammals, with D2 and D3 highly conserved and D1 the most variable; sea squirts and amphioxus, our closest invertebrate relatives, have selenodeiodinases that fit none of the three vertebrate types, amphioxus also has a deiodinase that uses no selenium, and deiodinase-like sequences turn up in animals outside the deuterostomes altogether, which suggests that removing iodine from thyroid hormones taken in from outside was useful long before any animal made its own. A phylogenetic reading places deiodination of tyrosine metabolites as an ancient feature of all chordates that precedes the integrated thyroid system of vertebrates, with D1 the oldest vertebrate deiodinase and D2, the most specialized and most finely regulated of the family, the most recent.","cites":["darras2012","orozco2012"],"grade":"C"},{"text":"Selenium is why. The deiodinases are selenoproteins, built by a dedicated synthesis machinery that reads a stop codon as selenocysteine, and selenium was identified in the 1990s as a component of the enzyme that activates thyroid hormone. The element comes mainly from meat, seafood and grains, and intake varies across the world largely with soil content; adverse effects have been seen at both extremes of intake, with a narrow optimum between them. The regulated step in thyroid hormone action thus depends on a trace element the body cannot make, which is the biological reason selenium status and thyroid function have been studied together ever since.","cites":["bianco2002","winther2020"],"grade":"C"},{"text":"The receptor completes the circuit. T3 acts by binding nuclear thyroid hormone receptors, TR-alpha and TR-beta, which regulate target genes; in amphioxus the receptor's true ligand turned out to be TRIAC, a T3 derivative, and thyroid hormones accelerate metamorphosis in sea squirts and sea urchins even though their receptors have not been shown to bind them, while insects and cnidarians have no thyroid receptor at all. In the human version the deiodinases provide the greatest amplitude of control: cells expressing D2 can rapidly build up T3 and intensify signaling, cells expressing D3 dampen it, and that is how one circulating level of hormone runs development, metabolism and growth differently in different tissues. The blood test reads the shared pool; it cannot read the local decision each tissue makes.","cites":["holzer2017","bianco2019"],"grade":"C"}],"labRange":{"typical":"About 0.8 to 1.8 ng/dL for free T4 and about 2.0 to 4.4 pg/mL for free T3, depending on the laboratory and the assay","claims":[{"text":"The printed limits are the 2.5th to 97.5th percentiles of a reference population, set without regard to the risk of any outcome. The Rotterdam Study used 0.85 to 1.95 ng/dL for free T4. In 3,875 euthyroid Italian adults the central 95 percent ran from 9.0 to 20.6 pmol/L for free T4 (about 0.70 to 1.60 ng/dL) and from 2.9 to 6.0 pmol/L for free T3 (about 1.9 to 3.9 pg/mL), with medians of 13.8 and 4.47 pmol/L (about 1.07 ng/dL and 2.91 pg/mL) and a median free T3 to free T4 ratio of 0.32; the ratio was higher in men than women and in people under 60 than over.","cites":["xu2023","chaker2016","gullo2011"],"grade":"B"},{"text":"The range belongs to the assay that made it. Free thyroid hormone methods differ enough that a standardization program has called for a reference measurement system, and the clearest demonstration is pregnancy: in healthy antibody-negative women, two free T4 immunoassays read the same as or lower than nonpregnant controls in the first trimester and had fallen to about 65 percent of control values by the second and third, while total T4 and the free T4 index kept their expected inverse relationship with TSH throughout. A free T4 that looks low in pregnancy may be the assay, not the thyroid.","cites":["thienpont2013","lee2009"],"grade":"B"},{"text":"Both hormones move with the clock and the calendar. In 33 healthy adults sampled over 24 hours, TSH peaked at about 2:40 in the morning and free T3 about 90 minutes later at about 4:04, with a rhythm detectable in 86 percent of people for free T3 and 76 percent for free T4, though the amplitude of both was low; free T3 tracked TSH with a delay of half an hour to two and a half hours, while free T4 showed no temporal relationship with TSH. Across 13 panel and 7 cross-sectional studies, TSH ran higher in winter, free T4 higher in autumn than winter, and free T3 lower in summer than in autumn and spring.","cites":["russell2008","kuzmenko2021"],"grade":"C"}]},"evidence":{"headline":"Across 134,346 adults in 26 cohorts, cardiovascular and mortality risk was lowest with free T4 in the 20th to 40th percentiles of the range (about 1.05 to 1.15 ng/dL) and rose in the top fifth; high-normal free T4 went with atrial fibrillation in 30,085 people from 11 cohorts, and with sudden cardiac death and about three fewer years of life in Rotterdam; a low T3 marked critical illness, long-term calorie restriction, and the offspring of long-lived families, and adding T3 to levothyroxine produced no consistent benefit in 14 trials.","scale":{"min":0,"max":2.5,"ticks":[0,0.5,1,1.5,2,2.5]},"bands":[{"label":"Common laboratory reference range for free T4","low":0.8,"high":1.8,"tone":"lab","source":"Typical US laboratories; Rotterdam used 0.85 to 1.95 (Chaker 2016)"},{"label":"Below the laboratory range: hypothyroidism, pituitary disease, serious illness or an assay problem","low":0,"high":0.8,"tone":"caution","source":"Fliers 2015; Lee 2009; Favresse 2018"},{"label":"Low-normal: longest life expectancy tertile in Rotterdam; slight upturn in risk at the lowest percentiles of the pooled cohorts","low":0.8,"high":1,"tone":"neutral","source":"Bano 2017; Xu 2023"},{"label":"Lowest cardiovascular and mortality risk: 20th to 40th percentiles in 26 pooled cohorts","low":1,"high":1.2,"tone":"evidence","source":"Xu 2023"},{"label":"Middle to upper range: risk rising gradually across quartiles, no threshold","low":1.2,"high":1.4,"tone":"neutral","source":"Baumgartner 2017; Cappola 2015; Xu 2023"},{"label":"High-normal: more atrial fibrillation, sudden cardiac death and mortality; over 70, absolute 10-year risk rose more than 5 percent above about 1.3 to 1.4","low":1.4,"high":1.8,"tone":"caution","source":"Xu 2023; Baumgartner 2017; Chaker 2016; Bano 2017"},{"label":"Above the laboratory range: hyperthyroidism, excess replacement, or assay interference","low":1.8,"high":2.5,"tone":"caution","source":"Favresse 2018; Stockigt 2009"}],"claims":[{"text":"The largest analysis is an individual-participant meta-analysis of 26 prospective cohorts and 134,346 adults with a median age of 59, followed for cardiovascular events and death. Free T4 had a J-shaped relationship with the composite of cardiovascular disease and mortality, with the lowest risk between the 20th and 40th percentiles (median values about 13.5 to 14.8 pmol/L, about 1.05 to 1.15 ng/dL). Compared with that band, free T4 in the top fifth of the range carried a hazard of 1.20 for the composite, 1.34 for all-cause mortality, 1.57 for cardiovascular death and 1.22 for cardiovascular events. In people aged 70 and over, the absolute 10-year risk rose by more than 5 percent above the 85th percentile in women (median 17.6 pmol/L, about 1.37 ng/dL) and above the 75th percentile in men (16.7 pmol/L, about 1.30 ng/dL). The authors propose the 20th to 40th percentiles as the optimal healthy range of free T4 on this evidence.","cites":["xu2023"],"grade":"A"},{"text":"Atrial fibrillation is the best-documented harm of a high-normal free T4. Pooling individual data from 30,085 participants in 11 prospective cohorts followed for 278,955 person-years, 2,574 people (8.6 percent) developed atrial fibrillation; among those with a normal TSH, the highest quartile of free T4 carried a hazard of 1.45 against the lowest quartile, with a trend across all four quartiles that did not change after adjusting for existing heart disease, while TSH itself was not associated with atrial fibrillation in the euthyroid or subclinically hypothyroid range.","cites":["baumgartner2017"],"grade":"A"},{"text":"In the Rotterdam Study the finding extended to sudden death and to life expectancy. Among 10,318 adults aged 45 and over followed for a median of 9.1 years with 261 sudden cardiac deaths, each 1 ng/dL of free T4 carried a hazard of 2.28 for sudden cardiac death, the association held in people with a normal TSH, and the absolute 10-year risk in euthyroid participants rose from 1 percent to 4 percent across the free T4 range. Among 7,785 participants (mean age 64.7) with TSH and free T4 inside the reference range followed for a median of 8.1 years, men and women in the highest free T4 tertile lived 3.2 and 3.5 fewer years than those in the lowest, 3.1 and 2.5 fewer of them free of cardiovascular disease.","cites":["chaker2016","bano2017"],"grade":"B"},{"text":"Older Americans showed the same pattern, and total T3 showed none of it. In 2,843 community-dwelling older adults in the Cardiovascular Health Study with TSH, free T4 and total T3 all in the euthyroid range and not taking thyroid medication, higher free T4 went with more atrial fibrillation, heart failure and death; the highest free T4 quartile had an excess of 11.0 atrial fibrillation cases, 8.0 coronary events, 7.8 heart failure cases and 14.3 deaths per 1,000 person-years over the lowest. Total T3 was not associated with any outcome, and the authors read the data as tolerance for lower thyroid hormone levels in this age group.","cites":["cappola2015"],"grade":"B"},{"text":"A low T3 is the body's response to being ill. Patients in intensive care typically show a low T3, a low T4 and a normal or slightly lowered TSH, the non-thyroidal illness syndrome; the depth of the change tracks prognosis without proof that it causes the outcome, and in its early phase it is read as a possibly beneficial adaptation to systemic illness and to macronutrient restriction. In 451 critically ill patients who stayed in intensive care more than five days, reverse T3 was higher and the T3 to reverse T3 ratio lower in those who later died, on the first day; the odds of survival for the highest versus the lowest quartile were 0.3 for reverse T3 and 2.9 for the ratio, and the ratio in the last sample correlated with liver D1 activity measured after death (R 0.83). Low T3 in a sick person is a reading of the illness, not a thyroid diagnosis.","cites":["fliers2015","peeters2005"],"grade":"B"},{"text":"Eating less does the same thing in healthy people, and the longevity literature treats it as a feature. In 28 lean adults who had practiced calorie restriction with adequate protein and micronutrients for 3 to 15 years (intake about 1,779 kcal a day against 2,433 in sedentary and 2,811 in exercising comparison groups), total T3 was 73.6 ng/dL against 91.0 and 94.3, while total and free T4, reverse T3 and TSH did not differ; the authors raised the possibility that a lower T3 is part of how calorie restriction slows aging. In the CALERIE randomized trial, 218 nonobese adults aged 21 to 51 were assigned to two years of calorie restriction or their usual diet; the restricted group achieved an 11.7 percent cut in intake and a 10.4 percent weight loss, and T3, a prespecified secondary outcome, fell more in that group at both 12 and 24 months.","cites":["fontana2006","ravussin2015"],"grade":"B"},{"text":"The people built for long life run slightly low, not high. In the Leiden Longevity Study, middle-aged offspring of nonagenarian siblings, compared with their own partners, had a trend toward higher TSH, a lower free T4 (15.0 versus 15.2 pmol/L, about 1.17 versus 1.18 ng/dL) and a lower free T3 (4.08 versus 4.14 pmol/L, about 2.66 versus 2.70 pg/mL). Among 859 nonagenarian siblings from 421 long-lived families, a lower family mortality history score in their parents went with higher TSH, lower free T4 and lower free T3. The differences are tiny and the design is cross-sectional, but the direction is consistent across animal models and these human families, and it runs against the idea that a free T3 in the upper half of the range is a goal.","cites":["rozing2010offspring","rozing2010siblings"],"grade":"C"},{"text":"The ratio of free T3 to free T4 is a crude readout of conversion, most informative on levothyroxine. Among 1,811 people without a thyroid whose TSH was normal on levothyroxine alone, compared with 3,875 euthyroid controls, free T4 was higher and free T3 lower; 15.2 percent had a free T3 below the control range and 7.2 percent a free T4 above it, the median ratio was 0.24 against 0.32, and 29.6 percent had a ratio below the controls' 2.5th percentile, a share that rose with the dose. In the general population the picture is weaker: among 6,243 euthyroid US adults, the highest quartile of the ratio had lower all-cause mortality than the lowest (odds 0.70), but the relationship was U-shaped with an inflection near 0.5, and the authors asked for more cohorts before drawing conclusions.","cites":["gullo2011","yu2024"],"grade":"C"},{"text":"The trials that tried to raise T3 directly did not help people feel better. A meta-analysis of 11 randomized trials with 1,216 patients found no difference between levothyroxine plus T3 and levothyroxine alone in bodily pain, depression, anxiety, fatigue, quality of life, weight or lipids. By 2021 the count was 14 trials without a consistent benefit, and the American, British and European thyroid associations agreed there was equipoise for a new trial designed around patient-reported outcomes, slow-release T3, and genotyping for deiodinase variants. The genetic lead comes from 552 people on levothyroxine, in whom the rarer CC genotype of a common DIO2 variant (16 percent of the group) had worse baseline well-being and improved by 2.3 points more on combination therapy at three months and 1.4 at twelve, with no effect on circulating hormone levels; the authors said the result requires replication. The 2014 American Thyroid Association guideline found no consistently strong evidence for any alternative to levothyroxine.","cites":["grozinsky2006","jonklaas2021","panicker2009","jonklaas2014"],"grade":"A"}]},"levers":[{"name":"Calorie intake, down or up","effect":"less food lowers T3; overfeeding and carbohydrate raise it; T4 barely moves","claim":{"text":"Long-term calorie restriction lowered total T3 by about a fifth without changing T4, free T4, reverse T3 or TSH, and two years of restriction lowered T3 in a randomized trial. The reverse is also true: in the Vermont overfeeding studies, three weeks of overeating raised the production rate of T3 from about 30 to about 50 micrograms a day per 70 kilograms whatever the extra calories were made of, while T4 production did not change, and substituting carbohydrate for fat at the same calories raised T3; restricting carbohydrate on an equal or lower calorie diet reproduced, in direction, the low T3 and high reverse T3 of fasting. A free T3 drawn during a diet reads the diet.","cites":["fontana2006","ravussin2015","danforth1979"],"grade":"B"}},{"name":"Illness and recovery","effect":"lowers T3 and raises reverse T3 within days; T4 falls when severe; both recover with health","claim":{"text":"Systemic illness and the acute-phase response lower T3 first, through changes in deiodinase activity, and lower T4 and TSH as illness persists; in 451 intensive-care patients, TSH, T4, T3 and the T3 to reverse T3 ratio rose over time in survivors and stayed flat or fell in those who did not survive. A thyroid panel drawn during or shortly after an infection, an operation or a flare of any serious condition should be repeated once well, before anyone reads a low T3 as a thyroid problem.","cites":["fliers2015","peeters2005"],"grade":"B"}},{"name":"Selenium","effect":"no measurable change in free T3, free T4 or their ratio in a randomized trial of older adults","claim":{"text":"Because the deiodinases are selenoproteins, selenium is the lever most often proposed for conversion. The evidence does not oblige. Epidemiology links low selenium status to autoimmune thyroiditis, Graves disease and goiter, and trials in autoimmune thyroiditis have lowered antibody levels without an apparent change in the clinical course; the only recommendation extends to mild Graves eye disease. In a double-blind randomized trial of 100 adults aged 60 to 80 in marginally selenium-deficient New Zealand, 100 micrograms of selenomethionine a day for three months raised plasma selenium and glutathione peroxidase activity and produced no treatment effect on TSH, free T3, free T4 or the T3 to T4 ratio.","cites":["winther2020","thomson2009"],"grade":"B"}},{"name":"Iodine","effect":"corrects deficiency and lowers thyroglobulin; no effect on free T4 or free T3 in the same trial","claim":{"text":"In the same trial, where the median urinary iodine of 48 micrograms per liter indicated moderate deficiency, 80 micrograms of iodine a day for three months raised urinary iodine and lowered thyroglobulin by 24 percent against placebo, the gland's signal that it was short, with no significant change in TSH, free T3 or free T4. In a population that is not iodine-deficient there is no trial evidence that extra iodine moves either free hormone, and the entry on TSH records that more iodine, once intake is adequate, raises the risk of autoimmune thyroiditis.","cites":["thomson2009"],"grade":"C"}},{"name":"Medications, in classes","effect":"some block conversion and raise free T4 while lowering T3; some lower TSH; some lower thyroid output","claim":{"text":"A few drug classes move these numbers in recognizable patterns, and none should be stopped over a lab result. The iodine-rich antiarrhythmic amiodarone inhibits 5-prime deiodinase, which raises serum T4 and reverse T3 and lowers T3 in most people who take it, and produces overt thyroid dysfunction in 14 to 18 percent; about 14 percent develop hypothyroidism. Lithium acts on hormone synthesis and release, and in one large cohort 6 percent of people starting it needed levothyroxine within 18 months. During illness, dopamine and high-dose glucocorticoids lower TSH, which can hide a hypothyroidism. The deiodination changes of illness and of amiodarone are reviewed together in the physiology literature because the mechanism is shared: less conversion, more reverse T3.","cites":["martino2001","chaker2017","fliers2015","bianco2002"],"grade":"B"}},{"name":"Sleep","effect":"acute loss raises TSH and thyroid hormones; two weeks of short sleep lowered TSH and free T4 modestly","claim":{"text":"Free T3 peaks in the small hours, about 90 minutes after TSH, so a draw after a night without sleep lands on a different part of the curve than one after a normal night. When 11 healthy adults spent 14 days with a 5.5-hour versus an 8.5-hour sleep opportunity in a randomized crossover, TSH and free T4 fell modestly on the short schedule, mainly in the women, the opposite of the rise in TSH and thyroid hormones seen with acute sleep loss. Free T3 was not reported, so the sleep effect on it is inferred from the rhythm, not measured.","cites":["russell2008","kessler2010"],"grade":"C"}}],"caveats":[{"text":"The assays can be wrong in ways that look like disease. Six main interferences affect automated thyroid immunoassays, among them biotin, heterophilic antibodies, antibodies to streptavidin or ruthenium, and antibodies to the thyroid hormones themselves; the prevalence of some approaches 1 percent, and across more than 150 documented cases half or more led to a misdiagnosis or an inappropriate treatment. Free T4 estimates are also distorted by medications that compete for binding proteins and by fatty acids released in the sample after heparin. A free T4 or free T3 that does not fit the TSH and the person is a reason to repeat it on a different platform, not to treat it.","cites":["favresse2018","stockigt2009","thienpont2013"],"grade":"B"},{"text":"Pregnancy has its own rules and its own assay problem. Free T4 immunoassays fell to about 65 percent of nonpregnant values by the second and third trimesters in healthy women whose total T4 and free T4 index behaved normally, and the American Thyroid Association maintains a separate guideline for preconception, pregnancy and the postpartum period with trimester-specific testing. Nothing on this page applies to a pregnant reader or one planning a pregnancy.","cites":["lee2009","korevaar2026"],"grade":"A"},{"text":"Each person has a narrow set point. In 16 healthy men sampled monthly for a year, every individual's range was about half the width of the group's; the index of individuality was 0.58 for T4 and 0.54 for T3, a single result located a person's set point only to within plus or minus 25 percent, and a change of about 0.55 nmol/L in T3 (range 0.3 to 0.9) or 28 nmol/L in T4 between two draws was needed to be 95 percent confident something had moved. A value inside the laboratory range can be abnormal for the individual, and the authors note that whether a given thyroid change is called subclinical or overt depends on where that person's set point sat to begin with.","cites":["andersen2002"],"grade":"B"},{"text":"Time of day and time of year are in the number. Free T3 has a nocturnal peak that lags TSH by about 90 minutes and a low amplitude, free T4 has no clear relationship to the TSH rhythm, and a meta-analysis of 20 studies found TSH higher in winter, free T4 higher in autumn than winter, and free T3 lower in summer than in autumn and spring. Draw the pair at the same time of day, and compare winter with winter.","cites":["russell2008","kuzmenko2021"],"grade":"C"},{"text":"On levothyroxine the free T3 means something different. Everyone taking levothyroxine alone makes all of their T3 by conversion, with no thyroidal contribution, and in 1,811 such patients with a normal TSH the free T3 ran lower and the free T4 higher than in controls, with more than 20 percent outside the control range for one or the other. The 2012 European Thyroid Association guideline estimates that 5 to 10 percent of treated patients with a normal TSH have persistent symptoms, recommends levothyroxine alone as the standard, and allows combination therapy only as an experimental approach, started by a specialist, stopped if there is no improvement at three months, and monitored to keep both TSH and the free T4 to free T3 ratio normal. The seminar literature states that no indications exist for routine free T3 measurement; the honest reading is that a free T3 is a test with specific uses, not a routine one.","cites":["chaker2017","gullo2011","wiersinga2012"],"grade":"A"},{"text":"Reverse T3 is a research marker that has not earned a routine place. In intensive care it predicts survival on the first day and correlates with tissue deiodinase activity measured after death; amiodarone raises it by blocking its clearance; long-term calorie restriction did not change it. No outpatient study has shown that a reverse T3 result changes a decision or an outcome in a well person, and the guidelines do not include it.","cites":["peeters2005","martino2001","fontana2006"],"grade":"C"}],"seeAPhysician":["A free T4 above or below the laboratory range on any draw, with or without symptoms, and especially with a TSH that points the same way.","Palpitations, a racing or irregular heartbeat, tremor, heat intolerance or unexplained weight loss, whatever the numbers say; a high-normal free T4 belongs in the conversation if atrial fibrillation has ever been diagnosed.","Any thyroid result while pregnant, trying to conceive or in the year after a birth, where the ranges, the assays and the stakes are all different.","Anyone taking levothyroxine, liothyronine, desiccated thyroid or a compounded thyroid preparation: dose changes are a prescriber's decision, and a free T3 on treatment is read differently from one off it.","A low free T3 with a normal TSH and free T4 during or after an illness, a crash diet, or a new medication such as amiodarone, lithium or a glucocorticoid, which needs a physician to decide whether it is the illness, the drug or the thyroid.","A result that does not fit the person or the other tests, which may be an assay interference and needs a laboratory conversation before any treatment."],"openQuestions":["No randomized trial has moved a free T3 or a free T4 from one position inside the laboratory range to another in people without thyroid disease and measured symptoms, cardiovascular events or mortality, so any optimal zone inside either range is an inference from cohorts, not a tested goal.","The cohorts are consistent that a high-normal free T4 is the risky end, but they cannot say whether the hormone itself, the pituitary set point it reflects, age, illness or undetected autoimmunity does the harm; the 26-cohort authors propose the 20th to 40th percentiles as an optimal healthy range and have not tested it.","Whether people who feel unwell on levothyroxine with a low free T3 or a low T3 to T4 ratio benefit from adding T3 is the question the 2021 ATA, BTA and ETA consensus designed a trial to answer, with slow-release T3, patient-reported outcomes and deiodinase genotyping; the 14 earlier trials did not show it, and the DIO2 finding awaits replication.","Whether a low free T3 in a healthy, calorie-restricted or long-lived person is protective, neutral or a cost paid for something else is unknown; the association with familial longevity is small and cross-sectional, and the animal data on low thyroid hormone and lifespan have not been tested in a human trial.","Reverse T3 has prognostic value in intensive care and rises with amiodarone, but no study has shown that measuring it in an outpatient changes any outcome; the T3 to reverse T3 ratio remains a research measure.","The free hormone assays themselves are unsettled: no method measures the truly unbound hormone, methods disagree, and a reference measurement system is only now being adopted, so a free T4 of 1.0 on one platform may not be a 1.0 on another."],"questions":[{"q":"Is a free T4 of 1.0 low?","a":"No. On a typical range of about 0.8 to 1.8 ng/dL it sits in the lower third, and in the largest pooled analysis, 134,346 adults in 26 cohorts, the lowest cardiovascular and mortality risk was in the 20th to 40th percentiles of free T4, about 1.05 to 1.15 ng/dL. The Rotterdam cohort found the longest life expectancy in the lowest free T4 tertile. A 1.0 with a normal TSH is where the cohorts would put a person; a 1.0 with a TSH above the range, or with symptoms, is a different question for a physician."},{"q":"What is an optimal free T3 level?","a":"No study has defined one, and the evidence that exists points away from aiming high. Total T3 was not associated with any outcome in 2,843 older Americans, long-term calorie restriction lowered T3 by about a fifth without changing T4 or TSH, offspring of long-lived families ran a very slightly lower free T3 than their partners, and a US cohort found a U-shaped relationship between the T3 to T4 ratio and mortality. A free T3 inside the laboratory range, drawn when well and not dieting, is normal for the purposes of the evidence; a very low value with a normal TSH usually reflects illness, calorie restriction or a medication rather than the thyroid."},{"q":"Why is my T3 low when my TSH is normal?","a":"Because most T3 is made outside the thyroid, by deiodinase enzymes that respond to the body's state, and the pituitary does not correct for that step. Illness, an operation, a low-calorie or low-carbohydrate diet, and drugs such as amiodarone, glucocorticoids or beta blockers reduce conversion of T4 to T3 and raise reverse T3 while TSH stays normal. On levothyroxine, a lower free T3 with a higher free T4 is common because all T3 then comes from conversion. Draw it again once well and eating normally, at the same time of day; if it stays low, that is a physician's question, and the trials of adding T3 have not shown a consistent benefit."}],"citations":[{"id":"bianco2002","authors":"Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR","title":"Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases","journal":"Endocrine Reviews","year":2002,"pmid":"11844744","doi":"10.1210/edrv.23.1.0455","type":"review","finding":"The three deiodinases D1, D2 and D3 are selenoproteins; D2 contributes significantly to human plasma T3 production; the review covers deiodination during illness and amiodarone therapy and D3 overexpression causing consumptive hypothyroidism.","url":"https://pubmed.ncbi.nlm.nih.gov/11844744/"},{"id":"bianco2019","authors":"Bianco AC, Dumitrescu A, Gereben B, Ribeiro MO, Fonseca TL, Fernandes GW, Bocco BMLC","title":"Paradigms of Dynamic Control of Thyroid Hormone Signaling","journal":"Endocrine Reviews","year":2019,"pmid":"31033998","doi":"10.1210/er.2018-00275","type":"review","finding":"T4 is activated to T3 or inactivated to reverse T3 by deiodinases; T3 binds TR-alpha and TR-beta; the deiodinases provide the greatest amplitude of control, so cells with DIO2 build up T3 and cells with DIO3 dampen signaling despite stable circulating levels.","url":"https://pubmed.ncbi.nlm.nih.gov/31033998/"},{"id":"pilo1990","authors":"Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R","title":"Thyroidal and peripheral production of 3,5,3'-triiodothyronine in humans by multicompartmental analysis","journal":"American Journal of Physiology","year":1990,"pmid":"2333963","doi":"10.1152/ajpendo.1990.258.4.E715","type":"laboratory","finding":"In 14 studies in normal subjects, the thyroid contributed 3.3 and the periphery 12.7 micrograms of T3 per day per square meter, about 80 percent from peripheral conversion.","url":"https://pubmed.ncbi.nlm.nih.gov/2333963/"},{"id":"chaker2017","authors":"Chaker L, Bianco AC, Jonklaas J, Peeters RP","title":"Hypothyroidism","journal":"Lancet","year":2017,"pmid":"28336049","doi":"10.1016/S0140-6736(17)30703-1","type":"review","finding":"About 20 percent of circulating T3 comes from direct thyroidal secretion and all of it from conversion on levothyroxine; no indications exist for routine measurement of free T3; about 14 percent on amiodarone develop hypothyroidism and 6 percent starting lithium needed levothyroxine within 18 months; combination therapy has not improved outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/28336049/"},{"id":"xu2023","authors":"Xu Y, Derakhshan A, Hysaj O, et al.; Thyroid Studies Collaboration","title":"The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis","journal":"Lancet Diabetes and Endocrinology","year":2023,"pmid":"37696273","doi":"10.1016/S2213-8587(23)00227-9","type":"meta-analysis","finding":"In 134,346 adults from 26 cohorts, free T4 had a J-shaped association with cardiovascular disease and mortality; the 20th to 40th percentiles (median 13.5 to 14.8 pmol/L) carried the lowest risk and the 80th to 100th percentiles hazards of 1.20 (composite), 1.34 (mortality), 1.57 (cardiovascular death) and 1.22 (events).","url":"https://pubmed.ncbi.nlm.nih.gov/37696273/"},{"id":"baumgartner2017","authors":"Baumgartner C, da Costa BR, Collet TH, et al.; Thyroid Studies Collaboration","title":"Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation","journal":"Circulation","year":2017,"pmid":"29061566","doi":"10.1161/CIRCULATIONAHA.117.028753","type":"meta-analysis","finding":"In 30,085 participants from 11 cohorts (278,955 person-years), 2,574 (8.6 percent) developed atrial fibrillation; the highest versus lowest quartile of free T4 in euthyroid people carried a hazard of 1.45, while TSH was not associated.","url":"https://pubmed.ncbi.nlm.nih.gov/29061566/"},{"id":"chaker2016","authors":"Chaker L, van den Berg ME, Niemeijer MN, et al.","title":"Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study","journal":"Circulation","year":2016,"pmid":"27601558","doi":"10.1161/CIRCULATIONAHA.115.020789","type":"cohort","finding":"In 10,318 Rotterdam participants with 261 sudden cardiac deaths over a median 9.1 years, each 1 ng/dL of free T4 carried a hazard of 2.28, within the normal range as well; absolute 10-year risk rose from 1 to 4 percent across the euthyroid free T4 range (reference 0.85 to 1.95 ng/dL).","url":"https://pubmed.ncbi.nlm.nih.gov/27601558/"},{"id":"bano2017","authors":"Bano A, Dhana K, Chaker L, et al.","title":"Association of Thyroid Function With Life Expectancy With and Without Cardiovascular Disease: The Rotterdam Study","journal":"JAMA Internal Medicine","year":2017,"pmid":"28975207","doi":"10.1001/jamainternmed.2017.4836","type":"cohort","finding":"In 7,785 euthyroid adults (mean age 64.7, median follow-up 8.1 years), men and women in the highest free T4 tertile lived 3.2 and 3.5 fewer years than the lowest tertile, 3.1 and 2.5 fewer without cardiovascular disease.","url":"https://pubmed.ncbi.nlm.nih.gov/28975207/"},{"id":"cappola2015","authors":"Cappola AR, Arnold AM, Wulczyn K, Carlson M, Robbins J, Psaty BM","title":"Thyroid function in the euthyroid range and adverse outcomes in older adults","journal":"Journal of Clinical Endocrinology and Metabolism","year":2015,"pmid":"25514105","doi":"10.1210/jc.2014-3586","type":"cohort","finding":"In 2,843 older US adults with euthyroid TSH, free T4 and total T3, higher free T4 went with mortality, atrial fibrillation and heart failure (top quartile excess 11.0, 8.0, 7.8 and 14.3 per 1,000 person-years for atrial fibrillation, coronary disease, heart failure and death); total T3 was not associated with any outcome.","url":"https://pubmed.ncbi.nlm.nih.gov/25514105/"},{"id":"fliers2015","authors":"Fliers E, Bianco AC, Langouche L, Boelen A","title":"Thyroid function in critically ill patients","journal":"Lancet Diabetes and Endocrinology","year":2015,"pmid":"26071885","doi":"10.1016/S2213-8587(15)00225-9","type":"review","finding":"Critical illness produces low T3, low T4 and normal or slightly low TSH (non-thyroidal illness syndrome); its extent tracks prognosis without proof of causality; the early phase follows the acute-phase response and macronutrient restriction and may be beneficial; dopamine and high-dose glucocorticoids lower TSH.","url":"https://pubmed.ncbi.nlm.nih.gov/26071885/"},{"id":"peeters2005","authors":"Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G","title":"Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities","journal":"Journal of Clinical Endocrinology and Metabolism","year":2005,"pmid":"15886232","doi":"10.1210/jc.2005-0535","type":"cohort","finding":"In 451 patients in intensive care more than 5 days, day-1 reverse T3 was higher and T3/rT3 lower in nonsurvivors; odds of survival for highest versus lowest quartile 0.3 for rT3 and 2.9 for T3/rT3; TSH, T4, T3 and T3/rT3 rose over time in survivors; liver D1 correlated with T3/rT3 (R 0.83).","url":"https://pubmed.ncbi.nlm.nih.gov/15886232/"},{"id":"fontana2006","authors":"Fontana L, Klein S, Holloszy JO, Premachandra BN","title":"Effect of long-term calorie restriction with adequate protein and micronutrients on thyroid hormones","journal":"Journal of Clinical Endocrinology and Metabolism","year":2006,"pmid":"16720655","doi":"10.1210/jc.2006-0328","type":"cross-sectional","finding":"In 28 adults practicing calorie restriction for 3 to 15 years (1,779 versus 2,433 and 2,811 kcal a day), total T3 was 73.6 versus 91.0 and 94.3 ng/dL, while total and free T4, reverse T3 and TSH were similar.","url":"https://pubmed.ncbi.nlm.nih.gov/16720655/"},{"id":"ravussin2015","authors":"Ravussin E, Redman LM, Rochon J, et al.; CALERIE Study Group","title":"A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity","journal":"Journals of Gerontology Series A","year":2015,"pmid":"26187233","doi":"10.1093/gerona/glv057","type":"rct","finding":"Among 218 nonobese adults aged 21 to 51 randomized to two years of calorie restriction or usual diet, the restricted group achieved 11.7 percent restriction and 10.4 percent weight loss, and T3 (a secondary outcome) decreased more at 12 and 24 months.","url":"https://pubmed.ncbi.nlm.nih.gov/26187233/"},{"id":"danforth1979","authors":"Danforth E Jr, Horton ES, O'Connell M, et al.","title":"Dietary-induced alterations in thyroid hormone metabolism during overnutrition","journal":"Journal of Clinical Investigation","year":1979,"pmid":"500814","doi":"10.1172/JCI109590","type":"laboratory","finding":"Three weeks of overfeeding raised the T3 production rate from about 30 to about 50 micrograms a day per 70 kg regardless of macronutrient, T4 production was unchanged, carbohydrate substituted for fat raised T3, and carbohydrate restriction mimicked the fasting pattern of T3 and reverse T3.","url":"https://pubmed.ncbi.nlm.nih.gov/500814/"},{"id":"rozing2010offspring","authors":"Rozing MP, Westendorp RG, de Craen AJ, et al.; Leiden Longevity Study Group","title":"Low serum free triiodothyronine levels mark familial longevity: the Leiden Longevity Study","journal":"Journals of Gerontology Series A","year":2010,"pmid":"20018826","doi":"10.1093/gerona/glp200","type":"cross-sectional","finding":"Middle-aged offspring of nonagenarian siblings had lower free T4 (15.0 versus 15.2 pmol/L) and lower free T3 (4.08 versus 4.14 pmol/L) than their partners, with a trend toward higher TSH.","url":"https://pubmed.ncbi.nlm.nih.gov/20018826/"},{"id":"rozing2010siblings","authors":"Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, et al.","title":"Familial longevity is associated with decreased thyroid function","journal":"Journal of Clinical Endocrinology and Metabolism","year":2010,"pmid":"20739380","doi":"10.1210/jc.2010-0875","type":"cross-sectional","finding":"In 859 nonagenarian siblings from 421 long-lived families, lower parental mortality was associated with higher TSH, lower free T4 and lower free T3.","url":"https://pubmed.ncbi.nlm.nih.gov/20739380/"},{"id":"gullo2011","authors":"Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R","title":"Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients","journal":"PLoS One","year":2011,"pmid":"21829633","doi":"10.1371/journal.pone.0022552","type":"cross-sectional","finding":"In 1,811 athyreotic patients with normal TSH on levothyroxine versus 3,875 euthyroid controls, free T4 was higher and free T3 lower; 15.2 percent had low free T3 and 7.2 percent high free T4; median FT3/FT4 ratio 0.24 versus 0.32; 29.6 percent had a ratio below the control 2.5th percentile; control ranges 9.0 to 20.6 pmol/L FT4 and 2.9 to 6.0 pmol/L FT3.","url":"https://pubmed.ncbi.nlm.nih.gov/21829633/"},{"id":"yu2024","authors":"Yu G, Liu S, Song C, et al.","title":"Association of sensitivity to thyroid hormones with all-cause mortality in euthyroid US adults: A nationwide cohort study","journal":"European Thyroid Journal","year":2024,"pmid":"38189656","doi":"10.1530/ETJ-23-0130","type":"cohort","finding":"In 6,243 euthyroid NHANES adults, the highest quartile of the FT3/FT4 ratio had lower all-cause mortality than the lowest (0.70), with a U-shaped relationship and an inflection near 0.5; the authors call for more cohorts.","url":"https://pubmed.ncbi.nlm.nih.gov/38189656/"},{"id":"grozinsky2006","authors":"Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L","title":"Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials","journal":"Journal of Clinical Endocrinology and Metabolism","year":2006,"pmid":"16670166","doi":"10.1210/jc.2006-0448","type":"meta-analysis","finding":"Across 11 randomized trials and 1,216 patients, T4 plus T3 did not differ from T4 alone in pain, depression, anxiety, fatigue, quality of life, weight or lipids.","url":"https://pubmed.ncbi.nlm.nih.gov/16670166/"},{"id":"jonklaas2021","authors":"Jonklaas J, Bianco AC, Cappola AR, et al.","title":"Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document","journal":"Thyroid","year":2021,"pmid":"33276704","doi":"10.1089/thy.2020.0720","type":"consensus","finding":"Fourteen trials have not shown a consistent benefit of combination therapy; the ATA, BTA and ETA agreed there is equipoise for a new trial powered for deiodinase and transporter polymorphisms, using slow-release or twice-daily T3 and patient-reported outcomes; 28 of 34 statements reached at least 75 percent agreement.","url":"https://pubmed.ncbi.nlm.nih.gov/33276704/"},{"id":"panicker2009","authors":"Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM","title":"Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients","journal":"Journal of Clinical Endocrinology and Metabolism","year":2009,"pmid":"19190113","doi":"10.1210/jc.2008-1301","type":"rct","finding":"In 552 people on T4, the CC genotype of DIO2 rs225014 (16 percent) had worse baseline well-being (GHQ 14.1 versus 12.8) and improved 2.3 points more on T4/T3 at 3 months and 1.4 at 12, with no effect on circulating hormone levels; the authors say replication is required.","url":"https://pubmed.ncbi.nlm.nih.gov/19190113/"},{"id":"wiersinga2012","authors":"Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP","title":"2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism","journal":"European Thyroid Journal","year":2012,"pmid":"24782999","doi":"10.1159/000339444","type":"guideline","finding":"Symptoms persist in 5 to 10 percent of levothyroxine-treated patients with a normal TSH; levothyroxine alone remains standard; combination therapy is experimental, specialist-initiated, stopped at 3 months without improvement, and monitored to normalize TSH, free T4 and the free T4 to free T3 ratio.","url":"https://pubmed.ncbi.nlm.nih.gov/24782999/"},{"id":"jonklaas2014","authors":"Jonklaas J, Bianco AC, Bauer AJ, et al.; American Thyroid Association Task Force on Thyroid Hormone Replacement","title":"Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement","journal":"Thyroid","year":2014,"pmid":"25266247","doi":"10.1089/thy.2014.0028","type":"guideline","finding":"Levothyroxine should remain the standard of care; no consistently strong evidence supports combination therapy, thyroid extract or other alternatives; mechanistic research on serum T3 levels and superior biomarkers of euthyroidism are named as research needs.","url":"https://pubmed.ncbi.nlm.nih.gov/25266247/"},{"id":"andersen2002","authors":"Andersen S, Pedersen KM, Bruun NH, Laurberg P","title":"Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease","journal":"Journal of Clinical Endocrinology and Metabolism","year":2002,"pmid":"11889165","doi":"10.1210/jcem.87.3.8165","type":"laboratory","finding":"In 16 healthy men sampled monthly for a year, individual ranges were about half the group range; index of individuality 0.58 for T4 and 0.54 for T3; one result located the set point to within 25 percent; a change of 0.55 nmol/L T3 (0.3 to 0.9) or 28 nmol/L T4 was needed for 95 percent confidence.","url":"https://pubmed.ncbi.nlm.nih.gov/11889165/"},{"id":"russell2008","authors":"Russell W, Harrison RF, Smith N, et al.","title":"Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels","journal":"Journal of Clinical Endocrinology and Metabolism","year":2008,"pmid":"18364382","doi":"10.1210/jc.2007-2674","type":"cross-sectional","finding":"In 33 healthy adults sampled over 24 hours, TSH peaked at 02:40 and free T3 about 90 minutes later at 04:04; a rhythm was present in 86 percent for free T3 and 76 percent for free T4 with low amplitude; free T4 showed no temporal relationship with TSH.","url":"https://pubmed.ncbi.nlm.nih.gov/18364382/"},{"id":"kuzmenko2021","authors":"Kuzmenko NV, Tsyrlin VA, Pliss MG, Galagudza MM","title":"Seasonal variations in levels of human thyroid-stimulating hormone and thyroid hormones: a meta-analysis","journal":"Chronobiology International","year":2021,"pmid":"33535823","doi":"10.1080/07420528.2020.1865394","type":"meta-analysis","finding":"Across 13 panel and 7 cross-sectional studies, TSH was higher in winter, free T4 higher in autumn than winter, total T3 higher in winter than summer, and free T3 lower in summer than in autumn and spring.","url":"https://pubmed.ncbi.nlm.nih.gov/33535823/"},{"id":"kessler2010","authors":"Kessler L, Nedeltcheva A, Imperial J, Penev PD","title":"Changes in serum TSH and free T4 during human sleep restriction","journal":"Sleep","year":2010,"pmid":"20815195","doi":"10.1093/sleep/33.8.1115","type":"rct","finding":"In 11 healthy adults, 14 days of a 5.5- versus 8.5-hour sleep opportunity produced a modest fall in TSH and free T4, mainly in women, in contrast to the rise in TSH and thyroid hormones during acute sleep loss.","url":"https://pubmed.ncbi.nlm.nih.gov/20815195/"},{"id":"thienpont2013","authors":"Thienpont LM, Van Uytfanghe K, Poppe K, Velkeniers B","title":"Determination of free thyroid hormones","journal":"Best Practice and Research Clinical Endocrinology and Metabolism","year":2013,"pmid":"24094639","doi":"10.1016/j.beem.2013.05.012","type":"review","finding":"No free hormone method measures the actual unbound hormone in serum; indirect methods approximate it and direct methods estimate it; methods lack comparability, and a reference measurement system is the route to standardization.","url":"https://pubmed.ncbi.nlm.nih.gov/24094639/"},{"id":"stockigt2009","authors":"Stockigt JR, Lim CF","title":"Medications that distort in vitro tests of thyroid function, with particular reference to estimates of serum free thyroxine","journal":"Best Practice and Research Clinical Endocrinology and Metabolism","year":2009,"pmid":"19942151","doi":"10.1016/j.beem.2009.06.004","type":"review","finding":"Free T4 estimates that dilute the sample underestimate the effect of circulating competitors such as many medications, and non-esterified fatty acids generated during storage, especially after heparin, spuriously raise the measured free T4.","url":"https://pubmed.ncbi.nlm.nih.gov/19942151/"},{"id":"lee2009","authors":"Lee RH, Spencer CA, Mestman JH, et al.","title":"Free T4 immunoassays are flawed during pregnancy","journal":"American Journal of Obstetrics and Gynecology","year":2009,"pmid":"19114271","doi":"10.1016/j.ajog.2008.10.042","type":"laboratory","finding":"In healthy antibody-negative pregnant women, two free T4 immunoassays read the same as or below controls in the first trimester and about 65 percent of control values by the second and third, while total T4 and the free T4 index kept their inverse relationship with TSH.","url":"https://pubmed.ncbi.nlm.nih.gov/19114271/"},{"id":"favresse2018","authors":"Favresse J, Burlacu MC, Maiter D, Gruson D","title":"Interferences With Thyroid Function Immunoassays: Clinical Implications and Detection Algorithm","journal":"Endocrine Reviews","year":2018,"pmid":"29982406","doi":"10.1210/er.2018-00119","type":"review","finding":"Six main interferences (macro-TSH, biotin, antistreptavidin, anti-ruthenium, thyroid hormone autoantibodies, heterophilic antibodies) affect TSH, free T4 and free T3 assays; prevalence of some approaches 1 percent; half or more of more than 150 documented cases led to misdiagnosis or inappropriate management.","url":"https://pubmed.ncbi.nlm.nih.gov/29982406/"},{"id":"korevaar2026","authors":"Korevaar TIM, Leung AM, Alexander EK, et al.","title":"American Thyroid Association 2026 Guidelines for Thyroid Disease in Preconception, Pregnancy, and Postpartum","journal":"Thyroid","year":2026,"pmid":"42219800","doi":"10.1177/10507256261445624","type":"guideline","finding":"The current ATA guideline for thyroid function testing, iodine, autoimmunity, hypothyroidism and hypothyroxinemia before, during and after pregnancy.","url":"https://pubmed.ncbi.nlm.nih.gov/42219800/"},{"id":"martino2001","authors":"Martino E, Bartalena L, Bogazzi F, Braverman LE","title":"The effects of amiodarone on the thyroid","journal":"Endocrine Reviews","year":2001,"pmid":"11294826","doi":"10.1210/edrv.22.2.0427","type":"review","finding":"Amiodarone typically raises serum T4 and reverse T3 and lowers T3 by inhibiting 5-prime deiodinase, and causes overt thyroid dysfunction in 14 to 18 percent of people taking it.","url":"https://pubmed.ncbi.nlm.nih.gov/11294826/"},{"id":"winther2020","authors":"Winther KH, Rayman MP, Bonnema SJ, Hegedüs L","title":"Selenium in thyroid disorders - essential knowledge for clinicians","journal":"Nature Reviews Endocrinology","year":2020,"pmid":"32001830","doi":"10.1038/s41574-019-0311-6","type":"review","finding":"Selenium was identified in the 1990s as a component of the enzyme that activates thyroid hormone; intake comes mainly from meat, seafood and grains and varies with soil; the optimum range is narrow; trials in autoimmune thyroiditis lower antibodies without clinical improvement; recommendations extend only to Graves ophthalmopathy.","url":"https://pubmed.ncbi.nlm.nih.gov/32001830/"},{"id":"thomson2009","authors":"Thomson CD, Campbell JM, Miller J, Skeaff SA, Livingstone V","title":"Selenium and iodine supplementation: effect on thyroid function of older New Zealanders","journal":"American Journal of Clinical Nutrition","year":2009,"pmid":"19692495","doi":"10.3945/ajcn.2009.28190","type":"rct","finding":"In 100 adults aged 60 to 80 randomized to 100 micrograms selenium, 80 micrograms iodine, both or placebo for 3 months, selenium raised plasma selenium and glutathione peroxidase, iodine lowered thyroglobulin by 24 percent, and neither changed TSH, free T3, free T4 or the T3 to T4 ratio; baseline median urinary iodine was 48 micrograms per liter.","url":"https://pubmed.ncbi.nlm.nih.gov/19692495/"},{"id":"darras2012","authors":"Darras VM, Van Herck SL","title":"Iodothyronine deiodinase structure and function: from ascidians to humans","journal":"Journal of Endocrinology","year":2012,"pmid":"22825922","doi":"10.1530/JOE-12-0204","type":"review","finding":"All three vertebrate deiodinases carry a catalytic selenocysteine and occur from fish to mammals; urochordates and cephalochordates have selenodeiodinases outside the three types, amphioxus also a non-selenodeiodinase, and deiodinase-like sequences exist in non-deuterostomes, suggesting deiodination of external thyroid hormones in many invertebrates.","url":"https://pubmed.ncbi.nlm.nih.gov/22825922/"},{"id":"orozco2012","authors":"Orozco A, Valverde-R C, Olvera A, García-G C","title":"Iodothyronine deiodinases: a functional and evolutionary perspective","journal":"Journal of Endocrinology","year":2012,"pmid":"22872760","doi":"10.1530/JOE-12-0258","type":"review","finding":"Deiodination of tyrosine metabolites is an ancient feature of all chordates that precedes the integrated vertebrate thyroid system; phylogenetics places D1 as the oldest vertebrate deiodinase and D2, the most specialized and finely regulated, as the most recent.","url":"https://pubmed.ncbi.nlm.nih.gov/22872760/"},{"id":"holzer2017","authors":"Holzer G, Roux N, Laudet V","title":"Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling","journal":"Molecular and Cellular Endocrinology","year":2017,"pmid":"28342854","doi":"10.1016/j.mce.2017.03.021","type":"review","finding":"In amphioxus TRIAC is a bona fide thyroid receptor ligand; thyroid hormones accelerate metamorphosis in tunicates and echinoderms whose receptors have not been shown functional; insects and cnidarians lack a thyroid receptor.","url":"https://pubmed.ncbi.nlm.nih.gov/28342854/"}],"written":"2026-10-10","updated":"2026-10-10","reviewed":true,"reviewedOn":"2026-10-12","related":{"essays":["tsh-of-3-8-with-symptoms","ferritin-of-20-what-the-lab-calls-normal"],"glossary":["Reverse T3","Reference range","Optimal range"],"symptoms":["thyroid-symptoms","fatigue","weight-loss-resistance","hair-loss"],"entries":["tsh","ferritin","fasting-insulin","shbg"]},"url":"https://taggehealth.com/labs/free-t4-t3","author":"Daniel Tagge, MD","publisher":"Tagge Health","license":"Free to read and cite with attribution to the URL above."}