Assessing the RATIO between Free T3 and Free T4 within the reference range is clinically relevant, even for people without thyroid disease.
Why, then, should these two tests be considered unnecessary for assessing the thyroid hormone status and the health risk of hypothyroid patients on therapy?
A 2018 study has demonstrated that a LOW free T3: free T4 thyroid hormone ratio within the reference range was the most powerful prognostic indicator of death within 1 year after a heart attack (Myocardial Infrarction), despite the usual subsequent therapy.
They compared the results of the T3:T4 ratio with the score on a standard tool that assesses the risk of 1-year all-cause mortality after a myocardial infarction (heart attack) — the “Global Registry of Acute Coronary Events” (GRACE) score.
“In a prospective cohort study with a 1-year follow-up, according to the clinical end point, 953 euthyroid individuals (61.0 ± 11.6; female, 25.8%) were divided into two groups: (1) the survival group (n = 915) and (2) the death group (n = 38).”
The cohort was stratified by Free T3, Free T4, and their Free T3: T4 ratio to determine “cut off values,” and these cutoffs then enabled the patient cohort to be stratified into subgroups by FT3, FT4 and T3:T4 ratio for further analysis.
After patients were divided into cohorts by the “cut-off” values for Free T3, Free T4 and the T3:T4 ratio,
- The subbroup with a Free T3 lower than 3.685 pmol/L (reference range: 2.63–5.71 pmol/L) had higher mortality (6.4% of this subgroup died).
- The subbroup with a Free T4 below 14.21 pmol/L (reference range: 9.01–19.05 pmol/L) had higher mortality (7.6% of them died).
Surprisingly, the Free T3:T4 ratio was almost twice as powerful in predicting mortality:
- Among patients who had ratios lower than 0.255, 11.8% died, compared to only 2.1% deaths in patients with a higher T3:T4 ratio.
- To calculate the ratio, divide the T3 result by the T4 result in pmol/L (FT3 3.685 / FT4 14.21 = 0.2593).
Overall statistics. See the NOTES below for interpretation.
- Free T4 : Free T3 ratio had a hazard ratio of 6.742 in univariate analysis and 3.546 in multivariate analysis, per 0.1 unit decrease below the “cut-off value” of 0.255. This was the only indicator with a statistical significance value of p=<0.001.
- Free T3 had a hazard ratio of 2.154 per 1 pmol/L decrease below the “cut-off value” of 3.685 in univariate analysis. The hazard ratio was 0.887 in multivariate analysis.
- Free T4 had a hazard ratio of 1.282 per 1 pmol/L decrease below the “cut-off value” of 14.21 in univariate and 1.249 in multivariate analysis.
- TSH was NOT associated with 1-year all cause mortality — Hazard ratio of 0.930 per 1 uIU/mL increase, and no results for multivarate analysis.
The “hazard ratios” indicate the relative risk of death based on the patients who died vs. those who survived in this study. A hazard ratio of 6.742 would increase the risk more than 6 times per 0.1 unit decrease, meaning that a T4-T3 ratio of 0.23 would yield more than 6x the risk of death than a T4-T3 ratio of 0.33.
“Univariate” analysis considered each indicator’s association with death independently from other factors.
“Multivariate” analysis considered the indicator’s association with death, but was adjusted for many other factors: “age, gender, history of hypertension, Killip class III/IV on admission, Heart rate on admission, creatinine on admission, albumin on admission”
Comparison with the patients’ GRACE score as prognostic of death:
- The most powerful indication was the Free T3:T4 ratio when combined with the GRACE score.
- The GRACE score alone did not perform as well as the T3:T4 ratio.
- The GRACE score alone did not perform as the Free T3 level in univariate analysis.
- The GRACE score was more indicative than Free T4.
“In euthyroid patients with AMI undergoing PCI, the fT3/fT4 ratio was an independent predictor of 1-year all-cause mortality. Its prognostic performance was similar to the GRACE score, and also improved its prognostic performance (GRACE score vs GRACE score + fT3/fT4 ratio).”
Yu, T., Tian, C., Song, J., He, D., Wu, J., Wen, Z., … Sun, Z. (2018). Value of the fT3/fT4 ratio and its combination with the GRACE risk score in predicting the prognosis in euthyroid patients with acute myocardial infarction undergoing percutaneous coronary intervention: a prospective cohort study. BMC Cardiovascular Disorders, 18(1), 181. https://doi.org/10.1186/s12872-018-0916-z
Even though this study focused on “euthyroid” subjects who were critically ill, it supports several important principles:
- Free T3 must be tested to yield the most relevant data on thyroid status.
- TSH and Free T4, both alone or in combination, are insignificant compared to Free T3 and the T3:T4 ratio, as clinical prognostic indicators in illness.
- The population statistical reference range for thyroid hormones does not determine health versus illness. You can be at higher risk of death with low values within the reference range.
- A normal TSH and high-normal Free T4 cannot predict Free T3 levels.
- Lower T3-T4 ratios are powerfully predictive of adverse outcomes in illness.
This is unsurprising, since T3 hormone is necessary for the health of every organ in the body.
Thyroid patients are at risk of chronic low T3:T4 ratios
Hypothyroid patients on T4 monotherapy do not have to have a myocardial infarction or be critically ill in order to have a low Free T3 or a low T3:T4 ratio.
- Many studies have shown lower T3 levels in patients on thyroid hormone therapy. (See thyroidpatients.ca rationale pages for a discussion of these studies.)
- Logically, maintaining a low T3:T4 ratio in any patient, regardless of whether they are critically or chronically ill at the time, could cause harm to health.
Thyroid patients’ poor T3:T4 ratio can be maintained by a combination of factors:
- Our lack of functional thyroid tissue that could have secreted variable amounts of T3 hormone under variable levels of TSH stimulation.
- Thyroid patietnts’ TSH is normalized, and therefore their TSH is not permitted to rise in order to stimulate more T3 via thyroidal secretion or extrathyroidal T4-T3 conversion.
- The paradigm of TSH-controlled T4 monotherapy mandates blindness to a patient’s T3 levels in blood. This blindness reinforces the medical dominance of TSH and T4 monotherapy, but it puts patients at risk by denying medically relevant evidence.
- Even when Free T3 is tested, medical ignorance results in misinterpretation of results. Extreme variation of individual “set points” within the population-wide thyroid hormone reference ranges means that merely “normal” level of T3 in bloodstream can cause a deficiency in an individual patient.
- A number of genetic defects in patients can significantly hinder T4-T3 conversion, reduce T4 transport into cells and tissues, and reduce thyroid hormone receptor sensitivity (DIO1, DIO2, SBP2, MCT8, MCT10).
- Autoimmune thyroid disease can have TSH-receptor-blocking antibodies (TBAb) that block TSH molecules from binding with TSH receptors. TSH receptors are not only located on the thyroid gland, but on the pituitary gland and throughout the body, where they can block the influence of TSH on T4-T3 conversion. According to Frohlich and Wahl, 2017, “Anti-TSHR antibodies are found in 90% of GD patients, 0–20% HT, and 10–75% of atrophic thyroiditis patients (9). Other studies noted TSHR antibodies in around 10% of HT patients (10, 11).” These TSHR antibodies are not commonly measured outside of research studies, so their effects on the T3:T4 ratio is one of the few indicators of their activity in thyroid patients.
- The normal human thyroid axis modifies TSH and T4 relationships over time in order to keep T3 levels optimal and steady, averaging at the middle of the Free T3 reference range during health in youth and middle age. But under the conditions of thyroid or pituitary dysfunction and artificial hormone therapy, the body cannot protect or adjust T3 levels to adapt to physical stressors. Instead, the patient’s medication must be adjusted and optimized with the goal of protecting T3 levels.
Low T3:T4 ratios hinder recovery from illness
The fact is, hypothyroid patients with absent or damaged thyroid glands cannot easily recover from low T3 like people with normal thyroid glands can.
In “Low T3 Syndrome,” a certain amount of functional thyroid tissue stimulated by higher TSH is required to generate the T3 to initiate recovery. In patients with normal thyroid glands who are lucky enough to recover from Low T3 syndrome, the TSH and T3 secretion increases first, before the disordered thyroid hormone metabolism is corrected.
Even if a hypothyroid patient’s thyroid gland is partly functional, a static dose of T4 monotherapy will prevent their TSH levels from rising, because TSH is controlled by Free T4 therapy alone whenever Free T3 is not dominant. This means that their remaining thyroid tissue will NOT secrete more T3 hormone, even if it could.
In addition, it is well known that T4-T3 conversion rates are decreased the higher the Free T4 level is in bloodstream. The body downregulates T4-T3 conversion in a state of Free T4 abundance in order to protect itself from thyrotoxicosis. To make matters worse, the body also upregulates the enzyme that inactivates both of the thyroid hormones, with a net result of T3 depletion that occurs simultaneously in the bloodstream and in peripheral tissues. This state will be maintained as long as Free T4 excess is maintained. There is no biological fail-safe mechanism to stop this syndrome when only T3 falls too low.
Therefore, a steady dose of T4 medication that is above a patient’s personal set-point will not give them more T3, but will deplete T3, rendering them truly hypothyroid. Their T3-T4 ratio will reduce.
The essence of the hypothyroid state is insufficient T3. Insufficiency is determined from the perspective of the individual organism and its organs — it is not judged from the perspective of the statistical population reference range. Because the reference ranges are 50% wider than the set point of any individual, A Free T3 value in the lower half of reference range may indeed be insufficient for any individual.
What we already say on thyroidpatients.ca about the high value of the T3:T4 Ratio in diagnosing poor thyroid hormone conversion during T4-based therapies in hypothyroidism.
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