Rationale: The T3:T4 ratio

Updated 2018-07-12

Verburg-2014-T3-T4-Ratio

The most clinically useful function of Free T3 and Free T4 testing is to determine the T3:T4 ratio.

Free T4 testing is not very useful in isolation. When testing T4 and TSH together, one can see very obvious derangements to the HPT axis when one is low and the other is high, but without measuring both Free T3 and Free T4, we can’t see the subtler yet still important imbalances in the two thyroid hormones within the reference range.

The low T3:T4 ratio is a well known feature of L-T4 therapy. They usually have a lower T3 and higher T4 than people with healthy thyroid glands, and more recently it has been shown that patients are at a higher risk of a T3 deficiency the less active thyroid tissue they have. [61, 121, 129, 130, 131]

In patients with no functional thyroid gland, we see some of the lowest T3:T4 ratios: the higher the T4, the lower the T3 is likely to be, even in cases when TSH is suppressed by the higher T4 level. [62, 63]

Gullo et al’s 2011 study

In Gullo et al’s 2011 study of 3,875 healthy controls and 1,811 athyreotic patients on L-T4 therapy, researchers proved that L-T4 monotherapy significantly shifted these patients T3:T4 ratio and made it unresponsive to TSH. In addition, they found TSH less responsive to treated patients’ actual T4 and T3 levels. [60]

A look at the data will outline the differences between the two cohorts. The difference can be attributed to two factors: 1) their athyreotic status combined with 2) their L-T4 monotherapy.

When both Free T3 and Free T4 are measured in pmol/L,

Among healthy control patients,

  • The average ratio was 0.31 pmol/L when TSH was 0.4-2.0, and 0.32-0.33 pmol/L when TSH was 2.01-4.00.
  • Therefore, as TSH increased, healthy controls’ T3 increased in relation to their T4. For example,
  • In the low-normal TSH cohort, the average
    • TSH was 0.7
    • Free T3 was 4.47
    • Free T4 was 14.2
    • (4.47 divided by 14.2 yields a ratio of 0.314)
  • In the high-normal TSH cohort, the average
    • TSH was 3.1
    • Free T3 was 4.47
    • Free T4 was 12.9
    • (4.47 divided by 12.9 yields a ratio of 0.35)

Observations:

  • Controls’ Free T3 levels remained stable. Controls’ TSH and T4 seemed to shift in order to maintain Free T3 levels. Controls’ TSH had a direct effect on altering their T3:T4 ratio; more TSH would stimulate more T4-T3 conversion.

In contrast, among patients on L-T4 monotherapy,

  • the average T3:T4 ratio remained between 0.23-0.24 across the entire “normal” range of TSH 0.40-4.00 (significance p=<0.001). For example,
    • in the low-normal TSH cohort, the average
      • TSH was 0.6,
      • Free T3 was 3.96
      • Free T4 was 15.7 (ratio = 0.24)
    • in the high-normal TSH cohort, the average
      • TSH was 3.32,
      • Free T3 was 3.39
      • Free T4 was 14.2 (ratio = 0.23)

Observations on the contrast:

  • Patients on L-T4 therapy always averaged less Free T3 per TSH than healthy controls. Even in the low-normal TSH cohort, patients’ average FT3 levels were approximately 0.5 pmol/L lower than controls (3.96 versus 4.47 pmol/L).
  • Patients had a T3/T4 ratio that averaged 0.11-12 mpol/L lower than controls, which points to their significantly reduced rate of T4-T3 conversion.
  • Patients’ increased TSH had no effect on improving their T3:T4 ratio. In their body, increased TSH cannot stimulate a net increase to T4-T3 conversion. Patients were never able to keep up with healthy controls’ rate of T4-T3 conversion despite having more T4 in serum to convert.
  • Patients’ bodies cannot protect and maintain Free T3 serum levels as effectively as controls.

Risks of continued hypothyroidism for patients on L-T4 monotherapy:

  • When their TSH is high-normal, patients are more likely to be deficient in Free T3. “15.2% had serum FT3 levels lower than the normal range.”
  • When their TSH is low-normal, patients are more at risk of having excess T4. “7.2% had FT4 levels higher than the normal range.”
    • It is known that even mild excesses of T4 can stimulate increased conversion to Reverse T3, which depletes T3 more powerfully than reduced D1 and D2 efficiency alone. (See our section on Deiodinase type 3).
    • If a patient becomes chronically or critically ill, their hormone inactivation and Low T3 state may decrease further, and as long as high-normal T4 is maintained, TSH may not rise to signal this crisis. (See our section on Deiodinase type 3).
  • Females are at two times higher risk of low Free T3 than males. “The percentage of athyreotic patients with FT3 serum levels lower than the normal range was 8.6% in males and 16.4% in females”

Finally, the researchers said that their data suggested “a less sensitive response of thyrotropic cells [in the pituitary gland] to thyroid hormones” in treated patients.

This is important—TSH secretion does not respond as sensitively to T4 and T3 hormone levels under these conditions.

Therefore, TSH by itself is not a fair judge of “insufficient,” “sufficient” or “excess” T3 or T4 levels in L-T4 treated patients.

While this study showed that the risk of low T3 and low T3:T4 ratio is significant if patients are athyreotic (post-thyroidectomy), one must keep in mind that autoimmune thyroid patients are not immune to this risk.

Autoimmune attack alone may also result in a non-functional or atrophic gland. It is difficult to estimate the percentage of functional gland tissue without looking at the patient’s T3:T4 ratio and/or looking for echogenicity and gland size in a thyroid ultrasound. L-T4 dose per kilogram is not a sufficient indicator of gland functionality because of patients’ varying levels of absorption through the GI tract.

As confirmation, another clinical study by Jonklaas et al aimed to achieve equivalent “average” Free T3 levels pre- and post- thyroidectomy and was able to approximate it through L-T4 therapy, but this was only on average, not in every individual patient. Also, Free T3 equivalence was obtained at the expense of a significantly higher average Free T4 than they had pre-thyroidectomy. [132]

Significance

LowT3T4Ratio-conditions

While some researchers and clinicians have dismissed L-T4 treated patients’ significantly lower ratio as insignificant, for others, “This has brought into question the inability of L-thyroxine monotherapy to universally normalize serum T3 levels” [32]

In other words, even when TSH is “normalized,” T3 is not necessarily “normalized” and the patient may remain hypothyroid.

L-T4 monotherapy simply cannot replace the sensitive TSH secretion of functional thyroid tissue, and their net deiodinase conversion of T4-T3 does not respond to TSH increase, either. All athyreotic patients will have less T3 than normal patients at the same TSH level, and some patients will be extremely deficient in their T3 but their TSH will not indicate this.

To the degree a patient’s thyroid gland is dysfunctional, inert, or absent, they will be dependent on an artificial state created by orally-dosed thyroid hormone. In this vulnerable state, their hormone therapy modality can significantly imbalance their T3:T4 ratio. These patients’ net conversion of T4-T3 does not respond normally to TSH increases. One simply cannot count on sufficient net thyroid hormone conversion to occur. Severely hypothyroid patients on T4 monotherapy will inevitably have less T3 than normal patients at the same TSH level, even if they have a higher level of T4. Some patients will be extremely deficient in their T3, but their TSH and T4 levels may not indicate this at all.

Other health factors that influence T3:T4 ratio

In addition, T4-T3 conversion can be worsened by functional DIO1 and DIO2 genetic polymorphisms. Even in people with healthy thyroid glands, these polymorphisms can reduce T3 availability without significantly raising TSH. They, too, alter the T3:T4 ratio, although their impact is not as large as L-T4 therapy itself. The DIO1 polymorphisms decrease serum levels of T3 more than the DIO2 polymorphisms do, because D1 is active in serum, whereas D2 is active within cells and tissues. However, while DIO2’s impact is less apparent in blood, the DIO2 polymorphism is damaging to certain organs that depend on local hormone conversion via D2. DIO2 appears therefore to influence bone loss and mental health significantly by creating a localized T3 deficiency in these organs and tissues. [133, 128, 134, 135]

Even in people with normal thyroid glands, various diseases, fasting, obesity, and psychiatric conditions are characterized by significantly altered T3:T4 ratios.

  • Some conditions, such as fasting and cardiovascular disease, are associated with a low T3:T4 ratio (poor conversion from T4 to T3).
  • Others, such as obesity and psychiatric conditions, are associated with a high ratio (excess conversion). [59, 136]

Therefore, one must consider the patient’s overall health when interpreting T3 and T4 levels and ratios. If the patient is not critically ill, a maladaptive ratio can be corrected by adjusting thyroid hormone therapy type and dose.

This imbalance is a significant metabolic factor in health. Even beyond thyroid patients, lower T3/T4 ratios within the “normal” range have been associated with disorders such as

  • metabolic syndrome in healthy “euthyroid” adults, [137]
  • hyperinsulinemia and insulin resistance in prediabetics,[138]
  • impaired selenium status, [139] and a shorter lifespan in general among seniors. [140]

Implications for thyroid therapy

No mode of thyroid hormone therapy can replace the functional thyroid tissue that is responsive to slight changes in TSH. All therapies are artificial and can impose an unnatural T3:T4 ratio.

However, we have more than enough scientific proof that L-T4 monotherapy can induce an imbalance that is harmfully biased against the active hormone, T3.

Biology simply does not permit this imbalance in a state of thyroid health. A healthy organism protects and maintains its T3 levels in serum. It does everything it can to maintain T3 within a very limited range. Why should we permit T3 to fall below the body’s set point? We have the tools at hand to measure this phenomenon. We have the tools to fix it.

Therefore, there is an ethical call to act on our knowledge.

  • The risks of a Low T3:T4 ratio should be noted in the product monographs of L-T4 medication
  • Thyroid therapy monitoring guidelines should mention the value of Free T3 testing and the relevance of patients’ relative lack of functional thyroid tissue.

In the monitoring of treatment, the T3:T4 ratio has more clinical significance than the TSH, as demonstrated above. When the ratio of Free T3 to T4 is abnormally low, perhaps one could arbitrarily say 0.23 pmol/L or lower, one can reasonably suspect one or more of the following causes:

  1. Very low levels of functional thyroid gland tissue,
  2. Excessive T3 hormone inactivation due to excess T4, beyond the patient’s set point, which has upregulated the epigenetically-sensitive DIO3 gene (see our section on Deiodinase type 3),
  3. And/or possibly a DIO1 or DIO2 genetic polymorphism.

If an individual patient’s low T3:T4 ratio renders them hypothyroid in symptoms and signs, one can reasonably judge such patients to be “likely hypothyroid in T3 levels” regardless of their rate of TSH secretion.

A trial of T3-based therapy would be the logical way to test this hypothesis and would subject the patient to no harm if the new treatment modality is safely administered.

If the problem is indeed a T3 deficiency, the patient’s hypothyroidism can be directly and effectively remediated by T3-based thyroid therapies. If the hypothesis is correct, hypothyroid symptoms would then dissipate, given enough time for the body to heal and for excess DIO3 gene expression to return to normal. More time may be necessary for peripheral tissues such as skin, bone and joints to reach a state of T3-based euthyroidism.

 

References

Next page: Rationale: Deiodinase Type 3, part 1

Related Blog Post: REVIEW: DIO1 gene affects T3:T4 ratio

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