Low-T3 syndrome, also known in the research literature as “Sick Euthyroid Syndrome,” is a condition in which normal thyroid hormone synthesis and/or absorption pathways are interrupted. Low T3 syndrome may occur in a wide range of illnesses from heart disease to kidney and liver diseases, to diabetes and anorexia.
Although researchers have debated whether a) Low-T3 Syndrome is a pathological condition that causes or exacerbates illness, or b) it is an “adaptive” response to illness, it has almost always been found to be an “independent predictor” of very poor disease outcomes and earlier mortality (see references).
Low-T3 gives an especially negative prognosis in heart disease, and some have recommended that it be used as a risk-stratification indicator.
The details on Low-T3
Normally, the healthy thyroid gland secretes an adequate amount of T4 hormone and smaller amounts of T3. T3, or Triiodothyronine, is the active hormone needed by the body’s tissues. The T4 hormone is converted to T3 at various rates in the liver, kidneys, and other tissues.
The heart, in particular, relies mainly on T3 for its energy and is very sensitive to T3 levels in the blood.
However, in Low-T3 syndrome, T3 levels in the blood drop below the normal reference range, while TSH and T4 levels often remain within “normal” reference ranges. How does this occur? One reason is that instead of breaking down T4 into T3, the body breaks down T4 into Reverse T3 at higher rates. Reverse T3 imitates the T3 molecule and blocks the T3 receptors in cells.
A wealth of research has been done on Low-T3 syndrome and/or excess Reverse T3 in patients with healthy thyroid glands who are experiencing chronic or acute illness. See the Reference list below for a sampling of articles.
The need for research on Low-T3 in treated hypothyroid patients
Unfortunately, however, not much research has been done on the existence of Low-T3 Syndrome in patients with primary thyroid dysfunction who are on thyroid hormone therapy.
Most studies of Low-T3 Syndrome intentionally exclude thyroid patients on T4 treatment!
This is a critical void that must be filled with research. The hypothyroid patient community has noted that low T3, often called “Reverse-T3 dominance,” is a common problem while on T4-only therapy with drugs such as Synthroid (See the page on Reverse T3 at Stop The Thyroid Madness, and Panicker, et al, 2008).
If Low-T3 is a common problem among this vast population of T4-medicated hypothyroid patients, it may contribute to the number of illnesses and deaths, especially deaths due to heart disease.
Tevaarwerk’s study of two thyroid patients with Low T3 Syndrome despite T4 treatment
Fortunately, I found one very helpful and enlightening article that presented a case study of two hypothyroid patients on L-thyroxine (T4-only) therapy who showed signs of Low-T3 Syndrome:
Low triiodothyronine (T3) concentrations in the presence of normal thyroxine (T4) and TSH levels, referred to as the low T3 syndrome (LT3S), are common. LT3S may be caused by starvation, various non-thyroidal illnesses (NTIs) and some medications. Reverse T3 (rT3) concentrations are elevated in the more severely ill, and they characteristically fail to respond to exogenous levothyroxine (l-T4) therapy. The biochemical abnormalities have been explained on the basis of altered peripheral deiodinase activities. Herein, we report on two patients with hypothyroid symptoms who on testing were found to have LT3S. They were atypical clinically in not having LT3S due to any of the usual causes, had no increased rT3 concentrations, and had a normal negative TSH feedback response to l-T4. One (patient 1) had previously been diagnosed with Hashimoto’s autoimmune primary hypothyroidism and was on l-T4 therapy. Both had T4 concentrations in the reference range. TSH levels were elevated in patient 1 and in the reference range in patient 2. Starting or increasing l-T4 doses resulted in no clinical improvement and no increase in T3 levels in spite of a marked increase in T4 levels. It is suggested that in the absence of the usual causes, lack of elevated rT3 levels, response to treatment and intact negative TSH feedback these two patients differ from the usual secondary causes of decreases in deiodinase activity. It is speculated that they may represent primary alterations in deiodinase enzymes possibly due to genetic variations in the deiodinase-encoding genes. LT3S is commonly found secondary to starvation, NTIs and use of some medications.Low T3 levels are the result of alterations in the activity of deiodinase enzymes.LT3S without the usual causes may represent a primary disturbance in deiodinase activity.
severe cold intolerance, low physical energy and marked mental lethargy in spite of free T4 concentrations being near the upper limit of the reference range on L-T4 replacement” (2). He was on medication for various health conditions including congestive heart failure.
- TSH 38.8 mU/L (0.38-5.5, mid-normal 1.5)
- Free T4 19.2 pmol/L (10.5-20, mid-normal 15.3)
- Free T3 3.0 pmol/L (3.5-6.5, mid-normal 5.0)
- T4/T3 ratio: 6.4 (mid-normal 3.1)
See that the TSH is above the lab range, which most physicians would believe to be caused by the Free T3 being far below range.
To prove that TSH does not necessarily reveal low T3, look at the next result showing a normal TSH despite a lower T4 and still very Low-T3, on the very same dose:
1) Still on 75 mcg L-thyroxine (T4):
- TSH 36.5 mU/L (0.38-5.5, mid-normal 1.5)
- Free T4 17.5 pmol/L (10.5-20, mid-normal 15.3)
- Free T3 3.1 pmol/L (3.5-6.5, mid-normal 5.0)
- T4/T3 ratio: 5.6 (mid-normal 3.1)
- Reverse T3 0.19 nmol/L (0.14-0.54, mid-normal 0.34)
- T4/RT3 ratio: 92.1 (mid-normal 45)
1) Raised to 100 mcg L-thyroxine (T4):
- TSH 20.6 mU/L (0.38-5.5, mid-normal 1.5)
- Free T4 23.6 pmol/L (10.5-20, mid-normal 15.3)
- Free T3 3.4 pmol/L (3.5-6.5, mid-normal 5.0)
- T4/T3 ratio: 6.9 (mid-normal 3.1)
1) Repeat on 100 mcg L-thyroxine (T4):
- TSH 14.7 mU/L (0.38-5.5, mid-normal 1.5)
- Free T4 22.5 pmol/L (10.5-20, mid-normal 15.3)
- Free T3 3.1 pmol/L (3.5-6.5, mid-normal 5.0)
- T4/T3 ratio: 7.3 (mid-normal 3.1)
- Reverse T3 0.23 nmol/L (0.14-0.54, mid-normal 0.34)
- T4/RT3 ratio: 97.8 (mid-normal 45)
Case 2 was a 60 year old woman who had “fatigue, cold intolerance, muscle cramps, depression and obesity of long duration” (2). She had normal TPO-antibodies (was not diagnosed with Hashimoto’s thyroiditis).
A) Before L-Thyroxine treatment
- TSH 1.5 mU/L (0.38-5.5, mid-normal 1.5)
- Free T4 19.8 pmol/L (10.5-20, mid-normal 15.3)
- Free T3 3.4 pmol/L (3.5-6.5, mid-normal 5.0)
- T4/T3 ratio: 5.8 (mid-normal 3.1)
B) On 150 L-Thyroxine (T4)
- TSH <0.06 mU/L (0.38-5.5, mid-normal 1.5)
- Free T4 21.6 pmol/L (10.5-20, mid-normal 15.3)
- Free T3 3.3 pmol/L (3.5-6.5, mid-normal 5.0)
- T4/T3 ratio: 6.5 (mid-normal 3.1)
- Reverse T3 0.54 nmol/L (0.14-0.54, mid-normal 0.34)
- T4/RT3 ratio: 40.8 (mid-normal 45)
Without any treatment, her TSH and T4 levels were normal, but her T3 was just below the low end of the range.
A normal physician responding to Case 2, either without testing for T3 levels or not recognizing a borderline T3 as a problem, would not have given her any thyroid medication.
Case 2 shows the extreme unresponsiveness of Low-T3 to changes in T4 dosage, since the dosage was increased from 0 (zero) to 150 micrograms, but T3 levels actually dropped by 0.01.
This summary shows the research value gained by presenting these as two comparative case studies. If this study were done with hundreds of patients, it would have to express values as averages and ranges. In the averages, the extreme ratios existing within an individual body would be overlooked.
Nevertheless, studies with larger numbers of patients should still be done, since only they can show how prevalent, and how harmful, Low-T3 can be in treated hypothyroid patients.
The author’s own discussion ruled out various potential causes of Low T3 Syndrome such as “chronic viral infections, starvation, and medications known to cause impaired T3 generation,” poor pituitary TSH-feedback mechanisms, or elevated iodine levels in the blood.
The author reports that raising their T4 dose did not provide any positive clinical response (no improvement to symptoms).
What was likely to have caused these anomalies? Problems with the “deoidinases” that are responsible for T4-T3 conversion. Case 1 was attributed to a decrease in D1 activity, while Case 2 was attributed to a decrease in D2 activity.
More importantly, to emphasize my point that more research must be done on Low-T3 syndrome in hypothyroid patients on thyroid medication, Tevaarwerk concludes the study with this review and reflection:
Panicker et al. … found that 26% of patients with primary hypothyroidism on replacement therapy had polymorphism in the DIO2 gene resulting in a decreased
T4:T3 ratio and clinical manifestations.
Considering this frequency in genetic polymorphism, it is not unexpected that patients might be encountered with primary D2 and D1 enzyme abnormalities causing LT3S.
Could we not put the final phrase in active voice instead of vague passive?
We may expect to encounter patients with Low T3 syndrome, since another study has found 26% of their hypothyroid population to have problems with T4-T3 conversion.
It is a very sad fact that most hypothyroid patients do not get their Free-T3 levels checked regularly, since standard treatment relies mainly on TSH and T4 testing.
Even if Free T3 levels are checked, they may not be interpreted properly in terms of how low the Free T3 is in relation to Free T4 and especially Reverse T3.
The calculation of fT3/fT4 ratios and T3/rT3 ratios, not just the use of lab ranges, must be used to confirm for the doctor and patient that the treatment is optimal.
I am one of those patients with an unresponsively Low T3. In my case, increasing my T4 dose above a critical level (but still within T4 lab reference ranges) caused distressing heart symptoms, and decreasing my T4 dose radically, despite a high TSH, has brought noticeable reduction in my heart pain. I will share my own clinical case study with lab results from 2013-2016 in a separate post.
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