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Written by Cort Johnson
Low T3 syndrome or nonthyroidal illness syndrome (NTIS) (or euthyroid sick syndrome ESS) is a debated illness found in some serious illness states including sepsis, starvation, surgery, heart attack, and others. Dr. Leslie J DeGroot, M.D., a top endocrinologist, reported in a 2015 review “The Non-Thyroidal Illness Syndrome” that this syndrome probably occurs in “any severe illness”.
DeGroot starts off his review stating that NTIS, “refers to a syndrome found in seriously ill or starving patients” who have low free T3, increased reverse T3, normal or low TSH, and, if the condition becomes chronic, low free T4. DeGroot asserts that these findings indicate, as Dr. Holtorf asserts, that low tissue thyroid hormone levels are present, and thus tissue hypothyroidism is present. (Note that low total T4 was not found in the ME/CFS group.)
In some ways, this syndrome is no surprise: serum thyroid hormone levels are known to drop during starvation and illness. Starvation (carbohydrate deprivation) inhibits the conversion of T4 to T3 (the active form of thyroid hormone) and prevents the metabolism of reverse T3 (which blocks the receptors for T3, thus reducing the production of T3.)
The reduction of active thyroid hormone levels seems to make sense, given a similar reduction in the basal metabolic rate induced by starvation: the body appears to be hunkering down and attempting to conserve its resources until food is present.
Starvation isn’t the only inducer of this process, though. DeGroot reports that a large proportion of people in intensive care also exhibit low T3 and T4 levels. They also tend to have increased sympathetic nervous system response – which is, of course, typical in ME/CFS.
Various hypotheses have been put forward which propose that NTIS is beneficial or inconsequential and should not be messed with. They include the possibilities that the abnormalities are artifacts, that they do not reflect true free hormone findings, and that they reflect the body’s way of dealing with the situation.
DeGroot, however, believes the findings reflect a pathological state. He does not appear to believe that pituitary thyroid hormone levels differ from those of the body in NTIS, but suggests that cortisol / cytokine levels / low O2 levels (hypoxia) / reduced leptin, etc. are likely responsible for the initiation of NTIS.
The T4 Paradox – When Treatments Make Things Worse
DeGroot’s personal experience is that treating patients with NTIS with T4 (unpublished) often results in significantly elevated rT3 levels (and T3 inhibition).
Nunez-Ruiz et. al. also suggest that standard thyroid therapy (T4) in the NTIS-like ME/CFS subset could actually induce a state of NTIS, and point out that T3, recommended by Holtorf for ME/CFS and FM, has been suggested for severe NTIS. They referred to the NHANES cohort, which found that T4 administration resulted in higher T4 levels but 5–10% lower T3 and FT3 levels, and a 15–20% lower T3/T4 ratio. They believe tissue levels of those factors are probably far lower.
"Low “T3 syndrome” in our study resembles the thyroid hormone profile of a subgroup of hypothyroid patients receiving T4 monotherapy." The authors
Holtorf also has found T4 supplementation unproductive and even harmful at times in his ME/CFS and fibromyalgia population. When high levels of rT3 (>150) are found, or free T3/reverse T3 ratio is greater than 0.2 (measured in picograms per milliliter (pg/mL), instead of T4 (Synthroid and Levoxyl or Amour thyroid – a pig glandular product) Holtorf will prescribe free T3 (compounded) instead.
The Worm (Dauer) Rides Again
Ruiz-Nunez et. al. believe the metabolomic studies in ME/CFS may be providing a clue. The impaired mitochondrial production and hypometabolic state they suggest appears to fit with their findings of NTIS in a subset of ME/CFS patients (and one would think the general state of reduced thyroid activity in the group as a whole). Hypothyroidism is, after all, associated with decreases in metabolic and heart rates, oxygen consumption, body temperature and oxidation of glucose, fatty acids, and amino acids.
They throw the whole kit and kaboodle into the mix (inflammation, infection, gut issues, psychological trauma (particularly during childhood) as they suggest that the cell danger response (aka Naviaux) could be behind the NTIS-like findings in some ME/CFS patients. Inflammation may or may not be the issue.
The authors believe that ME/CFS probably represents a common pathophysiological state that can be reached in any number of ways. In a refreshingly direct manner, they reported that their study findings presented one possible way of reaching that state, “but do not get us closer to the cause(s).”
Herpesviruses to the Fore?
Could one answer – HHV-6 – be hiding in plain sight?
Back in 2001, Wikiland reported in The Lancet that fine needle biopsies demonstrated that 40% of people with ME/CFS have lymphocytic thyroiditis. The fact that half of those found with diseased thyroid tissues had normal thyroid lab values suggests that lab values, as Holtorf believes, may not always tell the whole story.
Could HHV-6A be contributing to the thyroid issues in ME/CFS?
Hashimoto’s thyroiditis, the most common cause of hypothyroidism, occurs as a result of an autoimmune attack. Casselli’s 2012 study finding of a high incidence of HHV-6A DNA in Hashimoto’s thyroid tissues but not in controls (82% vs. 10%, p≤0.001), suggests that HHV-6 could be triggering Hashimoto’s. (HHV-6A was also active in the Hashimoto’s patients, but not in the healthy controls.) If HHV-6A is triggering Hashimoto’s, it might also be triggering the hypothyroidism that seems almost endemic in ME/CFS.
The fact that Caselli found HHV – 6A, not HHV- 6B was notable because while virtually everyone is infected with HHV-6B early in life not everyone is infected with HHV-6A – and when they are it tends to be later in life, which is when most cases of ME/CFS begin.
Kristin Loomis of the HHV-6 Foundation has tried for years to interest someone in examining the thyroid tissue of people with ME/CFS for pathogens. She’s noted that many of the suspected viral culprits in ME/CFS (HHV-6, parvovirus B19) can cause “smoldering” infections in the thyroid.
Now enter Bhupesh Prusty, a Solve ME/CFS Initiative-funded researcher who found HHV-6 in about 60% of a small group of ME/CFS patients’ cells. Prusty found that one HHV-6 infected ME/CFS cell was able to alter the mitochondrial functioning of neighboring, or even distant cells – apparently by secreting mitochondrial inhibitors. Prusty will be speaking at the NIH ME/CFS conference in April.
Kristin Loomis speculates that if HHV-6 is present in the thyroid, it may have found its way to the brainstem as well, where it could help produce the autonomic problems in ME/CFS. At the 2016 IACFS/ME Conference, Dr. Klimas presented evidence that indices of HHV-6 activation are correlated with symptom severity in ME/CFS. Learn more about HHV-6 here.
Conclusion
A fairly large Dutch study found evidence of low thyroid functioning in ME/CFS. The study needs to be replicated, but about 15% of the ME/CFS group met the criteria for Non-Thyroidal Illness Syndrome (NTIS) which occurs in starvation, sepsis and probably other serious illnesses. While most people with ME/CFS did not meet the criteria for NTIS, the overall findings – normal TSH levels, increased reverse T3, and reductions in a variety of thyroid tests – suggest the group as a whole trended in the direction of NTIS.
The findings may call for the use of T3 instead of T4 for some people with ME/CFS/FM.
While studies assessing the effectiveness of T3 are lacking, both Leslie DeGroot, a prominent endocrinologist, and Dr. Kent Holtorf, an ME/CFS/FM specialist, support using T3 (in Dr. Holtorf’s case, compounded T3) instead of the usual T4 preparation (such as Synthroid) in patients with NTIS (DeGroot) or ME/CFS/FM (Holtorf).
The cause of atypical thyroid issues (normal TSH/low T3/high rT3) found in some people with ME/CFS/FM is unknown but could reflect an attempt by the body to conserve resources (Dauer state), could be produced by cytokines, cortisol, hypoxia, etc.) or possibly a pathogen such as HHV-6.
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