Chronic Fatigue Syndrome Linked to Low T3 Syndrome

Miriam E Tucker

March 29, 2018

Some people with the condition known as chronic fatigue syndrome (CFS) have low circulating levels of the thyroid hormone triiodothyronine (T3) and normal levels of thyroid-stimulating hormone (TSH), new research shows. The results suggest these patients may be in a hypometabolic state, but one expert thinks the low levels are more likely a consequence, rather than a cause, of CFS.

The findings, based on 98 patients with CFS and 99 age- and sex-matched controls, were published online March 20 in Frontiers in Endocrinology by Begoña Ruiz-Núñez, a PhD student at the University of Groningen, the Netherlands, and colleagues.

Several CFS symptoms resemble those of hypothyroidism but without the marked increase in TSH. This is also the case, the authors point out, in the so-called low T3 syndrome. Low T3 syndrome, also known as euthyroid sick syndrome, is characterized by decreased serum T3 and/or thyroxin (T4) levels, increased reverse T3 (rT3), and no significant increase in TSH.

This low T3 syndrome might be in line with recent metabolomic studies that point to a hypometabolic state (Proc Natl Acad Sci U S A. 2016;113:E5472-E5480), and if confirmed, T3 and iodide supplements may be indicated as treatments, say Núñez and colleagues.

But endocrinologist Willard H Dere, MD, professor of internal medicine at the University of Utah, Salt Lake City, isn't convinced.

"The limited data are consistent with what is seen in other inflammatory and chronic disease states. There is no current evidence that thyroxine or tri-iodothyronine replacement in those with low T3 syndrome is beneficial. Furthermore, in hypothyroid patients on thyroxine replacement, the use of tri-iodothyronine, along with L-thyroxine, is thought by some experts to be beneficial, but this view is not a consensus," he told Medscape Medical News.

Differences Seen in Thyroid Hormones, Inflammatory Markers

The patients were recruited from a single clinic in Amsterdam, and all had been diagnosed with CFS based on 1994 criteria. However, those criteria differ in several ways from more recent definitions of what is now termed myalgic encephalomyelitis (ME)/CFS, including those published by the US Institute of Medicine (IOM) in 2015.

Both definitions include disabling fatigue that lasts more than 6 months and does not improve with rest, and cognitive impairment. However, the IOM criteria place post-exertional malaise as central to the diagnosis, whereas it's not required in older definitions. Moreover, the IOM criteria don't require that other potentially fatiguing illnesses be ruled out before making the diagnosis, whereas the older definition does.

In the current study, the 21 men and 77 women with CFS had a mean age of 43 years and body mass index (BMI) of 22 kg/m2. The 23 men and 76 women who were control participants had a mean age of 39 years and BMI of 23 kg/m2, which were not significantly different from the CFS group.

Compared with controls, the CFS group had lower levels of free triiodothyronine (FT3), total T4 (TT4), total T3 (TT3), percent TT3, sum activity of peripheral deiodinases (SPINA-GD), and secretory capacity of the thyroid gland (SPINA-GT), as well as lower ratios of TT3/TT4, FT3/FT4, TT3/FT3, and TT4/FT4, and higher percent rT3 and rT3/TT3 ratio.

There were no differences between groups in other thyroid hormone parameters, notably TSH, FT4, rT3, and percent TT4.

FT3 levels below the reference range were more frequent in the CFS group (16/98) compared with controls (7/99; P = .035), with an odds ratio of 2.56 (95% CI, 1.00 - 6.54).

However, Dere commented, "The subset of patients with the low T3 syndrome is relatively small, and their laboratory values don't vary substantively from that of the control group. Overall, I think the probability of a low T3 syndrome causing ME/CFS is low."

In measures of metabolic inflammation, no significant differences were found in white blood count, high-sensitivity C-reactive protein (hsCRP), tryptophan/kynurenine ratio, or urinary isoprostanes, but the CFS group did have lower kynurenine and tryptophan levels than controls.

Ferritin was higher and HDL-cholesterol was lower in patients with CFS. Zonulin, a parameter of intestinal permeability, was also lower in patients with CFS compared with controls.

Measures of nutritional factors influencing thyroid function and inflammation that differed between the groups included 24-hour urinary iodine output, a proxy of iodine status, which was lower in patients with CFS. Plasma selenium was similar, but intracellular selenium was higher in patients with CFS. Vitamin D [25(OH)D] status of patients with CFS was higher, but 59% of patients with CFS and 83% of controls presented with 25(OH)D levels below the optimal cutoff of 80 nmol/L, Ruiz-Núñez and colleagues report.

In two sensitivity analyses that excluded patients with the highest levels of inflammatory markers, all the prior findings remained significant except FT3, which was no longer significantly lower in the CFS group.

Markers of Inflammation: Cause or Consequence?

Overall in both groups, FT3, TT3, TT4, and rT3 were positively related with hsCRP.

"The limited data from this study correlates other markers of inflammation with the presence of low T3 and high reverse T3, and are consistent with what is seen with other inflammatory and chronic disease states," Dere noted.

He added that the low T3 state "seems to be the result, not the cause, of a systemic or localized inflammatory or chronic disease state. During caloric deprivation, the fall in T3 is believed to be an adaptive response directed to saving energy and protein for enduring this acute stress. Thus one can speculate that with some chronic disorders, the diminished plasma T3 helps to preserve caloric expenditure."

Overall, Dere said he wouldn't change clinical practice based on these findings. "A serum TSH is a good screening test to rule out primary thyroidal disorders."

The authors have reported no relevant financial relationships. Dere serves on the board of directors for Radius Health, BioMarin, Seres Therapeutics, Mersana Therapeutics, and has received grants from the Working Group of California Institute of Regenerative Medicine.

Front Endocrinol. Published March 20, 2018. Full article

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