Dr. Ron’s Research Review – April 19, 2017

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This week’s research review focuses on resistance to thyroid hormone and copper-selenium.

Patients with THR have elevated serum free thyroxine (FT4), free triiodothyronine (FT3), but normal or slightly elevated serum thyrotropin (TSH) values. (Agrawal et al., 2008)
Fibromyalgia may be due to thyroid hormone resistance. Overlapping symptom complexes suggest that chronic fatigue syndrome, Gulf war syndrome, premenstrual syndrome, post traumatic stress disorder, breast implant silicone sensitivity syndrome, bipolar affective disorder, systemic candidiasis, myofascial pain syndrome, and idiopathic environmental intolerance are similar enough to fibromyalgia to merit investigation for possible thyroid resistance. (Garrison and Breeding, 2003)
The most straightforward, and probably the most common, example of the interactions that occur is the following five-step sequence: 1) Infection by an indolent infectious agent, followed by 2) the initiation and maintenance of a chronic coagulopathy, followed by 3) perpetual stimulation of thyroid resistance, followed by 4) numerous hypometabolic manifestations including interference with capillary diffusion, followed by 5) development of multiple hormonal resistances. (Garrison and Breeding, 2003)

Copper-Selenium Ratio

Serum copper levels are regulated by thyroid hormone, which stimulates the synthesis and the export of the hepatic copper-transport protein ceruloplasmin into the serum. TRbeta is a regulator of serum copper and TRalpha1 is a specific regulation of serum selenium. The ratio of serum copper and selenium may be a valuable novel biomarker for RTHbeta. Moreover, it could also provide a suitable large-scale screening parameter to identify RTHalpha patients. (Mittag et al., 2012)

 

Dr. Ron


 

Articles

A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone.
            (Garrison and Breeding, 2003) Download
It has long been recognized that the symptom complex of fibromyalgia can be seen with hypothyroidism. Hypothyroidism may been categorized, like diabetes, into type I (hormone deficient) and type II (hormone resistant). Most cases of fibromyalgia fall into the latter category. The syndrome is reversible with treatment, and is usually of late onset. It is likely more often acquired than due to mutated receptors. Now that there is evidence to support the hypothesis that fibromyalgia may be due to thyroid hormone resistance, four major questions appear addressable. First, can a simple biomarker be found to help diagnose it? Second, what other syndromes similar to Fibromyalgia may share a thyroid-resistant nature? Third, in non-genetic cases, how is resistance acquired? Fourth, what other methods of treatment become available through this new understanding? Preliminary evidence suggests that serum hyaluronic acid is a simple, inexpensive, sensitive, and specific test that identifies fibromyalgia. Overlapping symptom complexes suggest that chronic fatigue syndrome, Gulf war syndrome, premenstrual syndrome, post traumatic stress disorder, breast implant silicone sensitivity syndrome, bipolar affective disorder, systemic candidiasis, myofascial pain syndrome, and idiopathic environmental intolerance are similar enough to fibromyalgia to merit investigation for possible thyroid resistance. Acquired resistance may be due most often to a recently recognized chronic consumptive coagulopathy, which itself may be most often associated with chronic infections with mycoplasmids and related microbes or parasites. Other precipitants of thyroid resistance may use this or other paths as well. In addition to experimentally proven treatment with supraphysiologic doses of thyroid hormone, the thyroid-resistant disorders might be treatable with anti-hypercoagulant, anti-infective, insulin-sensitizing, and hyaluronolytic strategies.

Serum copper as a novel biomarker for resistance to thyroid hormone.
            (Mittag et al., 2012) Download
Thyroid hormone action is mediated by the thyroid hormone receptors TRalpha1 and TRbeta. Defects in TRbeta lead to RTH (resistance to thyroid hormone) beta, a syndrome characterized by high levels of thyroid hormone and non-suppressed TSH (thyroid-stimulating hormone). However, a correct diagnosis of RTHbeta patients is difficult as the clinical picture varies. A biochemical serum marker indicative of defects in TRbeta signalling is needed and could simplify the diagnosis of RTHbeta, in particular the differentiation to TSH-secreting pituitary adenomas, which present with clinically similar symptoms. In the present paper we show that serum copper levels are regulated by thyroid hormone, which stimulates the synthesis and the export of the hepatic copper-transport protein ceruloplasmin into the serum. This is accompanied by a concerted reduction in the mRNA levels of other copper-containing proteins such as metallothioneins 1 and 2 or superoxide dismutase 1. The induction of serum copper is abolished in genetically hyperthyroid mice lacking TRbeta and human RTHbeta patients, demonstrating an important role of TRbeta for this process. Together with a previously reported TRalpha1 specific regulation of serum selenium, we show that the ratio of serum copper and selenium, which is largely independent of thyroid hormone levels, volume changes or sample degradation, can constitute a valuable novel biomarker for RTHbeta. Moreover, it could also provide a suitable large-scale screening parameter to identify RTHalpha patients, which have not been identified to date.

 

References

Agrawal, NK, et al. (2008), ‘Thyroid hormone resistance.’, Postgrad Med J, 84 (995), 473-77. PubMed: 18940949
Garrison, RL and PC Breeding (2003), ‘A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone.’, Med Hypotheses, 61 (2), 182-89. PubMed: 12888300
Mittag, J, et al. (2012), ‘Serum copper as a novel biomarker for resistance to thyroid hormone.’, Biochem J, 443 (1), 103-9. PubMed: 22220593