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Med Hypotheses. 2007;69(4):913-21. Epub 2007 Mar 26.

On commonness and rarity of thyroid hormone resistance: a discussion based on mechanisms of reduced sensitivity in peripheral tissues.

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Lillehammer University College, 2626 Lillehammer, Norway.


Reduced sensitivity to thyroid hormone (TH) in peripheral tissues can occur as defects in TH transport into the cell, intracellular TH metabolism, cytosolic mechanisms, TH entry into the nucleus, thyroxin receptors (TRs) and receptor binding, transcription and post-transcriptional mechanisms. Current literature reveals an extensive list of mutations, drugs, toxins, metabolites and autoimmune antibodies that may impair TH action in the cell, but such impairment may not be picked up by assays of TH and TSH in blood plasma. Substances may induce tissue specific resistance to thyroid hormone (RTH), e.g. by affecting numbers of different TR isoforms. Recent literature also indicates mechanisms by which different conditions, for example, chronic fatigue syndrome (CFS), chronic renal failure (CRF) and nonthyroidal illness, can be accompanied by acquired RTH caused by inhibition of TH metabolism, cell uptake, TR binding and transcription. This prompts us to reassess commonness and rarity of congenital vs. acquired RTH. We hypothesise that observed clinical symptoms of hypothyroidism in chemically euthyroid patients are typically caused by changes in hormonal systems, autoimmune antibodies, metabolites or other substances in the body, leading to reduced sensitivity to TH in peripheral tissues. These changes may be a by-product of other processes and a reversible biological response in the body, and may also result in chronic acquired RTH. Antibodies may prove to be the most common cause of chronic reduction in TH sensitivity. It is argued that the acquired form of RTH, caused by endogenous and exogenous sources, may indeed be more common than the congenital, as in insulin resistance. If acquired RTH exists, then it may not be picked up by blood assays of TH and TSH. An appropriate test to assess TH action in peripheral tissues is therefore greatly desired.

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